Trials In Melanoma Research Articles

Multicentre retrospective assessment of toxicity and response to immunotherapy in elderly patients with metastatic melanoma.

9565 Background: The incidence of melanoma increases with age, however, elderly patients remain under-represented in landmark immunotherapy trials for metastatic melanoma. This study aims to investigate the impact of age on efficacy and toxicity of immunotherapy, and complications of immunosuppression to treat toxicity. Methods: A multicentre retrospective study involving centres in Australia [Gold Coast University Hospital, Cairns Base Hospital, Townsville University Hospital] was performed to compare the efficacy and toxicity of immunotherapy in metastatic melanoma in patients ≥70 years versus patients < 70 years treated between 2015 and 2019. Data collected included: baseline demographics, PFS, OS, Grade 3 or higher (Gr3+) adverse events as per CTCAEv5, adverse events leading to discontinuation, duration of steroids used to treat toxicity and complications secondary to steroids. Comparison of survival outcomes between the groups was calculated using Kaplan Meier, Log rank test and multivariate Cox regression analysis. Fisher exact test was used to determine differences in toxicity between the two groups. Results: A total of 229 patients were included with 106 patients ≥70years and 123 patients < 70 years. Baseline demographics were similar. Dual immunotherapy (ipilimumab + nivolumab) was less commonly used in patients ≥70years [13 v 38% p < 0.001]. Although the median PFS was numerically higher amongst ≥70years [10.8 v 6.9months p = 0.99], the landmark PFS was not [3yr PFS: 31 v 39%; 4yr PFS: 22 v 39%]. The median OS was similar in patients ≥70 years v < 70years [27.5 v 28.7 months p = 0.91], with similar landmark survival [3yr OS: 46 v 49%; 4yr OS: 42 v 49%]. Age was not associated with a difference in overall survival on multivariate analysis. There was no increase in Gr3+ adverse events in patients ≥70 years [22 v 21% p = 1.00] or discontinuation rates [26 v 20% p = 0.35]. There was one death in a patient < 70years secondary to colitis. There was a significantly higher rate Gr3+ adverse events in ≥70years patients receiving dual immunotherapy [71 v 35% p = 0.029] and a similar rate of Gr3+ adverse events with PDL1 inhibitors [13 v 11% p = 0.7]. Median duration of steroids was similar in both group [15 v 17wks], as was the median duration of high dose steroids defined as greater than 10mg of prednisone [5 v 6wks]. Complications of steroids was numerically higher in the elderly population [42 v 25% p = 0.15]. The most common adverse event to immunosuppression was infection. Conclusions: Patients ≥70years received similar benefit from immunotherapy in comparison to their younger counterparts. Toxicity related to PDL1 inhibitors was similar in both groups and was higher in patients ≥70years receiving dual immunotherapy. Patients ≥70 years had a clinically significant higher rate of complications secondary to steroids.

Current Status and Prospects of Immunotherapy for Gynecologic Melanoma.

Gynecologic melanomas are rare and have a poor prognosis. Although immunotherapy (immune checkpoint inhibitors) and targeted therapy has greatly improved the systemic treatment of cutaneous melanoma (CM) in recent years, its efficacy in gynecologic melanomas remains uncertain because of the rarity of this malignancy and its scarce literature. This review aimed to evaluate the literature of gynecologic melanomas treated with immunotherapy and targeted therapy through a PubMed search. We identified one study focusing on the overall survival of gynecologic melanomas separately and five case series and nine case reports concentrating on gynecologic melanomas treated with an immune checkpoint inhibitor and/or targeted therapy. Furthermore, the KIT mutation has the highest rate among all mutations in mucosal melanoma types. The KIT inhibitors (Tyrosine kinase inhibitors: TKIs) imatinib and nilotinib could be the treatment options. Moreover, immune checkpoint inhibitors combined with KIT inhibitors may potentially treat cases of resistance to immune checkpoint inhibitors. However, because of the different conditions and a small number of cases, it is difficult to evaluate the efficacy of immunotherapy and targeted therapy for gynecologic melanoma rigorously at this time. Further prospective cohort or randomized trials of gynecologic melanoma alone are needed to assess the treatment with solid evidence.

