A Phase II Study of Cabozantinib in Metastatic or Unresectable Refractory Gastrointestinal Stromal Tumour: A Single-Centre Study from India

A Phase II Study of Cabozantinib in Metastatic or Unresectable Refractory Gastrointestinal Stromal Tumour: A Single-Centre Study from India | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Phase II Study of Cabozantinib in Metastatic or Unresectable Refractory Gastrointestinal Stromal Tumour: A Single-Centre Study from India Neelima Ventrapragada, Sameer Rastogi, Kinjal Singh, Akash Singh, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8910891/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background: Beyond third-line therapy, options for metastatic/advanced GIST are limited, especially in low- and middle-income countries (LMICs) where access to fourth-line ripretinib is often restricted. Cabozantinib, a multi-kinase inhibitor targeting KIT and related resistance pathways, could serve as a pragmatic alternative. This Phase II study evaluated the efficacy and safety of cabozantinib in patients with metastatic/advanced GIST who had progressed after ≥3 prior Tyrosine Kinase Inhibitors (TKIs). Methods: This is a single-arm phase II trial that enrolled patients with advanced GIST who had progressed on ≥3 TKIs with ECOG PS 0-2. Cabozantinib was given orally at 60 mg daily (40 mg if <40 kg and/or ECOG PS 02). The primary endpoint was 3-month Progression Free Rate (PFR) by RECIST v1.1. Overall Response Rate (ORR) was assessed by RECIST v1.1 and Choi Criteria. Quality of Life (QoL) was done by EORTC-QLQ-C30. Using Ahern’s single-stage phase II design, the trial tested whether cabozantinib could achieve a 3-month PFR of at least 25% in the fourth-line setting versus a null PFR of 5% or less. With a one-sided alpha of 0.05 and 90% power, the required sample size for this single-arm study was 25 patients. Results: Sixteen patients were enrolled. The cohort had a median age of 54.3 years, and most patients were male (75%). Median prior lines were 3 (range 3–5), and 44% had ECOG PS 02. Primary sites were stomach (50%) and small intestine (25%). Liver is the most predominant side of metastases (81.3%). Primary mutations included KIT exon 11 (56%), exon 9 (25%), and SDH-deficient GIST (12.5%); the most common secondary pattern was exon 11+17 (43%). The 3-month PFR was 62.5% by RECIST v1.1, with median PFS of 4.0 months. ORR was 6.2% by RECIST and 18.8% by Choi criteria. Common grade 3 adverse events were hand–foot skin reaction (18.8%), hypertension (18.8%), and diarrhoea (12.5%). Treatment interruptions and dose reductions occurred in 80% and 73.3%, respectively. Overall, QoL and Global Health Status remained stable. Conclusion: Cabozantinib demonstrated clinically meaningful activity with manageable toxicity in refractory metastatic/advanced GIST after ≥3 TKIs, supporting its role as a potential option in LMIC contexts where ripretinib access is limited. Larger, comparative phase III trials are warranted to confirm efficacy and better define optimal patient selection and dosing strategies. Trial registration: Trial Registration Number- CTRI/2024/06/068636 Our trial was “Retrospectively registered” with Clinical Trials Registry - India (CTRI) on 10/06/2024. Gastrointestinal Stromal Tumour Cabozantinib Tyrosine Kinase Inhibitors (TKIs) Quality of life (EORTC QLQ-C30) Choi Criteria Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. BACKGROUND Gastrointestinal stromal tumours (GIST) are most common mesenchymal malignancies arising in the gastrointestinal tract, with approximately 80% harbouring activating mutations in KIT and a further ~ 13% characterised by PDGFRA alterations. Sequential tyrosine kinase inhibition targeting these kinases constitutes the cornerstone of systemic therapy for patients with advanced or metastatic GIST ( 1 – 5 ). Over the past two decades, survival outcomes in advanced GIST have improved substantially following the introduction of imatinib and subsequent tyrosine kinase inhibitors. The FDA approval of imatinib in 2002 revolutionised the management of advanced GIST, producing durable disease control in more than 80% of patients in the first-line setting ( 6 ). However, despite initial sensitivity, approximately half of patients with advanced GIST experience disease progression within 24 months, and long-term disease control remains uncommon, with a 10-year progression-free survival of approximately 9% ( 2 , 3 , 7 , 8 ). This acquired resistance is commonly mediated by heterogeneous secondary KIT mutations involving the ATP-binding pocket or activation loop ( 9 – 11 ). As a result, advanced GIST typically requires multiple lines of systemic therapy over the course of the disease. Sunitinib and regorafenib were subsequently approved as second- and third-line therapies, respectively, yielding modest improvements in progression-free survival (PFS) of 5·6 months for sunitinib and 4·8 months for regorafenib each but with limited objective response rates ( 12 – 17 ). Avapritinib is approved mainly for PDGFRA exon 18 mutant GIST, which accounts for upto ~ 6% of the overall population ( 18 – 20 ). In the fourth-line setting, recently ripretinib, a switch-control inhibitor with broad activity against KIT and PDGFRA resistance mutations, demonstrated a significant improvement in PFS (6.3 months) compared with placebo in the phase III INVICTUS trial and is now established as the standard of care ( 21 ). Importantly, access to ripretinib remains restricted in many low- and middle- income countries (LMICs), creating a substantial treatment gap for patients who progress after three prior lines of therapy. In such settings, identifying alternative agents with clinically meaningful activity is critical, particularly for patients with declining performance status and heavy metastatic burden, in whom therapeutic choices are increasingly constrained. Several other TKIs, including nilotinib ( 22 ), sorafenib ( 23 ), and pazopanib ( 24 ), have been explored in this context with variable success. Cabozantinib is an oral multi-kinase inhibitor that targets KIT, VEGFR 1–3, MET and AXL, thereby combining anti-angiogenic activity with inhibition of signalling pathways implicated in acquired resistance to KIT-directed therapy ( 25 ). In the multicentre, single-arm EORTC 1317 “CaboGIST” phase II trial, cabozantinib showed modest but clinically meaningful activity in the third-line setting, achieving an objective response rate of 14% and a median progression-free survival of 5.5 months, with approximately 60% of patients remaining progression-free at 12 weeks ( 26 ). These findings support the capacity of cabozantinib to stabilise the disease in TKI-exposed GIST; however, CaboGIST primarily enrolled patients treated in the third-line setting with good Eastern Cooperative Oncology Group Performance Status (ECOG PS 0–1), and prospective evidence in fourth-line or later settings, particularly in poorer-performance populations, remains limited. Given the unmet need of fourth-line therapy in GIST, we conducted a prospective, single-arm phase II study to evaluate the efficacy and safety of cabozantinib in patients with unresectable or metastatic GIST who had progressed after at least three prior lines of TKI therapy. 2. METHODS 2.1 Aim, Study design and setting This is a prospective, single-arm, phase II clinical trial evaluating cabozantinib in patients with unresectable or metastatic, treatment-refractory gastrointestinal stromal tumours (GIST) following progression on at least three prior lines of systemic therapy. The study was conducted at the All India Institute of Medical Sciences (AIIMS), New Delhi, between January 2024 and December 2025 with January 2026 as the data cut off point. Written informed consent was obtained from all participants prior to enrolment. 2.2 Patient Characteristics Eligible patients were adults (≥ 18 years) with histologically confirmed GIST and unresectable or metastatic disease following progression on at least three prior lines of systemic therapy. Additional inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function, defined as absolute neutrophil count ≥ 1,000/µL, platelet count ≥ 100,000/µL, haemoglobin ≥ 8 g/dL, estimated glomerular filtration rate ≥ 30 mL/min/1.73 m², serum bilirubin ≤ 1.5 × upper limit of normal (ULN), and aspartate/alanine aminotransferase (AST/ALT) and alkaline phosphatase ≤ 2.5 × ULN. Key exclusion criteria included pregnancy or lactation, uncontrolled infection, locally recurrent disease amenable to curative surgery, significant cardiovascular disease, uncontrolled hypertension, recent arterial or venous thromboembolic events, and prior exposure to cabozantinib. Secondary mutational analysis was performed using next-generation sequencing (NGS) on tumour tissue in patients who consented to a repeat biopsy. NGS testing was exploratory and not mandatory for eligibility or study participation. 2.3 Study Intervention and assessments : All eligible patients received oral cabozantinib at a starting dose of 60 mg once daily. Patients with a body weight < 40 kg and/or ECOG performance status of 2 were initiated at a reduced starting dose of 40 mg once daily. Baseline assessments included clinical evaluation, complete blood counts, renal and hepatic function tests, baseline imaging, and quality-of-life assessment using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30 questionnaire) ( 27 ). Patients were evaluated monthly for treatment-related toxicities using clinical assessment, complete blood counts, and renal, hepatic, and thyroid function tests. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. In case of grade 3 toxicities, drug administration was interrupted until resolution to grade 2 or lower. Dose reduction was performed for recurrent grade 3 toxicities or any grade 4 toxicity. Two sequential dose reductions were allowed in the study: 40 mg OD and 20 mg OD. Criteria for treatment discontinuation included progressive disease, unacceptable toxicity, and prolonged treatment delay due to adverse events. Response assessment was conducted at 3 months after initiating cabozantinib or earlier if there is a clinical suspicion of progression, using FDG- PET-CT (18F-Flourodeoxyglucose Positron Emission Tomography Computed Tomography), according to RECIST (Response Evaluation Criteria in Solid Tumours) 1.1 and Choi criteria. Non-progressors were continued on the drug, with three monthly imaging until progression or unacceptable toxicity. Quality-of-life (QoL) assessment was performed at baseline and at 3 months using the EORTC quality of life (QLQ) C-30 questionnaire. 