supplemental figure 2 from Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab
Jeffrey S. WeberGeoffrey T. GibneyRagini R. KudchadkarBin YuPingyan ChengAlberto J. MartinezJodie KroegerAllison L. RichardsLori McCormickValerie E. MobergHeather CroninXiuhua ZhaoMichael J. SchellY. Ann Chen
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<p>Suppression of T-cell proliferation by MDSC</p>TPS9603 Background: Interrogation of the tumor microenvironment (TME) is crucial to provide insight into biological activity, resistance mechanisms and implementation of rational combination immunotherapies. Semaphorin 4D (SEMA4D, CD100) has broad immunomodulatory effects in the TME. In preclinical models, blockade of SEMA4D promoted immune infiltration and reduced recruitment of immunosuppressive myeloid cells. Preclinical combinations of anti-SEMA4D with immune checkpoint inhibitors (ICIs) enhanced T cell activity and tumor regression. VX15/2503 (pepinemab), an IgG4 humanized monoclonal antibody targeting SEMA4D, is being evaluated in an integrated biomarker trial to characterize immunomodulatory effects in melanoma (NCT03769155). Methods: Patients with biopsy-proven stage IIIB, C, and D melanoma are eligible. Prior to curative-intent surgery, patients receive pepinemab alone or in combination with nivolumab and/or ipilimumab every three weeks for two doses. A control cohort proceed directly to surgery. Resection specimens will be collected for comparison across treatment groups and with a pre-treatment biopsy. Blood will be collected for PK, PD, and correlative biomarker assessments. The primary objective is to evaluate effects on the immune profile in TME and peripheral blood. Additional objectives include safety of pepinemab (alone and in combination with ICI), and pathologic and radiographic responses. Multiplex flow cytometry panels were created to phenotype cells in the TME and periphery. A multiplex IHC assay utilizing a sequential probe and strip procedure has been qualified that allows co-localization, orientation, and quantification of multiple immune markers. Analysis of immune subsets include cytotoxic T cells, neutrophils, Tregs, DCs, monocytes, macrophages, and myeloid-derived suppressor cells. Target engagement and expression of SEMA4D and its receptors will be evaluated. As of 01 Feb 2019, 8 of 36 patients have been enrolled. This trial will provide the first biomarker-driven clinical assessment of anti-SEMA4D antibody activity to reprogram the TME. Clinical trial information: NCT03769155.
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e21513 Background: Combined ipilimumab (IPI) and nivolumab (NIVO) is the most advanced immune therapy for metastatic melanoma patients. However, high response rates can be achieved at the price of important immune-related toxicity. Hence, patient selection is paramount. To date, no biomarker can predict the benefit or lack of it, from IPI/NIVO. Hypothesis A pretreatment serum protein marker signature could predict the long-term benefit from combined ipilimumab and nivolumab therapy. Methods: We performed a retrospective analysis of 440 proteins in the serum of 89 patients. All patients were treatment naive with advanced metastatic melanoma, treated with ipilimumab and nivolumab in the BMS Checkmate 069 study (NCT01927419). The median follow-up of patients was long, at 36 months, providing a rational basis to identify factors of long-term progression-free and overall survival. Serum proteins were analyzed using a Raybiotechnology protein array. Results: We built decision tree classifiers that maximize the difference between Kaplan-Meier survival curves, using the exponential scaling method. The output classes of the trees were subsequently grouped into two categories to predict benefit vs. no benefit. We deliberately limited the complexity of the predictors to the minimum, to avoid overfitting and to create robust predictors. We could define a three-protein signature that can discriminate benefit. At 36 months, 90% of the biomarker-positive population did not progress, whereas only 25% of biomarker-negative population was without progression (p < 0.0001). Using the leave-one-out validation, we found that the rate of false positives is remarkably low (8% for PFS and 14% for OS). The same predictors are non-discriminate in the IPI monotherapy arm of the same study. We also compared protein biomarker data to clinicopathological parameters, notably to the neutrophil/lymphocyte ratio (NLR) and LDH levels and our protein signature outperformed these markers. Conclusions: It is possible to develop a simple, three protein classifier from serum to predict long term benefit from IPI/NIVO therapy. More samples will be required to validate these findings.
