Selecting I/O or Targeted Therapy as Adjuvant Treatment of BRAF-Mutant Melanoma

Janice M. Mehnert, MD

During a virtual presentation for the 38th Annual Chemotherapy Foundation Symposium (CFS), Janice M. Mehnert, MD explained the science behind selecting the optimal adjuvant therapy for patients with BRAF-mutant melanoma. The options Mehnert weighed were immunotherapy and BRAF-targeted therapy.¹

Moreover, BRAF-targeted treatment may be curative when used in an adjuvant setting, but not in the metastatic setting, while immunotherapy could have a curative impact in both settings. However, further research and longer follow-up will be needed to address those hypotheses, according to Mehnert.

In the meantime, several components should factor into the decision of which class of agents should be administered to a patient with earlier-stage disease.

“Without a head-to-head comparison, there is no right answer,” said Mehnert, who is an associate director for clinical research, disease management group leader of Melanoma and Cutaneous Oncology, at the NYU Langone Health Perlmutter Cancer Center, and NYU Grossman School of Medicine. “We’ll be dealing with the art of choice of therapy, which involves biologic behavior of the primary tumor, the balance of comorbid conditions, and patient-centered considerations.”

The 2020 Adjuvant Therapeutic Landscape

The current, more crowded landscape is a vast change from what was available prior to 2017, when options were limited to interferon and ipilimumab (Yervoy) as single agents in the adjuvant setting for resected patients. While both approaches demonstrated a benefit in recurrence-free survival (RFS), and for ipilimumab, an OS benefit, their uses were also outweighed by significant rates of toxicity.

Since then, new systemic therapeutic approaches came to light that impact how this patient population is treated, as demonstrated in the phase 3 KEYNOTE-054, CheckMate-238, and COMBI-AD trials.

There is still a great deal to learn about the optimal use of BRAF-targeted therapy, as well as immunotherapy, in the adjuvant setting for patients with melanoma, explained Janice M. Mehnert, MD, in a virtual presentation during the 38th Annual CFS® virtual conference.¹

Moreover, BRAF-targeted treatment may be curative when used in an adjuvant setting, but not in the metastatic setting, while immunotherapy could have a curative impact in both settings. However, further research and longer follow-up will be needed to address those hypotheses, according to Mehnert.

In the meantime, several components should factor into the decision of which class of agents should be administered to a patient with earlier-stage disease.

“Without a head-to-head comparison, there is no right answer,” said Mehnert, who is an associate director for clinical research, disease management group leader of Melanoma and Cutaneous Oncology, at the NYU Langone Health Perlmutter Cancer Center, and NYU Grossman School of Medicine. “We’ll be dealing with the art of choice of therapy, which involves biologic behavior of the primary tumor, the balance of comorbid conditions, and patient-centered considerations.”

The 2020 Adjuvant Therapeutic Landscape

The current, more crowded landscape is a vast change from what was available prior to 2017, when options were limited to interferon and ipilimumab (Yervoy) as single agents in the adjuvant setting for resected patients. While both approaches demonstrated a benefit in recurrence-free survival (RFS), and for ipilimumab, an OS benefit, their uses were also outweighed by significant rates of toxicity.

Since then, new systemic therapeutic approaches came to light that impact how this patient population is treated, as demonstrated in the phase 3 KEYNOTE-054, CheckMate-238, and COMBI-AD trials.

In KEYNOTE-054, adjuvant pembrolizumab (Keytruda) was compared with placebo in patients with resected, high-risk stage III melanoma. Results showed that at a median follow-up of 15 months, pembrolizumab was associated with a significantly longer RFS versus placebo in the overall intent-to-treat population (HR, 0.57; 98.4% CI, 0.43-0.74; P < .001).² The 1-year RFS rates were 75.4% versus 61.0% for pembrolizumab vs placebo, respectively. At 3 years, the RFS rates were 64.0% and 44.0%, respectively (HR, 0.56; 95% CI, 0.47-0.68).³

Similar activity was reported in the CheckMate-238 trial, in which patients who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma were randomized to receive either nivolumab (Opdivo) at 3 mg/kg every 2 weeks or ipilimumab at 10 mg/kg every 3 weeks for 4 doses and then every 12 weeks.

