Doubling the blockade for melanoma immunotherapy

Keywords:

• CTLA4
• ipilimumab
• metastatic melanoma
• nivolumab
• PD-1
• pembrolizumab

A few days ago, the US Food and Drug Administration (FDA) has granted accelerated approval to nivolumab (Opdivo®) in combination with ipilimumab (Yervoy®) for the treatment of individuals affected by unresectable or metastatic melanoma with wild-type BRAF^V600. This is the first time in history that a combinatorial immunotherapeutic regimen based on two distinct checkpoint blockers receives regulatory approval. Although not all patients respond to ipilimumab plus nivolumab and side effects are not negligible, our therapeutic armamentarium against melanoma now has a new weapon.

One of the most exciting clinical discoveries of the past few years was that ipilimumab (Yervoy®, from Bristol-Myers Squibb), a monoclonal antibody (mAb) that inhibits cytotoxic T lymphocyte-associated protein 4 (CTLA4), confers a significant survival advantage to (a relatively limited subset) of advanced melanoma patients.^1-3 These observations supported the approval of ipilimumab by the US FDA and other regulatory agencies for the treatment of unresectable or metastatic melanoma.² Subsequent studies demonstrated that CTLA4 was not the sole target for the development of clinically viable checkpoint blockers.⁴ Indeed, inhibiting programmed cell death 1 (PDCD1, best known as PD-1) or its main ligand CD274 (best known as PD-L1) also turned out to extend the survival of a proportion of subjects with advanced melanoma.^5-9 PD-1- and PD-L1-targeting regimens were generally associated with an increased overall response rate (ORR) and reduced side effects as compared to the blockage of CTLA4 with ipilimumab.^5-9 Moreover, melanoma patients relapsing on ipilimumab-based immunotherapy were found to be as likely as their ipilimumab-naive counterparts to respond to PD-1 blockers.^8,10,11 These clinical findings provided solid grounds in support of the recent approval by the US FDA of two distinct mAbs neutralizing PD-1: nivolumab (Opdivo®, from Bristol-Myers Squibb) and pembrolizumab (Keytruda®, from Merck), both of which were initially licensed for use in patients with unresectable melanoma who no longer respond to other drugs.^8,12 Recently, both nivolumab and pembrolizumab have also been licensed for use in non-small lung carcinoma (NSCLC) patients progressing on conventional treatments,^13,14 demonstrating that checkpoint blockers mediate clinical activity even against tumors that are considered poorly immunogenic.

Since the standalone blockade of CTLA4 was associated with a relatively low ORR (10–20%) and with severe side effects (mostly inflammatory and autoimmune reactions),^15-19 the regulatory approval of ipilimumab called for the identification of predictive biomarkers of efficacy.^20-22 An intensive wave of investigation in this sense unveiled that the likelihood of cancer patients to obtain a survival advantage by the blockade of a single immunological checkpoint is dictated by the mutational load of neoplastic lesions,^23-25 and by the existence of a T_H1-polarized CTLA4-suppressed pre-immunotherapy immune response.²⁶ Moreover, the commercialization of ipilimumab set off a large number of preclinical and clinical studies testing whether this CTLA4-targeting mAb could be conveniently combined with other immunotherapeutic interventions, including (but not limited to) (1) alternative checkpoint blockers;² (2) immunostimulatory mAbs;^2,27,28 (3) peptide-, DNA-, or dendritic cell (DC)-based cancer vaccines;^29-32 (4) adoptive cell therapy;^33,34 (5) recombinant cytokines and TLR agonists;^35-37 and (6) potentially immunogenic chemo- and radiotherapeutic regimens.^38-40 Although preclinical proof-of-principle has been obtained in support of the notion that ipilimumab can boost the activity of most (if not all) these forms of cancer immunotherapy,^41,42 clinical efforts obviously focused on the most promising strategies from a regulatory standpoint, i.e., the use of approved or nearly approved molecules.⁴³ Thus, ipilimumab has been tested in combination with various chemotherapeutics commonly employed in the clinic,⁴⁴ FDA-approved tumor-targeting mAbs,^45,46 and nivolumab (preferentially over pembrolizumab for industrial reasons).^47-49