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We report a case of sarcoidosis in a patient with metastatic melanoma managed with combination ipilimumab/nivolumab. Sarcoid development has been linked with single agent immunotherapy but, to our knowledge, it has not been reported with combination ipilimumab/nivolumab treatment. This case raises unique management challenges for both the melanoma and the immunotherapy-related toxicity.A 46 year old Caucasian female with M1c-metastatic melanoma was managed with ipilimumab/nivolumab combination. Patient experienced response in baseline lesions but developed new clinical and radiographic findings. Biopsy of new lesions at two different sites both demonstrated tumefactive sarcoidosis. Staining of the biopsy tissue for PD-L1 expression demonstrated strong PD-L1 staining of the histiocytes and lymphocytes within the granulomas. Monotherapy nivolumab was continued without progression of sarcoid findings or clinical deterioration.Tissue biopsy for evaluation of new lesions on immunotherapy is an important step to help guide decision making, as non-melanoma lesions can mimic disease progression.
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Since 2011, several effective drugs for patients with metastatic melanoma, including the BRAF inhibitors, the MEK inhibitors and the immune checkpoint inhibitors, have been ap- proved. Ipilimumab, nivolumab and the combination have shown response rates of 10-20%, 20-40% and up to 60% and a median progression-free survival of 2, 7 and 12 months, respec- tively. The management of immune related toxicities is keypoint for adequate use of these agents.
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Abstract: Historically, the median overall survival of metastatic melanoma patients was less than 1 year and long-term survivors were rare. Recent advances in therapies have dramatically shifted this landscape with increased survival rates and the real possibility that long-term disease control is achievable. Advances in immune modulators, including cytotoxic T-lymphocyte antigen-4 and programmed death-1 based treatments, have been an integral part of this success. In this article, we review previous and recent therapeutic developments for metastatic melanoma patients. We discuss advances in immunotherapy while focusing on the use of nivolumab alone and in combination with other agents, including ipilimumab in advanced melanoma. One major goal in melanoma research is to optimize combination strategies allowing for more patients to experience benefit while minimizing toxicity. A better understanding of the optimal sequencing, combinations, and mechanisms underlying the development of resistance may provide evidence for rational clinical trial designs of novel immunotherapy strategies in melanoma and other cancer subtypes. Keywords: PD-1, immunotherapy, pembrolizumab, PD-L1, resistance, checkpoint, BRAF
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An updated survival analysis by Callahan et al. published in the February 1, 2018 issue of the Journal of Clinical Oncology reported a 3-year overall survival (OS) rate of 63% for 94 patients with previously treated or untreated advanced melanoma who received ipilimumab and nivolumab as concurrent therapy in a phase 1 dose escalation study CA209–004 (n = 53) or in an expansion cohort with the dose and schedule of concurrent ipilimumab and nivolumab now approved for patients with unresectable or metastatic melanoma (n = 41). While this 3-year OS rate of 63% in patients with measurable, unresectable stage III or IV melanoma is an impressive accomplishment that compares very favorably with historical metastatic melanoma survival rates, findings from larger phase 3 studies are needed to determine whether combination immunotherapy significantly improves survival more than single agent immunotherapy with PD-1 blockade. This Commentary discusses the transition from the dark ages to the age of enlightenment in melanoma immunotherapy and provides a roadmap for a better tomorrow for patients with metastatic melanoma.
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Abstract: In the last years there has been great progress in the treatment of advanced melanoma patients. This explosion of melanoma research has not declined, but rather has continued exponentially growing. In this review, the Spanish Group of Melanoma (GEM) compiles the highlights of melanoma treatment communicated or published between ASCO 2016 and AACR 2017. In this period, definitive data have been published about the possibility of achieving a long term survival with the use of single anti-PD-1 antibodies, as well as data on the description of clinical subgroups of patients that can also obtain a long term survival with the use of targeted drugs combining the oral BRAF and MEK inhibitors. The first immunotherapy combination including nivolumab, an anti-PD-1 antibody, plus ipilimumab, an anti-CTLA-4 antibody, has been approved, based on its demonstrated benefit in terms of overall survival versus ipilimumab alone.
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Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases.
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<p>Kaplan-Meier curves for overall survival. (A) PD-1 monotherapy by driver class. (B) nivolumab plus ipilimumab by driver class. (C) PD-1 monotherapy by primary site of melanoma. (D) nivolumab plus ipilimumab by primary site of melanoma.</p>
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