Personal Neoantigen Vaccines for the Treatment of Cancer

Cancer vaccines can generate and amplify tumor-specific T cell responses with the promise to provide long-term control of cancer. All cancer cells harbor genetic alterations encoding neoantigens that are specific to the tumor and not present in normal tissue. Similar to foreign antigens targeted by T cells in infectious disease settings, neoantigens represent the long elusive immunogens for cancer vaccination. Since the vast majority of mutations are unique to individual tumors, neoantigen vaccines require custom design for each patient. The availability of rapid and cost-effective genome sequencing, along with advanced bioinformatics tools, now allows neoantigen-target discovery and vaccine manufacturing in sufficient time for the treatment of cancer patients. Clinical trials in melanoma and glioblastoma have demonstrated the feasibility, immunogenicity, and signals of efficacy of this personalized immunotherapy approach. Key unresolved areas include identification of the most effective vaccine delivery platforms, validation and consensus of neoantigen target selection, and optimal strategies for partnering immunotherapies. Given the universal presence of mutations in cancer and the patient-tailored paradigm, personalized neoantigen vaccines have potential applicability for all cancer patients.

Neoadjuvant Immunotherapy for High-Risk, Resectable Malignancies: Scientific Rationale and Clinical Challenges

Neoadjuvant immunotherapy involves administering immune checkpoint inhibitors before surgical resection in high-risk resectable disease. This strategy was shown to have a high pathological response rate and prolonged relapse-free survival in randomized trials in melanoma, glioblastoma, and colon cancer with small numbers of patients. In resectable cancers, immune checkpoint inhibitors such as anti-programmed cell death-1 (PD1) and anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) can enhance antitumor immunity by activating antigen-specific T cells found in the primary tumor. These tumor-reactive T cells continue to exert antitumor effects on remaining neoplastic cells after the resection of the primary tumor, potentially preventing relapses from occurring. Based on the scientific rationale and early clinical observations with surrogate survival endpoints, neoadjuvant immunotherapy may provide an effective alternative to other therapeutic strategies such as adjuvant treatment. However, this can be determined only by conducting randomized controlled trials comparing neoadjuvant immunotherapy with the current standard of care for each tumor site. This review discusses the cellular mechanisms that occur during successful neoadjuvant immunotherapy and highlights the clinical data from the available human studies that support the preclinical mechanistic data. Here we also discuss strategies required for successful neoadjuvant immunotherapy, including combination treatment strategies and resistance mechanisms to neoadjuvant treatment.

Expanded Tumor-infiltrating Lymphocytes From Soft Tissue Sarcoma Have Tumor-specific Function.

Adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TILs) can generate durable clinical responses in patients with metastatic melanoma and ongoing trials are evaluating efficacy in other advanced solid tumors. The aim of this study was to develop methods for the expansion of tumor-reactive TIL from resected soft tissue sarcoma to a degree required for the ACT. From 2015 to 2018, 70 patients were consented to an institutional review board-approved protocol, and fresh surgical specimens were taken directly from the operating room to the laboratory. Fragments of the tumor (1 mm3) or fresh tumor digest were placed in culture for a period of 4 weeks. Successfully propagated TIL from these cultures were collected and analyzed by flow cytometry. TIL were cocultured with autologous tumor and function was assessed by measurement of interferon-γ in the supernatant by enzyme-linked immunosorbent assay. Initial TIL cultures were further expanded using a rapid expansion protocol. Nearly all specimens generated an initial TIL culture (91% fragment method, 100% digest method). The phenotype of the TIL indicated a predominant CD3+ population after culture (43% fragment, 52% digest) and TIL were responsive to the autologous tumor (56% fragment, 40% digest). The cultured TIL expanded to a degree required for clinical use following rapid expansion protocol (median: 490-fold fragment, 403-fold digest). The data demonstrate the feasibility of TIL culture from fresh soft tissue sarcoma. The derived TIL have tumor-specific reactivity and can be expanded to clinically relevant numbers. An active ACT clinical trial using the methods described in this report is now approved for patients with metastatic soft tissue sarcoma.

