Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746. FINDINGS: Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred. INTERPRETATION: Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. FUNDING: Bristol-Myers Squibb.

Immunologic correlates of the abscopal effect in a patient with melanoma.

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.).

Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses.

Dendritic cell (DC) maturation and function are influenced by the surrounding cytokine milieu. We demonstrate tumor-associated suppression of DCs in stimulating allogeneic and tumor-specific CTL and type 1 (IFN-gamma-producing) responses in both CD4- and CD8-positive T cells. DCs from MB49-bearing female mice fail to stimulate proliferative and IFN-gamma-producing responses in allogeneic mixed lymphocyte cultures. MB49 also inhibited DC function in stimulating type 1 responses against our tumor-specific antigen, the male antigen, HY. DCs from MB49-bearing male mice were unable to restimulate effective HY-specific CTLs or IFN-gamma. Tumor-induced interleukin (IL) 10 was found to be specifically responsible for DC dysfunction in response to antigenic driven maturation. This was demonstrated by restoration of DC function in splenic DCs from MB49-bearing female IL-10 knockout mice (HY disparity), whereas not in MB49-bearing male IL-10 knockout mice (no HY disparity). Finally, any tumor-induced systemic inhibitory effect on bone marrow precursors could be overcome by generation of bone marrow-derived DCs ex vivo. These bone marrow-derived DCs derived from MB49-bearing B6 mice were capable of inducing control levels of proliferation in allogeneic mixed lymphocyte reactions and a type 1 (IFN-gamma) cytokine profile. The BM-DCs were also capable of restimulating HY-specific CTL and IFN-gamma production. These studies reveal the tumor-associated in vivo effects of IL-10 inhibition on DC function in eliciting a type 1 immune response in both allogeneic and tumor-specific responses.

Intratumoral vaccination with vaccinia-expressed tumor antigen and granulocyte macrophage colony-stimulating factor overcomes immunological ignorance to tumor antigen.

Using a murine transitional cell carcinoma tumor model, MB49, which naturally expresses the male antigen HY, we evaluated whether tumor ignorance as determined by lack of a systemic immune response could be overcome by immunization with vaccinia expressed tumor antigen and granulocyte macrophage colony-stimulating factor. Systemic tumor ignorance of MB49 was demonstrated by the lack of a splenic HY-specific CTL response in MB49-bearing female mice. In contrast, we demonstrated HY-specific CTL priming in the draining lymph nodes. MB49-bearing female B6 mice were immunized with VVHY+VVGMCSF intratumorally or in the contralateral flank. Intratumoral VVHY, VVGMCSF, and keyhole limpet hemocyanin (to produce CD4 help) generated splenic HY-specific CD8 CTLs, whereas immunization with the combination in the contralateral flank or single agents given intratumorally failed to yield a splenic response. Purified male T cells injected intratumorally, as a source of HY antigen, also generated a HY-specific response, whereas contralateral immunizations did not. These finding expand the understanding of tumor immunological ignorance and support intratumoral vaccination as a strategy for immunotherapy of established tumors.

Immune regulatory antibodies: are they the next advance?

During the past decade, new insights into the mechanisms by which T-cell activation and proliferation are regulated have led to the identification of checkpoint proteins that either up- or down-modulate T-cell reactivity. In the presence of active malignancy, pathophysiologic inhibition of T-cell activity may predominate over stimulation. A number of antibodies have been generated that can block inhibitory checkpoint proteins or promote the activity of activating molecules. In murine models, their use alone or with a vaccine strategy has resulted in regression of poorly immunogenic tumors and cures of established tumors. The prototypical immune regulatory antibodies are those directed against cytotoxic T-lymphocyte antigen-4, a molecule present on activated T cells. In this review, the preclinical rationale and clinical experience with 2 anticytotoxic T-lymphocyte antigen-4 antibodies are extensively discussed, demonstrating that abrogation of an immune inhibitory molecule can result in significant regression of tumors and long-lasting responses. The unique kinetics of antitumor response and the characteristic immune-related side effects of ipilimumab are also discussed. This clinical efficacy of this promising antitumor agent has been evaluated in 2 randomized phase III trials, whose results are eagerly awaited. Programmed death (PD)-1 is another immune inhibitory molecule against which an abrogating human antibody has been prepared. Initial preclinical testing with anti-PD-1 and anti-PD-L1 has shown encouraging results. Stimulatory molecules such as CD40, 41-BB, and OX-40 are also targets for antibody binding and activation, not blockade, and early dose ranging trials with antibodies against all 3 have shown that they can mediate regression of tumors, albeit with their own spectrum of side effects that are different from those that occur with abrogation of immune inhibition.

The history and future of chemotherapy for melanoma.

Melanoma is considered a chemotherapy-resistant cancer, but in reality there are several chemotherapy drugs with significant single-agent activity. Response rates to combination regimens are reproducibly higher than with standard dacarbazine, but of the randomized trials comparing combination regimens with dacarbazine, none were of sufficient size to detect a realistic effect on survival. Similarly, adjuvant chemotherapy has not had a realistic test in melanoma. Response to chemotherapy is associated reproducibly with better survival rates suggesting that regimens with higher response rates are needed. Recent observations suggest that combining antiangiogenic agents with either dacarbazine or temozolomide can double response rates. These combinations are worthy of further investigation and might serve as a foundation on which to build a combination regimen that improves overall survival in metastatic melanoma patients.