2.4 Study endpoints : The primary endpoint was the 3-month progression-free rate (PFR), defined as the proportion of patients alive and progression-free at 3 months after initiation of cabozantinib. Secondary endpoints included objective response rate (ORR), complete or partial response, 6-month progression-free rate, median progression-free survival (PFS), overall survival (OS), safety, and quality-of-life outcomes. 2.5 Sample size and statistical analysis : Sample size estimation was based on a single-stage phase II design as described by A'Hern ( 28 ). The study was designed to test the hypothesis that cabozantinib would achieve a 3-month progression-free rate (PFR) of at least 25% in the fourth-line setting, compared with a null PFR of ≤ 5%, representing minimal activity. With a one-sided alpha level of 0.05 and 90% power, the required sample size for this single-arm phase II study was calculated to be 25 patients. Efficacy analyses were performed on the intention-to-treat population. Progression-free survival (PFS) was defined as the interval from initiation of cabozantinib to radiologically confirmed disease progression or death from any cause. Survival outcomes were estimated using the Kaplan–Meier method. All statistical analyses were performed using SPSS version 29.0. 3. RESULTS 3.1 Patient population and baseline characteristics A total of 16 patients were enrolled between January 2024 and October 2025, and the patients are still recruiting. Baseline demographic and disease characteristics are summarised in Table 1 . Table 1 Baseline Demographics Of Patients Enrolled In The Study Variable Value Age (Median) 54.3 years (IQR: 35–70) Sex (%) Male: 12 (75) Female: 4 ( 25 ) ECOG PS 1: 09 2: 07 Metastatic vs Unresectable Metastatic: 16 Locally advanced: 0 Primary site Stomach: 8 (50%) Jejunum: 4 (25%) Retroperitoneum: 3 (18.75%) Mesentery: 1 (6.25%) Histology type Spindle type: 10 (62.5%) Epithelioid: 2 (12.5%) Mixed: 4 (25%) Mutation status at enrollment Exon 9 = 3 Exon 9 + 17 = 1 Exon 11 = 1 Exon 11 + 17 = 6 Exon 11 + 10+17 = 1 Exon 11 + 13 =1 SDH B = 2 N/A = 1 Sites of Metastases Liver: 13(81.3%) Peritoneal/serosal/omental deposits: 13(81%) Lung: 06(37.5%) Muscle deposits: 03(18.8%) Bone metastases: 03(18.8%) Prior Treatment Details Number of previous lines of treatment (Median): 3 (IQR: 3–5) Prior surgery Yes − 15 No − 1 Prior Palliative Radiotherapy Yes − 5 No − 11 Prior systemic treatment Imatinib- 16 Sunitinib − 16 Regorafenib − 16 Dasatinib − 1 Pazopanib − 1 Sorafenib − 1 Median duration of prior TKI treatment Imatinib- 33 months Sunitinib-9.5 months Regorafenib-7.5 months ECOG PS, Eastern Cooperative Oncology Group performance status; TKI= Tyrosine Kinase Inhibitor 3.2 Efficacy endpoints All 16 patients were evaluable for the primary endpoint. At the data cut-off, 13 patients had experienced disease progression, while 3 patients remained on cabozantinib treatment as shown in the CONSORT diagram (Fig. 1 ). The primary endpoint, 3-month progression-free rate (PFR) was 62.5% according to RECIST version 1.1. Objective responses were limited. One patient achieved a partial response by RECIST 1.1, corresponding to an objective response rate (ORR) of 6.25%. Using Choi criteria, three patients achieved a partial response, yielding an ORR of 18.8%. According to RECIST 1.1, best responses included partial response in 1 patient (6.3%), stable disease in 8 patients (50%), and progressive disease in 7 patients (43.8%). By Choi criteria, best responses were partial response in 3 patients (18.8%), stable disease in 5 patients (31.3%), and progressive disease in 8 patients (50%). The efficacy endpoints were summarised in Table 2 . Table 2 Key clinical Efficacy end- points Efficacy: RECIST 1.1 3 months PFR (%) 62.5% 6 months PFR (%) 48.6% Median PFS 4 months (95% CI: 2–10) Median OS 10 months (95% CI: 3–16) RECIST 1.1 Choi Best Overall response PR: 1 (6.3%) SD: 8 (50%) PD: 7 (43.8%) PR: 3 (18.8%) SD: 5 (31.2%) PD: 8 (50%) ORR – (CR + PR) 6.25% 18.8% CBR (CR/PR/SD) No: 7 (43.8%) Yes: 9 (56.3%) Yes: 08 (50%) No: 08 (50%) ORR: Objective Response Rate, OS: Overall Survival, PFS: Progression-Free Survival, PFR: Progression Free Rate, PD: Progressive Disease, SD: Stable Disease, PR: Partial Response, CR: Complete Response. The median progression-free survival was 4 months (95% CI, 2–10) (Fig. 2 ), and the median overall survival was 10 months (95% CI, 3–16) (Fig. 3 ). The 6-month PFR was 48.6%. Waterfall and Swimmer plots illustrating tumour response at 3 months and treatment response with time are shown in Figs. 4 and 5 , respectively. 3.3 Safety Safety was evaluable in all 16 patients. Treatment-related adverse events are summarised in Tables 3 & 4 . Hand–foot skin reaction was the most frequent adverse event, occurring in all patients (100%), with grade 3 events observed in 3 patients (18.8%). Other common adverse events included hypothyroidism (9 patients, 56.3%), diarrhoea (9 patients, 56.3%; grade 3 in 2 patients, 12.5%), oral mucositis (8 patients, 50%), and hypertension (6 patients, 37.5%; grade 3 in 3 patients, 18.8%). Fatigue and nausea were reported in 10 patients each, predominantly grade 1–2. Less frequent adverse events included scrotal ulceration (2 patients), cutaneous vasculitis (1 patient), and central retinal vein occlusion (1 patient). Table 3 Salient Toxicities Seen in the Study Adverse event Any grade no. (%) Grade 3 (%) HFSR 16 (100%) 3 (18.8%) Diarrhea 9 (56.3%) 2 (12.5%) Hypothyroidism 9 (56.3%) - Oral mucositis 8 (50%) - Hypertension 6 (37.5%) 3 (18.8%) Non-HFSR cutaneous reaction 2 (12.5%) - Fatigue 10 (62.5%) - Anorexia 10 (62.5%) - Nausea 6 (37.5%) - Dysgeusia 5 (31.3%) - HFSR : Hand Foot Skin Reaction Table 4 Haematological and biochemical toxicities Adverse event Any grade no. (%) Grade 3 (%) Anemia 2 (12.5) 2 (12.5) Neutropenia 2 (12.5) 1 (6.2) Thrombocytopenia 1 (6.2) - Bilirubin increase 1 (6.2) - SGOT 7 (43.8) - SGPT 5 (31.2) - Alkaline Phosphatase 3 (18.8) 1 (6.2) Hyponatremia 3 (18.8) 1 (6.2) Hypocalcemia 2 (12.5) - Hypokalemia 1 (6.2) - Renal toxicity 1 (6.2) - Urine protein 7 (43.8) - SGOT: serum glutamic oxaloacetic transaminase. SGPT: serum glutamic-pyruvic transaminase. 3.4 Treatment exposure and dose modifications Dose modifications during treatment are detailed in Table 5 . The median duration of cabozantinib therapy was 13 weeks (IQR, 8.5–30.5), and the median daily dose delivered was 44.2 mg (IQR, 40–50.5). Thirteen patients (81.3%) required at least one dose modification, including dose reductions in 11 patients (68.8%) and treatment interruptions in 12 patients (75%). Treatment discontinuation occurred primarily due to disease progression (11 of 16 patients). Two patients discontinued treatment because of toxicity and subsequently experienced disease progression following treatment delay. Table 5 Study treatment, exposure to cabozantinib. Duration of treatment (weeks) Median Range 13 weeks (IQR- 8.6–30.7) Daily cabozantinib dose during the course of treatment Median Range 44.2 mg (IQR- 40.0-50.5) Treatment Modification Dose Modification Dose Reduction Treatment interruption 13/16 (81.3%) 11/16 (68.8%) 12/16 (75%) The major reason for discontinuation Progression of disease Toxicity 11/16 2/16 3.5 Quality of Life QoL analysis in our study was done using EORTC QLQ C-30 questionnaire at baseline and 3 months. All functional scales demonstrated numerical declines over time, most notably in social functioning (mean change − 10.3), emotional functioning (− 5.8), and physical functioning (− 5.6). Among symptom domains, fatigue, appetite loss, pain, and financial difficulties had the highest baseline scores. At 3 months, numerical improvements were observed in nausea/vomiting, insomnia, fatigue, constipation, and financial difficulties, whereas numerical worsening was observed for pain, dyspnoea, anorexia, and diarrhoea; however, none of these changes reached statistical significance. Diarrhoea scores increased by more than 10 points from baseline to 3 months (mean 23.1 to 35.9; p = 0.27), suggesting clinically relevant worsening without reaching statistical significance. Global health status/QoL remained stable over time (mean 44.9 to 42.3; p = 0.62). 3.6 Post-progression Therapy At the time of data cut-off, 13 patients had progressed on cabozantinib. Of these, 7 patients received subsequent systemic therapy, including imatinib rechallenge as per the RIGHT trial ( 29 ) (4 patients), ripretinib (1 patient), and temozolomide in 2 patients with SDH-deficient GIST. 4. DISCUSSION This is the first prospective study evaluating cabozantinib in metastatic GIST in the fourth-line setting. The median age in our cohort is 54.3 years which is less when compared to previous pivotal studies like INVICTUS (59 years) ( 21 ) and CaboGIST (63 years) ( 26 ), and similar to other Indian studies by Baa et al ( 30 ) (53 years) and Anant et al ( 31 ) (50–58 years) showing median onset of presentation of GIST at a younger age in Indian subcontinent when compared to western population( 32 ). Notably, 43% of our patients had ECOG PS − 2, whereas CaboGIST enrolled only ECOG PS 0–1 patients, and INVICTUS study had only 8.5% ECOG PS -2 cohort, which mirrors the real-world population. In the later lines of therapy, performance status in patients with GIST declines rapidly, as reported in the INVICTUS trial where one-third of the patients who progressed on placebo could not be crossed over to the ripretinib arm due to poor PS ( 21 ). 