Safety of pembrolizumab with concurrent radiotherapy in early stage breast cancer: preliminary prospective real-world evidence

Safety of pembrolizumab with concurrent radiotherapy in early stage breast cancer: preliminary prospective real-world evidence | 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 Safety of pembrolizumab with concurrent radiotherapy in early stage breast cancer: preliminary prospective real-world evidence Riccardo Ray Colciago, Daniele Presti, Carlotta Giandini, Eliana La Rocca, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4006571/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract INTRODUCTION Data on the feasibility and potential synergy of concomitant immunotherapy with radiation therapy (RT) is still scarce for early breast cancer (BC). We aimed to assess the safety profile of adjuvant pembrolizumab with concomitant radiotherapy (RT) in breast cancer patients. MATERIAL AND METHODS: We prospectively collected data from ten patients with triple-negative breast cancer treated with neoadjuvant chemotherapy with pembrolizumab (as per Keynote-522 criteria) followed by surgery and at least 1 cycle of adjuvant pembrolizumab with concomitant RT. A total dose of 40.05 Gy delivered in 15 fractions was prescribed to the breast or chest wall, with regional nodes and tumor bed boost administered as clinically indicated. The study endpoint was to assess acute toxicity according to the Radiation Therapy Oncology Group scale, and to report the rate of discontinuation of RT and/or pembrolizumab. RESULTS A median of 8 (range 4 – 9) cycles of neoadjuvant Pembrolizumab were prescribed. Before RT, patients received a median of 3 (range 2 – 4) cycles of adjuvant Pembrolizumab. Severe acute toxicity occurred in 2 patients. Specifically, G4 myositis led to permanent discontinuation of adjuvant pembrolizumab in one case, whereas G3 electrolyte imbalance caused definitive RT interruption and temporary discontinuation of adjuvant pembrolizumab in the second case. Among the remaining 8 patients, only 2 patients experienced G2 skin erythema with no treatment discontinuation. CONCLUSIONS The combination of adjuvant pembrolizumab with concurrent radiotherapy proved feasible in the real world, as toxicity was minimal and consistent with existing literature. Introduction Breast cancer accounts for 30% of oncological patients [ 1 ]. Triple-negative breast cancer (TNBC) represents the molecular subtype lacking expression of estrogen, progesterone, and HER2 receptors [ 2 , 3 ], comprising 10–20% of all invasive breast cancer cases.[ 2 , 3 ]. TNBCs are characterized by abundant tumor cell proliferation, and thus considered moderate/high-grade tumors, with a worse prognosis [ 4 ]. Recently, the therapeutic landscape of TNBC has been dramatically reshaped by the advent of novel anticancer drugs. Namely, immune checkpoint inhibitors like pembrolizumab have demonstrated impressive results in clinical trials and have entered the therapeutic algorithm in TNBC [ 5 – 7 ]. In both the Keynote-355 and Impassion-130 trials [ 8 , 9 ], immunotherapy was integrated into the standard care to evaluate its benefits for inoperable or metastatic TNBC. Patients were randomly assigned to receive either pembrolizumab or atezolizumab versus placebo, in addition to chemotherapy, respectively. The two studies included a total of 1,749 patients. The use of immunotherapy demonstrated significantly better outcomes in terms of progression-free and overall survival. In both studies, severe toxicities did not differ between the experimental and placebo groups, with most of high-grade adverse events (AEs) attributed to chemotherapy. Furthermore, immunotherapy proved to be effective also in early TNBC. Results of the Keynote 522 phase III trial [ 10 ] – which randomly assigned 602 previously untreated stage II or stage III TNBC patients to receive standard neoadjuvant chemotherapy with anthracyclines, carboplatin, and taxanes plus pembrolizumab or placebo – showed a significant increase of pathological complete response with neoadjuvant chemotherapy when combined with immunotherapy. Prompted by this strong evidence, international guidelines now recommend pembrolizumab plus chemotherapy as a new standard of care [ 11 ]. In this ever-evolving clinical scenario, it is crucial to determine the role of adjuvant radiotherapy (RT) and its possible interaction with these novel drugs. To date, experience gained in various oncological settings suggests a favorable toxicity profile [ 12 ]. However, specific evidence regarding breast cancer is still scarce. Thus, the aim of our prospective study was to assess the feasibility and safety of adjuvant pembrolizumab with concomitant RT in patients with early TNBC. Material and Methods We prospectively analyzed patients with stage II-III TNBC undergoing treatment according to the Keynote-522 study protocol, which includes four cycles of pembrolizumab (200 mg flat dose every 3 weeks) in combination with weekly paclitaxel (80 mg/m²) and weekly carboplatin (AUC 1.5) for 12 weeks, followed by 4 cycles of pembrolizumab combined with 4 cycles of doxorubicin (60 mg/m²) plus cyclophosphamide (600mg/m²) every 3 weeks. Subsequently, all patients underwent surgery, consisting of lumpectomy or mastectomy, with or without axillary surgery. In the adjuvant phase, patients received pembrolizumab as systemic therapy (200 mg once every 3 weeks) with concurrent RT, started at least 60 days post-surgery. Prescribed radiation dose to the breast or chest wall was 40.05 Gy in 15 fractions, with regional nodes being irradiated when clinically indicated. A boost to the tumor bed was permitted if required. Clinical target volumes (CTV) and organs at risk were contoured based on national recommendations [ 17 ], with planning target volumes delineated as CTVs + 5 mm of isotropic expansion. Both Volumetric Arc Modulated Therapy (VMAT) and 3D conventional therapy were permitted as delivery techniques. For left-sided breast cancer patients, breathing management with deep inspiration technique was employed through the Respiratory Gating for Scanners system (RGSC; Varian Medical Systems, Palo Alto, California). Photons plans were elaborated on Eclipse treatment planning system version 15.6 (Varian Medical Systems, Palo Alto, California) and calculated using the Analytical Anisotropic Algorithm with a dose grid resolution of 2.5 mm 3 . Photon energy of 6 and/or 15 MV were employed for planning. The accrual spanned from February to November 2023. The primary endpoint was to assess the feasibility of the treatment concerning acute AEs, both local and systemic, as defined by the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) scale [ 18 ]. Patients were evaluated by a radiation oncologist at the midpoint and at the end of RT. Another visit was conducted one month upon completion of RT. For the analysis, we considered all events occurring during this time span. Blood samples and a medical oncologist's visit were conducted for each patient before the administration of a Pembrolizumab cycle. Treatment discontinuations, whether temporary or permanent, were recorded for both radiotherapy and immunotherapy. Results A total of 11 patients were analyzed. One patient developed grade 4 (G4) pancytopenia during neoadjuvant pembrolizumab, leading to permanent discontinuation of systemic treatment and was then excluded from the analysis. Among the 10 patients treated per-protocol, median age was 58 (range: 27–68). Three patients were taking at least one medication for clinical comorbidities. Left-sided breast cancer was observed in 7 patients, while 3 had right-sided breast cancer. All patients were diagnosed with a highly aggressive TNBC, with a median Ki-67 of 80% (range: 50–90). Seven patients had stage II TNBC, three patients had stage III TNBC. Patients received a median of 8 (range: 4–9) neoadjuvant pembrolizumab cycles. Breast-conserving surgery was performed in 8 patients, while 2 had mastectomy, 1 of which included a two-stage implant-based reconstruction. Sentinel lymph node biopsy was conducted in 9 patients, with 1 undergoing complete axillary lymph node dissection. Overall, 90% of patients obtained a pathological complete response after neoadjuvant chemo-immunotherapy, with only one patient left with residual disease in the breast (ypT1N0) after receiving neoadjuvant treatment. Before RT, a median of 3 (range: 2–4) cycles of adjuvant pembrolizumab were administered. Radiotherapy treatment specifications are illustrated in Table 1 . Table 1 Adjuvant Radiation Therapy Surgery type Local RT Tumor Bed Boost Nodal Irradiation Dose (Gy/fx) Volumes Dose (Gy/fx) Technique Dose (Gy/fx) Axillary levels Patient 1 BCS 40.05/15 WBI 48/15 SIB 40.05/15 IMN Patient 2 BCS 40.05/15 WBI 48/15 SIB Patient 3 BCS 40.05/15 WBI 48/15 SIB Patient 4 BCS 40.05/15 WBI 48/15 SIB Patient 5 Mastectomy 40.05/15 PMRT None 40.05/15 All Patient 6 BCS 40.05/15 WBI 10/4 SEQ Patient 7 Mastectomy 40.05/15 PMRT None 40.05/15 III-IV Patient 8 BCS 40.05/15 WBI 10/5 SEQ Patient 9 BCS 40.05/15 WBI 48/15 SIB Patient 10 BCS 40.05/15 WBI 48/15 SIB 40.05/15 III-IV RT: radiation therapy; fx: fractions; BCS: breast-conserving surgery; WBI: whole breast irradiation; PMRT: post-mastectomy radiation therapy; SIB: simultaneous integrated boost; SEQ: sequential boost; IMN: internal mammary chain. Safety Treatment-related toxicities are summarized in Table 2 . All patients experienced G1 AEs, mainly radiodermatitis, whilst 5 patients developed G2 toxicity (two radiodermatitis, two fatigue, one nausea). Pneumonia, breast pain, diarrhea, anemia, thrombocytopenia, or neutropenia did not occur. Table 2 Acute Toxicities Grade 1 N Grade 2 N Grade 3 N Grade 4 N Any Adverse Events 11 5 1 1 Grade 1 N Grade 2 N Grade 3 N Grade 4 N Fatigue 3 2 - - Radiodermatitis 8 2 - - Hepatotoxicity - - - 1 Myositis - - - 1 Nausea - 1 - - Electrolyte Imbalance - - 1 - Two patients experienced severe toxicity. One patient receiving nodal irradiation to the III and IV axillary levels developed G2 dysphagia and 13 days later G3 electrolyte imbalance (serum potassium = 2.69 mEq/l), which prompted a temporary discontinuation of pembrolizumab, while RT was definitively interrupted at 14 out of 15 fractions. The patient received supportive care resulting in the normalization of electrolyte levels in 5 days. In the other case, G4 myositis occurred one month after the completion of RT. The clinical scenario evolved into a G4 hepatotoxicity (there was a rapid and severe reduction in hepatic function, accompanied by elevated serum levels of transaminase) followed by patient hospitalization and, eventually, a definitive interruption of pembrolizumab. Supportive care measures were implemented, leading to the patient complete recovery. Discussion To our knowledge, the current series carries one of the first real-world analysis on patients with stage II-III TNBC uniformly treated with adjuvant pembrolizumab plus concomitant RT. The combination was overall well-tolerated, with most patients completing the adjuvant treatment and only two cases experiencing severe AEs. Among the two patients exhibiting severe toxicity, G3 electrolyte imbalance prompting the definitive cessation of radiotherapy was primarily attributed to non-compliance with supportive care measures, indicating a potentially preventable origin. Conversely, the G4 toxicity observed in the second patient, characterized by severe myositis and transaminase alterations, was mostly associated with the immunotherapy drug. Notably, G ≥ 3 liver toxicity is a relatively common adverse effect of pembrolizumab, with an incidence of 5.2% in the