Beyond Ipilimumab: a review of immunotherapeutic approaches in clinical trials in melanoma.

SummaryIn this first in a series of ‘Trials Watch’ articles, we briefly review a highly selected set of clinical trials that are currently recruiting or about to open to recruitment in melanoma, the disease first transformed by the introduction of immune checkpoint blockade inhibitors (ICI). We place equal emphasis on phase I/II studies investigating the activity of biologically compelling novel immunotherapeutics, and on randomised trials of ICI with and without novel agents, as these latter studies optimise the standard-of-care use of ICI, and determine whether novel agents become part of the approved therapeutic armamentarium. We do not consider here combination therapy with other checkpoint antagonists or agonists besides combination of anti-PD-1/PD-L1 monoclonal antibodies (mAbs) with anti-CTLA4 mAbs, as these will be reviewed in a subsequent article in this series. A glossary of agents to be discussed is found at the end of this article.

Exploring the relationship between Overall Survival (OS), Progression Free Survival (PFS) and Objective Response Rate (ORR) in patients with advanced melanoma

PurposeFrom 2011 to 2016, 13 randomized clinical trials with active controls were submitted to U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma. While regular approval is generally granted due to a substantial improvement in overall survival (OS), or a large, clinically meaningful improvement in progression-free survival (PFS), accelerated approval can be granted based on incremental change in a surrogate end point reasonably likely to predict clinical benefit, such as objective response (ORR) of large magnitude and long duration. However, the relationship between objective response rate and progression free survival or objective response rate and overall survival in advanced melanoma has not been established. Patients and MethodsWe conducted analyses to assess the correlation of objective response rate with progression free survival as well as overall survival by examining all advanced melanoma trials submitted to the FDA between 2011 and 2016. In order to examine these relationships, associations between trial-level hazard ratio (HR) of progression free survival, hazard ration of survival and odds ratio of objective response rate were analyzed using a weighted linear regression model. Patient-level responder analyses comparing progression free survival and overall survival between patients with and without an objective response were performed using pooled data from all studies. ResultsIn the trial-level analysis, the linear relationships between progression free survival and objective response rate, and overall survival and objective response rate were weak (R²adj = 0.019 and 0.093, respectively). The linear relationship between overall survival and progression free survival (R²adj = 0.075) was also weak. In the patient-level responder analyses, patients who achieved a response had better progression free survival and overall survival compared with non-responders in both the control drug treatment and the experimental drug treatment. ConclusionBased on this analysis, use of objective response rate as a surrogate endpoint for overall survival or progression free survival in this population appears not appropriate. However, due to the nature of heterogeneity, interpretation needs to be cautious.

UVR-sensor wearable device intervention to improve sun behaviors and reduce sunburns in melanoma survivors: study protocol of a parallel-group randomized controlled trial

BackgroundIndividuals who have been diagnosed with melanoma have more than a 9-fold increased risk of developing another melanoma. Ultraviolet radiation (UVR) exposure following a melanoma diagnosis can be modified to reduce risk of a new melanoma diagnosis. Yet research shows that many melanoma survivors do not report optimal sun protection practices. The objective of this study is to evaluate the effectiveness of a UVR-sensor wearable device to improve sun protection behaviors and reduce sunburns in a randomized controlled trial (RCT) in melanoma survivors.MethodsWe will conduct an RCT among 368 melanoma survivors in two waves (Summer 2020, Summer 2021). This approach allows for adequate recruitment of the required sample and potential improvements to recruitment, compliance, and retention strategies between waves. The intervention includes an informational brochure about sun protection behaviors and a commercially available UVR-sensor wearable device (Shade), which accurately measures UVR. The device, along with its associated mobile application, measures and stores UVR exposure. As UVR exposure accumulates, the device provides notifications to increase sun protection action. Survivors in the control group receive the device and a separate mobile application that does not provide notifications or summary UVR exposure data. Participants will be asked to wear the device for 12 weeks. They will complete surveys about their sun behaviors at study entry, every 4 weeks during the intervention, and 1 year later. At the end of the intervention period, intervention and control groups will be compared for differences in a summary measure of sun protection habits and experience of a sunburn. We will also measure self-reported physical activity, depression, and anxiety to examine potential unintended negative consequences of the intervention.DiscussionThe study intervention will be completed Fall 2021, with anticipated results available in 2022. If this intervention improves sun protection behaviors in melanoma survivors, these findings would support expanding the use of this technology with other populations at high risk for melanoma.Trial registrationClinicalTrials.gov NCT03927742. Registered on April 15, 2019.

