Immunotherapy has revolutionized treatment for patients with metastatic melanoma, yet data are lacking regarding the effectiveness and tolerability of these treatments for older patients. In this study, we demonstrated that patients with melanoma safely tolerate immunotherapy and achieve similar outcomes regardless of their age. Specifically, we utilized data from two academic cancer centers and found no significant difference in overall survival, progression free survival, or immune-related toxicities, other than arthritis, across age groups. As the population ages, studies such as this will become critical to help us understand how best to treat older adults with cancer.

Novel agents targeting immune checkpoint molecules or mutated BRAF are active therapeutic options for patients with BRAF-mutant melanoma. However, the most effective first-line treatment and the optimal sequencing of these agents have not been well characterized. To explore this, we retrospectively assessed 114 patients from 4 centers with advanced, BRAF-mutant melanoma who received anti-programmed cell death-1 (PD-1)/PD-L1 antibodies. We evaluated clinical outcomes, including objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) to initial and subsequent therapies in patients that received anti-PD-1 first (n=56) versus those that received BRAF±MEK inhibitors (BRAFi) first (n=58). Median OS was similar between these groups (27.5 vs. 40.3 mo, P=0.71). Patients who progressed on anti-PD-1 during the study timeframe had worse outcomes after starting subsequent BRAFi than those who had not received prior anti-PD-1 (median PFS 5 vs. 7.4 mo, median OS 10.6 vs. 40.3 mo). Similarly, patients who previously progressed on BRAFi had seemingly inferior outcomes after starting anti-PD-1 compared with those without prior BRAFi, including ORR (25% vs. 41%), median PFS (2.8 vs. 10.6 mo) and median OS (8.2 vs. 27.6 mo). Notably, patients who benefited >6 months from BRAFi had superior ORR to subsequent anti-PD-1 compared with those with more rapid progression (<6 mo) on BRAFi (34% vs. 15%, P=0.04). We conclude that either BRAFi or anti-PD-1 may be effective regardless of treatment sequence in patients with BRAF-mutant melanoma, but clinical outcomes to front-line therapy are superior. In addition, we suggest a shared "responder phenotype" between BRAFi and anti-PD-1.

BackgroundAnti-PD-1 therapy is increasingly used in various advanced malignancies. Patients with baseline organ dysfunction are largely excluded from clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or effective in this setting. Further, these patients are often not candidates for other anti-cancer therapies, highlighting their need for active treatment options.MethodsWe performed a retrospective analysis of patients from multiple centers with advanced solid tumors and baseline organ dysfunction who received anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular ejection fraction ≤45 %), renal (creatinine ≥2 mg/dL or GFR ≤30 ml/min) or hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin ≥3x ULN). We assessed change in organ dysfunction, immune related adverse events (irAEs), response rate, progression free survival (PFS) and overall survival (OS).ResultsWe identified 27 patients eligible for inclusion with the following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4). Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective response or stable disease) at data collection (48 %). Eleven patients had primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial responses (15 %), and one had a complete response (4 %). Overall, median PFS was 168 days. Median OS was not reached.ConclusionsIn our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable irAEs and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.

Platinum-based chemotherapy is usually curative for patients with testicular germ cell tumors (TGCT), but a subset of patients experience disease progression and poor clinical outcomes. Here, we tested whether immune profiling of TGCT could identify novel prognostic markers and therapeutic targets for this patient cohort. We obtained primary and metastatic TGCT samples from one center. We performed immune profiling using multiplexed fluorescence immunohistochemistry (FIHC) for T-cell subsets and immune checkpoints, and targeted gene expression profiling (Nanostring nCounter Immune panel). Publically available data sets were used to validate primary sample analyses. Nearly all samples had some degree of T-cell infiltration and immune checkpoint expression. Seminomas were associated with increased CD3 T-cell infiltration, decreased Regulatory T-cells, increased PD-L1, and increased PD-1/PD-L1 spatial interaction compared with non-seminomas using FIHC. Gene expression profiling confirmed these findings and also demonstrated increased expression of T-cell markers (e.g., IFNγ, and LAG3) and cancer/testis antigens (e.g., PRAME) in seminomas, whereas non-seminomas demonstrated high neutrophil and macrophage gene signatures. Irrespective of histology, advanced TGCT stage was associated with decreased T-cell and NK-cell signatures, while Treg, neutrophil, mast cell and macrophage signatures increased with advanced stage. Importantly, cancer/testis antigen, neutrophil, and CD8/regulatory T-cell signatures correlated with recurrence free survival. Thus, deep immune characterization of TGCT using IHC and gene expression profiling identified activated T-cell infiltration which correlated with seminoma histology and good prognosis. These results may provide a rationale for testing of anti-PD-1/PD-L1 agents and suggest prognostic markers.

Anti–programmed cell death protein‐1 (anti‐PD‐1) therapy has greatly improved outcomes of patients with melanoma; however, many fail to respond. Although preclinical studies suggest a potentially synergistic relationship with anti‐PD‐1 therapy and certain concurrent medications, their clinical role remains unclear. Here, we retrospectively evaluated the use of nonsteroidal anti‐inflammatory drugs (NSAIDs) and other drugs in 330 patients with melanoma treated with anti‐PD‐1 therapy from four academic centers. In the cohort, 37% of patients used NSAIDs including aspirin (acetylsalicylic acid; ASA; 47%), cyclooxygenase (COX)‐2 inhibitors (2%), and non‐ASA/nonselective COX inhibitor NSAIDs (59%). The objective response rates (ORRs) were similar in patients with NSAID (43.4%) and no NSAID (41.3%) use with no significant difference in overall suvival (OS). There was a trend toward improved progression‐free survival (PFS) in patients who took NSAIDs (median PFS: 8.5 vs. 5.2 months; p = .054). Most patients (71.3%) took NSAIDs once daily or as needed. Multivariate analysis did not reveal an association with NSAID use with ORR, PFS, or OS. Concurrent use of metformin or beta blockers did not affect ORR, PFS, or OS. Our study found no conclusive association of concurrent NSAID or other medication use with improved outcomes in patients with melanoma treated with anti‐PD‐1 therapy. Larger and more systematic analysis is required to confirm these findings.