Keynote 552 trial cohort [ 10 ]. While myositis is infrequent, documented cases exist [ 20 ] No acute pulmonary or cardiac toxicities were observed. Breast pain was minimal, and the most notable local side effect was G2 radiodermatitis, noted in two patients. The original KEYNOTE-522 [ 10 ] study protocol initially prohibited concurrent radiotherapy with pembrolizumab, but it was later amended [ 19 ]. However, only 144 out of 1174 study patients received concurrent adjuvant pembrolizumab and radiotherapy, resulting in most patients undergoing sequential treatment with radiotherapy [ 19 ]. Importantly, the comparison between efficacy and safety profiles did not reveal differences based on the pattern of administration of adjuvant radiotherapy; indeed, the number of events and toxicities seemed to favor patients treated concurrently with pembrolizumab. While these data are reassuring, doubts persist regarding whether patients were inadvertently selected within the clinical trial. Moreover, these findings require further confirmation in everyday clinical practice, where logistical constraints often impede the immediate post-operative administration of radiotherapy, potentially leading to delays in starting adjuvant pembrolizumab. Finally, many patients in clinical trials are generally fitter than those in the real world, not just due to protocol requirements, but also due to inadvertent selection by the physicians offering the trial. For all these reasons, we decided to analyze the concurrent treatment of pembrolizumab and radiotherapy in consecutive patients eligible for the treatment outlined in the KEYNOTE-522 protocol within a calendar year and observed for at least 1 month after the completion of radiotherapy. Owing to the growing body of interest, literature about the combination of RT and immunotherapy seems to carefully suggest a safe and well-tolerated combination [ 21 ] and has been mainly derived from other solid tumors. Pneumonia is one of the major side effects, followed by hepatic toxicities, both attributed to the direct damage of combined therapies. [ 21 – 23 ] Thoracic irradiation combined with Pembrolizumab is primarily reported in the context of lung cancer. Jabbour et al. [ 24 ] aimed to assess the effectiveness and safety of administering Pembrolizumab alongside concurrent chemo-radiotherapy in patients with locally advanced non-small cell lung cancer (NSCLC). Radiation therapy consisted in 60 Gy in 30 daily fractions of 2 Gy each. Severe AEs were observed in 64.3% of the patients, predominantly attributed to systemic therapy. G3 or higher pneumonitis, including radiation-induced pneumonitis, occurred in 8.0% of the cases. Wu et al. [ 25 ] performed a metanalysis of 3652 articles of NSCLC treated with immunotherapy plus RT with a reported incidence of G ≥ 3 pneumonitis up to 5.8%. To date, evidence regarding breast cancer patients is limited. Pooled data from 68 prospective trials involving immune checkpoint inhibitors suggested that the administration of these drugs within 90 days after radiotherapy did not seem to increase the risk of serious AEs [ 26 ]. The European Society for Radiotherapy and Oncology recently published a multidisciplinary expert consensus on the integration of RT with drugs [ 27 ], with 95% of the experts agreeing on the concurrent delivery of Pembrolizumab and RT. Tison et al. [ 28 ] reported a real-life experience, on patients treated as per KeyNote-522. Radiation therapy schedules were 50 Gy in 25 fractions of 2 Gy, 40.05 Gy in 15 fractions of 2.67 Gy, or 50.4 Gy in 28 fractions of 1.8 Gy when chest wall, whole breast or regional nodal irradiation were performed, respectively. Of the 28 patients analyzed, toxicities were mild, with the worse severe AEs being G3 breast pain. We acknowledge that this analysis has few limitations. The cohort is relatively small, with a short follow-up. We only reported data on acute toxicity, without addressing the onset of late AEs. Nevertheless, our findings suggest that the concurrent use of RT and pembrolizumab is safe, with no increase in local toxicity. The systemic synergy of this combination warrants further investigation. In this regard, our analysis serves as a starting point for future real-world evaluations of the efficacy and safety of adjuvant radio-immunotherapy combinations in patients with early stage TNBC. Declarations Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Ethics approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the IRB of the participating center. Informed consent was obtained from all individual participants involved in the study. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Author Contribution RRC conceptualization, data curation, formal analysis and writing original draft; DP investigations, writing original draft; ELR conceptualization; CG, MCG, RL, CL, AC, EP and LL investigation; ARF supervision and validation; MCDS conceptualization, supervision and validation. Each author contributed to the reviewing process of the original article. References Han HS, Vikas P, Costa RLB, Jahan N, Taye A, Stringer-Reasor EM. Early-Stage Triple-Negative Breast Cancer Journey: Beginning, End, and Everything in Between. Am Soc Clin Oncol Educ Book. 2023 Jun;43:e390464. doi: 10.1200/EDBK_390464. PMID: 37335956. Almansour NM. Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence. 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Thais Tison, Pierre Loap, Emilie Arnaud, Kim Cao, Solene Bringer, Manon Kissel, Safia Maaradji, Juliette Mainguene, Jean-Yves Pierga, Florence Lerebours, Anne Vincent-Salomon, Mariana Mirabelle, Francois-Clement Bidard, Delphine Loirat, Youlia M. Kirova. Tolerance of concurrent adjuvant radiotherapy and pembrolizumab for triple negative breast cancer: real life experience. Advances in Radiation Oncology, 2023, 101384, ISSN 2452-1094, doi: 10.1016/j.adro.2023.101384. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-4006571","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":276144221,"identity":"824575f0-678e-4ad4-9e24-9c8894291616","order_by":0,"name":"Riccardo Ray Colciago","email":"","orcid":"","institution":"Department of Radiation Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan","correspondingAuthor":false,"prefix":"","firstName":"Riccardo","middleName":"Ray","lastName":"Colciago","suffix":""},{"id":276144222,"identity":"0f741de2-05fd-4783-9353-1ccf6d763856","order_by":1,"name":"Daniele Presti","email":"","orcid":"","institution":"Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan","correspondingAuthor":false,"prefix":"","firstName":"Daniele","middleName":"","lastName":"Presti","suffix":""},{"id":276144223,"identity":"1762a9d5-bfd0-4135-a00d-c35f0db86382","order_by":2,"name":"Carlotta Giandini","email":"","orcid":"","institution":"Department of Radiation Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan","correspondingAuthor":false,"prefix":"","firstName":"Carlotta","middleName":"","lastName":"Giandini","suffix":""},{"id":276144224,"identity":"cc278d82-4f2f-4445-9c2e-307fcf6441ea","order_by":3,"name":"Eliana La Rocca","email":"","orcid":"","institution":"Department of Radiation Oncology, Azienda Ospedaliero Universitaria Integrata, Verona","correspondingAuthor":false,"prefix":"","firstName":"Eliana","middleName":"La","lastName":"Rocca","suffix":""},{"id":276144225,"identity":"c898624a-9c25-4fbd-b715-7b3425900f6d","order_by":4,"name":"Maria Grazia Carnevale","email":"data:image/png;base64,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","orcid":"","institution":"Department of Radiation Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan","correspondingAuthor":true,"prefix":"","firstName":"Maria","middleName":"Grazia","lastName":"Carnevale","suffix":""},{"id":276144226,"identity":"77adf94e-4945-4e49-8ad8-fc47a66d26b9","order_by":5,"name":"Anna Cavallo","email":"","orcid":"","institution":"Medical Physics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Cavallo","suffix":""},{"id":276144227,"identity":"f91d016b-814c-4e31-a734-1e6a6387a7cd","order_by":6,"name":"Emanuele Pignoli","email":"","orcid":"","institution":"Medical Physics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan","correspondingAuthor":false,"prefix":"","firstName":"Emanuele","middleName":"","lastName":"Pignoli","suffix":""},{"id":276144228,"identity":"bed03dd9-4ed0-4323-b123-7c050795d8af","order_by":7,"name":"Riccardo Lobefaro","email":"","orcid":"","institution":"Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan","correspondingAuthor":false,"prefix":"","firstName":"Riccardo","middleName":"","lastName":"Lobefaro","suffix":""},{"id":276144229,"identity":"490d49ca-5043-4df9-9b9e-6b3406ed1b4c","order_by":8,"name":"Serena Di Cosimo","email":"","orcid":"","institution":"Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan","correspondingAuthor":false,"prefix":"","firstName":"Serena","middleName":"Di","lastName":"Cosimo","suffix":""},{"id":276144230,"identity":"b112fe82-c41a-4e62-ad89-56f6f659a717","order_by":9,"name":"Chiara Listorti","email":"","orcid":"","institution":"Breast Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan","correspondingAuthor":false,"prefix":"","firstName":"Chiara","middleName":"","lastName":"Listorti","suffix":""},{"id":276144231,"identity":"c10744dc-ebc7-4877-9ae3-dd5e364acdbd","order_by":10,"name":"Laura Lozza","email":"","orcid":"","institution":"Department of Radiation Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Lozza","suffix":""},{"id":276144232,"identity":"2cbcf50d-07fa-424f-930b-72718db76c74","order_by":11,"name":"Andrea Riccardo Filippi","email":"","orcid":"","institution":"Department of Radiation Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"Riccardo","lastName":"Filippi","suffix":""},{"id":276144233,"identity":"ff5f85c8-ebb0-41a7-b764-e675647625bd","order_by":12,"name":"Maria Carmen De Santis","email":"","orcid":"","institution":"Department of Radiation Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Carmen","lastName":"De Santis","suffix":""}],"badges":[],"createdAt":"2024-03-02 13:20:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4006571/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4006571/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52058413,"identity":"18d3d26a-a744-4669-8f0d-25f941089e13","added_by":"auto","created_at":"2024-03-06 04:24:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":262942,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4006571/v1/2aaf6542-f90d-4d1d-88d4-a2b6fcb5f18a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Safety of pembrolizumab with concurrent radiotherapy in early stage breast cancer: preliminary prospective real-world evidence","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer accounts for 30% of oncological patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Triple-negative breast cancer (TNBC) represents the molecular subtype lacking expression of estrogen, progesterone, and HER2 receptors [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], comprising 10\u0026ndash;20% of all invasive breast cancer cases.