Immunotherapies and novel combinations: the focus of advances in the treatment of melanoma

Abstract

Since 2011, the approval of four different classes of novel drugs (the anti-CTLA-4 agent, ipilimumab; BRAF inhibitors [BRAFi]; MEK inhibitors [MEKi]; and the anti-PD-1 drug, pembrolizumab) has revolutionized the care of advanced melanoma, with the disease becoming a model for the development of new treatments for other types of cancer. Further advances in the treatment of melanoma represented some of the key highlights of the European Society of Medical Oncology (ESMO) 2014 congress. The first phase III trial of an anti-PD-1 agent to report the CA209-037 study included 405 patients with metastatic melanoma previously treated with ipilimumab who were randomized 2:1 to receive nivolumab 3 mg/kg every 2 weeks or investigator’s choice chemotherapy. Nivolumab was associated with a higher response rate than chemotherapy and was well tolerated, with adverse events mostly low grade and manageable using recommended treatment algorithms. New data on other immunotherapies, namely ipilimumab and pembrolizumab, were also reported. In addition, outside of immunotherapy, combination approaches involving targeted agents were also a major focus of ESMO this year, with two major phase III studies of combined BRAF inhibition and MEK inhibition being reported. Overall, new clinical trial findings reported at ESMO further endorse the view that melanoma, given the continued development of novel, effective compounds, can accurately be described as the most “dynamic” field of oncology at present.

Since 2011, the approval of four different classes of novel drugs (the anti-CTLA-4 agent, ipilimumab; BRAF inhibitors [BRAFi]; MEK inhibitors [MEKi]; and the anti-PD-1 drug, pembrolizumab) have revolutionized the care of advanced melanoma, with the disease becoming a model for the development of new treatments for other types of cancer. Further advances in the treatment of melanoma represented some of the key highlights of the European Society of Medical Oncology (ESMO) 2014 congress, recently held in Madrid, Spain (26–30 September). For the first time in the history of the ESMO annual meeting, the results of three pivotal phase III studies in advanced melanoma were reported in a presidential symposium: the CA209-037 study of the anti-PD-1 agent nivolumab versus investigator’s choice of chemotherapy in patients who had failed ipilimumab treatment, the COMBI-v study of the BRAFi dabrafenib plus the MEKi trametinib versus vemurafenib (a BRAFi), and the CoBRIM study of vemurafenib plus cobimetinib (a MEKi) versus vemurafenib in BRAF-mutated patients. The findings from these studies are likely to have a significant impact on how patients with advanced melanoma are treated.

A highlight of ESMO was the presentation of the first phase III trial of an anti-PD-1 agent. The CA209-037 study included 405 patients with metastatic melanoma previously treated with ipilimumab who were randomized 2:1 to receive nivolumab 3 mg/kg every 2 weeks (n = 268) or investigator’s choice chemotherapy (dacarbazine or carboplatin plus paclitaxel; n = 102) until progression or unacceptable toxicity. The co-primary end points were overall response rate (ORR) and overall survival (OS), although only ORR data were available at the time of this preliminary analysis. Median time on therapy was 5.3 months in the nivolumab arm and 2 months in the chemotherapy arm, with disease progression the most common reason for discontinuation in both the nivolumab and chemotherapy arms (43 and 61 %, respectively). In the nivolumab arm, the central review assessed response was 32 % [95 % confidence interval (CI) 24–41] for the nivolumab arm compared to 11 % (95 % CI 4–23) with chemotherapy [1]. Median duration of response was not yet reached. Treatment-related adverse events (AEs) of grade 3–4 severity were reported for 9 % of patients in the nivolumab arm and 31 % in the chemotherapy arm. The majority of nivolumab-related AEs were low grade and manageable using recommended treatment algorithms.

Of interest, the study evaluated response according to the RECIST 1.1 criteria (nine weeks after randomization, followed by assessments every six weeks for the first 12 months and then assessments every 12 weeks). However, 8 % of patients experienced progression using these criteria (progression in nontarget lesions, clinical progression, or occurrence of new lesions), but subsequently had a >30 % reduction in target lesions. This demonstrates that the unconventional immune-related response, described for the first time with ipilimumab therapy [2], can also occur with nivolumab treatment. As such, in addition to the classic RECIST criteria, the use of immune-related response criteria should also be considered when evaluating response with nivolumab therapy.