The 1-year rate of RFS was 70.5% with nivolumab and 60.8% with ipilimumab (HR, 0.65; 97.56% CI, 0.51-0.83; P <.001).⁴ At 3 years of follow-up, the RFS rates were 56% and 45%, respectively (HR, 0.68; 95% CI, 0.56-0.82).⁵ In even longer follow-up, looking at the secondary end point, the 4-year overall survival (OS) rate was 77.9% and 76.6% with nivolumab and ipilimumab, respectively (HR, 0.87; 95% CI, 0.66-1.14; P = .31).⁶ With 73% of the anticipated events reported, the OS benefit is not a meaningful difference, but those on the ipilimumab arm were more likely to receive subsequent therapy. 

“It’s important to note that this benefit [was seen] regardless of mutation status. Just like metastatic disease, where we know we can achieve quite meaningful results in patients who have a BRAF mutation versus those who [have] BRAF wild-type [disease], the same holds true in the adjuvant setting,” Mehnert explained. “It’s important to remember that regardless of the mutation status of the patient in front of you, you do have a therapeutic option that can achieve meaningful benefit.” 

When comparing the toxicity data of the 2 checkpoint inhibitor trials, Mehnert noted no new safety concerns. Grade 3/4 treatment-related adverse effects (TRAEs) occurred in 14.7% and 3.4% of patients on pembrolizumab and placebo, respectively, in KEYNOTE-054, and then in 14.4% and 45.9% of patients on nivolumab and ipilimumab alone, respectively, in CheckMate-238.

Early discontinuations occurred in 17.4% of patients on pembrolizumab versus 13.3% of those on placebo, respectively, in the KEYNOTE-054 trial, and in 7.7% of those on nivolumab versus 41.7% of patients on ipilimumab in the CheckMate-238 trial.

“At the end of the day, we need to remember that some of these patients will receive therapy that quite frankly they may not need,” Mehnert said. “Until we have a molecular biomarker that we’ll be able to use to prognosticate or monitor for relapse, we’re charged with this very challenging discussion in talking about AEs that can sometimes be permanent or life threatening with checkpoint inhibitor therapy.”

COMBID-AD: The Next Turn in the Road

The phase 3 randomized, double-blind COMBI-AD trial evaluated the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) in the adjuvant setting for patients with high-risk, BRAF V600 mutation–positive melanoma following surgical resection. Patients with stage IIIA were also eligible for enrollment. 

Results showed that the median RFS was not reached with the combination versus 16.6 months with placebo, leading to a 53% reduction in the risk of disease recurrence or death (HR, 0.47; 95% CI, 0.39-0.58; P <.001).⁷ The 1-, 2-, and 3-year RFS rates were 88%, 67%, and 58%, respectively, with the combination versus 56%, 44%, and 39% with placebo, respectively. 

The median OS was not reached in either arm at the first interim analysis; however, this favored the combination with a 43% reduction in the risk of death (HR, 0.57; 95% CI, 0.42-0.79; P =.0006). The 1-, 2-, and 3-year OS rates were 97%, 91%, and 86%, respectively, with dabrafenib/trametinib compared with 94%, 83%, and 77%, respectively, with placebo.

Although Mehnert stressed the difficulties with cross-trial comparisons, she explained how the distant metastasis-free survival (DMFS) was similar in KEYNOTE-054 (HR, 0.53; 99% CI, 0.36-0.77) compared with COMBI-AD (HR, 0.55; 95% CI, 0.44-0.70). In KEYNOTE-054, the 3.5-year DMFS rates were 63.7% with pembrolizumab and 43.4% with placebo. In COMBI-AD, the 4- and 5-year DMFS rates were 67% and 65%, respectively, with the combination and 56% and 54%, respectively, with placebo.⁸

Of note on COMBI-AD, TRAEs occurred in 91% of patients on the combination compared with 63% of those on placebo; however, no TRAEs were fatal. Twenty-six percent of patients on dabrafenib/trametinib experienced AEs that led to treatment discontinuation compared with 3% of those on placebo.

“What is always very striking to me is that many of these [AEs] are not necessarily grade 3 or 4; however, even grade 1 or 2 events with this particular therapeutic regimen can be particularly disruptive to patient quality of life,” said Mehnert. “More often than that, when [targeted] therapy is stopped, AEs reverse, and that is not always the case with immunotherapy. That is an important distinction to make when we’re discussing the different [toxicity] profiles with patients.”

Evidence for Targeted Therapy and Immunotherapy-based Approaches

Therefore, Mehnert asked, How does one choose the most optimal therapy for a patient with BRAF-positive disease in the adjuvant setting?

