Site‐specific response patterns, pseudoprogression, and acquired resistance in patients with melanoma treated with ipilimumab combined with anti–PD‐1 therapy

Abstract

Background Patients with metastatic melanoma have variable responses to combination ipilimumab and nivolumab. The objectives of this study were to examine the patterns of response and survival in patients treated with combination ipilimumab and anti–PD‐1 therapy (IPI + PD1) and to explore the nature of pseudoprogression and acquired resistance. Methods Patients with metastatic melanoma who received treatment with first‐line IPI + PD1 had all metastases ≥5 mm measured on computed tomography/magnetic resonance imaging studies. The lesional response rate (LRR) and the overall response rate (ORR) were determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. Results In total, 140 patients who had 833 metastases were studied. The ORR and the overall complete response (CR) rate decreased as tumor burden or the number of metastases increased. Metastases that had a CR (49%) were smaller than metastases without a CR (median, 13 vs 17 mm; P < .0001). Soft‐tissue and lung metastases had the highest LRR (79% and 77%, respectively), whereas liver metastases had the lowest (46%). In multivariate analysis, patients with lung metastases had superior ORR (odds ratio [OR], 2.75; P = .02) and progression‐free survival (hazard ratio [HR], 0.46; P = .02), whereas those with liver metastases had inferior ORR (OR, 0.33; P = .02), progression‐free survival (HR, 4.03; P < .01), and overall survival (HR, 3.17; P = .01). Pseudoprogression occurred in one‐third of patients who had progressive disease as their best response, with an overall survival that was comparable to that of patients without disease progression. Acquired resistance occurred in 12% of responders after a median of 9.6 months, with an overall survival rate of 83% at 1 year from progression. Conclusions Metastases in different anatomical locations display distinct response patterns and also are associated with overall response and survival with combination immunotherapy. Specific sites of disease may hold unique mechanisms of resistance and should allow for more personalized treatment.

Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition

“…The longitudinal analyses of multiple pre-treatment biopsies derived from various sites will be required to validate the influence of tumor heterogeneity on clinical outcomes and on the accuracy of baseline predictive signatures. In this study we observed significant variation in the response of individual lesions to immune checkpoint inhibition within melanoma patients, with heterogeneity of tumor responses observed in 85% and 69% of melanoma patients who did not achieve an objective response to pembrolizumab monotherapy or combination ipilimumab plus nivolumab, respectively 23,57 . This heterogeneity presumably reflects genetic, molecular and cellular variables, which may include the presence of neoantigens in only a subset of tumor clones, the expression of PD-L1 in a small proportion of tumor cells, variable expression of PD-1 on immune cells and intra-tumoral differences in T-cell density and clonality [58][59][60] .…”

MDM2, MDM4 and EGFR Amplifications and Hyperprogression in Metastatic Acral and Mucosal Melanoma

“…In our cohort, patients with liver metastases had a significant worse rate of survival. The inferior outcome of patients with liver metastases treated by ICI has already been shown in other collectives, including patients treated with pembrolizumab and combined ipilimumab and nivolumab [42][43][44]. This might be due to a lower density of CD8 + T cells in the liver metastases and also in the distant non-liver metastases of these patients [42].…”

Checkpoint inhibitors: Better outcomes among advanced cutaneous head and neck melanoma patients

“…Our series show that specific metastatic sites are associated with better CPI response including neck lymph nodes (70%) and lung spread (58.6%), compared with unfavorable metastatic sites such as brain (7%) and bones (0%). Similarly, metastatic sites and survival association following CPI treatment, was lately demonstrated among advanced melanoma [24], renal cell carcinoma and non-small cell lung carcinoma [25] patients. Head and neck melanoma patients treated with CPI had a significantly better ORR (50%, p = 0.03) and an improved, durable, although non-significant, median overall survival of 60.2 months CI 95% [47.…”