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. TNBCs are characterized by abundant tumor cell proliferation, and thus considered moderate/high-grade tumors, with a worse prognosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecently, the therapeutic landscape of TNBC has been dramatically reshaped by the advent of novel anticancer drugs. Namely, immune checkpoint inhibitors like pembrolizumab have demonstrated impressive results in clinical trials and have entered the therapeutic algorithm in TNBC [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn both the Keynote-355 and Impassion-130 trials [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], immunotherapy was integrated into the standard care to evaluate its benefits for inoperable or metastatic TNBC. Patients were randomly assigned to receive either pembrolizumab or atezolizumab versus placebo, in addition to chemotherapy, respectively. The two studies included a total of 1,749 patients. The use of immunotherapy demonstrated significantly better outcomes in terms of progression-free and overall survival. In both studies, severe toxicities did not differ between the experimental and placebo groups, with most of high-grade adverse events (AEs) attributed to chemotherapy.\u003c/p\u003e \u003cp\u003eFurthermore, immunotherapy proved to be effective also in early TNBC. Results of the Keynote 522 phase III trial [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] \u0026ndash; which randomly assigned 602 previously untreated stage II or stage III TNBC patients to receive standard neoadjuvant chemotherapy with anthracyclines, carboplatin, and taxanes plus pembrolizumab or placebo \u0026ndash; showed a significant increase of pathological complete response with neoadjuvant chemotherapy when combined with immunotherapy. Prompted by this strong evidence, international guidelines now recommend pembrolizumab plus chemotherapy as a new standard of care [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this ever-evolving clinical scenario, it is crucial to determine the role of adjuvant radiotherapy (RT) and its possible interaction with these novel drugs. To date, experience gained in various oncological settings suggests a favorable toxicity profile [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, specific evidence regarding breast cancer is still scarce.\u003c/p\u003e \u003cp\u003eThus, the aim of our prospective study was to assess the feasibility and safety of adjuvant pembrolizumab with concomitant RT in patients with early TNBC.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003eWe prospectively analyzed patients with stage II-III TNBC undergoing treatment according to the Keynote-522 study protocol, which includes four cycles of pembrolizumab (200 mg flat dose every 3 weeks) in combination with weekly paclitaxel (80 mg/m\u0026sup2;) and weekly carboplatin (AUC 1.5) for 12 weeks, followed by 4 cycles of pembrolizumab combined with 4 cycles of doxorubicin (60 mg/m\u0026sup2;) plus cyclophosphamide (600mg/m\u0026sup2;) every 3 weeks. Subsequently, all patients underwent surgery, consisting of lumpectomy or mastectomy, with or without axillary surgery. In the adjuvant phase, patients received pembrolizumab as systemic therapy (200 mg once every 3 weeks) with concurrent RT, started at least 60 days post-surgery. Prescribed radiation dose to the breast or chest wall was 40.05 Gy in 15 fractions, with regional nodes being irradiated when clinically indicated. A boost to the tumor bed was permitted if required. Clinical target volumes (CTV) and organs at risk were contoured based on national recommendations [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], with planning target volumes delineated as CTVs\u0026thinsp;+\u0026thinsp;5 mm of isotropic expansion. Both Volumetric Arc Modulated Therapy (VMAT) and 3D conventional therapy were permitted as delivery techniques. For left-sided breast cancer patients, breathing management with deep inspiration technique was employed through the Respiratory Gating for Scanners system (RGSC; Varian Medical Systems, Palo Alto, California). Photons plans were elaborated on Eclipse treatment planning system version 15.6 (Varian Medical Systems, Palo Alto, California) and calculated using the Analytical Anisotropic Algorithm with a dose grid resolution of 2.5 mm\u003csup\u003e3\u003c/sup\u003e. Photon energy of 6 and/or 15 MV were employed for planning. The accrual spanned from February to November 2023.\u003c/p\u003e \u003cp\u003eThe primary endpoint was to assess the feasibility of the treatment concerning acute AEs, both local and systemic, as defined by the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) scale [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Patients were evaluated by a radiation oncologist at the midpoint and at the end of RT. Another visit was conducted one month upon completion of RT. For the analysis, we considered all events occurring during this time span. Blood samples and a medical oncologist's visit were conducted for each patient before the administration of a Pembrolizumab cycle. Treatment discontinuations, whether temporary or permanent, were recorded for both radiotherapy and immunotherapy.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 11 patients were analyzed. One patient developed grade 4 (G4) pancytopenia during neoadjuvant pembrolizumab, leading to permanent discontinuation of systemic treatment and was then excluded from the analysis.\u003c/p\u003e \u003cp\u003eAmong the 10 patients treated per-protocol, median age was 58 (range: 27\u0026ndash;68). Three patients were taking at least one medication for clinical comorbidities. Left-sided breast cancer was observed in 7 patients, while 3 had right-sided breast cancer. All patients were diagnosed with a highly aggressive TNBC, with a median Ki-67 of 80% (range: 50\u0026ndash;90). Seven patients had stage II TNBC, three patients had stage III TNBC.\u003c/p\u003e \u003cp\u003ePatients received a median of 8 (range: 4\u0026ndash;9) neoadjuvant pembrolizumab cycles. Breast-conserving surgery was performed in 8 patients, while 2 had mastectomy, 1 of which included a two-stage implant-based reconstruction. Sentinel lymph node biopsy was conducted in 9 patients, with 1 undergoing complete axillary lymph node dissection.