INITIAL THERAPY FOR METASTATIC MELANOMA

The question of what is the most appropriate front-line therapy for BRAF-positive patients is one of the most pressing in the field of metastatic melanoma today, noted Jason John Luke, MD (The University of Chicago School of Medicine), introducing a debate on the topic at the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO). During the debate, speakers voiced their support for and reservations about the currently available range of molecular targeted therapies (BRAF and MEK inhibitors) and immunotherapies (CTLA-4 and PD-1 inhibitors) as monotherapy and in combination.

Combo Immunotherapy Versus Combo Targeted Therapy

"No other therapy has shown a better overall response rate (ORR) in BRAF-mutant melanoma than combination BRAF/MEK inhibition," declared Georgina V. Long, PhD, MBBS (Melanoma Institute Australia and the University of Sydney). She noted that ORR was nearly 70% across all phase 3 trials (COMBI-d,^[1]COMBI-v,^[2] and coBRIM^[3]) as well as phase 1/2 studies with the investigational combination encorafenib plus binimetinib.^[4]"There is no other therapy in melanoma that gives such a great response rate so rapidly with such resolution of symptoms. The complete response (CR) rate of about 15% is highest among all phase 3 trials," said Dr Long. Median overall survival (OS) was "well above 2 years" (25.6 months) with combination dabrafenib plus trametinib in COMBI-v^[1,2,5] and was 22.3 months with vemurafenib plus cobimetinib in coBRIM.^[6] BRAF inhibitors as single agents have also been shown to be very effective in the brain, Dr Long noted, with over 80% of melanoma patients with brain metastases achieving disease control in clinical trials.^[7,8]

"We have had great success with inhibition of PD-1 (with nivolumab or pembrolizumab) and CTLA-4 (ipilimumab) as single-agent therapy,"^[9-11] Dr Long continued. Pembrolizumab has also shown activity in patients with asymptomatic brain metastases.^[12] Combination therapy with ipilimumab plus nivolumab appears to have greater efficacy than either agent alone, regardless of BRAF mutation status, as shown in the CheckMate 067 study.^[13] The latest data presented at ASCO^[14] showed that the combination reduced risk for progression by 58% compared with ipilimumab alone. ORR was 57.6% for nivolumab plus ipilimumab compared with 19% for ipilimumab monotherapy (P<.001) and 43.7% for nivolumab alone (P<.001). A descriptive analysis showed that the response rate for the combination was numerically higher than for nivolumab monotherapy. Median progression-free survival (PFS) for nivolumab plus ipilimumab, nivolumab, and ipilimumab was 15.5, 5.6, and 4.0 months, respectively, in patients with a BRAF mutation.

"What is interesting is how well tolerated anti-PD-1 therapy is," she stressed. "Never before have we worked with a drug that has been so well tolerated and with such little negative effect on quality of life."

However, "the sting" is the safety of combination therapy, as demonstrated in CheckMate 067.^[15] Almost every patient on nivolumab plus ipilimumab (96%) had a treatment-emergent adverse event (TEAE), Dr Long noted, and 55% had grade 3/4 toxicities that required hospitalization. TEAEs leading to discontinuation were high, occurring in over one third of patients on nivolumab plus ipilimumab.

By focusing on the group that seems to benefit from the combination but not from nivolumab (about 15%), it may be possible to identify which patients need the more toxic treatment, Dr Long suggested. Patients with elevated lactate dehydrogenase (LDH) or patients who are negative for certain biomarkers, such as PDL-1, might benefit from combination therapy. It might also be possible to reduce the dose of the CTLA-4 inhibitor, as indicated by the latest data from the expanded KEYNOTE-029 cohort, also presented at ASCO, in which a combination of pembrolizumab with reduced-dose ipilimumab showed a manageable toxicity profile with "robust" antitumor activity in advanced melanoma.^[16]

Immunotherapy as First-Line Option

"There is no better targeted therapy than to have a T cell that has a T-cell receptor that specifically recognizes a specific tumor antigen," declared Antoni Ribas, MD, PhD (UCLA Jonsson Comprehensive Cancer Center, Los Angeles), speaking in support of immunotherapy as first-line therapy in BRAF-mutant disease. "By blocking adaptive immune resistance with anti-PD-1, we have got the biology right," he said.

