Post-progression survival in advanced non-small cell lung cancer treated with anti-PD-1/PDL-1 monotherapy: progression after durable clinical benefit versus primary resistance

ABSTRACT Aims Anti-PD-1/PD-L1 can face the issue of tumor resistance in advanced non-small cell lung cancer (aNSCLC), mostly as primary resistance to the treatment. Still, disease progression (PD) also occurs after prior durable clinical benefit (DCB). Comparison of both situations and tools to evaluate residual benefit of PD-1/PD-L1 blockade are needed to understand and manage resistance. Methods We reviewed aNSCLCs with anti-PD-1/PD-L1 monotherapy, and disease progression per RECIST 1.1 (PD) in our center. Primary objective was comparison of post-progression survival (PPS) in primary resistance versus PD after DCB. Secondary objectives were to characterize patterns of PD after DCB; assess the feasibility and relevance of Tumor Growth Rate (TGR) in PD after DCB. Results 148 patients were included. Median PPS were 5.2months (95% CI: 2.6-6.5) and 21.3months (95% CI: 18.5-36.3) (p<0.0001) for primary resistance and PD after DCB respectively. Multivariable hazard ratio for death in PD after DCB versus primary resistance was 0.14 (95% CI: 0.07-0.30). 76.7% of PD after DCB occurred in ≤3 lesions; 72.1% occurred only in preexisting lesions. TGR suggested a persistent benefit of PD-1/PD-L1 blockade in at least 44.2% of cases. Conclusions PD after DCB was an independent factor of longer post-progression survival, with specific patterns of progression. TGR is a promising tool to assess residual benefit of immunotherapy. Highlights Anti-PD-(L)1 immunotherapy still faces the problem of resistance in lung cancer Resistance can be classified as primary or secondary (acquired) Outcomes and mechanisms of both situations need to be characterized This unique comparative study reveals diverging survival and progression patterns Prior durable clinical benefit associates with longer post-progression survival This data benefits our understanding and management of resistance to anti-PD-(L)1