\u003c/p\u003e \u003cp\u003eOverall, 90% of patients obtained a pathological complete response after neoadjuvant chemo-immunotherapy, with only one patient left with residual disease in the breast (ypT1N0) after receiving neoadjuvant treatment.\u003c/p\u003e \u003cp\u003eBefore RT, a median of 3 (range: 2\u0026ndash;4) cycles of adjuvant pembrolizumab were administered. Radiotherapy treatment specifications are illustrated 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\u003eAdjuvant Radiation Therapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSurgery type\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e\u003cem\u003eLocal RT\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e\u003cem\u003eTumor Bed Boost\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e\u003cem\u003eNodal Irradiation\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eDose (Gy/fx)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eVolumes\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eDose (Gy/fx)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eTechnique\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eDose (Gy/fx)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eAxillary levels\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePatient 1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e48/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eIMN\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePatient 2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e48/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePatient 3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e48/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePatient 4\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e48/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePatient 5\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePMRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePatient 6\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSEQ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePatient 7\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePMRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eIII-IV\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePatient 8\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSEQ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePatient 9\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e48/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePatient 10\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e48/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e40.05/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eIII-IV\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003eRT: radiation therapy; fx: fractions; BCS: breast-conserving surgery; WBI: whole breast irradiation; PMRT: post-mastectomy radiation therapy; SIB: simultaneous integrated boost; SEQ: sequential boost; IMN: internal mammary chain.\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\u003e \u003cem\u003eSafety\u003c/em\u003e \u003c/p\u003e \u003cp\u003eTreatment-related toxicities are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. All patients experienced G1 AEs, mainly radiodermatitis, whilst 5 patients developed G2 toxicity (two radiodermatitis, two fatigue, one nausea). Pneumonia, breast pain, diarrhea, anemia, thrombocytopenia, or neutropenia did not occur.\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\u003eAcute Toxicities\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eGrade 1\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eGrade 2\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eGrade 3\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eGrade 4\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAny Adverse Events\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003e5\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e1\u003c/em\u003e\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\u003cem\u003eGrade 1\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eGrade 2\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eGrade 3\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eGrade 4\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eFatigue\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eRadiodermatitis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eHepatotoxicity\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMyositis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eNausea\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eElectrolyte Imbalance\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\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\u003eTwo patients experienced severe toxicity. One patient receiving nodal irradiation to the III and IV axillary levels developed G2 dysphagia and 13 days later G3 electrolyte imbalance (serum potassium\u0026thinsp;=\u0026thinsp;2.69 mEq/l), which prompted a temporary discontinuation of pembrolizumab, while RT was definitively interrupted at 14 out of 15 fractions. The patient received supportive care resulting in the normalization of electrolyte levels in 5 days.\u003c/p\u003e \u003cp\u003eIn the other case, G4 myositis occurred one month after the completion of RT. The clinical scenario evolved into a G4 hepatotoxicity (there was a rapid and severe reduction in hepatic function, accompanied by elevated serum levels of transaminase) followed by patient hospitalization and, eventually, a definitive interruption of pembrolizumab. Supportive care measures were implemented, leading to the patient complete recovery.