14 patients in our cohort received cabozantinib in 4th line, while one each received in 5th line and 6th line, respectively which indicates a heavily pre-treated cohort. In addition, baseline disease burden was substantial in our cohort, with the predominant metastatic site being the liver (81%) and other frequent sites being the peritoneal cavity involvement, including serosal and omental deposits. Mutation profile in our cohort revealed exon 11 in 56.2% and exon 9 in 25% as compared to 55% (exon 11) and 17% (exon 9) in the INVICTUS study and 62% (exon 11) and 13.5% (exon 9) in the CaboGIST study respectively. The study met its primary endpoint: the 3-month PFR was 62.5%, clearly exceeding our prespecified threshold of 25%, supporting clinically meaningful activity of cabozantinib in this population. The 6-month PFR was 48.6%, broadly consistent with CaboGIST data (PFR 70% at 3 months and 45.6% at 6 months) and INVICTUS data (6 month PFR of 51%). This concordance supports the view that durable disease control, reflected by lack of progression may be a more meaningful marker of clinical benefit than objective response alone in advanced, heavily pre-treated GIST ( 33 ). The median PFS in our cohort was 4 months, which falls between the outcomes reported with imatinib rechallenge in later-line GIST (median PFS 1.8 months) ( 28 ) and ripretinib in the fourth-line setting (median PFS 6.3 months) ( 21 ). This gradient is biologically plausible. Ripretinib is a selective “switch-control” KIT/PDGFRA inhibitor with a more favourable tolerability profile, whereas cabozantinib is a broader multi-kinase TKI with a substantial burden of off-target, anti-angiogenic toxicities; these differences could partly explain the shorter PFS observed with cabozantinib in our cohort. Notably, the median PFS in our study was also shorter than the 5.5 months reported by Schöffski et al.( 26 ). However, CaboGIST evaluated cabozantinib predominantly in a third-line population, whereas our patients were treated in the more refractory fourth-line setting after progression on ≥ 3 prior TKIs, which limits direct cross-trial comparability. In our cohort, cabozantinib produced an objective response rate of 6.2% by RECIST v1.1, but a higher response by Choi criteria (18.7%). As expected in GIST, response estimates are often higher with Choi than with RECIST because early TKI effects such as reduced enhancement, intra-tumoral necrosis, and falling tumour density can precede measurable tumour shrinkage. Accordingly, size-based RECIST assessments may underestimate TKI activity in GIST, underscoring the value of incorporating both size and density changes when evaluating response( 34 ). An exploratory analysis of the CaboGIST study further corroborated these observations. In this analysis, a partial response was observed in 12% and 7% by local RECIST v1.1 assessment and central RECIST review respectively, however 50% showed a PR when applying Choi criteria ( 35 ). These findings highlighted the ongoing relevance of Choi-based assessment, even in later-line settings. We evaluated differential efficacy according to primary KIT genotype (exon 11 vs exon 9). No statistically significant difference in median PFS was observed between these groups (p = 0.37). A planned comparison based on secondary mutation status (exon 13/14 vs exon 17/18) could not be performed because of the small numbers in each subgroup. Among the two SDH-deficient GIST patients in our cohort, one achieved stable disease on cabozantinib, suggesting potential activity across a broad spectrum of molecular subtypes. Overall, these subgroup analyses should be interpreted cautiously, as they were exploratory and hypothesis-generating. We also explored outcomes by baseline performance status (ECOG PS 0–1 vs 2) and did not observe a significant difference in median PFS (p = 0.65). Cabozantinib showed a typical VEGFR-TKI toxicity profile in our cohort, with frequent HFSR (100%), diarrhoea (56.2%), mucositis (50%), fatigue (62.5%), and hypertension (37.5%) which are consistent with previously reported literature ( 26 ). However, the HFSR rate was universal in our cohort (100% incidence). In the CaboGIST trial, hand–foot skin reaction (HFSR) was reported in 60% of patients, a rate lower than that observed in our cohort. The possible interpretation could be cumulative TKI toxicity and poor performance status in our 4th line cohort. This resulted in a high rate of dose modifications (81%). Most of the toxicities were manageable, but they reduced treatment continuity and dose intensity. In contrast, ripretinib had a unique and more favourable tolerability profile, with alopecia being the most common adverse effect (51%) and fewer treatment-related events (HFSR 21%, diarrhoea 20%, hypertension 5%) and low rates of dose reductions (6%). Clinically, this supports more consistent dosing and likely contributes to superior disease control. Overall, cabozantinib did not improve QoL in our heavily pre-treated cohort. Among the symptom scales, diarrhoea showed a clinically meaningful worsening, consistent with the expected gastrointestinal toxicity profile of cabozantinib while nausea/ vomiting and insomnia showed improvement. Notably, overall global QoL and symptom scores did not significantly deteriorate despite the frequent HFSR and diarrhoea. This emphasizes the need for QoL assessments specifically designed to capture treatment-related symptoms and highlights a limitation of general instruments, such as the QLQ-C30, for TKI-specific toxicities. Strengths of the study This is the first prospective drug trial done in India in GIST. This trial included ECOG PS-2 patients, and response assessment was also done by Choi criteria besides the RECIST v 1.1, which is done in very few studies across the globe. Limitations of the study Our study has some limitations, chief among them being a single-centre design and the lack of a comparator arm. However, given the rarity of these tumours, conducting a comparative study would have been logistically challenging. The prespecified sample size was not reached; enrolment was planned to continue until the target was met, but the anticipated approval of ripretinib in India was expected to halt further accrual. A translational approach via ctDNA-based mutation profiling could not be incorporated because GIST-focused ctDNA assays were not available in India at the time the study was initiated, and the high cost of broad solid-tumour ctDNA panels posed a significant financial barrier. 5. CONCLUSION Overall, our findings suggest cabozantinib has clinically meaningful activity in heavily treated fourth-line GIST patients, primarily through disease stabilization, but its effectiveness is constrained by toxicity-driven dose modifications leading to compromised dose intensity. However, where ripretinib access is limited, cabozantinib can serve as a pragmatic alternative if proactive supportive care and structured dose-modification strategies are implemented early to preserve exposure and maximize benefit. Abbreviations 1.GIST: Gastro Intestinal Stromal Tumour 2. LMICs: Low- and Middle- Income Countries 3. TKI: Tyrosine Kinase Inhibitor 4. ECOG PS: Eastern Cooperative Oncology Group Performance Status 5. RECIST: Response Evaluation Criteria in Solid Tumours 6. EORTC QLQ-C30: European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 7. QoL: Quality of Life 8. PD: Progressive Disease 9. SD: Stable Disease 10. PR: Partial Response 11. CR: Complete Response 12. ORR: Objective Response Rate 13. PFS: Progression-Free Survival 14. PFR: Progression Free Rate 15. AST: Aspartate Transaminase 16. ALT: Alanine Transaminase 17. NGS: Next Generation Sequencing 18. FDG PET-CT: 18F-Flourodeoxyglucose Positron Emission Tomography Computed Tomography 19. ctDNA: circulating tumour DNA Declarations Ethics approval and consent to participate: The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and its subsequent amendments, and was initiated after approval from the Institute Ethics Committee for Post Graduate Research, All India Institute of Medical Sciences, New Delhi (IEC No. 455/24.08.2023). Written informed consent was obtained from all participants prior to enrolment. Consent for publication: All participants provided written informed consent for publication of anonymized clinical information. Availability of data and materials: The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests. Funding: None. Authors’ contributions: Ventrapragada Neelima: Patient enrolment, data curation, formal analysis, writing - original draft, and writing - review & editing. Sameer Rastogi: Conceptualization, supervision, interpretation of results, and writing - review & editing with critical intellectual input. Kinjal Singh: Formal analysis, and writing - review & editing. Akash Singh: Writing - review & editing. Shamim A. Shamim: Investigation (imaging review/response assessment), and writing - review & editing. Shivanand Gamanagatti: Investigation (imaging review/response assessment), and writing - review & editing. Rajni Yadav: Resources (NGS testing), and writing - review & editing. Nihar Ranjan Dash: Investigation (surgical management/inputs), and writing - review & editing. All authors read and approved the final manuscript and agree to be accountable for all aspects of the work. Acknowledgements: We sincerely thank all study participants and their families for their trust and cooperation. 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Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(33):5352–9. Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU, Heinicke T, et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res Off J Am Assoc Cancer Res. 2006;12(6):1743–9. Liegl B, Kepten I, Le C, Zhu M, Demetri GD, Heinrich MC, et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol. 2008;216(1):64–74. Garner AP, Gozgit JM, Anjum R, Vodala S, Schrock A, Zhou T, et al. Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20(22):5745–55. Serrano C, Mariño-Enríquez A, Tao DL, Ketzer J, Eilers G, Zhu M, et al. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. Br J Cancer. 2019;120(6):612–20. Mühlenberg T, Ketzer J, Heinrich MC, Grunewald S, Marino-Enriquez A, Trautmann M, et al. KIT-Dependent and KIT-Independent Genomic Heterogeneity of Resistance in Gastrointestinal Stromal Tumors - TORC1/2 Inhibition as Salvage Strategy. Mol Cancer Ther. 2019;18(11):1985–96. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329–38. Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295–302. US Food and Drug Administration. Sutent. New York, NY: Pfizer Labs. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021938s13s17s18lbl.pdf (accessed February 10, 2026). US Food and Drug Administration. Ayvakit. Cambridge, MA: Blueprint Medicines Corp. 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212608s000lbl.pdf (accessed February 10, 2026). Hemming ML, Heinrich MC, Bauer S, George S. Translational insights into gastrointestinal stromal tumor and current clinical advances. Ann Oncol Off J Eur Soc Med Oncol. 