Prior anti-CTLA-4 therapy impacts molecular characteristics associated with anti-PD-1 response in advanced melanoma
Campbell, Katie M; Amouzgar, Meelad; Pfeiffer, Shannon M; Howes, Timothy R; Medina, Egmidio; Travers, Michael; Steiner, Gabriela; Weber, Jeffrey S; Wolchok, Jedd D; Larkin, James; Hodi, F Stephen; Boffo, Silvia; Salvador, Lisa; Tenney, Daniel; Tang, Tracy; Thompson, Marshall A; Spencer, Christine N; Wells, Daniel K; Ribas, Antoni
Immune checkpoint inhibitors (ICIs), including CTLA-4- and PD-1-blocking antibodies, can have profound effects on tumor immune cell infiltration that have not been consistent in biopsy series reported to date. Here, we analyze seven molecular datasets of samples from patients with advanced melanoma (N = 514) treated with ICI agents to investigate clinical, genomic, and transcriptomic features of anti-PD-1 response in cutaneous melanoma. We find that prior anti-CTLA-4 therapy is associated with differences in genomic, individual gene, and gene signatures in anti-PD-1 responders. Anti-CTLA-4-experienced melanoma tumors that respond to PD-1 blockade exhibit increased tumor mutational burden, inflammatory signatures, and altered cell cycle processes compared with anti-CTLA-4-naive tumors or anti-CTLA-4-experienced, anti-PD-1-nonresponsive melanoma tumors. We report a harmonized, aggregate resource and suggest that prior CTLA-4 blockade therapy is associated with marked differences in the tumor microenvironment that impact the predictive features of PD-1 blockade therapy response.
Nivolumab versus placebo as adjuvant therapy for resected stage III melanoma: a propensity weighted indirect treatment comparison and number needed to treat analysis for recurrence-free survival and overall survival
Weber, Jeffrey S; Poretta, Tayla; Stwalley, Brian D; Sakkal, Leon A; Du, Ella X; Wang, Travis; Chen, Yan; Wang, Yan; Betts, Keith A; Shoushtari, Alexander N
BACKGROUND:Recurrence-free survival (RFS) and overall survival (OS) data for adjuvant nivolumab versus placebo (proxy for routine surveillance) in patients with high-risk, resected melanoma are lacking. This post hoc, indirect treatment comparison (ITC) used pooled data from the phase 3 EORTC 18,071 (ipilimumab vs. placebo) and CheckMate 238 (nivolumab vs. ipilimumab) trials to assess RFS and OS with nivolumab versus placebo and the numbers needed to treat (NNT) over 4Â years. METHODS:Patients with resected stage IIIB-C cutaneous melanoma (American Joint Committee on Cancer seventh edition) were included. Inverse probability treatment weighting (IPTW) was used to balance baseline characteristics. RFS NNTs were calculated for nivolumab versus ipilimumab and placebo. OS NNTs were calculated for nivolumab versus placebo. To adjust for different post-recurrence treatments, the difference in post-recurrence survival between the two ipilimumab arms was added to OS of the placebo arm. RESULTS:This ITC included 278, 643, and 365 patients treated with nivolumab, ipilimumab, and placebo, respectively. Following IPTW, nivolumab was associated with improved RFS versus placebo (hazard ratio [HR]: 0.49; 95% confidence interval [CI] 0.39-0.61) and ipilimumab (HR: 0.69; 95% CI 0.56-0.85). RFS NNT was 4.2 for nivolumab versus placebo and 8.9 for nivolumab versus ipilimumab. After post-recurrence survival adjustment, weighted 4-year OS rates were 75.8% for nivolumab and 64.1% for placebo; OS NNT for nivolumab versus placebo was 8.5. CONCLUSIONS:In patients with resected stage IIIB-C cutaneous melanoma in this ITC, nivolumab improved RFS versus placebo and ipilimumab, and OS versus placebo after post-recurrence survival adjustment.