Abstract IA21: Translating immunotherapy from melanoma to other skin cancers

Abstract The PD-1 pathway, including the immune cell receptor Programmed Cell Death 1 (PD-1) and its ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), mediates immunosuppression within the tumor microenvironment. Drugs designed to “release the brakes” on antitumor immunity by blocking PD-1 have demonstrated substantial and durable activity in patients with advanced unresectable melanoma, as well as those with resected melanomas having a high risk for postsurgical relapse. These findings supported FDA approvals for anti-PD-1 drugs in the adjuvant and advanced melanoma settings. Research in melanoma subtypes and other kinds of cancers has identified two tumor markers associated with the likelihood of anti-PD-1 response: PD-L1 protein expression and tumor mutational burden (TMB), reflecting neoantigen load. Cutaneous melanomas are often caused by UV irradiation, harbor high TMBs, and frequently express PD-L1. Other types of skin cancers caused by UV irradiation, such as squamous cell and basal cell carcinomas, harbor high TMBs, express PD-L1, and have shown sensitivity to anti-PD-1. Merkel cell carcinoma has a unique biology, since only ~20% of cases are caused by UV light (high TMB), while the remaining 80% are associated with the oncogenic Merkel cell polyomavirus (very low TMB). Interestingly, both varieties are highly responsive to PD-1 pathway blockade, indicating that a limited number of strong tumor antigens (viral antigens) can compensate for low TMB to elicit antitumor immunity and tumor rejection. Anti-PD-1 has shown promising activity in neoadjuvant (presurgical) trials in melanoma and Merkel cell carcinoma. Neoadjuvant trials afford the opportunity for in-depth tissue analysis, and a variety of tumor markers are under investigation for correlation with treatment outcomes. The continued interrogation of tumor markers potentially predictive of clinical outcomes is expected to further refine the risk:benefit profile for PD-1/PD-L1 antagonists in melanoma and other skin cancers. Future clinical investigations will focus on difficult-to-treat populations such as immunosuppressed patients, including solid organ transplant recipients and those with HIV infection, who are at increased risk to develop aggressive skin cancers. Supported by National Institutes of Health R01 CA142779, Bristol-Myers Squibb, Melanoma Research Alliance, Barney Foundation, Laverna Hahn Charitable Trust, and Moving for Melanoma of Delaware. Citation Format: Suzanne L. Topalian. Translating immunotherapy from melanoma to other skin cancers [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA21.

PCN85 Comparison of Observed LONG-TERM Overall Survival with Extrapolated Overall Survival for Pembrolizumab Monotherapy Assessed By Australian Reimbursement Authorities

For PD(L)-1 inhibitors such as pembrolizumab, OS is a key driver of clinical- and cost-effectiveness. Submissions to the reimbursement authorities often require the extrapolation of observed OS data from the pivotal clinical trials to project patients’ survival beyond the trial period. The aims of this study are: to analyse the accuracy of extrapolations accepted by the PBAC for pembrolizumab submissions for advanced melanoma and metastatic NSCLC PD-L1 TPS>=50% compared with what was subsequently observed in long-term trial follow-up; and to understand whether the time horizon accepted by the PBAC adequately captures the treatment benefit of pembrolizumab. To focus on treatments with a high disease burden and budget impact, the study was limited to indications with a treated population of greater than 500 patients per year. A search was conducted for pembrolizumab public summary documents (PSDs) as well as published long-term OS data with at least 2 years follow-up. Extrapolations and recommended time horizons reported in the relevant PSDs were extracted to compare the accuracy of OS projections versus the most mature data available. The review identified two comparisons of OS extrapolations: the KN-006 trial in patients with advanced melanoma (median follow-up duration 57.7 months; maximum 62.1 months) and KN-024 trial in patients with metastatic NSCLC PD-L1 TPS>50% (median follow-up duration 44.4 months, maximum 52.9 months). The extrapolations accepted by the PBAC in recommending pembrolizumab for advanced melanoma estimated an overall survival rate of 24.0% at 49 months and 33.2% at 40.5 months for metastatic NSCLC PD-L1 TPS>=50%. This underestimated OS of pembrolizumab monotherapy by absolute percentages of 18.2% and 9.1%, respectively compared to the most mature OS trial data available. The results demonstrate that the extrapolation accepted by PBAC underestimated OS compared to longer-term data for pembrolizumab monotherapy in advanced melanoma and metastatic NSCLC PD-L1 TPS>=50%.