2018;29(10):2037–45. Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(23):5357–64. Blay JY, Serrano C, Heinrich MC, Zalcberg J, Bauer S, Gelderblom H, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(7):923–34. Reichardt P, Blay JY, Gelderblom H, Schlemmer M, Demetri GD, Bui-Nguyen B, et al. Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol Off J Eur Soc Med Oncol. 2012;23(7):1680–7. Park SH, Ryu MH, Ryoo BY, Im SA, Kwon HC, Lee SS, et al. Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase II study of Korean gastrointestinal stromal tumors study group. Invest New Drugs. 2012;30(6):2377–83. Mir O, Cropet C, Toulmonde M, Cesne AL, Molimard M, Bompas E, et al. Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial. Lancet Oncol. 2016;17(5):632–41. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–308. Schöffski P, Mir O, Kasper B, Papai Z, Blay JY, Italiano A, et al. Activity and safety of the multi-target tyrosine kinase inhibitor cabozantinib in patients with metastatic gastrointestinal stromal tumour after treatment with imatinib and sunitinib: European Organisation for Research and Treatment of Cancer phase II trial 1317 CaboGIST. Eur J Cancer. 2020;134:62–74. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: A Quality-of-Life Instrument for Use in International Clinical Trials in Oncology. JNCI J Natl Cancer Inst. 1993;85(5):365–76. A'Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med. 2001;20(6):859–66. Kang YK, Ryu MH, Yoo C, Ryoo BY, Kim HJ, Lee JJ, et al. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1175–82. Baa AK, Rastogi S, Fernandes S, Shrivastava S, Yadav R, Barwad A, et al. Insights into the medical management of gastrointestinal stromal tumours: lessons learnt from a dedicated gastrointestinal stromal tumour clinic in North India. Ecancermedicalscience. 2023;17:1497. Ramaswamy A, Chaudhari V, Bhargava P, Bhandare M, Kumar R, Shrikhande SV, Ostwal V. Gastrointestinal stromal tumor: an overview. Indian J Med Paediatr Oncol. 2020;41(6):809–18. Casali PG, Blay JY, Abecassis N, Bajpai J, Bauer S, Biagini R, et al. Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol. 2022;33(1):20–33. Le Cesne A, Van Glabbeke M, Verweij J, Casali PG, Findlay M, Reichardt P, et al. Absence of progression as assessed by response evaluation criteria in solid tumors predicts survival in advanced GI stromal tumors treated with imatinib mesylate: the intergroup EORTC-ISG-AGITG phase III trial. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(24):3969–74. Dudeck O, Zeile M, Reichardt P, Pink D. Comparison of RECIST and Choi criteria for computed tomographic response evaluation in patients with advanced gastrointestinal stromal tumor treated with sunitinib. Ann Oncol Off J Eur Soc Med Oncol. 2011;22(8):1828–33. Kyriazoglou A, Jespers P, Vandecavaye V, Mir O, Kasper B, Papai Z, et al. Exploratory analysis of tumor imaging in a Phase 2 trial with cabozantinib in gastrointestinal stromal tumor: lessons learned from study EORTC STBSG 1317 CaboGIST. Acta Oncol. 2022;61(6):663–8. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 14 Apr, 2026 Reviews received at journal 03 Apr, 2026 Reviews received at journal 31 Mar, 2026 Reviewers agreed at journal 25 Mar, 2026 Reviewers agreed at journal 19 Mar, 2026 Reviewers invited by journal 17 Mar, 2026 Editor assigned by journal 16 Mar, 2026 Editor invited by journal 24 Feb, 2026 Submission checks completed at journal 23 Feb, 2026 First submitted to journal 23 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8910891","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":608461476,"identity":"fcb15224-74b7-4a29-9869-56ee0f37aac8","order_by":0,"name":"Neelima Ventrapragada","email":"","orcid":"","institution":"All India Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Neelima","middleName":"","lastName":"Ventrapragada","suffix":""},{"id":608461477,"identity":"088b91ba-82ae-4663-937a-f7bfc793b0b8","order_by":1,"name":"Sameer Rastogi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYJACCSjN+ICB4QBpWpgNSNbCJkGUFvn204k3PtQwRPNPO/ysmqfmjhw/A/PDRzfwaDE4k7vZcsYxhtwZt9PMbvMce2Ys2cBmbJyDTwtD7jZp3gaG3IbbOWy3edgOJ244wMMmjU+LfP9biJb5QC3FPP+I0MJwA2rLBqAWZt42IrQY3HgL8cvG22nGknP7DhtLNhPwi3x/7kZQiOXOu5388MObb4fl+NmbHz7G6zAI+A8mmXhAJDNh5QjA+IMU1aNgFIyCUTBiAADIMk7jjNqXlAAAAABJRU5ErkJggg==","orcid":"","institution":"All India Institute of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Sameer","middleName":"","lastName":"Rastogi","suffix":""},{"id":608461478,"identity":"d5a191a6-51ee-4eae-bd5b-1948cf282854","order_by":2,"name":"Kinjal Singh","email":"","orcid":"","institution":"All India Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Kinjal","middleName":"","lastName":"Singh","suffix":""},{"id":608461479,"identity":"54a7c8e6-0c9a-402e-9dd4-d9e9915c48a2","order_by":3,"name":"Akash Singh","email":"","orcid":"","institution":"All India Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Akash","middleName":"","lastName":"Singh","suffix":""},{"id":608461480,"identity":"9de4f572-00dd-4ae2-8eb2-07d0f16aad19","order_by":4,"name":"Shamim A. Shamim","email":"","orcid":"","institution":"All India Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Shamim","middleName":"A.","lastName":"Shamim","suffix":""},{"id":608461481,"identity":"ec3b9ad8-b2a1-4642-8b0f-9ef5dca0b1ed","order_by":5,"name":"Shivanand Gamanagatti","email":"","orcid":"","institution":"All India Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Shivanand","middleName":"","lastName":"Gamanagatti","suffix":""},{"id":608461482,"identity":"56ed65d2-40f1-4ff6-816b-8af920151bcd","order_by":6,"name":"Rajni Yadav","email":"","orcid":"","institution":"All India Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Rajni","middleName":"","lastName":"Yadav","suffix":""},{"id":608461483,"identity":"a743ee4a-24da-4f1f-a492-fd0873134c67","order_by":7,"name":"Nihar Ranjan Dash","email":"","orcid":"","institution":"All India Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Nihar","middleName":"Ranjan","lastName":"Dash","suffix":""}],"badges":[],"createdAt":"2026-02-18 16:26:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8910891/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8910891/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104998550,"identity":"811d2809-07c4-4de6-b86f-e8a965330fa1","added_by":"auto","created_at":"2026-03-19 16:30:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":79472,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCONSORT Flow Diagram\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8910891/v1/c92708774127373c5152fea3.png"},{"id":104998549,"identity":"5f61a488-c1c4-4616-b1c7-e49ebaa33676","added_by":"auto","created_at":"2026-03-19 16:30:26","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":208853,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier curve showing PFS (months). PFS = progression-free survival\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8910891/v1/f16601956164d3e31fd5bc52.jpeg"},{"id":104998554,"identity":"fc6bb749-4ae5-4324-a4c9-3302eceecd89","added_by":"auto","created_at":"2026-03-19 16:30:27","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":196679,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier curve showing OS (months). OS = Overall survival\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8910891/v1/16c47e55f0914ce7b0769359.jpeg"},{"id":104998551,"identity":"9d843318-53f5-44fc-87c7-ab7886ffce31","added_by":"auto","created_at":"2026-03-19 16:30:26","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":202380,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWaterfall Plot\u003c/strong\u003e \u003cstrong\u003eshowing responses to cabozantinib at 3 months\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8910891/v1/de281eec857dd2d346672652.jpeg"},{"id":104998552,"identity":"2e92191a-17c4-4e1b-b160-a3d9bcd79529","added_by":"auto","created_at":"2026-03-19 16:30:26","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":17397,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSwimmer plot showing the individual response of each patient with time using RECIST v 1.1 criteria\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8910891/v1/c498cf44493ce14bb3252315.png"},{"id":105035434,"identity":"3f07d73a-a63e-40c5-92ca-ea2da278907b","added_by":"auto","created_at":"2026-03-20 07:26:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1841813,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8910891/v1/de8c5830-e86f-4773-be82-29859870d434.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Phase II Study of Cabozantinib in Metastatic or Unresectable Refractory Gastrointestinal Stromal Tumour: A Single-Centre Study from India","fulltext":[{"header":"1. BACKGROUND","content":"\u003cp\u003eGastrointestinal stromal tumours (GIST) are most common mesenchymal malignancies arising in the gastrointestinal tract, with approximately 80% harbouring activating mutations in \u003cem\u003eKIT\u003c/em\u003e and a further\u0026thinsp;~\u0026thinsp;13% characterised by \u003cem\u003ePDGFRA\u003c/em\u003e alterations. Sequential tyrosine kinase inhibition targeting these kinases constitutes the cornerstone of systemic therapy for patients with advanced or metastatic GIST (\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOver the past two decades, survival outcomes in advanced GIST have improved substantially following the introduction of imatinib and subsequent tyrosine kinase inhibitors. The FDA approval of imatinib in 2002 revolutionised the management of advanced GIST, producing durable disease control in more than 80% of patients in the first-line setting (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). However, despite initial sensitivity, approximately half of patients with advanced GIST experience disease progression within 24 months, and long-term disease control remains uncommon, with a 10-year progression-free survival of approximately 9% (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). This acquired resistance is commonly mediated by heterogeneous secondary \u003cem\u003eKIT\u003c/em\u003e mutations involving the ATP-binding pocket or activation loop (\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). As a result, advanced GIST typically requires multiple lines of systemic therapy over the course of the disease.