Correction to: Nivolumab versus placebo as adjuvant therapy for resected stage III melanoma: a propensity weighted indirect treatment comparison and number needed to treat analysis for recurrence-free survival and overall survival
Weber, Jeffrey S; Poretta, Tayla; Stwalley, Brian D; Sakkal, Leon A; Du, Ella X; Wang, Travis; Chen, Yan; Wang, Yan; Betts, Keith A; Shoushtari, Alexander N
Dichotomous Nitric Oxide"“Dependent Post-Translational Modifications of STAT1 Are Associated with Ipilimumab Benefits in Melanoma
Garg, Saurabh K.; Sun, James; Kim, Youngchul; Whiting, Junmin; Sarnaik, Amod; Conejo-Garcia, JosÃ© R.; Phelps, Mitch; Weber, Jeffrey S.; MulÃ©, James J.; Markowitz, Joseph
Although Ipilimumab (anti-CTLA-4) is FDA-approved for stage III/IV melanoma adjuvant treatment, it is not used clinically in first-line therapy, given the superior relapse-free survival (RFS)/toxicity benefits of anti-PD-1 therapy. However, it is important to understand anti-CTLA-4"™s mechanistic contribution to combination anti-PD-1/CTLA-4 therapy and investigate anti-CTLA-4 therapy for BRAF-wild type melanoma cases reresected after previous adjuvant anti-PD-1 therapy. Our group published that nitric oxide (NO) increased within the immune effector cells among patients with longer RFS after adjuvant ipilimumab, whereas NO increased within the immune suppressor cells among patients with shorter RFS. Herein, we measured the post-translational modifications of STAT1 (nitration-nSTAT1 and phosphorylation-pSTAT1) that are important for regulating its activity via flow cytometry and mass spectrometry approaches. PBMCs were analyzed from 35 patients undergoing adjuvant ipilimumab treatment. Shorter RFS was associated with higher pSTAT1 levels before (p = 0.007) and after (p = 0.036) ipilimumab. Ipilimumab-treated patients with high nSTAT1 levels before and after therapy in PBMCs experienced decreased RFS, but the change in nSTAT1 levels before and after ipilimumab therapy was associated with longer RFS (p = 0.01). The measurement of post-translational modifications in STAT1 may distinguish patients with prolonged RFS from ipilimumab and provide mechanistic insight into responses to ipilimumab combination regimens.
First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1)
Postel-Vinay, Sophie; Lam, Vincent K; Ros, Willeke; Bauer, Todd M; Hansen, Aaron R; Cho, Daniel C; Stephen Hodi, F; Schellens, Jan H M; Litton, Jennifer K; Aspeslagh, Sandrine; Autio, Karen A; Opdam, Frans L; McKean, Meredith; Somaiah, Neeta; Champiat, Stephane; Altan, Mehmet; Spreafico, Anna; Rahma, Osama; Paul, Elaine M; Ahlers, Christoph M; Zhou, Helen; Struemper, Herbert; Gorman, Shelby A; Watmuff, Maura; Yablonski, Kaitlin M; Yanamandra, Niranjan; Chisamore, Michael J; Schmidt, Emmett V; Hoos, Axel; Marabelle, Aurelien; Weber, Jeffrey S; Heymach, John V
BACKGROUND:The phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors. METHODS:GSK3174998 (0.003-10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity. RESULTS:138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56-CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response. CONCLUSIONS:GSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers. TRIAL REGISTRATION NUMBER:NCT02528357.
