The Evolving Treatment Landscape of Metastatic Melanoma: From Ipilimumab to New Checkpoint Inhibitors

The Evolving Treatment Landscape of Metastatic Melanoma: From Ipilimumab to New Checkpoint Inhibitors

During the ASCO Annual Meeting Plenary Sessions in 2010 and 2011, promising data from MDX010-20 and CA184-024 phase III studies, respectively, were presented that strove to change the treatment paradigm for patients with metastatic melanoma. Years later, the question that remains is whether these expectations have been realized. To answer that question, the ASCO Daily News revisited the treatment landscape of metastatic melanoma, beginning with the promise of ipilimumab.

Based on data from MDX010-20, on March 25, 2011, the U.S. Food and Drug Administration (FDA) approved ipilimumab 3 mg/kg for the treatment of patients with unresectable or metastatic melanoma.1 The FDA approval of ipilimumab was the culmination of more than 14 years of research and development.2

In 2010, Steven J. O’Day, MD, now director of immuno-oncology with the John Wayne Cancer Institute, presented “historic” data from MDX010-20—a randomized, double-blind, phase III study that showed a statistically significant improvement in overall survival (OS) for patients with previously treated, unresectable stage III/IV metastatic melanoma receiving ipilimumab compared with patients receiving the vaccine gp100 (p = 0.003).3

Dr. Steven J. O'Day Photo courtesy of Casey Marx
It was hoped that the combination of a vaccine and a checkpoint inhibitor, ipilimumab, would be significantly better than either agent alone. Today, it is irrelevant that the study was designed to show whether combination ipilimumab/gp100 was significantly better than ipilimumab or gp100 alone because ipilimumab alone was as effective as ipilimumab plus gp100 and was indicated as monotherapy for patients with metastatic melanoma.3

One-year OS was 46%, 44%, and 25% for patients receiving ipilimumab alone, ipilimumab plus gp100, and gp100, respectively. In the study, patients receiving ipilimumab 3 mg/kg, given once every 3 weeks for four cycles, had a 34% reduced risk for death (p = 0.0026) versus those receiving gp100.3

According to Dr. O’Day, the excitement following the study presentation was palpable. The reason was simple. “Before ipilimumab, which followed 30 years of failed studies, patients only had dacarbazine or interleukin-2 as available options, which provided transient responses and a median survival of 7 to 8 months,” Dr. O’Day said.

Ipilimumab, a monoclonal antibody against immune checkpoint inhibitor CTLA-4, targets the immune response, not the cancer directly. “Prior to the development of ipilimumab, the immune system was viewed as a limited area of benefit. Ipilimumab broke the paradigm wide open,” Dr. O’Day said.

“The fact that just four doses of a drug, which turned on the immune system, could keep melanoma under control was exciting news,” Vernon K. Sondak, MD, of the Moffitt Cancer Center, said.

Dr. Vernon K. Sondak Photo courtesy of Todd Buchanan

One year later, Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center, presented CA184-024 data at the ASCO Annual Meeting that proved the OS seen with ipilimumab was not a chance event. In this study, combination ipilimumab/dacarbazine significantly increased OS for patients with metastatic melanoma who were treatment naive compared with dacarbazine alone, which was the standard of care at most institutions. In this study, ipilimumab was administered at 10 mg/kg every 4 weeks for four doses.4

One-year, 2-year, and 3-year survival rates were 47.3%, 28.5%, and 20.8%, respectively, for patients receiving combination ipilimumab/dacarbazine. Corresponding survival rates for patients on dacarbazine were 36.3%, 17.9%, and 12.2%, respectively.

“Even though CA184-024 data were presented in June 2011, the totality of the data from two phase III studies defined ipilimumab as the first drug to be approved based on an extension of survival and changed the standard of care for patients,” Dr. Wolchok said in an interview with the ASCO Daily News.

Dr. Jedd D. Wolchok

Physicians interviewed have patients treated with ipilimumab who have lived for longer than 10 years without recurrence. However, cautious in their optimism, they hesitate to indicate that some patients are indeed cured.