\u003c/p\u003e \u003cp\u003eSunitinib and regorafenib were subsequently approved as second- and third-line therapies, respectively, yielding modest improvements in progression-free survival (PFS) of 5\u0026middot;6 months for sunitinib and 4\u0026middot;8 months for regorafenib each but with limited objective response rates (\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Avapritinib is approved mainly for PDGFRA exon 18 mutant GIST, which accounts for upto\u0026thinsp;~\u0026thinsp;6% of the overall population (\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the fourth-line setting, recently ripretinib, a switch-control inhibitor with broad activity against KIT and PDGFRA resistance mutations, demonstrated a significant improvement in PFS (6.3 months) compared with placebo in the phase III INVICTUS trial and is now established as the standard of care (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Importantly, access to ripretinib remains restricted in many low- and middle- income countries (LMICs), creating a substantial treatment gap for patients who progress after three prior lines of therapy. In such settings, identifying alternative agents with clinically meaningful activity is critical, particularly for patients with declining performance status and heavy metastatic burden, in whom therapeutic choices are increasingly constrained. Several other TKIs, including nilotinib (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), sorafenib (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), and pazopanib (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), have been explored in this context with variable success.\u003c/p\u003e \u003cp\u003eCabozantinib is an oral multi-kinase inhibitor that targets KIT, VEGFR 1\u0026ndash;3, MET and AXL, thereby combining anti-angiogenic activity with inhibition of signalling pathways implicated in acquired resistance to KIT-directed therapy (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). In the multicentre, single-arm EORTC 1317 \u0026ldquo;CaboGIST\u0026rdquo; phase II trial, cabozantinib showed modest but clinically meaningful activity in the third-line setting, achieving an objective response rate of 14% and a median progression-free survival of 5.5 months, with approximately 60% of patients remaining progression-free at 12 weeks (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). These findings support the capacity of cabozantinib to stabilise the disease in TKI-exposed GIST; however, CaboGIST primarily enrolled patients treated in the third-line setting with good Eastern Cooperative Oncology Group Performance Status (ECOG PS 0\u0026ndash;1), and prospective evidence in fourth-line or later settings, particularly in poorer-performance populations, remains limited. Given the unmet need of fourth-line therapy in GIST, we conducted a prospective, single-arm phase II study to evaluate the efficacy and safety of cabozantinib in patients with unresectable or metastatic GIST who had progressed after at least three prior lines of TKI therapy.\u003c/p\u003e"},{"header":"2. METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Aim, Study design and setting\u003c/h2\u003e \u003cp\u003eThis is a prospective, single-arm, phase II clinical trial evaluating cabozantinib in patients with unresectable or metastatic, treatment-refractory gastrointestinal stromal tumours (GIST) following progression on at least three prior lines of systemic therapy. The study was conducted at the All India Institute of Medical Sciences (AIIMS), New Delhi, between January 2024 and December 2025 with January 2026 as the data cut off point. Written informed consent was obtained from all participants prior to enrolment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Patient Characteristics\u003c/h2\u003e \u003cp\u003eEligible patients were adults (\u0026ge;\u0026thinsp;18 years) with histologically confirmed GIST and unresectable or metastatic disease following progression on at least three prior lines of systemic therapy. Additional inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0\u0026ndash;2 and adequate organ function, defined as absolute neutrophil count\u0026thinsp;\u0026ge;\u0026thinsp;1,000/\u0026micro;L, platelet count\u0026thinsp;\u0026ge;\u0026thinsp;100,000/\u0026micro;L, haemoglobin\u0026thinsp;\u0026ge;\u0026thinsp;8 g/dL, estimated glomerular filtration rate\u0026thinsp;\u0026ge;\u0026thinsp;30 mL/min/1.73 m\u0026sup2;, serum bilirubin\u0026thinsp;\u0026le;\u0026thinsp;1.5 \u0026times; upper limit of normal (ULN), and aspartate/alanine aminotransferase (AST/ALT) and alkaline phosphatase\u0026thinsp;\u0026le;\u0026thinsp;2.5 \u0026times; ULN.\u003c/p\u003e \u003cp\u003eKey exclusion criteria included pregnancy or lactation, uncontrolled infection, locally recurrent disease amenable to curative surgery, significant cardiovascular disease, uncontrolled hypertension, recent arterial or venous thromboembolic events, and prior exposure to cabozantinib.\u003c/p\u003e \u003cp\u003eSecondary mutational analysis was performed using next-generation sequencing (NGS) on tumour tissue in patients who consented to a repeat biopsy. NGS testing was exploratory and not mandatory for eligibility or study participation.\u003c/p\u003e \u003cp\u003e \u003cb\u003e2.3 Study Intervention and assessments\u003c/b\u003e: All eligible patients received oral cabozantinib at a starting dose of 60 mg once daily. Patients with a body weight\u0026thinsp;\u0026lt;\u0026thinsp;40 kg and/or ECOG performance status of 2 were initiated at a reduced starting dose of 40 mg once daily. Baseline assessments included clinical evaluation, complete blood counts, renal and hepatic function tests, baseline imaging, and quality-of-life assessment using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30 questionnaire) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Patients were evaluated monthly for treatment-related toxicities using clinical assessment, complete blood counts, and renal, hepatic, and thyroid function tests. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.\u003c/p\u003e \u003cp\u003eIn case of grade 3 toxicities, drug administration was interrupted until resolution to grade 2 or lower. Dose reduction was performed for recurrent grade 3 toxicities or any grade 4 toxicity. Two sequential dose reductions were allowed in the study: 40 mg OD and 20 mg OD. Criteria for treatment discontinuation included progressive disease, unacceptable toxicity, and prolonged treatment delay due to adverse events.\u003c/p\u003e \u003cp\u003eResponse assessment was conducted at 3 months after initiating cabozantinib or earlier if there is a clinical suspicion of progression, using FDG- PET-CT (18F-Flourodeoxyglucose Positron Emission Tomography Computed Tomography), according to RECIST (Response Evaluation Criteria in Solid Tumours) 1.1 and Choi criteria. Non-progressors were continued on the drug, with three monthly imaging until progression or unacceptable toxicity. Quality-of-life (QoL) assessment was performed at baseline and at 3 months using the EORTC quality of life (QLQ) C-30 questionnaire.\u003c/p\u003e \u003cp\u003e \u003cb\u003e2.4 Study endpoints\u003c/b\u003e: The primary endpoint was the 3-month progression-free rate (PFR), defined as the proportion of patients alive and progression-free at 3 months after initiation of cabozantinib. Secondary endpoints included objective response rate (ORR), complete or partial response, 6-month progression-free rate, median progression-free survival (PFS), overall survival (OS), safety, and quality-of-life outcomes.\u003c/p\u003e \u003cp\u003e \u003cb\u003e2.5 Sample size and statistical analysis\u003c/b\u003e: Sample size estimation was based on a single-stage phase II design as described by A'Hern (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The study was designed to test the hypothesis that cabozantinib would achieve a 3-month progression-free rate (PFR) of at least 25% in the fourth-line setting, compared with a null PFR of \u0026le;\u0026thinsp;5%, representing minimal activity. With a one-sided alpha level of 0.05 and 90% power, the required sample size for this single-arm phase II study was calculated to be 25 patients.\u003c/p\u003e \u003cp\u003eEfficacy analyses were performed on the intention-to-treat population. Progression-free survival (PFS) was defined as the interval from initiation of cabozantinib to radiologically confirmed disease progression or death from any cause. Survival outcomes were estimated using the Kaplan\u0026ndash;Meier method. All statistical analyses were performed using SPSS version 29.0.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. RESULTS","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Patient population and baseline characteristics\u003c/h2\u003e \u003cp\u003eA total of 16 patients were enrolled between January 2024 and October 2025, and the patients are still recruiting. Baseline demographic and disease characteristics are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Demographics Of Patients Enrolled In The Study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (Median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54.3 years (IQR: 35\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale: 12 (75)\u003c/p\u003e \u003cp\u003eFemale: 4 (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1: 09\u003c/p\u003e \u003cp\u003e2: 07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic vs Unresectable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMetastatic: 16\u003c/p\u003e \u003cp\u003eLocally advanced: 0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary site\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStomach: 8 (50%)\u003c/p\u003e \u003cp\u003eJejunum: 4 (25%)\u003c/p\u003e \u003cp\u003eRetroperitoneum: 3 (18.75%)\u003c/p\u003e \u003cp\u003eMesentery: 1 (6.25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistology type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSpindle type: 10 (62.5%)\u003c/p\u003e \u003cp\u003eEpithelioid: 2 (12.5%)\u003c/p\u003e \u003cp\u003eMixed: 4 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutation status at enrollment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExon 9\u0026thinsp;=\u0026thinsp;3\u003c/p\u003e \u003cp\u003eExon 9\u0026thinsp;+\u0026thinsp;17\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003cp\u003eExon 11\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003cp\u003eExon 11\u0026thinsp;+\u0026thinsp;17\u0026thinsp;=\u0026thinsp;6\u003c/p\u003e \u003cp\u003eExon 11\u0026thinsp;+\u0026thinsp;10+17\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003cp\u003eExon 11\u0026thinsp;+\u0026thinsp;13 =1\u003c/p\u003e \u003cp\u003eSDH B\u0026thinsp;=\u0026thinsp;2\u003c/p\u003e \u003cp\u003eN/A\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSites of Metastases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver: 13(81.3%)\u003c/p\u003e \u003cp\u003ePeritoneal/serosal/omental deposits: 13(81%)\u003c/p\u003e \u003cp\u003eLung: 06(37.5%)\u003c/p\u003e \u003cp\u003eMuscle deposits: 03(18.8%)\u003c/p\u003e \u003cp\u003eBone metastases: 03(18.