With expanding availability of effective single-agent and combination immunotherapies and combination BRAF/MEK inhibitor regimens, all of which have been shown to improve survival and reduce risk of progression, the optimal sequencing of therapies has become increasingly complex.
Preferred frontline regimens for patients withBRAFV600-mutant tumors, representing approximately 40% to 50% of patients, include both targeted agents and immunotherapy with checkpoint inhibitors.1The most relevant factors that influence choice of first-line therapy includeBRAFmutation status, the tempo of disease, and the presence or absence of cancer-related symptoms.1
“In patients withBRAF-mutant melanoma who have extensive, symptomatic disease, most clinicians would favor the use of BRAF-targeted therapy (dabrafenib/trametinib). Subgroup analyses from multiple BRAF trials have demonstrated strong clinical benefit in patients with the most advanced and aggressive disease (elevated LDH, M1c),” according to Geoffrey T. Gibney, MD, and Michael B. Atkins, MD, with the Medstar-Georgetown University Hospital in Washington, DC.2“In patients withBRAF-mutant melanoma without extensive central nervous system disease or symptomatic systemic metastases, the decision for upfront therapy has become debated. The focus has largely shifted to the durability of response with each therapy.”
Potential benefits with immunotherapy include a more durable antitumor immune response compared with BRAF and MEK inhibitor therapies with 2-year OS rates as high as 60% with first-line pembrolizumab and 4-year OS rates of 32% with first-line nivolumab.3,4However, long-term analyses with combined BRAF/MEK inhibitor therapy have shown that approximately 20% of patients remained progression-free after 3 years, with 2- and 3-year OS rates in the range of 51% to 60% and 38% to 47% in all patients, and up to 63% in patients with favorable prognostic baseline criteria.5
Retrospective analyses with single-agent therapies have suggested better outcomes with front-line immunotherapy with ipilimumab or interleukin-2 followed by BRAF inhibitor therapy with vemurafenib or dabrafenib compared with the inverse approach.6,7However, prospective data with the newer more effective therapies are not yet available and a retrospective analysis showed that nivolumab had similar efficacy and safety regardless of prior BRAF inhibitor or ipilimumab treatment.4Study author James Larkin, MD, PhD, with the Royal Marsden Hospital, London, England, and co-authors conclude that: “Nivolumab monotherapy may be an effective treatment for mutatedBRAFpatients regardless of whether they have previously received aBRAFinhibitor.”
Addressing the lack of prospective data on the choice of immunotherapy versus targeted therapy in the frontline treatment of patients withBRAF-mutant melanoma, the ongoing phase III Intergroup EA6134 study (ClinicalTrials.gov identifier NCT02224781) is comparing frontline targeted BRAF/MEK inhibitor combination therapy (dabrafenib/trametinib) followed by combination immunotherapy ipilimumab/nivolumab with the inverse regimen, i.e., immunotherapy followed by targeted therapy, in patients withBRAFV600E or K mutations.
Examining the Optimal Sequencing of Agents:Immunotherapies
Frontline single agent nivolumab and nivolumab/ipilimumab have become available to patients with advanced melanoma irrespective ofBRAFmutation status, and have demonstrated significant reductions in the risk for progression compared with ipilimumab monotherapy.8,9Available PD-1 inhibitors also include pembrolizumab, associated with an ORR of 33%, a 12-month progression-free survival (PFS) rate of 35%, and median overall survival (OS) of 23 months when given as single agent.10
Potential PFS benefits of nivolumab/ipilimumab combination therapy versus single-agent nivolumab or ipilimumab come at the cost of significantly increased toxicity. According to Jeffery S. Weber, MD, PhD, with the NYU Langone Medical Center, New York, “The spider plots show that very steep immediate rapid response, which makes it the perfect therapy for aBRAFwild-type patient who has aggressive, high-LDH bulk rapidly growing disease, or even aBRAF-mutated patient. I also think it’s a great neoadjuvant therapy. It’s got a 50-plus percent response rate, which is really what you want in a neoadjuvant therapy. In a patient with low burden disease, low LDH that’s not rapidly progressive, you can probably get away with PD-1 alone and do very well.”