He pointed out that the pharmacokinetics and pharmacodynamics of targeted therapies are short whereas for immunotherapy they are long. In targeted therapy, what kills the cancer is "a small molecule stopping an oncogenic signal"; in immunotherapy "a body system is designed to kill its targets anywhere in the body." Body distribution of targeted therapy is passive (blood distribution), but with immunotherapy it is active (T cells searching for antigen). With immunotherapy, "if you turn on a T cell, it will remember, because it has memory." These properties translate into results like the 34% 5-year OS rate seen with nivolumab monotherapy,^[17] and the 40% 3-year OS rate with pembrolizumab monotherapy, shown in updated findings from the KEYNOTE-001 study presented at ASCO this year.^[18]

"It is a common belief that patients with more aggressive melanoma should get targeted therapies and patients with less aggressive melanoma should get immunotherapies, and that targeted drugs are more effective in patients with high LDH, but that is not true," Dr Ribas said. "Patients with the most aggressive melanoma, with high LDH, have much lower benefit with BRAF/MEK inhibition compared with those with normal LDH, as demonstrated in the COMBI-v trial."^[2] A PD-1 inhibitor will have a lower response rate in patients with a high LDH, "but once you have a response, you have a response," he said. "The LDH will no longer be a factor; it does not lead to more resistance." In a pooled analysis of all melanoma patients enrolled in the KEYNOTE-001 study, 74% of the 205 responders to pembrolizumab had a durable response, regardless of whether they had low or high LDH,^[19] Dr Ribas recalled.

Giving a run-in with targeted therapy "may not make much sense" because it could lead to cross-resistance with immunotherapy, Dr Ribas suggested. Mitogen-activated protein kinase (MAPK)-targeted therapy, ie, BRAF/MEK inhibitors, was recently shown to induce a signature similar to the "innate anti-PD-1 resistance" (IPRES) gene signature found in patients who fail to respond to anti-PPD-1 therapy.^[20]More data about the sequencing of treatment are needed from randomized controlled trials such as the ongoing EA6134 trial, which is comparing first-line ipilimumab and nivolumab, followed by dabrafenib, and trametinib, with the treatments given in reverse order.

Dr Ribas suggested that the treatment for the future may be combinations of targeted therapy and immunotherapy. At ASCO he presented early data from the phase 1/2 KEYNOTE-022 study, in which triplet combination pembrolizumab, dabrafenib, and trametinib as first-line therapy for BRAF-mutant melanoma in 15 patients resulted in nine partial responses, five of which were confirmed, with a manageable toxicity profile.^[21]

Targeted Therapy as First-Line Option

Most BRAF mutant–positive patients in clinical practice should get a doublet BRAF/MEK regimen, stated Keith Flaherty, MD (Massachusetts General Hospital and Dana-Farber Cancer Institute, Boston). "Unquestionably, the BRAF/MEK combination provides most confident early disease control," he said. However, development of acquired resistance is a problem in a proportion of patients, he noted.

As the COMBI-d study showed,^[1] dabrafenib plus trametinib combination therapy resulted in "unbelievably reliable protection against fatality within the first few months" and "near-perfect protection against disease progression" in all patients, even those with the highest disease burden, but "thereafter there was a falloff." Dr Flaherty stressed, "By learning more about the baseline characteristics and the unique biology of the patients when they develop resistance, we will evolve our understanding about the status of those patients' tumors and their ability to be treated."

Pooled analysis of the baseline characteristics of patients in trials of dabrafenib plus trametinib^[22,23]revealed that LDH level and number of disease sites exerted the strongest influence on PFS and OS. ECOG performance status was also a factor, although "at a lower level of priority," Dr Flaherty noted. "So discrimination is achievable with these very simple factors, and the information can be taken into clinical practice."

"We are struggling trying to pull out data elements from datasets for PD-1 and CTLA-4 inhibitors that have the same type of discriminating information in them, because we want to know how and in whom to use these therapies," Dr Flaherty added.

"My fundamental problem with relying on anti-PD-1 therapy is the inability to control the disease in a notable portion of patients," Dr Flaherty acknowledged. In the KEYNOTE-006 study, he observed, over 40% of patients on pembrolizumab progressed within the first 3 months.^[24]

Another key point about immune checkpoint therapy as front-line choice (whether as anti-PD-1 monotherapy or anti-PD-1 plus CTLA-4) is the effect on quality of life, Dr Flaherty continued. He cited the superior toxicity profile of combination dabrafenib and trametinib therapy over dabrafenib monotherapy, even during disease progression.^[25] An analysis of the toxicities time course with dabrafenib plus trametinib presented at ASCO^[26] showed that "the dust settles after 3 months of treatment, partially explaining how over time patients are able to maintain this type of persistent difference in benefit," Dr Flaherty added. Immunotherapy remains an option post–BRAF/MEK inhibition, he believes. "Should Dr Ribas's insights make us worry that there could be a problem of cross-resistance between the two types of therapies? I hope that is not completely the story," he admitted.