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrior Treatment Details\u003c/b\u003e\u003c/p\u003e \u003cp\u003eNumber of previous lines of treatment (Median): 3 (IQR: 3\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u0026thinsp;\u0026minus;\u0026thinsp;15\u003c/p\u003e \u003cp\u003eNo\u0026thinsp;\u0026minus;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior Palliative Radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u0026thinsp;\u0026minus;\u0026thinsp;5\u003c/p\u003e \u003cp\u003eNo\u0026thinsp;\u0026minus;\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior systemic treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eImatinib- 16\u003c/p\u003e \u003cp\u003eSunitinib\u0026thinsp;\u0026minus;\u0026thinsp;16\u003c/p\u003e \u003cp\u003eRegorafenib\u0026thinsp;\u0026minus;\u0026thinsp;16\u003c/p\u003e \u003cp\u003eDasatinib\u0026thinsp;\u0026minus;\u0026thinsp;1\u003c/p\u003e \u003cp\u003ePazopanib\u0026thinsp;\u0026minus;\u0026thinsp;1\u003c/p\u003e \u003cp\u003eSorafenib\u0026thinsp;\u0026minus;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian duration of prior TKI treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eImatinib- 33 months\u003c/p\u003e \u003cp\u003eSunitinib-9.5 months\u003c/p\u003e \u003cp\u003eRegorafenib-7.5 months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eECOG PS, Eastern Cooperative Oncology Group performance status; TKI= Tyrosine Kinase Inhibitor\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Efficacy endpoints\u003c/h2\u003e \u003cp\u003eAll 16 patients were evaluable for the primary endpoint. At the data cut-off, 13 patients had experienced disease progression, while 3 patients remained on cabozantinib treatment as shown in the CONSORT diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The primary endpoint, 3-month progression-free rate (PFR) was 62.5% according to RECIST version 1.1.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eObjective responses were limited. One patient achieved a partial response by RECIST 1.1, corresponding to an objective response rate (ORR) of 6.25%. Using Choi criteria, three patients achieved a partial response, yielding an ORR of 18.8%. According to RECIST 1.1, best responses included partial response in 1 patient (6.3%), stable disease in 8 patients (50%), and progressive disease in 7 patients (43.8%). By Choi criteria, best responses were partial response in 3 patients (18.8%), stable disease in 5 patients (31.3%), and progressive disease in 8 patients (50%). The efficacy endpoints were summarised in Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eKey clinical Efficacy end- points\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEfficacy:\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eRECIST 1.1\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 months PFR (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e62.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 months PFR (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e48.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian PFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e4 months (95% CI: 2\u0026ndash;10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian OS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e10 months (95% CI: 3\u0026ndash;16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eRECIST 1.1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eChoi\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBest Overall response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePR: 1 (6.3%)\u003c/p\u003e \u003cp\u003eSD: 8 (50%)\u003c/p\u003e \u003cp\u003ePD: 7 (43.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePR: 3 (18.8%)\u003c/p\u003e \u003cp\u003eSD: 5 (31.2%)\u003c/p\u003e \u003cp\u003ePD: 8 (50%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eORR \u0026ndash; (CR\u0026thinsp;+\u0026thinsp;PR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCBR (CR/PR/SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo: 7 (43.8%)\u003c/p\u003e \u003cp\u003eYes: 9 (56.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes: 08 (50%)\u003c/p\u003e \u003cp\u003eNo: 08 (50%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eORR: Objective Response Rate, OS: Overall Survival, PFS: Progression-Free Survival, PFR: Progression Free Rate, PD: Progressive Disease, SD: Stable Disease, PR: Partial Response, CR: Complete Response.\u003c/p\u003e \u003cp\u003eThe median progression-free survival was 4 months (95% CI, 2\u0026ndash;10) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), and the median overall survival was 10 months (95% CI, 3\u0026ndash;16) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The 6-month PFR was 48.6%. Waterfall and Swimmer plots illustrating tumour response at 3 months and treatment response with time are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Safety\u003c/h2\u003e \u003cp\u003eSafety was evaluable in all 16 patients. Treatment-related adverse events are summarised in Tables\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e \u0026amp; \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Hand\u0026ndash;foot skin reaction was the most frequent adverse event, occurring in all patients (100%), with grade 3 events observed in 3 patients (18.8%). Other common adverse events included hypothyroidism (9 patients, 56.3%), diarrhoea (9 patients, 56.3%; grade 3 in 2 patients, 12.5%), oral mucositis (8 patients, 50%), and hypertension (6 patients, 37.5%; grade 3 in 3 patients, 18.8%). Fatigue and nausea were reported in 10 patients each, predominantly grade 1\u0026ndash;2. Less frequent adverse events included scrotal ulceration (2 patients), cutaneous vasculitis (1 patient), and central retinal vein occlusion (1 patient).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSalient Toxicities Seen in the Study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAny grade no. (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade 3 (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHFSR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (18.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (56.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypothyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (56.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOral mucositis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (18.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-HFSR cutaneous reaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (62.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnorexia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (62.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysgeusia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (31.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eHFSR : Hand Foot Skin Reaction\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHaematological and biochemical toxicities\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAny grade no. (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade 3 (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (12.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (6.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (6.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBilirubin increase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (6.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSGOT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSGPT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (31.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlkaline Phosphatase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (6.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyponatremia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (6.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypocalcemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypokalemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (6.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal toxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (6.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine protein\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSGOT: serum glutamic oxaloacetic transaminase. SGPT: serum glutamic-pyruvic transaminase.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Treatment exposure and dose modifications\u003c/h2\u003e \u003cp\u003eDose modifications during treatment are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. The median duration of cabozantinib therapy was 13 weeks (IQR, 8.5\u0026ndash;30.5), and the median daily dose delivered was 44.2 mg (IQR, 40\u0026ndash;50.5). Thirteen patients (81.3%) required at least one dose modification, including dose reductions in 11 patients (68.8%) and treatment interruptions in 12 patients (75%). Treatment discontinuation occurred primarily due to disease progression (11 of 16 patients). Two patients discontinued treatment because of toxicity and subsequently experienced disease progression following treatment delay.\u003c/p\u003e \n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab5\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eStudy treatment, exposure to cabozantinib.