The Evolving Treatment Landscape in Advanced Melanoma

Jeffrey Sosman, MD

Metastatic melanoma is associated with a poor prognosis, but recent breakthroughs in tumor biology and immune regulation have led tothe development of agents that could change clinical practice, according to a panel of experts who participated in a recent OncLive PeerExchange.

And, while standard high-dose interferon for patients with advanced melanoma remains an option, a recent study from the 2014 ESMO Congress involving the PD-1 inhibitor nivolumab, as well as results from ongoing phase III studies of ipilimumab, may well mark a change in the treatment paradigm for this population.

The panelists cited two major developments in the treatment of melanoma. The first was the identification of BRAF mutations in the mitogen activated protein kinase (MAPK) pathway that has led to the development of therapies that inhibit their activity. “Clinical trials are under way that explore the use of BRAF inhibitors alone or in combination with MEK inhibitors for patients with BRAF-mutated, high-risk melanoma,” said Jeffrey A. Sosman, MD.

The second advancement is the development of immune checkpoint—blocking agents, including PD-1 and PD-L1 antibodies.

“From an immunotherapy point of view, PD-1 and PD-L1 antibodies have demonstrated 30% to 40% response rates for long durations,” said Jeffrey S. Weber, MD, PhD. For targeted therapies, the BRAF inhibitor, vemurafenib, was approved in 2011 as a treatment for BRAF-mutated metastatic melanoma. “The efficacy of the BRAF/MEK combination is somewhat questionable,” said Weber. “But in the long run, the combination will likely show superiority once more clinical trial data are available.”

Adjuvant Ipilimumab

The current explosion of novel therapies was initially sparked by the FDA’s approval of ipilimumab in 2011. But choosing an optimal adjuvant therapy for patients with high-risk melanoma remains a challenge for the clinician. “Given the level of efficacy seen in patients with metastatic disease, the next phase for these novel immunotherapy agents will be the adjuvant setting,” Weber said, “particularly as more data are compiled for adjuvant ipilimumab.”

Jeffery Weber, MD, PhD

In the EORTC 18701 study,1 treatment with adjuvant ipilimumab improved recurrence-free survival (RFS) compared with placebo for patients with stage III node-positive melanoma. At a median follow-up of 2.7 years, RFS rates were 46.5% with ipilimumab versus 34.8% with placebo. Patients experienced high rates of toxicity, including hypophysitis and colitis. The most common grade 3/4 immune-related adverse events for ipilimumab compared with placebo were gastrointestinal (15.9% vs 0.8%), hepatic (10.6% vs 0.2%), and endocrine (8.5% vs 0%). Approximately half of ipilimumab-treated patients discontinued treatment (52%) and 1.1% died as a result of treatment-related side effects.

The trial used a 10 mg/kg dose of ipilimumab, which is not approved in the United States, and the costs associated with this large of a dose in the adjuvant setting would be astronomical, Sosman added.

Mario Sznol, MD, panel moderator, pointed out that experience among community oncologists with ipilimumab varies greatly. He recommends that community oncologists who are unfamiliar with ipilimumab contact him prior to administration. “In addition to community oncologists and nurses, patients also need education on the side effects of ipilimumab,” added Sosman. Side effect management remains an important aspect of treatment with ipilimumab, especially as its role continues to expand as a treatment for patients with melanoma. Clinical trials have demonstrated that ipilimumab is an effective adjuvant therapy, placing it earlier in the treatment paradigm.

Omar Hamid, MD, said that “Toxicity management strategies and treatment algorithms for ipilimumab are better understood now than in 2011, when the drug was first approved. As a result, the utilization of this agent in the adjuvant setting is more likely.” With the emergence of new therapies, the next major question facing researchers will be the discovery of an optimal treatment sequence. “The question of whether to begin with a BRAF/MEK combination or a checkpoint inhibitor will be addressed by an upcoming ECOG study,” said Sosman. The study will compare trametinib plus dabrafenib followed by ipilimumab plus nivolumab to the reverse sequence in patients with advanced BRAF-mutated melanoma (NCT02224781).² “This study will hopefully provide more information on an optimal sequence,” he said.

Immunotherapy Combinations in Advanced Melanoma

For patients with metastatic melanoma who do not have an actionable mutation, there are limited treatment options. An option to consider is the administration of ipilimumab as a single agent, or administering chemotherapy until a response is achieved, and then switching to ipilimumab or interleukin-2. “The combination of nivolumab and ipilimumab could be utilized for patients with metastatic melanoma who do not have actionable mutations,” Hamid said.

In a phase I study examining the combination of ipilimumab and nivolumab, the 1- and 2-year overall survival (OS) rate was 85% and 79%, regardless of BRAF and PD-L1 status. However, the objective response rate was 40%, suggesting that a majority of patients do not respond. Patients with BRAF mutations who do not respond can receive a combination of a BRAF and a MEK inhibitor. “Unfortunately, those with BRAF wild-type tumors have even fewer options,” said Sznol.

Combination therapies have generated interest in inhibitor clinical trials, including the exploration of MEK and CDK4/6 inhibition in patients with NRAS-driven melanoma, and combinations of targeted therapies and checkpoint inhibitors. However, in initial studies, the combination of the BRAF inhibitor vemurafenib with ipilimumab was associated with high levels of toxicity, Weber said.