Moreover, the response to nivolumab was similar and higher than with chemotherapy in BRAF-mutated (23 vs. 9 %) and BRAF wild-type (34 vs. 11 %) patients, suggesting that nivolumab, such as ipilimumab, is effective regardless of BRAF mutational status. Also of note is that the response rate for nivolumab was similar in patients regardless of whether they had previously benefited from ipilimumab treatment or not (ORR 30 and 33 %, respectively). This finding is surprising because patients who had responded to ipilimumab might have also been expected to benefit from nivolumab treatment; this was the reason for the stratification of patients according to prior anti-CTLA-4 benefit. Finally, in the PD-L1-positive and PD-L1-negative subgroups, response rates were 44 and 20 %, respectively. Despite the higher response rate in the PD-L1-positive group, the 20 % response in patients who were PD-L1 negative clearly indicates that PD-L1 status cannot be considered a predictive marker to be used for patient selection.

In addition to this pivotal phase III study, updated data from a phase I trial of nivolumab in ipilimumab-naïve patients with metastatic melanoma confirmed findings presented at ASCO this year, with an ORR of 32 % observed for all treated patients and an ORR of 40 % for the cohort of patients treated with the 3 mg/kg dosage selected for phase III studies [3]. One-, two-, and three-year OS rates with nivolumab were 63, 48, and 41 %, respectively.

New data on other immunotherapies in the management of melanoma were also presented. An update on a phase IB study with pembrolizumab included an additional cohort of 244 patients (both ipilimumab-naïve and those previously treated with ipilimumab) who were randomized to one of two dosing schedules (10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks) [4]. Overall, no differences were reported between schedules in terms of ORR, PFS, or OS or between ipilimumab-naïve and pretreated patients. These results, together with the previous evidence reported at ASCO of this year [5], support the choice of the 2 mg/kg every three-week schedule for pembrolizumab that was approved by the FDA in the USA.

Other studies provided confirmatory evidence of previous observations. In the EORTC 18071 trial, 951 patients were randomized to adjuvant therapy with ipilimumab or placebo after complete resection of stage III melanoma [6]. The study met its primary end point of relapse-free survival (RFS), with a RFS of 26.1 months for the ipilimumab arm versus 17.1 months in the placebo arm [hazard ratio (HR) 0.75; 95 % CI 0.64–0.90; p = 0.0013]. Forty-two percent of patients treated with ipilimumab experienced grade 3–4 AEs. However, despite this high occurrence, no overall impact on health-related quality of life was observed during ipilimumab treatment and AEs were treated according to well-recognized guidelines/algorithms for the management of immune-related events.

Combination approaches are likely to be increasingly important in melanoma. In immunotherapy, a phase I trial of the combination of ipilimumab plus nivolumab (CA209-004) confirmed the results reported at ASCO earlier this year [7]. Patients receiving concurrent ipilimumab plus nivolumab achieved an ORR of 40 % with 17 % being complete responses (CR). In the sequential cohort (nivolumab after ipilimumab), the ORR was 44 with 6 % of patients having a CR. The one- and two-year OS rates for all patients were 85 and 79 %, respectively, while in patients with the dose selected for the phase III study, the one- and two-year OS rates were 94 and 88 %. However, this exceptional efficacy was accompanied by a high occurrence of grade 3–4 AEs (64 % of patients). Having said this, there were no new safety signals and immune-related AEs could be managed by following guidelines.

The study also included subgroup analyses of response rate according to BRAF and PD-L1 status. Concurrent ipilimumab plus nivolumab showed a good response rate in both BRAF-mutated (20 %) and BRAF wild-type (50 %) patients, while in the sequential cohort response rate was 33 % in both groups. There was no significant difference in response rate in the concurrent group by PD-L1 status (PD-L1 positive, 57 %; PD-L1 negative, 41 %). In the sequential group, response rates were 63 % in the PD-L1-positive cohort and 20 % in the PD-L1-negative group. An interesting finding in the sequenced cohort was the correlation between residual plasma ipilimumab levels and response to subsequent nivolumab. Patients with plasma ipilimumab levels above the median value (obtained from all patients enrolled in this study) had a higher response rate to nivolumab treatment (57.1 %) than those with levels below the median (14.3 %). These data could be interpreted in favor of the combination, since higher ipilimumab residual levels result in a better response to subsequent nivolumab.