A randomized phase II study evaluating sequential induction immunotherapy followed by nivolumab found that the order of agents matters. Induction with nivolumab followed by ipilimumab was associated with a two-fold higher ORR than the inverse induction sequencing (41.2% vs 20.0%); in both arms, nivolumab maintenance was given subsequently.11Weber, lead investigator on the study, explained that many patients experienced combination toxicity “much of which may well be the ipilimumab,” he said. Patients were able to “stop, recover, and then go to the nivolumab maintenance.”
The availability of combination immunotherapy may also influence the decision of when to switch a patient from BRAF/MEK therapy to immunotherapy. According to Rene Gonzalez, MD, with the University of Colorado Melanoma Research Clinics, data with the combination of ipilimumab/nivolumab have prompted him to more often consider switching some patients to immunotherapy from the BRAF/MEK combination, “because with BRAF/MEK combination, half the patients will die in about 2 years,” Gonzales said, “we might be able to impact better now rather than later.”
Observation that at least a quarter of the resistance that develops to combination therapy is immunologically driven12 suggest that moving patients to immunotherapy earlier than later may be beneficial, because, according to Jason Luke, MD, from the University of Chicago, “It very well could be that treating all the way to progression actually could kill the immune response.”
Optimizing the Use of BRAF/MEK inhibition
Intermittent and sequential dosing regimens are being evaluated as potential approaches to optimize combination BRAF/MEK inhibitor therapies, in which resistance is observed in one third of patients after 6 months, with underlying mechanisms including BRAF amplification and MAPK activation.13,14
Preclinical studies suggest that discontinuous dosing may delay the emergence of acquired resistance to BRAF inhibitor therapy.15Melanoma xenograft studies have shown that vemurafenib-resistant tumor cell clones became dependent on drug exposure for continued growth, which has been termed “melanoma drug addiction.”16Suspension of treatment caused loss of selective growth advantage and resultant repopulation with drug-sensitive cells.16
High sensitivity to acute drug withdrawal has also been observed in melanoma cells with acquired resistance to dual BRAF/MEK inhibitor therapy. Gatien Moriceau, PhD, with the University of California Los Angeles, and co-authors reported that, “Paradoxically, acute removal of BRAF inhibitor plus MEK inhibitor disrupts this fine-tuning and results in a p-ERK rebound favoring cell arrest/death (i.e., drug addiction),” rendering these cells “exquisitely sensitive to acute drug withdrawal.”14
According to Flaherty, an interrupted schedule may be associated with a retreatment effect, which “has been seen with other oncogene-targeted therapies in other cancers, such as with EGFR and ALK inhibitors in lung cancer, imatinib in GIST. It is known to be the case that if patients are off, away from their targeted therapy for a period of time, they can resensitize.”
An intermittent dosing schedule of dabrafenib and trametinib is being evaluated in the phase II Southwest Oncology Group (SWOG) study S1320 (NCT02196181). Patients are receiving dabrafenib/trametinib (150mg BID/2mg QD) during an 8-week lead in period, followed by random allocation of patients without disease progression at the end of the lead in period to either continuous dosing or to intermittent dosing on days 1 to 7 and 29 to 56 of a 56-day course.
Sequential administration of BRAF and MEK inhibitor therapy is the focus of a 3-arm randomized phase II study (NCT02314143) comparing continuous dabrafenib/trametinib combination therapy with upfront monotherapy with dabrafenib or trametinib for 8 weeks followed by combination therapy. Biomarkers associated with progression and drug resistance are assessed at randomization, week 2, week 8, week 10, and at progression.
Combining Targeted and Immunotherapies
Early clinical trial data are becoming available from combination regimens of targeted and immunotherapeutic agents. Potential synergy between these approaches may result in higher frequency of long-lasting responses.
Findings in tumor biopsies and mouse models have shown that BRAF and MEK inhibitors increase the presence of tumor-infiltrating T cells and expression of melanoma-specific antigens within the tumor microenvironment.17,18However, as Alexander Menzies, MD, and Georgina Long, MD, with the Melanoma Institute, Sydney, Australia, explain,19“the initial immune response is then counteracted by tumor PD-L1 expression within days of initiation of BRAF inhibition. By the time of BRAF inhibitor resistance, melanoma antigen expression and T-cell infiltrates fall to below pretreatment values.” According to the authors, “these data support the use BRAF inhibitors in combination with immunotherapy (especially PD-1PD-L1 antibodies) from the outset, so that when an antigenic stimulus is generated by BRAF inhibition, immune escape is prevented by blockage of the compensatory PD-1–PD-L1 tumor defense.”19
Findings in model studies have demonstrated effective tumor size reduction with trametinib in combination with antiPD-1 agents18 or a triple combination of BRAF and MEK inhibitors with anti-PD1 therapy.20
Early reports from an ongoing phase I/II study (NCT02027961) evaluating the PD-L1 agent durvalumab (MEDI4736; 10mg/kg every 2 weeks) in combination with dabrafenib/trametinib (150 mg BID/2 mg QD) found that the regimen had promising clinical efficacy with a manageable side effect profile and no substantial increase in immune-related adverse events. Among 26 patients treated with the triple combination, the ORR was 69%, and responses were ongoing in most patients.21PD-1 checkpoint blockade in combination with dual BRAF/MEK inhibition with dabrafenib/trametinib is also the focus of the ongoing phase I/II KEYNOTE-022 study (NCT02130466).
According to Michael Postow, MD, with Memorial Sloan Kettering Cancer Center, New York, PD-1 combination therapies are likely “more tolerable than ipilimumab combinations with targeted therapy drugs.” Phase II study findings have shown that the combination of ipilimumab and vemurafenib “unfortunately, resulted in a high rate of liver inflammation and skin rash.22Therefore, it was decided that the combination should not be given outside of clinical studies,” said Postow. In the same phase II study, “dabrafenib, trametinib, and ipilimumab were combined in a triplet that resulted in a high rate of gastrointestinal events, mainly colitis and perforation,” such that enrollment to the triple combination arm was stopped.22
BRAF/MEK Inhibitor Strategies in Patients With Brain Metastases
In addition to new dosing strategies, BRAF/MEK inhibitors are also being examined specifically in patients withBRAF-mutant melanoma that has metastasized to the brain, which is associated with a poor prognosis and frequently an exclusion criterion in clinical trials.19
Evidence exists that dabrafenib and vemurafenib are active in patients with brain metastases and can reduce brain lesions.23,24An open-label phase II study reported intracranial responses to dabrafenib in patients withBRAFV600E or K mutant melanoma who had undergone previous local treatment for brain metastases (V600E, 30.8%; V600K, 22.2%) and who had not (V600E, 39.2%; V600K, 6.7%).23A small cohort study including patients with measurable intracranial disease found that in response to vemurafenib, >30% intracranial tumour regression occurred in 37% (n = 7), including confirmed partial responses.24
To evaluate potential benefits with dual BRAF/MEK inhibitor therapy in patients with melanoma that has metastasized to the brain, an ongoing phase II study (NCT02039947) is examining dabrafenib/trametinib in patients withBRAFV600 E, K, D, or R mutation-positive tumors. The 4-cohort design includes patients with symptomatic and asymptomatic brain metastases, and with or without prior therapy to the brain.
“In view of the substantial molecular heterogeneity of melanoma and the potential for drug synergy, a multi-targeted upfront approach, including immunotherapy, is likely to yield the greatest survival benefit to patients, although toxicity might limit this multi-drug approach,” Menzies and Long wrote.19
“MAPK inhibitors and immunotherapies will continue to have a major role in the treatment ofBRAF-mutant melanoma, and a real possibility exists of long-term disease control or cure for many patients in the near future.”