The various BRAF inhibitors demonstrate toxicity differences, especially when used in combination with ipilimumab. To explore these combinations further, a phase I study examined ipilimumab plus dabrafenib with or without trametinib. Dabrafenib plus ipilimumab was well tolerated, without the occurrence of new adverse events. However, the combination of dabrafenib, trametinib, and ipilimumab was associated with a higher rate of grade 3 colitis and perforation.³

Combination studies have shifted toward targeted therapies plus PD-1 and PD-L1 inhibitors. A phase I/ II study is currently looking at the combination of MEDI4736, an anti-PD-L1 antibody, in combination with dabrafenib and trametinib or trametinib alone in patients with advanced melanoma.⁴ Additionally, a phase IB study is exploring the anti-PD-L1 agent MPDL3280A in combination with vemurafenib.⁵ The emergence of BRAF mutations in melanomas has resulted in targeted therapies with high response rates, statistically significant progression-free survival (PFS), and OS benefits. These benefits are seen when the MAPK pathway is inhibited at either the BRAF level or downstream MEK.

Pembrolizumab and Nivolumab

On September 4, 2014, the FDA approved pembrolizumab (Keytruda) as a treatment for patients with advanced or unresectable melanoma following progression on prior therapies. This decision makes pembrolizumab the first PD-1 inhibitor to gain approval in the United States.

The accelerated approval was based on response rates demon¬strated in clinical trial data from 173 patients with melanoma in the KEYNOTE-001 study. At the recommended dose for pembrolizumab of 2 mg/kg, the overall response rate (ORR) was 24%, with a response duration lasting from 1.4 to 8.5 months.

The approval was based on a portion of patients enrolled in the phase IB KEYNOTE-001 study that examined pembrolizumab in 276 patients with ipilimumab-naïve (n = 102) and refractory (n = 173) melanoma. In the study, patients received treatment with pembrolizumab at 2 mg/kg or 10 mg/kg every 3 weeks. The primary endpoint was ORR, with second¬ary outcome measures focused on investigator-assessed immune-related response criteria.

The news about nivolumab is just as promising. A phase III trial of previously treated patients with advanced metastatic melanoma demonstrated that nivolumab (approved in Japan under the brand name Opdivo) demonstrated superior ORR and longer durations of response compared with chemotherapy. 6 These patients were previously treated with anti- CTLA-4 therapy (ipilimumab plus a BRAF inhibitor). In phase I trials of pretreated patients with metastatic melanoma, nivolumab induced tumor regression and showed promise in extending OS, with OS rates of 63%, 48%, and 41% at 1, 2, and 3 years, respectively.

In the data presented at the 2014 ESMO Congress,⁶ a total of 405 patients with advanced melanoma whose disease progressed after treatment with ipilimumab were evaluated. Patients who tested positive for the BRAF V600 mutation were also included.

Treatment continued until progression of disease or unacceptable toxicity. The primary endpoints were ORR and OS. Results were stratified by PD-L1 expression, BRAF status, and best overall response to anti-CTLA-4 therapy. PD-L1 positivity was defined as ≥5% tumor cell membrane staining measured using a proprietary immunohistochemistry assay.

The median time to response favored nivolumab at 2.1 months compared with 3.5 months in the chemotherapy arm. Treatment responses were also longer-lasting in the nivolumab arm. The median duration of response was 3.6 months in the chemotherapy and had not been reached in the nivolumab arm. Responses with nivolumab were observed regardless of pretreatment PD-L1 expression status, BRAF mutation status, and prior anti-CTLA-4 benefit.

In patients with BRAF-mutated melanoma, the ORR was 23% with nivolumab compared with 9% for chemotherapy. In BRAF wild-type patients, the ORR was 34% with nivolumab versus 11% with chemotherapy. Patients with PD-L1 positive tumors (n = 77) experienced an ORR of 44% versus 20% for PD-L1-negative. Side effect profile and toxicity favored nivolumab. The rates of drug-related grade 3/4 adverse events were 9% in the nivolumab arm compared with 31% in the chemotherapy arm. The rates of treatment-related adverse events that led to discontinuation also favored nivolumab over chemotherapy (2% vs 8%). Serious drug-related adverse events of any grade occurred in 6% of nivolumab-treated patients compared with 10% with chemotherapy. Therapies that target the MAPK pathway are a significant advancement in treating metastatic melanoma and may lead to improved patient outcomes and survival.

References

1. NIH Clinical Trials Registry. Efficacy study of ipilimumab versus placebo to prevent recurrence after complete resection of high risk stage III melanoma. EORTC-18071. ClinicalTrials.gov Identifier: NCT00636168.
2. NIH Clinical Trials Registry. Dabrafenib and trametinib followed by ipilimumab and nivolumab or ipilimumab and nivolumab followed by dabrafenib and trametinib in treating patients with stage III-IV BRAFV600 melanoma. ClinicalTrials.gov Identifier: NCT02224781.
3. NIH Clinical Trials Registry. Study of dabrafenib +/- trametinib in combination with ipilimumab for V600E/K mutation positive metastatic or unresectable melanoma. ClinicalTrials.gov Identifier: NCT01767454.
4. NIH Clinical Trials Registry. Phase 1 safety and tolerability of MEDI4736 in combination with dabrafenib and trametinib or with trametinib alone. ClinicalTrials.gov Identifier: NCT02027961.
5. A Phase 1b study of MPDL3280A (an engineered anti-PDL1 antibody) in combination with vemurafinib (Zelboraf) in patients with previously untreated BRAFV600-mutation positive metastatic melanoma. ClinicalTrials.gov Identifier: NCT01656642. 6. Weber J, Minor D, D’Angelo SP, et al. A phase 3 randomized, openlabel study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator’s choice chemotherapy (ICC) in patients with advanced melanoma with prior anti-CTLA-4 therapy. Presented at: ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. Abstract LBA3.