Data from early Phase I and Phase II trials indicated that the combination of ipilimumab and nivolumab is associated with an improved progression-free survival (PFS) and ORR among advanced melanoma patients as compared to ipilimumab-based immunotherapy (61% vs. 11%), and exhibits an acceptable safety profile.^48-50 In a subsequent double-blind Phase 3 study, 945 previously untreated patients with unresectable Stage III or IV melanoma were randomly assigned (1:1:1) to receive ipilimumab alone, nivolumab alone or a combination of the two, until disease progression or unacceptable toxicity (NCT01844505).⁴⁷ Alongside, a double-blind Phase 2 study was initiated to test the clinical profile of ipilimumab plus nivolumab in 142 previously untreated subjects with metastatic melanoma, who were randomly assigned (2:1) to receive ipilimumab plus nivolumab or ipilimumab plus placebo (NCT01927419).⁴⁸ The results of these studies lent scientific ground to the recent decision of the FDA to grant accelerated approval to nivolumab (Opdivo®) in combination with ipilimumab (Yervoy®) for the treatment of individuals affected by unresectable or metastatic melanoma with wild-type BRAF^V600 (source http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm465274.htm, consulted on 2015, October 1st).

Melanoma patients in the ipilimumab plus nivolumab arm had an improved PFS (11.5 mo, 95% CI: 8.9–16.7) as compared to subjects treated with ipilimumab only (2.9 mo, 95% CI: 2.8–3.4) or nivolumab only (6.9 mo 95%, CI: 4.3–9.5).⁴⁷ Along similar line, in individuals affected by advanced melanoma with wild-type BRAF^V600, the combination of ipilimumab and nivolumab was associated with an improved ORR (61%) as compared to ipilimumab-based immunotherapy (19%).⁴⁸ In this patient subset, median PFS was not reached by patients receiving ipilimumab plus nivolumab, while it was 4.4 mo for subjects treated with ipilimumab only.⁴⁸ Both these studies report an incidence of Grade 3–4 (severe) treatment-related adverse effects of 55% among patients subjected to dual checkpoint blockade, as compared to 16–24% for patients receiving ipilimumab only, and 27.3% for individuals treated with nivolumab monotherapy.^47,48 Thus, although most of these side effects could be controlled by treatment discontinuation and/or immunosuppressive medications,⁴⁷ the increased efficacy of simultaneous CTLA4 and PD-1 blockade is accompanied by a non-negligible increase in toxicity.

The approval of ipilimumab plus nivolumab for use in previously untreated patients affected by advanced melanoma with wild-type BRAF^V600 marks another milestone in the history of tumor immunology, as it identifies a precise clinical indication for which checkpoint blockers can be employed as first-line treatment (which is not the case of ipilimumab, pembrolizumab and nivolumab employed as standalone interventions). It will be very interesting to see whether simultaneously blocking CTLA4- and PD-1-dependent immunosuppression also confers an additional survival advantage to NSCLC patients as compared to the blockade of PD-1 only. Also, it will be important to understand whether all these immunotherapeutic regimens can be successfully employed as adjuvant treatment of localized Stage II–III melanoma (which currently relies on recombinant interferon-α2b).⁵¹ So far, only ipilimumab has been evaluated as an adjuvant immunotherapeutic regimen for patients with Stage III melanoma at high risk of relapse, with promising results.¹⁹ Indeed, patients receiving ipilimumab-based immunotherapy had a recurrence-free survival (RFS) of 26.1 mo (95% CI: 19.3–39.3), while the RFS of individuals treated with placebo was 17.1 mo (95% CI: 13.4–21.6).¹⁹ Additional studies comparing the clinical profile of ipilimumab vs. high-dose interferon-α2b, ipilimumab vs. nivolumab, and pembrolizumab vs. placebo in this patient population are underway.⁵² The results of these clinical trials may further revolutionize the treatment of melanoma.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Funding

Authors are supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI).