Background The results of phase 1 and phase 2 studies suggest that nivolumab (a PD-1 checkpoint inhibitor) and ipilimumab (a CTLA-4 checkpoint inhibitor) have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab combined with ipilimumab versus ipilimumab alone were evaluated in patients with metastatic melanoma. Methods We randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma, in 1:1:1 ratio, to nivolumab alone (3 mg per kilogram of body weight every 2 weeks), or to nivolumab (at a dose of 1 mg per kilogram) plus ipilimumab (at a dose of 3 mg per kilogram) every 3 weeks for 4 doses followed by nivolumab (3 mg per kilogram every 2 weeks), or to ipilimumab alone (3 mg per kilogram every 3 weeks for 4 doses). Progression-free and overall survival were co-primary end points. Patients continue to be followed for overall survival. Results Median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) for nivolumab plus ipilimumab as compared with 2.9 months (95% CI, 2.8 to 3.4) for ipilimumab alone (hazard ratio, 0.42; 95% CI, 0.31 to 0.57; P<0.00001), and was 6.9 months (95% CI, 4.3 to 9.5) for nivolumab alone (hazard ratio in the comparison with ipilimumab alone, 0.57; 95% CI, 0.43 to 0.76; P<0.00001). In PD-L1-positive patients, median progression-free survival was 14.0 months in both the nivolumab plus ipilimumab and nivolumab alone groups, but in PD-L1-negative patients, progression-free survival was longer with the combination as compared with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] versus 5.3 months [95% CI, 2.8 to 7.1]). Grade 3–4 drug-related adverse events occurred in 16.3%, 55.0%, and 27.3% of patients in the nivolumab, nivolumab plus ipilimumab, and ipilimumab alone groups, with 1, 0, and 1 drug-related deaths, respectively. Conclusions Nivolumab alone or combined with ipilimumab significantly improved progression-free survival, as compared with ipilimumab, among previously untreated patients with metastatic melanoma. Results with the combination versus either agent alone suggest complementary activity between PD-1 and CTLA-4 blockade, particularly for patients with PD-L1-negative tumors. (Funded by Bristol-Myers Squibb; CheckMate 067, ClinicalTrials.gov number, NCT01844505.)
Tumor-derived exosomes are emerging mediators of tumorigenesis with tissue-specific addresses and messages. We explored the function of melanoma-derived exosomes in the formation of primary tumor and metastases in mouse and human subjects. Exosomes from highly metastatic melanoma increased the metastatic behavior of primary tumors by permanently “educating” bone marrow (BM) progenitors via the MET receptor. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites, and reprogrammed BM progenitors towards a c-Kit+Tie2+Met+ pro-vasculogenic phenotype. Reducing Met expression in exosomes diminished the pro-metastatic behavior of BM cells. Importantly, MET expression was elevated in circulating CD45−C-KITlow/+TIE2+ BM progenitors from metastatic melanoma subjects. RAB1a, RAB5b, RAB7, and RAB27a were highly expressed in melanoma cells and Rab27a RNA interference decreased exosome production, preventing BM education, tumor growth and metastasis. Finally, we identified an exosome-specific “melanoma signature” with prognostic and therapeutic potential, comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein.
Background In patients with melanoma, ipilimumab (anti-CTLA-4) prolongs overall survival and nivolumab (anti-PD-1) produced durable tumor regressions in a phase 1 trial. Based on their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in advanced melanoma patients. Methods Patients received nivolumab and ipilimumab every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). Combined treatment was subsequently continued every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks. Results Fifty-three patients received concurrent nivolumab/ipilimumab and 33 received sequenced treatment. The objective response rate, for all concurrent-regimen patients was 40% (modified WHO criteria). Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease ≥24 weeks) was observed in 65% of patients. At the maximum tolerated dose (1 mg/kg nivolumab + 3 mg/kg ipilimumab), 53% of patients achieved an objective response, all with ≥80% tumor reduction. Grade 3–4 related adverse events occurred in 53% of concurrent-regimen patients, but were qualitatively similar to historical monotherapy experience and were generally reversible. Among sequenced-regimen patients, 18% had grade 3–4 related adverse events and the objective response rate was 20%. Conclusions Concurrent nivolumab/ipilimumab had a manageable safety profile and achieved clinical activity that is distinct from published monotherapy data, with rapid and deep tumor regressions in a substantial number of patients.
BACKGROUND Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. METHODS We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)
Immunologic checkpoint blockade with antibodies that target cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) have demonstrated promise in a variety of malignancies. Ipilimumab (CTLA-4) and pembrolizumab (PD-1) are approved by the US Food and Drug Administration for the treatment of advanced melanoma, and additional regulatory approvals are expected across the oncologic spectrum for a variety of other agents that target these pathways. Treatment with both CTLA-4 and PD-1/PD-L1 blockade is associated with a unique pattern of adverse events called immune-related adverse events, and occasionally, unusual kinetics of tumor response are seen. Combination approaches involving CTLA-4 and PD-1/PD-L1 blockade are being investigated to determine whether they enhance the efficacy of either approach alone. Principles learned during the development of CTLA-4 and PD-1/PD-L1 approaches will likely be used as new immunologic checkpoint blocking antibodies begin clinical investigation.
Executive Summary PURPOSE With prospective clinical sequencing of tumors emerging as a mainstay in cancer care, there is an urgent need for a clinical support tool that distills the clinical implications associated with specific mutation events into a standardized and easily interpretable format. To this end, we developed OncoKB, an expert-guided precision oncology knowledge base. METHODS OncoKB annotates the biological and oncogenic effect and the prognostic and predictive significance of somatic molecular alterations. Potential treatment implications are stratified by the level of evidence that a specific molecular alteration is predictive of drug response based on US Food and Drug Administration (FDA) labeling, National Comprehensive Cancer Network (NCCN) guidelines, disease-focused expert group recommendations and the scientific literature. RESULTS To date, over 3000 unique mutations, fusions, and copy number alterations in 418 cancer-associated genes have been annotated. To test the utility of OncoKB, we annotated all genomic events in 5983 primary tumor samples in 19 cancer types. Forty-one percent of samples harbored at least one potentially actionable alteration, of which 7.5% were predictive of clinical benefit from a standard treatment. OncoKB annotations are available through a public web resource (http://oncokb.org/) and are also incorporated into the cBioPortal for Cancer Genomics to facilitate the interpretation of genomic alterations by physicians and researchers. CONCLUSION OncoKB, a comprehensive and curated precision oncology knowledge base, offers oncologists detailed, evidence-based information about individual somatic mutations and structural alterations present in patient tumors with the goal of supporting optimal treatment decisions.
Summary The abscopal effect is a phenomenon in which local radiotherapy is associated with the regression of metastatic cancer at a distance from the irradiated site. The abscopal effect may be mediated by activation of the immune system. Ipilimumab is a monoclonal antibody that inhibits an immunologic checkpoint on T cells, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). We report a case of the abscopal effect in a patient with melanoma treated with ipilimumab and radiotherapy. Temporal associations were noted: tumor shrinkage with antibody responses to the cancer–testis antigen NY-ESO-1, changes in peripheral-blood immune cells, and increases in antibody responses to other antigens after radiotherapy. (Funded by the National Institutes of Health and others.)
Pneumonitis is an uncommon but potentially fatal toxicity of anti-programmed death-1 (PD-1)/ programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. MethodsPatients who received anti-PD-1/PD-L1 monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 mAb were identified at two institutions (Memorial Sloan Kettering Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. ConclusionPneumonitis associated with anti-PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti-PD-1/PD-L1 mAbs are combined with anti-cytotoxic T-cell lymphocyte-4 mAb. Most events are low grade and improve/ resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.
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