While MAPK-directed therapy has a more pronounced benefit in the first year, there is evidence of increased relapse following completion of treatment, she explained. Immunotherapy, however, has less of an impact in the first 12 months of treatment but could potentially have a more sustained benefit over time. Mehnert added that disease biology should start to be utilized as a factor to consider when choosing neoadjuvant approaches, which can impact the overall treatment arsenal.

Although the 2 approaches have not been compared directly, she emphasized one belief from the community that, in most patients with BRAF V600–mutant tumors, adjuvant PD-1 inhibition may be a preferred approach over targeted therapy based on tolerability profiles, as well as the durability of off-treatment responses with targeted therapy.

To counteract that, however, Mehnert reflected on the BRIM8 study, in which vemurafenib (Zelboraf) was evaluated against placebo in a 2-cohort design of patients with BRAF V600–mutant melanoma who were at high risk of recurrence. Patients were stratified into a cohort of stage IIC, IIIA, and IIIB disease (n = 314; cohort 1) or a cohort of stage IIIC disease (n = 184; cohort 2). In both cohorts, patients were randomized to either vemurafenib at 960 mg twice daily or placebo, both for 52 weeks. The primary end point of the trial was disease-free survival (DFS). 

In cohort 1, the median DFS was not estimated (NE) with vemurafenib and 36.9 months with placebo (HR, 0.54; 95% CI, 0.37-0.78; P = .0010).⁹ In cohort 2, the median DFS was 23.1 months and 15.4 months, respectively (HR, 0.80; 95% CI, 0.54-1.18; P = .2598). Overall, the median DFS was NE with vemurafenib and 25.8 months with placebo (HR, 0.65, 95% CI, 0.50-0.85; P =.0013); these data failed to meet the primary end point of the trial.

However, Mehnert noted in cohort 2 that relapse-free survival was significantly improved with vemurafenib over placebo (HR, 0.54; 95% CI, 0.37-0.78; P = .0010).

“This suggests that patients [with] earlier-stage [disease] can do quite well with targeted therapy, and we need to think [about this] as we’re approaching trials—especially in the earlier-stage space,” said Mehnert.

Patient-Centered Considerations

An individual patient’s goals are key to determining their choice of adjuvant treatment, Mehnert stressed, along with cost, schedule and convenience of administration, AE profiles, life circumstances such as fertility, concomitant medical conditions, and safety considerations. Regarding safety profiles, she said it’s imperative to discuss the effects of immunotherapy and targeted therapy with patients before making a decision on their treatment course.

“This fully informed discussion is critical,” Mehnert said. “At the end of the day, we generally try to reach a scenario that meets a patient’s goal.”

Ongoing clinical trials are also important options to consider in an effort to improve upon standards of care. The Revised S1901-Intergroup Adjuvant Trial is evaluating patients with high-risk, resected melanoma who have a BRAF mutation. Patients will be randomized to receive pembrolizumab plus dabrafenib and trametinib or physician’s choice of therapy, which will comprise nivolumab, pembrolizumab, or dabrafenib/trametinib.

The KEYNOTE-716 (NCT03553836) trial, which is comparing pembrolizumab versus placebo in patients with high-risk, resected, stage II melanoma, and the CheckMate-76K (NCT0409925) trial, which is comparing nivolumab with placebo to prevent melanoma recurrence after complete section in patients with stage IIB/C disease, are both recruiting patients for enrollment.

_References:

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_{6. Ascierto PA, Vecchio MD, Mandalá M, et al. Adjuvant nivolumab versus ipilimumab in resected stage IIIB–C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. Published online September 18, 2020. doi:10.1016/S1470-2045(20)30494-0}

_{7. Hauschild A, Santinami M, Long GV, et al. COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K–mutant melanoma. Ann Oncol. 2017; 28(suppl 5):v605-v649. doi:10.1093/annonc/mdx440}

_{8. Hauschild A, Dummer R, Santinami M, et al. Long-term benefit of adjuvant dabrafenib + trametinib (D+T) in patients (pts) with resected stage III BRAF V600–mutant melanoma: Five-year analysis of COMBI-AD. J Clin Oncol. 2020;38(suppl_15):10001-10001. doi:10.1200/JCO.2020.38.15_suppl.10001}

_{9. Lewis K, Maio M, Demidov M, et al. BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+ melanoma at high risk for recurrence. Ann Oncol. 2017;28(suppl 5):v631-v632. doi:10.1093/annonc/mdx440.047}