Abstract CT042: Pembrolizumab 400 mg Q6W dosing: First clinical outcomes data from Keynote-555 cohort B in metastatic melanoma patients

Abstract Background: Pembrolizumab is approved globally in multiple cancer indications at a dose of 200 mg or 2 mg/kg every three weeks (Q3W). An alternative dosing regimen of 400 mg every six weeks (Q6W), which provides convenience and flexibility to patients and prescribers, is also approved in markets including the European Union (EU), Australia and New Zealand based on pharmacokinetic (PK) modeling and simulation. KEYNOTE-555 Cohort B is an open-label, clinical study in patients with metastatic melanoma designed evaluate the Q6W dosing. The preliminary PK data to validate the model-based assessments as well as efficacy and safety of the Q6W regimen compared to historical data will be described. Methods: A total of 101 patients are enrolled in this study; complete cycle 1 PK data from 37 patients are available. Observed concentration-time profiles from cycle 1 were compared with predictions from the model, which is based on 2993 patients from 5 clinical trials across tumor types. The associated efficacy and safety from these patients will be reviewed and compared to previous clinical trials in advanced melanoma. Results: The demographics from KN-555 Cohort B were similar to previous trials of pembrolizumab in metastatic melanoma, with mean age: 62 years, mean body weight: 85 kg, and 34% female patients. The observed concentrations for 400 mg Q6W were well within the 90% prediction intervals of simulated concentrations using the model. The geometric mean (GM) of observed trough concentration at six weeks (Ctrough) at 400 mg Q6W is 14.5 ug/mL, which is 18% lower than at 200 mg Q3W (18.1 ug/mL) and 11% higher than at 2 mg/kg Q3W (13.4 ug/mL). The GM of observed peak concentration at the end of infusion at 400 mg Q6W is 136 ug/mL, which is below (38% lower) that at the highest clinically tested dose of 10 mg/kg Q2W (220 ug/mL). The ORR in KN-555 Cohort B is comparable to the ORR in previous pembrolizumab studies in metastatic melanoma, indicating similarity of efficacy between the Q6W and Q3W regimens. The safety of the Q6W regimen is comparable to the extensive pembrolizumab safety profile that has been demonstrated in over twelve tumor types. Conclusion: The preliminary PK, efficacy and safety analyzed from KN-555 Cohort B validates the findings from the model-based assessment, of a consistent benefit-risk profile for a 400 mg Q6W regimen as compared to the 200 mg (or 2 mg/kg) Q3W regimen. The study supports that pembrolizumab Q6W is a safe and effective dosing regimen and offers a more convenient option for patients and physicians. Citation Format: Mallika Lala, Omobolaji Akala, Elliot Chartash, Mizuho Kalabis, Shu-Chih Su, Dinesh de Alwis, Vikram Sinha, Lokesh Jain. Pembrolizumab 400 mg Q6W dosing: First clinical outcomes data from Keynote-555 cohort B in metastatic melanoma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT042.

Abstract NG13: Metabolomic adaptations and correlates of survival to immune checkpoint blockade

Abstract NG13: Metabolomic adaptations and correlates of survival to immune checkpoint blockade

An Update on the Role of Talimogene Laherparepvec (T-VEC) in the Treatment of Melanoma: Best Practices and Future Directions.