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDuration of treatment (weeks)\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e13 weeks\u003c/p\u003e\n \u003cp\u003e(IQR- 8.6\u0026ndash;30.7)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDaily cabozantinib dose during the course of treatment\u003c/p\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e44.2 mg\u003c/p\u003e\n \u003cp\u003e(IQR- 40.0-50.5)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTreatment Modification\u003c/p\u003e\n \u003cp\u003eDose Modification\u003c/p\u003e\n \u003cp\u003eDose Reduction\u003c/p\u003e\n \u003cp\u003eTreatment interruption\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e13/16 (81.3%)\u003c/p\u003e\n \u003cp\u003e11/16 (68.8%)\u003c/p\u003e\n \u003cp\u003e12/16 (75%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eThe major reason for discontinuation\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eProgression of disease\u003c/p\u003e\n \u003cp\u003eToxicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e11/16\u003c/p\u003e\n \u003cp\u003e2/16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.5 Quality of Life\u003c/h2\u003e\n \u003cp\u003eQoL analysis in our study was done using EORTC QLQ C-30 questionnaire at baseline and 3 months. All functional scales demonstrated numerical declines over time, most notably in social functioning (mean change\u0026thinsp;\u0026minus;\u0026thinsp;10.3), emotional functioning (\u0026minus;\u0026thinsp;5.8), and physical functioning (\u0026minus;\u0026thinsp;5.6).\u003c/p\u003e\n \u003cp\u003eAmong symptom domains, fatigue, appetite loss, pain, and financial difficulties had the highest baseline scores. At 3 months, numerical improvements were observed in nausea/vomiting, insomnia, fatigue, constipation, and financial difficulties, whereas numerical worsening was observed for pain, dyspnoea, anorexia, and diarrhoea; however, none of these changes reached statistical significance. Diarrhoea scores increased by more than 10 points from baseline to 3 months (mean 23.1 to 35.9; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.27), suggesting clinically relevant worsening without reaching statistical significance. Global health status/QoL remained stable over time (mean 44.9 to 42.3; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.62).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.6 Post-progression Therapy\u003c/h2\u003e\n \u003cp\u003eAt the time of data cut-off, 13 patients had progressed on cabozantinib. Of these, 7 patients received subsequent systemic therapy, including imatinib rechallenge as per the RIGHT trial (\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e) (4 patients), ripretinib (1 patient), and temozolomide in 2 patients with SDH-deficient GIST.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eThis is the first prospective study evaluating cabozantinib in metastatic GIST in the fourth-line setting. The median age in our cohort is 54.3 years which is less when compared to previous pivotal studies like INVICTUS (59 years) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) and CaboGIST (63 years) (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), and similar to other Indian studies by Baa et al (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) (53 years) and Anant et al (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) (50\u0026ndash;58 years) showing median onset of presentation of GIST at a younger age in Indian subcontinent when compared to western population(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Notably, 43% of our patients had ECOG PS\u0026thinsp;\u0026minus;\u0026thinsp;2, whereas CaboGIST enrolled only ECOG PS 0\u0026ndash;1 patients, and INVICTUS study had only 8.5% ECOG PS -2 cohort, which mirrors the real-world population. In the later lines of therapy, performance status in patients with GIST declines rapidly, as reported in the INVICTUS trial where one-third of the patients who progressed on placebo could not be crossed over to the ripretinib arm due to poor PS (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). 14 patients in our cohort received cabozantinib in 4th line, while one each received in 5th line and 6th line, respectively which indicates a heavily pre-treated cohort. In addition, baseline disease burden was substantial in our cohort, with the predominant metastatic site being the liver (81%) and other frequent sites being the peritoneal cavity involvement, including serosal and omental deposits. Mutation profile in our cohort revealed exon 11 in 56.2% and exon 9 in 25% as compared to 55% (exon 11) and 17% (exon 9) in the INVICTUS study and 62% (exon 11) and 13.5% (exon 9) in the CaboGIST study respectively.\u003c/p\u003e \u003cp\u003eThe study met its primary endpoint: the 3-month PFR was 62.5%, clearly exceeding our prespecified threshold of 25%, supporting clinically meaningful activity of cabozantinib in this population. The 6-month PFR was 48.6%, broadly consistent with CaboGIST data (PFR 70% at 3 months and 45.6% at 6 months) and INVICTUS data (6 month PFR of 51%). This concordance supports the view that durable disease control, reflected by lack of progression may be a more meaningful marker of clinical benefit than objective response alone in advanced, heavily pre-treated GIST (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe median PFS in our cohort was 4 months, which falls between the outcomes reported with imatinib rechallenge in later-line GIST (median PFS 1.8 months) (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) and ripretinib in the fourth-line setting (median PFS 6.3 months) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). This gradient is biologically plausible. Ripretinib is a selective \u0026ldquo;switch-control\u0026rdquo; KIT/PDGFRA inhibitor with a more favourable tolerability profile, whereas cabozantinib is a broader multi-kinase TKI with a substantial burden of off-target, anti-angiogenic toxicities; these differences could partly explain the shorter PFS observed with cabozantinib in our cohort. Notably, the median PFS in our study was also shorter than the 5.5 months reported by Sch\u0026ouml;ffski et al.(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). However, CaboGIST evaluated cabozantinib predominantly in a third-line population, whereas our patients were treated in the more refractory fourth-line setting after progression on \u0026ge;\u0026thinsp;3 prior TKIs, which limits direct cross-trial comparability.\u003c/p\u003e \u003cp\u003eIn our cohort, cabozantinib produced an objective response rate of 6.2% by RECIST v1.1, but a higher response by Choi criteria (18.7%). As expected in GIST, response estimates are often higher with Choi than with RECIST because early TKI effects such as reduced enhancement, intra-tumoral necrosis, and falling tumour density can precede measurable tumour shrinkage. Accordingly, size-based RECIST assessments may underestimate TKI activity in GIST, underscoring the value of incorporating both size and density changes when evaluating response(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). An exploratory analysis of the CaboGIST study further corroborated these observations. In this analysis, a partial response was observed in 12% and 7% by local RECIST v1.1 assessment and central RECIST review respectively, however 50% showed a PR when applying Choi criteria (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). These findings highlighted the ongoing relevance of Choi-based assessment, even in later-line settings.\u003c/p\u003e \u003cp\u003eWe evaluated differential efficacy according to primary KIT genotype (exon 11 vs exon 9). No statistically significant difference in median PFS was observed between these groups (p\u0026thinsp;=\u0026thinsp;0.37). A planned comparison based on secondary mutation status (exon 13/14 vs exon 17/18) could not be performed because of the small numbers in each subgroup. Among the two SDH-deficient GIST patients in our cohort, one achieved stable disease on cabozantinib, suggesting potential activity across a broad spectrum of molecular subtypes. Overall, these subgroup analyses should be interpreted cautiously, as they were exploratory and hypothesis-generating. We also explored outcomes by baseline performance status (ECOG PS 0\u0026ndash;1 vs 2) and did not observe a significant difference in median PFS (p\u0026thinsp;=\u0026thinsp;0.65).\u003c/p\u003e \u003cp\u003eCabozantinib showed a typical VEGFR-TKI toxicity profile in our cohort, with frequent HFSR (100%), diarrhoea (56.2%), mucositis (50%), fatigue (62.5%), and hypertension (37.5%) which are consistent with previously reported literature (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). However, the HFSR rate was universal in our cohort (100% incidence). In the CaboGIST trial, hand\u0026ndash;foot skin reaction (HFSR) was reported in 60% of patients, a rate lower than that observed in our cohort. The possible interpretation could be cumulative TKI toxicity and poor performance status in our 4th line cohort. This resulted in a high rate of dose modifications (81%). Most of the toxicities were manageable, but they reduced treatment continuity and dose intensity. In contrast, ripretinib had a unique and more favourable tolerability profile, with alopecia being the most common adverse effect (51%) and fewer treatment-related events (HFSR 21%, diarrhoea 20%, hypertension 5%) and low rates of dose reductions (6%). Clinically, this supports more consistent dosing and likely contributes to superior disease control.\u003c/p\u003e \u003cp\u003eOverall, cabozantinib did not improve QoL in our heavily pre-treated cohort. Among the symptom scales, diarrhoea showed a clinically meaningful worsening, consistent with the expected gastrointestinal toxicity profile of cabozantinib while nausea/ vomiting and insomnia showed improvement. Notably, overall global QoL and symptom scores did not significantly deteriorate despite the frequent HFSR and diarrhoea. This emphasizes the need for QoL assessments specifically designed to capture treatment-related symptoms and highlights a limitation of general instruments, such as the QLQ-C30, for TKI-specific toxicities.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eStrengths of the study\u003c/strong\u003e \u003cp\u003eThis is the first prospective drug trial done in India in GIST. This trial included ECOG PS-2 patients, and response assessment was also done by Choi criteria besides the RECIST v 1.1, which is done in very few studies across the globe.