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, the current series carries one of the first real-world analysis on patients with stage II-III TNBC uniformly treated with adjuvant pembrolizumab plus concomitant RT. The combination was overall well-tolerated, with most patients completing the adjuvant treatment and only two cases experiencing severe AEs. Among the two patients exhibiting severe toxicity, G3 electrolyte imbalance prompting the definitive cessation of radiotherapy was primarily attributed to non-compliance with supportive care measures, indicating a potentially preventable origin. Conversely, the G4 toxicity observed in the second patient, characterized by severe myositis and transaminase alterations, was mostly associated with the immunotherapy drug. Notably, G\u0026thinsp;\u0026ge;\u0026thinsp;3 liver toxicity is a relatively common adverse effect of pembrolizumab, with an incidence of 5.2% in the Keynote 552 trial cohort [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. While myositis is infrequent, documented cases exist [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] No acute pulmonary or cardiac toxicities were observed. Breast pain was minimal, and the most notable local side effect was G2 radiodermatitis, noted in two patients.\u003c/p\u003e \u003cp\u003eThe original KEYNOTE-522 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] study protocol initially prohibited concurrent radiotherapy with pembrolizumab, but it was later amended [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, only 144 out of 1174 study patients received concurrent adjuvant pembrolizumab and radiotherapy, resulting in most patients undergoing sequential treatment with radiotherapy [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Importantly, the comparison between efficacy and safety profiles did not reveal differences based on the pattern of administration of adjuvant radiotherapy; indeed, the number of events and toxicities seemed to favor patients treated concurrently with pembrolizumab. While these data are reassuring, doubts persist regarding whether patients were inadvertently selected within the clinical trial. Moreover, these findings require further confirmation in everyday clinical practice, where logistical constraints often impede the immediate post-operative administration of radiotherapy, potentially leading to delays in starting adjuvant pembrolizumab. Finally, many patients in clinical trials are generally fitter than those in the real world, not just due to protocol requirements, but also due to inadvertent selection by the physicians offering the trial. For all these reasons, we decided to analyze the concurrent treatment of pembrolizumab and radiotherapy in consecutive patients eligible for the treatment outlined in the KEYNOTE-522 protocol within a calendar year and observed for at least 1 month after the completion of radiotherapy.\u003c/p\u003e \u003cp\u003eOwing to the growing body of interest, literature about the combination of RT and immunotherapy seems to carefully suggest a safe and well-tolerated combination [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and has been mainly derived from other solid tumors. Pneumonia is one of the major side effects, followed by hepatic toxicities, both attributed to the direct damage of combined therapies. [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThoracic irradiation combined with Pembrolizumab is primarily reported in the context of lung cancer. Jabbour et al. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] aimed to assess the effectiveness and safety of administering Pembrolizumab alongside concurrent chemo-radiotherapy in patients with locally advanced non-small cell lung cancer (NSCLC). Radiation therapy consisted in 60 Gy in 30 daily fractions of 2 Gy each. Severe AEs were observed in 64.3% of the patients, predominantly attributed to systemic therapy. G3 or higher pneumonitis, including radiation-induced pneumonitis, occurred in 8.0% of the cases. Wu et al. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] performed a metanalysis of 3652 articles of NSCLC treated with immunotherapy plus RT with a reported incidence of G\u0026thinsp;\u0026ge;\u0026thinsp;3 pneumonitis up to 5.8%.\u003c/p\u003e \u003cp\u003eTo date, evidence regarding breast cancer patients is limited. Pooled data from 68 prospective trials involving immune checkpoint inhibitors suggested that the administration of these drugs within 90 days after radiotherapy did not seem to increase the risk of serious AEs [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The European Society for Radiotherapy and Oncology recently published a multidisciplinary expert consensus on the integration of RT with drugs [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], with 95% of the experts agreeing on the concurrent delivery of Pembrolizumab and RT. Tison et al. [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] reported a real-life experience, on patients treated as per KeyNote-522. Radiation therapy schedules were 50 Gy in 25 fractions of 2 Gy, 40.05 Gy in 15 fractions of 2.67 Gy, or 50.4 Gy in 28 fractions of 1.8 Gy when chest wall, whole breast or regional nodal irradiation were performed, respectively. Of the 28 patients analyzed, toxicities were mild, with the worse severe AEs being G3 breast pain.\u003c/p\u003e \u003cp\u003eWe acknowledge that this analysis has few limitations. The cohort is relatively small, with a short follow-up. We only reported data on acute toxicity, without addressing the onset of late AEs. Nevertheless, our findings suggest that the concurrent use of RT and pembrolizumab is safe, with no increase in local toxicity. The systemic synergy of this combination warrants further investigation. In this regard, our analysis serves as a starting point for future real-world evaluations of the efficacy and safety of adjuvant radio-immunotherapy combinations in patients with early stage TNBC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003eThe study was approved by the IRB of the participating center.