Talimogene laherparepvec (T-VEC) is the first agent approved for cancer in the emerging class of oncolytic viral therapies. While T-VEC was approved for the treatment of advanced melanoma in 2015, clinical utilization has been hampered by rapid changes in the therapeutic landscape of melanoma related to advances in both immune checkpoint blockade and targeted therapy, cumbersome logistics involved in T-VEC administration, biosafety concerns, and a perception that T-VEC has limited impact on uninjected, visceral disease. However, with further survival follow-up from the phase III OPTiM (OncovexGM-CSF Pivotal Trial in Melanoma), along with new real-world data and consensus guidelines on safe administration of oncolytic viruses, a roadmap for when and how to use T-VEC has been emerging. In addition, preliminary data have demonstrated improved therapeutic responses to T-VEC in combination with immune checkpoint blockade in patients with melanoma without additive toxicity. This review provides an update on recent data with T-VEC alone and in combination with other agents. The emerging data provide guidance for how to better utilize T-VEC for patients with melanoma and identifies critical areas for clinical investigation to expand the role of T-VEC in combination strategies for the treatment of melanoma and perhaps other cancers.

The Role of Neoadjuvant Therapy in Melanoma.

Neoadjuvant therapy in melanoma is an area of active investigation with numerous completed and ongoing trials studying a variety of therapeutic interventions utilizing diverse designs. Here, we review completed and ongoing neoadjuvant trials in melanoma, discuss endpoint assessment, and highlight biomarker development in this context. High-risk resectable melanoma with clinically detectable lymph node (LN) with or without in-transit and/or satellite metastases represent ~ 20% of melanoma patients and have a high risk of relapse despite definitive surgery. Adjuvant therapy with anti-PD-1 immunotherapy or BRAF/MEK-targeted therapy has improved relapse-free survival (RFS) and overall survival (OS) in large phase III trials and is approved for this indication. However, despite surgery and adjuvant therapy, many patients relapse and/or experience treatment-related toxicity, underscoring the need to identify and understand mechanisms of response and resistance. In melanoma, neoadjuvant therapy is an active area of research with numerous completed and ongoing trials utilizing FDA-approved and novel agents with intriguing results. Neoadjuvant therapy for regionally metastatic disease is an established standard in multiple cancers, where it has been shown to improve operability, facilitate biomarker development, and even is a registrational endpoint for drug development in breast cancer. Recently, a spate of neoadjuvant studies in melanoma has looked at a swathe of agents with promising clinical and biomarker results. Coordinated efforts are underway to translate these findings to earlier stage disease while prioritizing the evaluation of new strategies in unresectable disease.

4322 Structure-guided design of the TIL1383I T cell receptor

OBJECTIVES/GOALS: Our goal is to employ a structure-guided design approach to engineering a safer and more effective variant of the TIL1383I T cell receptor (TCR) currently under study in clinical trials for malignant melanoma METHODS/STUDY POPULATION: Using our unpublished structure of TIL1383I we are in process of designing a panel of TCR variants with the goal of identifying candidates that improve “focus” towards the tyrosinase antigen presented on the MHC class I molecule HLA-A2. RESULTS/ANTICIPATED RESULTS: Structural analysis of TIL1383I revealed key residues, particularly beta-chain residues E97, G101, L102, responsible for engaging the tyrosinase peptide bound to HLA-A2. The crystal structure of TIL1383I in complex with tyrosinase-HLA-A2 also highlighted its uncharacteristic binding geometry and we therefore hypothesize that this binding orientation is associated with the observed CD8 co-receptor independence of TIL1383I. Indeed, functional analysis with TIL1383I-transduced CD8-positive and CD8-negative T cells, transduced T cells expressing a truncated CD8 lacking the intracellular LCK signaling domain, and tyrosinase peptide variants presented by HLA-A2 mutants outline this co-receptor independence. Combined with our interrogation of tyrosinase peptide cross-reactivity via a peptide positional scanning library approach, structure-guided design resulted in the identification of TIL1383I variants with improved binding affinities to the tyrosinase peptide as well as an understanding of structural characteristics that may contribute to TIL1383I’s co-receptor independence.

Surrogate endpoints for overall survival in anti-programmed death-1 and anti-programmed death ligand 1 trials of advanced melanoma.