Lessons for Developing Immunotherapy

The clinical development of ipilimumab provided important lessons for the clinical development of immunotherapies: the need to develop immune-related response criteria (irRC) and the need to manage immune-related adverse events (irAEs).

Although ipilimumab was approved based on OS, overall response rate was initially the primary endpoint of MDX010-020.3 The primary endpoint was amended to OS based on phase II data and data from the ongoing, blinded phase III study, said Jeffrey S. Weber, MD, PhD, now with New York University’s Langone Medical Center, who was involved in the clinical development of ipilimumab.

Dr. Jeffrey S. Weber

Investigators discovered that response to ipilimumab took time and that the normal RECIST criteria used for identifying responses were not appropriate for immunotherapy, as response kinetics showed progression before the establishment of antitumor immunity. In midstream, before the study was unblinded, the protocol was amended, and the FDA accepted OS, not overall response rate, as the primary endpoint.3,4

Dr. Wolchok explained that exploratory response criteria—the irRC—were proposed for immunotherapies, which allowed for transient increase in tumor volume or new lesions. For immunotherapies, it was recommended that responses be confirmed with a second assessment at least 4 weeks later.

Secondly, in dose-escalation phase II studies, investigators also learned that turning up the immune system presented unique irAEs as the most common toxicities. Through the course of these studies, irAEs were managed with effective treatment guidelines developed in collaboration with clinical trial investigators and the study sponsor. The management of irAEs are now standard as these immunotherapies move into other indications.4,5

Dr. Wolchok said that the close collaboration between clinical trial investigators and the scientists at the sponsoring companies was integral to the success of ipilimumab.

New Treatment Landscape for Metastatic Melanoma

Although ipilimumab was the first “prototypical” immunotherapy approved for metastatic melanoma in decades, the pace of approvals has not stopped. New immunotherapies, alone or in combination, offer even better clinical outcomes for patients. The clinical development of nivolumab and pembrolizumab, which target a different immune checkpoint molecule, PD-1, culminated in accelerated approvals for these two agents between September 2014 and December 2014 based on promising response rates for patients with ipilimumab-refractory metastatic melanoma.6,7 In 2015, they were rapidly approved for the first-line treatment of metastatic melanoma, and the data reviewed by the FDA for these indications are now published.8,9

In October 2015, the FDA approved the combination of nivolumab and ipilimumab for the treatment of BRAFV300 wild-type unresectable or metastatic melanoma based on the 60% response rate compared with 11% response rate for ipilimumab—the current standard of care.10 Ipilimumab set the bar high for the approval of these therapies, Dr. Weber said.

Dr. O’Day pointed out that before ipilimumab, patients with metastatic melanoma had a median survival of 6 to 9 months and 5-year OS of less than 10%. In the current treatment landscape, significant improvements in survival have been noted—2-year and 3-year OS rates of 48% and 41%, respectively, have been reported, with median survival as high as 17 months and median response time close to 24 months with nivolumab.11,12

Other exciting reports from studies with immunotherapies indicated that responses were durable, with responses occurring even in patients who discontinued treatment because of adverse events.

Dr. Wolchok explained that for patients whose disease is unlikely to respond, which includes approximately 40% of affected patients, the combinations of BRAF and MEK inhibitors (dabrafenib/trametinib and vemurafenib/cobimetinib, respectively) offer additional options.13-15 How these options are sequenced in clinical practice depends on treatment protocols in place at the cancer center. Dr. Sondak indicated that at his center, patients typically start on a PD-1 inhibitor as monotherapy; other oncologists, however, use the combination of nivolumab and ipilimumab.

Indeed, the new checkpoint inhibitors nivolumab and pembrolizumab have hastened the pace of the immunotherapy revolution into other malignancies. PD-1 inhibitors have now been approved for the treatment of non–small cell lung cancer—another difficult-to-treat malignancy—and advanced renal cell carcinoma, and are inching toward approval in other solid and hematologic malignancies.

Immunotherapy is here to stay, is the sentiment echoed by everyone interviewed. But it all started with ipilimumab, which, yet again, is the first immunotherapy to be approved for the adjuvant treatment of fully resected stage III melanoma.  

– Alexander Castellino, PhD