Radiological dynamics and SITC-defined resistance types of advanced melanoma during anti-PD-1 monotherapy: an independent single-blind observational study on an international cohort

Abstract

BackgroundAlthough the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Taskforce recently defined primary and secondary resistance to anti-programmed cell death protein 1 (anti-PD-1) therapy, there is lack of real-world data regarding differences in these resistance subtypes with respect to radiological dynamics and clinical manifestations.MethodsWe performed single-blind re-evaluations of radiological images by independent radiologists on a retrospectively assembled cohort of patients with advanced melanoma (n=254, median follow-up 31 months) receiving anti-PD-1 monotherapy at Massachusetts General Hospital and Peking University Cancer Hospital. Radiological characteristics and timing at multiple crucial time points were analyzed and correlated with each other and with survival. Primary and secondary resistance was defined as per the SITC Immunotherapy Resistance Taskforce definitions.ResultsThe most significant target lesion measurement change took place within the first 3 months after anti-PD-1 initiation. Patients with stable disease with versus without tumor shrinkage at the initial evaluation exhibited distinct disease trajectory, as the rate of further upgrade to a partial or complete remission (CR/PR) was 44% and 0%, respectively. Eleven per cent of PR patients ultimately achieved a CR. In multivariate analyses, deeper response depth was independently associated with a more limited progression pattern, fewer involved organs, lower tumor burden, slower growth rate at disease progression (PD) (all p≤0.001), and longer post-progression survival (PPS) (bivariate analysis, p=0.005). Compared with primary resistance, secondary resistance was associated with less widespread PD pattern, lower tumor burden and slower tumor growth (all p≤0.001). Patients with secondary resistance were less likely to receive further systemic therapy (28% vs 57%, p<0.001) yet had significantly better PPS (HR 0.503, 95% CI 0.288 to 0.879, p=0.02).ConclusionsRadiological dynamics were variable, yet significantly correlated with survival outcomes. SITC-defined primary and secondary resistance are distinct clinical manifestations in patients with melanoma, suggesting the possibility of resistance-type-based therapeutic decision-making and clinical trial design, once further validated by future prospective studies.

Early Use of High-Dose Glucocorticoid for the Management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti–PD-1 Monotherapy

“…Our previous data showed that major antitumor response was established within 6 months after anti–PD-1 monotherapy initiation ( 12 ), we thus hypothesized the timing of high-dose GCC use in patients who were irAE(+) may affect subsequent outcomes. Noticeably, there was a high degree of variability in terms of onset time of high-dose GCC–associated irAEs ( Table 2 ).…”

Benefit, recurrence pattern, and toxicity to adjuvant anti-PD-1 monotherapy varies by ethnicity and melanoma subtype: An international multicenter cohort study

“…By contrast, traditional chemotherapy, even with previous immunotherapy exposure, remains associated with dismal outcomes, as previously observed after anti-PD-1 monotherapy failure in the metastatic setting. 16 , 17 …”

Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy

“…24 Resistance was defined based on minimum drug exposure requirement, best response, and confirmatory scans for primary resistance, secondary resistance, and disease progression after discontinuation of therapy. These definitions have been shown to be associated with distinct clinical outcomes 25 and incorporated into a number of clinical trials' eligibility criteria, supporting their utility for drug development. An ever-increasing number of patients, however, are being treated with ICIs in the context of combination regimens, warranting the revisiting of resistance definitions for ICIs administered in combination with chemotherapy.…”