Paul B. Chapman, MD
For the treatment of BRAF V600-mutated advanced melanoma, we now have three BRAF/MEK inhibitor combinations that are approved by the U.S. Food and Drug Administration: dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib. Although the toxicity profiles for these combinations are somewhat different, the combinations are fairly equivalent in terms of efficacy; the response rates range from 63% to 69%, and the progression-free survival rates at 18 months range from 30% to 40% for each combination.1-4
How melanoma develops resistance to these therapies has been well worked out. In almost all cases, melanoma develops genetic or epigenetic changes that reactivate the ERK pathway, even in the presence of RAF inhibitors. Most commonly, the changes either lead to enhanced RAF-RAF dimerization (by acquiring an activating NRAS mutation or developing a BRAF V600E splice variant that allows RAS-independent dimerization) or an increased concentration of BRAF-mutant protein either through amplification or overexpression of the gene.
Among the three BRAF/MEK inhibitor combinations, dabrafenib/trametinib was the first to be approved, so we have the longest follow-up for patients with metastatic melanoma treated with this combination. As reviewed in this issue of The ASCO Post, Robert et al have now published 5-year follow-up data on patients treated with dabrafenib/trametinib5 and reported an estimated overall 5-year progression-free survival of 19%. Their data indicate that better progression-free survival was associated with older age, lower lactate dehydrogenase (LDH) levels, fewer than three metastatic sites, a better performance status, female sex, and V600E mutation rather than V600K mutation. They reported that the 5-year progression-free survival rate in patients with normal LDH levels and fewer than three metastatic sites was 31%. Among patients who achieved a radiographic complete response, the good news was that the 5-year progression-free survival was 49%. The bad news was that despite having no radiographically detectable disease, 51% of patients still harbored melanoma capable of developing resistance and recurrence.
This raises the question of whether it is ever safe to discontinue RAF/MEK inhibitor therapy, even in patients who have had an excellent response. An interesting subset was the 88 patients with complete or partial responses who stopped treatment prior to disease progression for one reason or another. Unfortunately, there was follow-up information on just 15 of these patients, and so this question remains unanswered.
Dangers of Cross-Trial Comparisons
It is natural to ask how these outcomes compare with patients treated upfront with checkpoint inhibitors. There are limited data available on 5-year follow-up for checkpoint inhibitor therapy, and such cross-trial comparisons are fraught with validity issues anyway. The KEYNOTE-001 trial reported an estimated 5-year progression-free survival of 29% in treatment-naive patients, but that was based on few patients followed for that long.6
Recently, Larkin et al reported the 5-year follow-up of CheckMate 067.7 The 5-year progression-free survival for patients with BRAF V600 mutations treated with combination nivolumab/ipilimumab was 38%, and with nivolumab alone, it was 22%. Although 38% is quite a bit higher than the 19% seen in the Robert et al report, 22% is not much different from 19%.
For more on two high-impact clinical studies in the treatment of stage III melanoma, see an interview with Caroline Robert, MD, PhD, on The ASCO Post Newsreels at ascopost.com/videos.
This result might tempt clinicians to conclude that long-term progression-free survival with dabrafenib/trametinib treatment is similar to treatment with nivolumab but inferior to treatment with ipilimumab/nivolumab. However, such cross-trial comparisons cannot be considered reliable, and a randomized comparative trial would be needed to determine relative efficacy. The overall survival data are even more difficult to interpret given that the frequency and quality of treatment after disease progression have been variable.
For a previously untreated patient with a BRAF V600E mutation, these trial results still cannot answer the question of whether upfront BRAF/MEK inhibitor therapy is superior or inferior to upfront checkpoint inhibitor therapy. Fortunately, randomized trials that should help answer this question are underway. In the meantime, an argument in favor of upfront ipilimumab/nivolumab therapy is superior 5-year progression-free survival data. The other advantage of either ipilimumab/nivolumab or nivolumab monotherapy is the fact that patients who respond can discontinue therapy with a low risk of relapse. It is not clear whether patients responding to BRAF/MEK inhibitor therapy can be safely taken off therapy. A disadvantage of checkpoint inhibitor therapy is the association with some permanent toxicities such as vitiligo and endocrinopathies (hypopituitarism, hypothyroidism, hypoadrenalism, type 1 diabetes).
Future Therapeutic Strategies
Going forward, how might we improve BRAF/MEK inhibitor therapy? One strategy is to test intermittent dosing schedules. In vitro data have shown that inhibition of the ERK pathway quickly leads to loss of feedback inhibition of RAS.8 With increased levels of activated RAS, there is enhanced RAF-RAF dimer formation that is not sensitive to our current BRAF inhibitors. Thus, the melanoma cells that have not died are able to stay alive and ultimately accumulate genetic and epigenetic changes leading to resistance. Intermittent dosing is thought to reestablish feedback inhibition of RAS, preventing RAF dimerization and thus reestablishing sensitivity to the inhibitors. In addition, intermittent dosing may allow higher doses of inhibitors to be administered, leading to more complete pathway inhibition. Although there are preclinical data supporting this concept,9 clinical data supporting this strategy are lacking.
Another strategy to improve BRAF/MEK inhibitor therapy is to add checkpoint inhibitors. Several such trials are underway, although early experiences would caution that these combinations can be associated with unexpected toxicities.10
Clinical Preference for Now
For most patients with BRAF V600E mutations, I currently favor upfront checkpoint inhibitor therapy, given that the durability of the responses may allow patients to discontinue therapy. For patients who cannot tolerate the toxicities associated with checkpoint inhibitor therapy, the 5-year follow-up data for dabrafenib/trametinib reported by Robert et al confirm that durable benefits can also be seen with BRAF/MEK inhibition, especially in patients with normal LDH levels and fewer than three metastatic sites. ■
Dr. Chapman is a medical oncologist practicing at Memorial Sloan Kettering Cancer Center, New York, and Professor of Medicine at the Weill Cornell Medical College.
DISCLOSURE: Dr. Chapman has received consulting fees from Merck, Immunocore, Cell Medica, Scancell, and Array, and research support from Pfizer.
1. Dummer R, Ascierto PA, Gogas HJ, et al: Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 19:603-615, 2018.
2. Larkin J, Ascierto PA, Dréno B, et al: Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371:1867-1876, 2014.
3. Robert C, Karaszewska B, Schachter J, et al: Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372:30-39, 2015.
4. Long GV, Stroyakovskiy D, Gogas H, et al: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386:444-451, 2015.
5. Robert C, Grob JJ, Stroyakovskiy D, et al: Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med 381:626-636, 2019.
6. Hamid O, Robert C, Daud A, et al: Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol 30:582-588, 2019.
7. Larkin J, Chiarion-Sileni V, Gonzalez R, et al: Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 381:1535-1546, 2019.
8. Lito P, Pratilas CA, Joseph EW, et al: Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22:668-682, 2012.
9. Das Thakur M, Salangsang F, Landman AS, et al: Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494:251-255, 2013.
10. Ribas A, Hodi FS, Callahan M, et al: Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 368:1365-1366, 2013.