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eLimitations of the study\u003c/strong\u003e \u003cp\u003eOur study has some limitations, chief among them being a single-centre design and the lack of a comparator arm. However, given the rarity of these tumours, conducting a comparative study would have been logistically challenging. The prespecified sample size was not reached; enrolment was planned to continue until the target was met, but the anticipated approval of ripretinib in India was expected to halt further accrual. A translational approach via ctDNA-based mutation profiling could not be incorporated because GIST-focused ctDNA assays were not available in India at the time the study was initiated, and the high cost of broad solid-tumour ctDNA panels posed a significant financial barrier.\u003c/p\u003e \u003c/p\u003e"},{"header":"5. CONCLUSION","content":"\u003cp\u003eOverall, our findings suggest cabozantinib has clinically meaningful activity in heavily treated fourth-line GIST patients, primarily through disease stabilization, but its effectiveness is constrained by toxicity-driven dose modifications leading to compromised dose intensity. However, where ripretinib access is limited, cabozantinib can serve as a pragmatic alternative if proactive supportive care and structured dose-modification strategies are implemented early to preserve exposure and maximize benefit.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e1.GIST: Gastro Intestinal Stromal Tumour\u003c/p\u003e\n\u003cp\u003e2. LMICs: Low- and Middle- Income Countries\u003c/p\u003e\n\u003cp\u003e3. TKI: Tyrosine Kinase Inhibitor\u003c/p\u003e\n\u003cp\u003e4. ECOG PS: Eastern Cooperative Oncology Group Performance Status\u003c/p\u003e\n\u003cp\u003e5. RECIST: Response Evaluation Criteria in Solid Tumours\u003c/p\u003e\n\u003cp\u003e6. EORTC QLQ-C30: European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30\u003c/p\u003e\n\u003cp\u003e7. QoL: Quality of Life\u003c/p\u003e\n\u003cp\u003e8. PD: Progressive Disease\u003c/p\u003e\n\u003cp\u003e9. SD: Stable Disease\u003c/p\u003e\n\u003cp\u003e10. PR: Partial Response\u003c/p\u003e\n\u003cp\u003e11. CR: Complete Response\u003c/p\u003e\n\u003cp\u003e12. ORR: Objective Response Rate\u003c/p\u003e\n\u003cp\u003e13. PFS: Progression-Free Survival\u003c/p\u003e\n\u003cp\u003e14. PFR: Progression Free Rate\u003c/p\u003e\n\u003cp\u003e15. AST: Aspartate Transaminase\u003c/p\u003e\n\u003cp\u003e16. ALT: Alanine Transaminase\u003c/p\u003e\n\u003cp\u003e17. NGS: Next Generation Sequencing\u003c/p\u003e\n\u003cp\u003e18. FDG PET-CT: 18F-Flourodeoxyglucose Positron Emission Tomography Computed Tomography\u003c/p\u003e\n\u003cp\u003e19. ctDNA: circulating tumour DNA\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and its subsequent amendments, and was initiated after approval from the Institute Ethics Committee for Post Graduate Research, All India Institute of Medical Sciences, New Delhi (IEC No. 455/24.08.2023). Written informed consent was obtained from all participants prior to enrolment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e All participants provided written informed consent for publication of anonymized clinical information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVentrapragada Neelima: Patient enrolment, data curation, formal analysis, writing - original draft, and writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eSameer Rastogi: Conceptualization, supervision, interpretation of results, and writing - review \u0026amp; editing with critical intellectual input.\u003c/p\u003e\n\u003cp\u003eKinjal Singh: Formal analysis, and writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eAkash Singh: Writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eShamim A. Shamim: Investigation (imaging review/response assessment), and writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eShivanand Gamanagatti: Investigation (imaging review/response assessment), and writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eRajni Yadav: Resources (NGS testing), and writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eNihar Ranjan Dash: Investigation (surgical management/inputs), and writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe sincerely thank all study participants and their families for their trust and cooperation. We thank Sachin Sarcoma Society for providing the study drug. The funder had no role in the study design; data collection, analysis, or interpretation; manuscript preparation; or the decision to submit the manuscript for publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21(23):4342\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCasali PG, Zalcberg J, Le Cesne A, Reichardt P, Blay JY, Lindner LH et al. 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Indian J Med Paediatr Oncol. 2020;41(6):809\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCasali PG, Blay JY, Abecassis N, Bajpai J, Bauer S, Biagini R, et al. Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol. 2022;33(1):20\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLe Cesne A, Van Glabbeke M, Verweij J, Casali PG, Findlay M, Reichardt P, et al. Absence of progression as assessed by response evaluation criteria in solid tumors predicts survival in advanced GI stromal tumors treated with imatinib mesylate: the intergroup EORTC-ISG-AGITG phase III trial. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(24):3969\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDudeck O, Zeile M, Reichardt P, Pink D. Comparison of RECIST and Choi criteria for computed tomographic response evaluation in patients with advanced gastrointestinal stromal tumor treated with sunitinib. Ann Oncol Off J Eur Soc Med Oncol. 2011;22(8):1828\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKyriazoglou A, Jespers P, Vandecavaye V, Mir O, Kasper B, Papai Z, et al. Exploratory analysis of tumor imaging in a Phase 2 trial with cabozantinib in gastrointestinal stromal tumor: lessons learned from study EORTC STBSG 1317 CaboGIST. Acta Oncol. 2022;61(6):663\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Gastrointestinal Stromal Tumour, Cabozantinib, Tyrosine Kinase Inhibitors (TKIs), Quality of life (EORTC QLQ-C30), Choi Criteria","lastPublishedDoi":"10.21203/rs.3.rs-8910891/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8910891/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eBeyond third-line therapy, options for metastatic/advanced GIST are limited, especially in low- and middle-income countries (LMICs) where access to fourth-line ripretinib is often restricted. Cabozantinib, a multi-kinase inhibitor targeting KIT and related resistance pathways, could serve as a pragmatic alternative. This Phase II study evaluated the efficacy and safety of cabozantinib in patients with metastatic/advanced GIST who had progressed after ≥3 prior Tyrosine Kinase Inhibitors (TKIs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis is a single-arm phase II trial that enrolled patients with advanced GIST who had progressed on ≥3 TKIs with ECOG PS 0-2. Cabozantinib was given orally at 60 mg daily (40 mg if \u0026lt;40 kg and/or ECOG PS 02). The primary endpoint was 3-month Progression Free Rate (PFR) by RECIST v1.1. Overall Response Rate (ORR) was assessed by RECIST v1.1 and Choi Criteria. Quality of Life (QoL) was done by EORTC-QLQ-C30.\u003c/p\u003e\n\u003cp\u003eUsing Ahern’s single-stage phase II design, the trial tested whether cabozantinib could achieve a 3-month PFR of at least 25% in the fourth-line setting versus a null PFR of 5% or less. With a one-sided alpha of 0.05 and 90% power, the required sample size for this single-arm study was 25 patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Sixteen patients were enrolled. The cohort had a median age of 54.3 years, and most patients were male (75%). Median prior lines were 3 (range 3–5), and 44% had ECOG PS 02. Primary sites were stomach (50%) and small intestine (25%). Liver is the most predominant side of metastases (81.3%). Primary mutations included KIT exon 11 (56%), exon 9 (25%), and SDH-deficient GIST (12.5%); the most common secondary pattern was exon 11+17 (43%). The 3-month PFR was 62.5% by RECIST v1.1, with median PFS of 4.0 months. ORR was 6.2% by RECIST and 18.8% by Choi criteria. Common grade 3 adverse events were hand–foot skin reaction (18.8%), hypertension (18.8%), and diarrhoea (12.5%). Treatment interruptions and dose reductions occurred in 80% and 73.3%, respectively. Overall, QoL and Global Health Status remained stable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eCabozantinib demonstrated clinically meaningful activity with manageable toxicity in refractory metastatic/advanced GIST after ≥3 TKIs, supporting its role as a potential option in LMIC contexts where ripretinib access is limited. Larger, comparative phase III trials are warranted to confirm efficacy and better define optimal patient selection and dosing strategies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: Trial Registration Number-\u003c/strong\u003eCTRI/2024/06/068636\u003c/p\u003e\n\u003cp\u003eOur trial was “Retrospectively registered” with Clinical Trials Registry - India (CTRI) on 10/06/2024.\u003c/p\u003e","manuscriptTitle":"A Phase II Study of Cabozantinib in Metastatic or Unresectable Refractory Gastrointestinal Stromal Tumour: A Single-Centre Study from India","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-19 16:30:21","doi":"10.21203/rs.3.rs-8910891/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-14T08:17:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-03T15:26:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-31T10:55:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58897557929985110557717142469898124884","date":"2026-03-25T13:55:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"336685062181715499128206595700524196123","date":"2026-03-19T10:58:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-17T10:09:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-16T06:46:04+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-24T05:17:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-23T17:27:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-02-23T17:21:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f3367006-7dd9-40a2-9a9a-72260e314fca","owner":[],"postedDate":"March 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-28T07:08:46+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-19 16:30:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8910891","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8910891","identity":"rs-8910891","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}