10030 Background: The mechanisms of action of anti-PD-1/PD-L1 agents are markedly distinct from those of cytotoxic agents, thus a critical issue that is under investigation is what is the optimal endpoint and how should tumor response be evaluated in anti-PD-1/PD-L1 trials for metastatic melanoma. Here, we assessed surrogacy of objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) for overall survival (OS) in anti-PD-1/PD-L1 trials of metastatic melanoma through a meta-analysis of randomized controlled trials (RCTs). Methods: PubMed and EMBASE were searched for phase 2/3 RCTs till June 2019 investigating anti-PD-1/PD-L1 agents. Treatment effect (hazard ratio or odds ratio) on potential surrogates (ORR/DCR/PFS) and OS were collected. At trial level, we assessed the correlation between treatment effect on potential surrogates and OS, weighted by sample size, fixed and random effect models, and calculated the surrogate threshold effect (STE). Sensitivity analyses and leave-one-out cross-validation approach were performed to evaluate the robustness of our findings. Results: We included 8 RCTs (4,110 patients; 11 comparisons). We did not identify strong correlations between ORR (coefficient of determination [ R2]: 0.09 to 0.25), DCR (0.41 to 0.57) and OS. However, we noted a strong correlation between PFS and OS, with R2 of 0.82 in sample size, 0.75 in fixed effect, and 0.72 in random effect model weighting, the robustness of which was further verified by leave-one-out cross-validation approach. Sensitivity analyses with restriction to trials with less than 50% crossover ( R2: 0.94-0.94), phase 3 trials ( R2: 0.94-0.95), large trials ( R2: 0.78-0.86) and first-line trials ( R2: 0.83-0.91) strengthened the correlation. The STE for PFS was 0.78. Conclusions: PFS may be the appropriate surrogate for OS in anti-PD-1/PD-L1 trials of metastatic melanoma. A future anti-PD-1/PD-L1 trial would need less than 0.78 for PFS of the upper limit of confidence interval to predict an OS benefit.

Comparison of baseline patient characteristics in immunotherapy versus targeted therapy trials for advanced melanoma.

e22012 Background: Immune checkpoint inhibitors (ICI) or BRAF/MEK targeted therapy are both FDA approved first line options for BRAF mutant advanced melanoma. However, the optimal sequencing of these approaches and the profile of patients who benefit the most from one treatment over the other is suboptimally defined. Methods: We compared the baseline characteristics of the participants enrolled in the immunotherapy (IT) and targeted therapy (TT) trials quoted in the NCCN guidelines as the guidelines are used by many oncologists who do not subspecialize in melanoma to formulate treatment plans. Data was gathered about age, sex, race, ECOG score, LDH levels, stage, BRAF mutation status, PD-L1 expression and prior lines of therapy. Results: Median age range was younger in the TT population (48-57 y) as compared to the IT population (56-65 y); > 50% were males. 54-82% patients in the IT trials had an ECOG score of 0. Relatively more patients (pts) with ECOG score of 1 were included in Dabrafenib/ Trametinib and Vemurafenib/Cobimetinib trials (62-65%). Most pts had stage IV M1c disease. LDH levels were similar in IT and TT trials. V600E mutation was uniformly more common in the TT trials as expected. PD-L1 expression varied widely; from 23% to 81% patients with a high PD-L1 expression. Trials evaluating pembrolizumab included patients (7-26%) who were previously treated with BRAF/MEK inhibitor, however TT trials did not include as many pts exposed to ICI. Conclusions: Age range and sex ratio of the pts included in the trials were representative of the epidemiology of melanoma, but race was underreported. TT studies trended towards a younger median age range than patients treated in the IT studies. However optimal biomarkers for initial treatment choice cannot be determined by the patient demographics and characteristics presented in the studies discussed in the NCCN guidelines. Studies randomizing treatment sequence and identification of biomarkers prognostic of patient specific treatment efficacy are needed. Comparison of the IT and TT studies support the choice of either approach as initial treatment in pts with BRAF mutant melanoma lacking contraindications.