\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants involved in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRRC conceptualization, data curation, formal analysis and writing original draft; DP investigations, writing original draft; ELR conceptualization; CG, MCG, RL, CL, AC, EP and LL investigation; ARF supervision and validation; MCDS conceptualization, supervision and validation. Each author contributed to the reviewing process of the original article. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHan HS, Vikas P, Costa RLB, Jahan N, Taye A, Stringer-Reasor EM. Early-Stage Triple-Negative Breast Cancer Journey: Beginning, End, and Everything in Between. Am Soc Clin Oncol Educ Book. 2023 Jun;43:e390464. doi: 10.1200/EDBK_390464. PMID: 37335956. \u003c/li\u003e\n\u003cli\u003eAlmansour NM. Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence. Front Mol Biosci. 2022 Jan 25;9:836417. doi: 10.3389/fmolb.2022.836417. PMID: 35145999; PMCID: PMC8824427.\u003c/li\u003e\n\u003cli\u003eBianchini, G., Balko, J. M., Mayer, I. A., Sanders, M. E., and Gianni, L. (2016). Triple-negative Breast Cancer: Challenges and Opportunities of a Heterogeneous Disease. Nat. Rev. Clin. 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American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med 2010;134:907-922.\u003c/li\u003e\n\u003cli\u003eHammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010;28:2784-2795.\u003c/li\u003e\n\u003cli\u003eWolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007;25:118-145.\u003c/li\u003e\n\u003cli\u003eEdge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. 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Safety and efficacy of radiotherapy/chemoradiotherapy combined with immune checkpoint inhibitors for non-small cell lung cancer: A systematic review and meta-analysis. Front Immunol. 2023 Mar 13;14:1065510. doi: 10.3389/fimmu.2023.1065510. PMID: 36993952; PMCID: PMC10040597.\u003c/li\u003e\n\u003cli\u003eAnscher MS, Arora S, Weinstock C, et al. Association of radiation therapy with risk of adverse events in patients receiving immunotherapy: a pooled analysis of trials in the US Food and Drug Administration database. JAMA Oncol 2022; 8: 232\u0026ndash;40.\u003c/li\u003e\n\u003cli\u003eIcro Meattini, Carlotta Becherini, Saverio Caini, Charlotte E Coles, Javier Cortes, Giuseppe Curigliano, et al. International multidisciplinary consensus on the integration of radiotherapy with new systemic treatments for breast cancer: European Society for Radiotherapy and Oncology (ESTRO)-endorsed recommendations. The Lancet Oncology. 2024 Feb. doi:10.1016/S1470-2045(23)00534-X.\u003c/li\u003e\n\u003cli\u003eThais Tison, Pierre Loap, Emilie Arnaud, Kim Cao, Solene Bringer, Manon Kissel, Safia Maaradji, Juliette Mainguene, Jean-Yves Pierga, Florence Lerebours, Anne Vincent-Salomon, Mariana Mirabelle, Francois-Clement Bidard, Delphine Loirat, Youlia M. Kirova. Tolerance of concurrent adjuvant radiotherapy and pembrolizumab for triple negative breast cancer: real life experience. Advances in Radiation Oncology, 2023, 101384, ISSN 2452-1094, doi: 10.1016/j.adro.2023.101384.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4006571/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4006571/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eINTRODUCTION Data on the feasibility and potential synergy of concomitant immunotherapy with radiation therapy (RT) is still scarce for early breast cancer (BC). We aimed to assess the safety profile of adjuvant pembrolizumab with concomitant radiotherapy (RT) in breast cancer patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMATERIAL AND METHODS:\u0026nbsp; We prospectively collected data from ten patients with triple-negative breast cancer treated with neoadjuvant chemotherapy with pembrolizumab (as per Keynote-522 criteria) followed by surgery and at least 1 cycle of adjuvant pembrolizumab with concomitant RT.\u0026nbsp;A total dose of 40.05 Gy delivered in 15 fractions was prescribed to the breast or chest wall, with regional nodes and tumor bed boost administered as clinically indicated. The study endpoint was to assess acute toxicity according to the Radiation Therapy Oncology Group scale, and to report the rate of discontinuation of RT and/or pembrolizumab.\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRESULTS A median of 8 (range 4 – 9) cycles of neoadjuvant Pembrolizumab were prescribed. Before RT, patients received a median of 3 (range 2 – 4) cycles of adjuvant Pembrolizumab.\u0026nbsp;Severe acute toxicity occurred in 2 patients. Specifically, G4 myositis led to permanent discontinuation of adjuvant pembrolizumab in one case, whereas G3 electrolyte imbalance caused definitive RT interruption and temporary discontinuation of adjuvant pembrolizumab in the second case. Among the remaining 8 patients, only 2 patients experienced G2 skin erythema with no treatment discontinuation.\u003c/p\u003e\n\u003cp\u003eCONCLUSIONS The combination of adjuvant pembrolizumab with concurrent radiotherapy proved feasible in the real world, as toxicity was minimal and consistent with existing literature.\u003c/p\u003e","manuscriptTitle":"Safety of pembrolizumab with concurrent radiotherapy in early stage breast cancer: preliminary prospective real-world evidence","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-05 16:30:59","doi":"10.21203/rs.3.rs-4006571/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"68f87484-54b3-437d-928f-6dd67f9e8183","owner":[],"postedDate":"March 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-06T04:14:37+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-05 16:30:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4006571","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4006571","identity":"rs-4006571","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}