Outside of immunotherapy, combination approaches involving targeted agents were also a major focus of ESMO this year. The combination of a BRAFi with a MEKi represents a very promising strategy for patients with mutated BRAF V600 melanoma. In the USA, the FDA has approved this combination on the basis of a phase I–II study of combined treatment with dabrafenib and trametinib. Progression-free survival (PFS) with this combination was 9.4 months compared with 5.8 months with dabrafenib monotherapy [8]. Another phase III trial, the COMBI-d study of dabrafenib plus trametinib versus dabrafenib alone, was also recently reported [9]. This study met its primary end point with a median PFS of 9.3 months in the combination group and 8.8 months in the dabrafenib only group (HR for progression or death in the combination group: 0.75; 95 % CI 0.57–0.99; p = 0.03). Despite the combination arm being favoured, the good results observed in the dabrafenib monotherapy arm somewhat reduced enthusiasm for the BRAFi plus MEKi combination. The positive response to dabrafenib alone could be largely explained through the enrollment of a high percentage (about 70 %) of patients with normal lactate dehydrogenase (LDH) levels in the trial, who are known to have an increased benefit from BRAFi therapy.

The findings of the COMBI-d study meant the results of the COMBI-v study presented at ESMO were eagerly anticipated. In this study, 704 patients with advanced BRAF V600E/K mutation-positive melanoma were randomized to first-line therapy with a combination of dabrafenib plus trametinib or vemurafenib monotherapy [10]. In a preplanned interim analysis after a median follow-up of 11 months, the primary end point of median OS was not reached in the dabrafenib plus trametinib arm, but was 17.2 months with vemurafenib alone (HR 0.69; 95 % CI 0.59–0.89, p = 0.002). The Independent Data Monitoring Committee recommended stopping the study based on this analysis, since the OS benefit with the combination met the prespecified boundary. In addition, median PFS (investigator-assessed) was 11.4 months with the combination versus 7.5 months with vemurafenib (HR 0.56; 95 % CI 0.46–0.69; p < 0.001) and the ORRs were 64 and 51 %, respectively.

Another combination study, the CoBRIM trial, was presented during the same symposium. In this study, 495 previously untreated BRAFV600 mutation-positive patients with unresectable locally advanced or metastatic melanoma were randomized to receive vemurafenib plus cobimetinib or vemurafenib alone. Patients in the combination arm showed a significantly improved investigator-assessed median PFS of 9.9 versus 6.2 months with monotherapy (HR 0.51; 95 % CI 0.39–0.68; p < 0.001). PFS assessed by independent review was comparable with investigator-assessed PFS (11.3 months with the combination and 60 months with vemurafenib; HR 0.60; 95 % CI 0.45–0.79; p < 0.001). ORR was 68 % in the vemurafenib plus cobimetinib arm and 45 % with vemurafenib alone. OS data are not yet mature. However, at a median follow-up of 7.3 months (range 0.5–16.5 months), the observed HR for death was 0.65 (95 % CI 0.42–1.00, p = 0.046). Full publication of this study occurred in parallel with the ESMO congress [11].

The impact of these two studies of combined BRAFi and MEKi therapy may be to change the standard of treatment for melanoma patients with the BRAF V600 mutation. Efficacy of the two combinations, with regard to ORR, PFS, and OS, was very similar. However, safety profiles differed with a higher occurrence of pyrexia (53 %), nausea (35 %), vomiting (29 %), and hypertension (26 %) with the dabrafenib plus trametinib combination, and more diarrhea (56 %), fatigue (32 %), photosensitivity (28 %), and liver toxicity (16 %) with the vemurafenib plus cobimetinib combination. These differences in safety profiles confirm those already observed between dabrafenib and vemurafenib as monotherapies.

Overall, these important new clinical trial findings reported at ESMO further endorse the view that melanoma, given the continued development of novel, effective compounds, can accurately be described as the most “dynamic” field of oncology at present. With the advent of the “fantastic four” of ipilimumab, BRAFi, MEKi, and anti-PD-1, the face of melanoma management has been fundamentally changed. The various combinations of these compounds being assessed represent the next stage of evidence. While we await the results of the phase III study of ipilimumab plus nivolumab combined therapy, the positive data on anti-PD-1 therapy together with combination strategies reported at ESMO are a current reality and offer another new opportunity for our patients.

List of abbreviations

AE

Adverse events

ASCO

American Society of Clinical Oncology

CI

Confidence interval

CTLA-4

Cytotoxic T-lymphocyte-associated protein 4

CR

Complete response

ESMO

European Society of Medical Oncology

FDA

Food and drug administration

HR

Hazard ratio

ORR

Overall response rate

OS

Overall survival

PD-1

Programmed cell death protein 1

PFS

Progression-free survival

RECIST

Response evaluation criteria in solid tumors

RFS

Relapse-free survival