Combinatorial immunotherapy with checkpoint blockers solves the problem of metastatic melanoma—An exclamation sign with a question mark

Abstract

Results from recent clinical trials demonstrate that a combinatorial immunotherapeutic regimen based on 2 distinct checkpoint blockers, namely, the CTLA4-targeting agent ipilimumab and the PD-1-specific molecule nivolumab, causes objective responses in a majority of subjects with advanced melanoma. These findings revolutionize the treatment of a neoplasm that was considered incurable until recently. Nonetheless, announcing the defeat of melanoma appears premature. Indeed, a sizeable fraction of patients does not respond to ipilimumab plus nivolumab, and the long-term efficacy of this immunotherapeutic regimen has not yet been investigated. Moreover, many patients experience severe side effects, calling for the development of strategies that uncouple the efficacy of ipilimumab plus nivolumab from their toxicity.

Keywords:

• CTLA4
• Opdivo™
• PD-1
• PD-L1
• pembrolizumab
• Yervoy™

At odds with many other cancers, melanoma has been treated with immunotherapy for a long time, with some success. Melanocytes are indeed particularly immunogenic and a low (but sizeable) proportion of melanoma patients respond to relatively unspecific immunostimulatory regimens such as the systemic administration of interleukin-2 (IL-2) and interferon-α2b (IFN-α2b).^1,2 This said, adjuvant IFN-α2b has been demonstrated to extend relapse-free but not overall survival, and IL-2-based immunotherapy is associated with considerable toxicities.^1,2 The first real breakthrough in the clinical management of melanoma with immunotherapy came from the discovery that ipilimumab (Yervoy™), a monoclonal antibody (mAb) that neutralizes cytotoxic T lymphocyte-associated protein 4 (CTLA4), significantly extends the survival of a proportion of patients with advanced metastatic melanoma.^3-5 However, blocking the CTLA4-dependent immunological checkpoint with ipilimumab causes severe side effects, including inflammatory and autoimmune reactions.^6-9

Subsequent clinical studies demonstrated that another checkpoint-blocking strategy, i.e., the systemic neutralization of programmed cell death 1 (PDCD1, best known as PD-1) or its main ligand (CD274, best known as PD-L1), is associated with a higher frequency of objective responses and reduced side effects as compared to ipilimumab-based immunotherapy.^10-14 It was also revealed that individuals with melanoma who failed to obtain clinical benefits from ipilimumab, or relapsed after an initial response to ipilimumab, are as likely as ipilimumab-naïve patients to respond to PD-1-neutralizing mAbs.^13,15,16 These findings suggested that a combinatorial strategy based on CTLA4 and PD-1 blockers could constitute a superior immunotherapeutic regimen against melanoma.¹⁷ Indeed, successive Phase I and II trials demonstrated that combining ipilimumab with the anti-PD-1 mAb nivolumab (Opdivo™) is associated with superior efficacy as compared to ipilimumab monotherapy (61% versus 11% objective response rate), and an acceptable safety profile.^18-21

Data from a Phase III trial testing this combinatorial immunotherapeutic paradigm in melanoma patients have just been released at the latest Annual Meeting of the American Society of Clinical Oncology (ASCO).²² In this study, 945 treatment-naïve patients with unresectable or metastatic melanoma were randomized 1:1:1 to receive either ipilimumab monotherapy, either nivolumab monotherapy, or a combinatorial regimen involving both mAbs until disease progression or unacceptable toxicity.²² Strikingly, objective response rates were 19.0% (95% CI = 14.9–23.8%) in the ipilimumab arm, 43.7% (95% CI = 38.1–49.3%) in the nivolumab arm, and 57.6% (95% CI = 52.0–63.2%) in the ipilimumab plus nivolumab arm. This demonstrates that simultaneously blocking the CTLA4 and PD-1 checkpoints is associated with superior clinical efficacy as compared to the inhibition of either checkpoint alone.²² However, 55.0% of the subjects receiving ipilimumab plus nivolumab experienced severe (Grade 3–4) side effects, which led to treatment discontinuation in 29.4% of the cases. Severe toxicities were less frequent in the ipilimumab (27.3%) and nivolumab (16.3%) arms, and rarely required treatment discontinuation (in 13.2% of ipilimumab-receiving patients and 5.1% of nivolumab-receiving patients).²² Thus, although the efficacy of this combinatorial immunotherapeutic regimen appears to be high, strategies must be conceived to uncouple it from toxicity.

Combinatorial immunotherapy marks a turning point in the history of advanced melanoma. For the first time, patients can hope to be cured, albeit with a significant risk for side effects. It will be crucial to identify biomarkers that predict therapeutic efficacy and/or toxicity, for improving patient stratification.^23-26 Moreover, it will be essential to develop strategies for the control of inflammatory/autoimmune side effects other than treatment discontinuation and the administration of glucocorticoids. Finally, it will be important to identify novel immuno(chemo)therapeutic regimens for the management of melanoma patients who do not benefit from dual CTLA4/PD-1 blockade.^27,28 These strategies may rely on BRAF inhibitors,^29,30 immunological adjuvants,³¹ other checkpoint blockers,³² adoptive cell transfer,^33,34 or anticancer vaccines.^35,36

Yet another issue that requires further investigation regards the possibility to harness immunotherapy to ameliorate the clinical management of early, localized melanomas. Will it be useful to combine the surgical resection of neoplastic lesions with an adjuvant immunotherapeutic regimen based on CTLA4 and PD-1 blockers? Moreover, can we envisage the local delivery of checkpoint-blocking mAbs (or other immunotherapeutic agents) as an alternative to systemic administration? These questions require urgent responses, for the benefit of patients and the health care system.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.