Society for Immunotherapy of Cancer (SITC) consensus definitions for immune checkpoint inhibitor-associated immune-related adverse events (irAEs) terminology
Naidoo, Jarushka; Murphy, Catherine; Atkins, Michael B; Brahmer, Julie R; Champiat, Stephane; Feltquate, David; Krug, Lee M; Moslehi, Javid; Pietanza, M Catherine; Riemer, Joanne; Robert, Caroline; Sharon, Elad; Suarez-Almazor, Maria E; Suresh, Karthik; Turner, Michelle; Weber, Jeffrey; Cappelli, Laura C
Immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy may vary substantially in their clinical presentation, including natural history, outcomes to treatment, and patterns. The application of clinical guidelines for irAE management can be challenging for practitioners due to a lack of common or consistently applied terminology. Furthermore, given the growing body of clinical experience and published data on irAEs, there is a greater appreciation for the heterogeneous natural histories, responses to treatment, and patterns of these toxicities, which is not currently reflected in irAE guidelines. Furthermore, there are no prospective trial data to inform the management of the distinct presentations of irAEs. Recognizing a need for uniform terminology for the natural history, response to treatment, and patterns of irAEs, the Society for Immunotherapy of Cancer (SITC) convened a consensus panel composed of leading international experts from academic medicine, industry, and regulatory agencies. Using a modified Delphi consensus process, the expert panel developed clinical definitions for irAE terminology used in the literature, encompassing terms related to irAE natural history (ie, re-emergent, chronic active, chronic inactive, delayed/late onset), response to treatment (ie, steroid unresponsive, steroid dependent), and patterns (ie, multisystem irAEs). SITC developed these definitions to support the adoption of a standardized vocabulary for irAEs, which will have implications for the uniform application of irAE clinical practice guidelines and to enable future irAE clinical trials.
A genome-wide association study of germline variation and melanoma prognosis
Chat, Vylyny; Dagayev, Sasha; Moran, Una; Snuderl, Matija; Weber, Jeffrey; Ferguson, Robert; Osman, Iman; Kirchhoff, Tomas
Background: The high mortality of cutaneous melanoma (CM) is partly due to unpredictable patterns of disease progression in patients with early-stage lesions. The reliable prediction of advanced disease risk from early-stage CM, is an urgent clinical need, especially given the recent expansion of immune checkpoint inhibitor therapy to the adjuvant setting. In our study, we comprehensively investigated the role of germline variants as CM prognostic markers. Methods: We performed a genome-wide association analysis in two independent cohorts of N=551 (discovery), and N=550 (validation) early-stage immunotherapy-naÃ¯ve melanoma patients. A multivariable Cox proportional hazard regression model was used to identify associations with overall survival in the discovery group, followed by a validation analysis. Transcriptomic profiling and survival analysis were used to elucidate the biological relevance of candidate genes associated with CM progression. Results: We found two independent associations of germline variants with melanoma prognosis. The alternate alleles of these two SNPs were both associated with an increased risk of death [rs60970102 in MELK: HR=3.14 (2.05"“4.81), p=1.48Ã—10-7; and rs77480547 in SH3BP4: HR=3.02 (2.02"“4.52), p=7.58Ã—10-8, both in the pooled cohort]. The addition of the combined risk alleles (CRA) of the identified variants into the prognostic model improved the predictive power, as opposed to a model of clinical covariates alone. Conclusions: Our study provides suggestive evidence of novel melanoma germline prognostic markers, implicating two candidate genes: an oncogene MELK and a tumor suppressor SH3BP4, both previously suggested to affect CM progression. Pending further validation, these findings suggest that the genetic factors may improve the prognostic stratification of high-risk early-stage CM patients, and propose putative biological insights for potential therapeutic investigation of these targets to prevent aggressive outcome from early-stage melanoma.