SAT-LB112 An Unusual Case of Ipilimumab/Nivolumab Induced Fulminant Diabetic Ketoacidosis (DKA) in a Non Diabetic Patient - a Case Report

SAT-LB112 An Unusual Case of Ipilimumab/Nivolumab Induced Fulminant Diabetic Ketoacidosis (DKA) in a Non Diabetic Patient - a Case Report

Structure-guided design of the TIL1383I T cell receptor

Abstract T cell therapy is an exciting form of cancer immunotherapy in which T cells are engineered to target specific tumor antigens. We employed a structure-guided design approach with the goal of engineering a safer and more effective variant of the TIL1383I T cell receptor (TCR) currently under study in clinical trials for malignant melanoma. Using our unpublished structure of TIL1383I we are in process of designing a panel of TCR variants with the goal of identifying candidates that improve “focus” towards the tyrosinase antigen presented on the MHC class I molecule HLA-A2. Structural analysis of TIL1383I revealed key residues, particularly beta-chain residues E97, G101, L102, responsible for engaging the tyrosinase peptide bound to HLA-A2. The crystal structure of TIL1383I in complex with tyrosinase-HLA-A2 also highlighted its uncharacteristic binding geometry and we therefore hypothesize that this binding orientation is associated with the observed CD8 co-receptor independence of TIL1383I. Indeed, functional analysis with TIL1383I-transduced CD8-positive and CD8-negative T cells, transduced T cells expressing a truncated CD8 lacking the intracellular LCK signaling domain, and tyrosinase peptide variants presented by HLA-A2 mutants outline this co-receptor independence. Combined with our interrogation of tyrosinase peptide cross-reactivity via a peptide positional scanning library approach, structure-guided design resulted in the identification of TIL1383I variants with improved binding affinities to the tyrosinase peptide as well as an understanding of structural characteristics that may contribute to TIL1383I’s co-receptor independence.

Drug-induced sarcoidosis-like reaction in adjuvant immunotherapy: Increased rate and mimicker of metastasis

BackgroundAnti-[programmed cell death protein 1 (PD-1)] antibodies nivolumab and pembrolizumab were approved for adjuvant treatment of melanoma as they demonstrated improved relapse-free survival. Currently, combined anti-PD-1 plus anti-[cytotoxic T-lymphocyte-associated protein 4 (CTLA4)] blockade is being investigated in adjuvant and neoadjuvant trials. Sarcoidosis-like reactions have been described for immune checkpoint inhibitors and are most likely drug-induced. The reported rate of sarcoidosis/sarcoidosis-like reactions within clinical melanoma trials is <2%. We observed that a remarkably higher number of melanoma patients (10/45 patients, 22%) treated with immune checkpoint inhibitor (ICI) within an adjuvant clinical trial-developed drug induced sarcoidosis-like reaction (DISR) mimicking metastasis. Case presentationOf 45 stage III melanoma patients who were treated at our institute with adjuvant ICI (either nivolumab alone or in combination with ipilimumab) within a two-armed, blinded clinical trial, ten developed a DISR. Three of the ten patients were men, median age was 52 years (range, 32–70 years). DISRs were asymptomatic and generally detected radiographically at first radiographic imaging after the start of therapy (median time, 2.8 months) and described as a differential diagnosis to tumour progression. In one patient, DISR was only apparent 13.1 months after start of therapy and 4 weeks after the end of ICI treatment. DISR presented as mediastinal/hilar lymphadenopathy in 8/10 patients (as only site or in addition to lung, skin and/or bone involvement), one patient had only lung and cutaneous, one patient only cutaneous DISR. Biopsies from lymph nodes, skin and bone were taken in 8/10 patients, and histology confirmed sarcoidosis-like reactions (SLRs). As patients were asymptomatic, no treatment for DISR was required, and study treatment was stopped for DISR in only one patient due to bone involvement. DISRs have resolved or are in remission in all patients. At a median follow-up time of 15.3 months (range, 12–17.6 months), two patients experienced melanoma relapse. ConclusionsIn most cases, sarcoidosis could only be differentiated from melanoma progression on biopsy. Treating physicians as well as radiologists have to be aware of the potentially higher rate of DISR in patients receiving adjuvant ICI. A thorough interdisciplinary workup is required to discriminate from true melanoma progression and to decide on continuation of adjuvant ICI treatment.