Combination Nivolumab, CD137 Agonism, and Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes for Patients with Metastatic Melanoma
Hall, MacLean S; Mullinax, John E; Cox, Cheryl A; Hall, Amy M; Beatty, Matthew S; Blauvelt, Jamie; Innamarato, Patrick; Nagle, Luz; Branthoover, Holly; Wiener, Doris; Schachner, Benjamin; Martinez, Alberto J; Richards, Allison D; Rich, Carolyn J; ColÃ³n ColÃ³n, Marjorie; Schell, Michael J; Teer, Jamie K; Khushalani, Nikhil I; Weber, Jeffrey S; Mule, James J; Sondak, Vernon K; Pilon-Thomas, Shari; Sarnaik, Amod A
PURPOSE/OBJECTIVE:Metastatic melanoma is a tumor amenable to immunotherapy in part due to the presence of antigen-specific tumor-infiltrating lymphocytes (TIL). These T cells can be activated and expanded for adoptive cell transfer (ACT), which has resulted in relatively high rates of clinical responses. Similarly, immune checkpoint inhibitors, specifically PD-1 blocking antibodies, augment antitumor immunity and increase the influx of T cells into tumors. Thus, we hypothesized that addition of PD-1 inhibition may improve the outcomes for patients undergoing ACT with TIL. PATIENTS AND METHODS/METHODS:Stage III/IV metastatic melanoma patients with unresectable disease who were anti-PD-1 treatment-naÃ¯ve were enrolled. TIL were generated in the presence of anti-4-1BB antibody in vitro and expanded for ACT. Patients in Cohort 1 received TIL infusion followed by nivolumab. Patients in Cohort 2 also received nivolumab prior to surgical harvest and during TIL production. RESULTS:A total of 11 patients were enrolled, all of whom were evaluated for response, and nine completed ACT. Predominantly CD8+ TIL were successfully expanded from all ACT-treated patients and were tumor-reactive in vitro. The trial met its safety endpoint, as there were no protocol-defined dose-limiting toxicity events. The objective response rate was 36% and median progression-free survival was 5 months. Two non-responders who developed new metastatic lesions were analyzed to determine potential mechanisms of therapeutic resistance, which included clonal divergence and intrinsic TIL dysfunction. CONCLUSIONS:Combination therapy with TIL and nivolumab was safe and feasible for metastatic melanoma patients and provides important insights for future therapeutic developments in ACT with TIL.
Intra-tumoral therapy to make a "cold" tumor "hot": the jury is still out
Punekar, Salman R; Weber, Jeffrey S
Tilsotolimod, an oligodeoxynucleotide TLR9 agonist, administered intra-tumorally, has been clinically evaluated. This compound has demonstrated the ability to induce changes within the tumor microenvironment, to convert non-inflamed cold tumors into inflamed hot tumors, with the hope that these tumors will be more responsive to immune checkpoint blockade.
Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study
Chesney, Jason; Lewis, Karl D; Kluger, Harriet; Hamid, Omid; Whitman, Eric; Thomas, Sajeve; Wermke, Martin; Cusnir, Mike; Domingo-Musibay, Evidio; Phan, Giao Q; Kirkwood, John M; Hassel, Jessica C; Orloff, Marlana; Larkin, James; Weber, Jeffrey; Furness, Andrew J S; Khushalani, Nikhil I; Medina, Theresa; Egger, Michael E; Graf Finckenstein, Friedrich; Jagasia, Madan; Hari, Parameswaran; Sulur, Giri; Shi, Wen; Wu, Xiao; Sarnaik, Amod
BACKGROUND:Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma. METHODS:Eligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing practice facility for 22-day lifileucel manufacturing. Patients received a non-myeloablative lymphodepletion regimen, a single lifileucel infusion, and up to six doses of high-dose interleukin-2. The primary endpoint was IRC-assessed ORR (Response Evaluation Criteria in Solid Tumors V.1.1). RESULTS:The Full Analysis Set consisted of 153 patients treated with lifileucel, including longer-term follow-up on the 66 patients previously reported. Patients had received a median of 3.0 lines of prior therapy (81.7% received both anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4) and had high disease burden at baseline (median target lesion sum of diameters (SOD): 97.8 mm; lactate dehydrogenase (LDH) >upper limit of normal: 54.2%). ORR was 31.4% (95% CI: 24.1% to 39.4%), with 8 complete responses and 40 partial responses. Median duration of response was not reached at a median study follow-up of 27.6 months, with 41.7% of the responses maintained for ≥18 months. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status demonstrated that elevated LDH and target lesion SOD >median were independently correlated with ORR (p=0.008); patients with normal LDH and SOD <median had greater likelihood of response than those with either (OR=2.08) or both (OR=4.42) risk factors. The most common grade 3/4 treatment-emergent adverse events (≥30%) were thrombocytopenia (76.9%), anemia (50.0%), and febrile neutropenia (41.7%). CONCLUSIONS:Investigational lifileucel demonstrated clinically meaningful activity in heavily pretreated patients with advanced melanoma and high tumor burden. Durable responses and a favorable safety profile support the potential benefit of one-time lifileucel TIL cell therapy in patients with limited treatment options in ICI-refractory disease.