Dr. Negrao is an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center. Dr. Negrao has a diverse experience in medical oncology, specializing in the diagnosis and treatment of thoracic malignancies, most notably lung cancer.
Q. Can you describe the mechanism of action of vemurafenib?
A. We know that BRAF mutations account for approximately 4% of mutations in NSCLC, and approximately 50% of those are V600 mutations. BRAF mutations belong to one of three functional classes: Class 1 BRAF V600 mutations are RAS independent and promote downstream signaling in the form of a monomer; the BRAF non-V600 mutations are divided into class 2 and class 3 mutations. Class 2 mutations are RAS independent and promote downstream signaling in the form of a dimer. Class 3 mutations have enhanced binding to RAS, and promote downstream signaling as RAS-dependent dimers.
This classification is important because it clarifies why the first-generation BRAF inhibitors such as vemurafenib and dabrafenib are only active for the class 1 mutations. With class 2 and 3 mutations, when the BRAF inhibitor binds to the αC helix in the “out” inactive conformation of the BRAF mutant protein, this leads the second RAF protein in the dimer to shift to an active conformation that cannot be bound to the BRAF inhibitor at therapeutic doses due to steric hindrance. This ultimately leads to persistent RAF dimer signaling and, consequently, to an increase in downstream signaling in the MAPK pathway.1,2
There are two prospective trials reporting clinical outcomes for patient with lung cancer treated with single-agent vemurafenib. In the VE-BASKET trial, there was an objective response rate of 42% for patients with BRAF V600-mutant NSCLC who were treated with vemurafenib; PFS was 7.3 months.3 Updated results of this trial with 62 patients with lung cancer reported a 40% response rate and a PFS of 6.5 months regardless of line of therapy.4 The French AcSé trial showed that patients with BRAF-mutant lung cancer had an objective response rate of 45%, PFS of 5.2 months, and median duration of response of approximately 6 months upon treatment with vemurafenib.5 Both trials show similar results and confirm that vemurafenib is active for targeting BRAF V600E mutations in NSCLC.
Q. What are the differences in terms of efficacy, safety, and cost when considering single versus combination therapy?
A. There is limited data on vemurafenib combinations for treatment of lung cancer, so unfortunately most of the clinical data comes from melanoma trials.
When vemurafenib alone was compared with vemurafenib plus the MEK inhibitor cobimetinib in the melanoma COBRIM trial, a significant increase in PFS, objective response rate, duration of response, and OS was observed in favor of the combination. 6,7 The COMBI-v trial compared vemurafenib alone versus combination of dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor). This trial also showed an increase in PFS, objective response rate, duration of response and OS in the combination arm.8
For NSCLC harboring BRAF V600E mutations, comparisons between BRAF/MEK-inhibitor combinations and a single-agent BRAF inhibitor are limited to cross-trial comparisons. Treatment with dabrafenib and trametinib led to objective response rates ranging from 63% to 64%, a median PFS of 9.7-10.9 months, and an OS of approximately 24 months.9,10 These outcomes are superior to vemurafenib single-agent3-5 and also to dabrafenib single-agent (objective response rate: 33%; PFS 5.5 months).
Taken together, the melanoma and the NSCLC data suggest that the combination of a BRAF and a MEK inhibitor have higher efficacy than BRAF inhibitor monotherapy.
There are some interesting safety findings when the single agent BRAF inhibitors are compared with BRAF/MEK-inhibitor combinations. In general, the combination of BRAF/MEK inhibition is more toxic, with more treatment delays. For the combination of dabrafenib and trametinib this is due in large part to increased incidence of pyrexia, diarrhea, and vomiting. The combination of vemurafenib and cobimetinib is also associated with an increased incidence of diarrhea and vomiting. These side effects can be troublesome and can significantly impair a patient’s quality of life.
However, when BRAF and MEK inhibitors are combined, the incidence of some toxicities can decrease. For instance, treatment with single agent BRAF inhibitors have been associated with increased skin toxicities, including development of squamous cell carcinomas (SCC). Increased incidence of skin SCC seems to be a consequence of paradoxical wild-type RAF dimerization and activation in normal skin cells, which ultimately leads to increased MAPK pathway signaling. When combined with a MEK inhibitor, this effect of single-agent BRAF inhibitor treatment in normal cells is mitigated with decreased incidence of skin toxicity.
Moving on to cost, when two different medications are used, cost will increase. One has to weigh this in the decision-making process: the combination may have higher efficacy but may be more toxic and more costly for the patient and the health care system. It is important to be mindful of this potential financial burden, especially if these medications are not completely covered by private insurers and public health systems.
Q. Is the melanoma data for dabrafenib relevant to lung cancer?
A. When it comes to single-agent activity for all the first-generation BRAF inhibitors, there are fewer data in the context of lung cancer. The majority of the work to date has been focused on melanoma where these mutations are more prevalent. With that being acknowledged, vemurafenib and dabrafenib have a similar mechanism of action, as mentioned previously, and both effectively inhibit mutant BRAF V600 monomer activity. Although head-to-head comparisons are lacking, objective response rates and PFS are similar for both compounds both for lung cancer and melanoma.
Q. What are the considerations for second-line therapy?
A. Resistance to vemurafenib and other BRAF inhibitors can occur through reactivation of downstream signaling of the MAPK pathway. This can occur through acquired BRAF V600E splice-site alterations and amplifications, c-Raf mutations, and NRAS/MEK mutations. Therefore, there is special interest in clinical development of inhibitors of other downstream elements of the MAPK pathway, such as ERK inhibitors, of upstream regulators of the MAPK pathway, such as SOS1 and SHP2 inhibitors, and of BRAF dimer inhibitors. This is an area of active clinical investigation, and clinical trial enrollment is warranted for patients with lung cancer that progress on treatment with vemurafenib or dabrafenib.
As for standard of care options, data from our group and others suggest that PD-1/PD-L1 inhibitors have activity for treatment of BRAF-mutant NSCLC.5,12,13 Also, patients with BRAF-mutant NSCLC were included in the clinical trials that led to the approval of PD-1/PD-L1 inhibitors as single-agents, and in combination with chemotherapy or with CTLA4 inhibitors. Therefore, a second- or later-line regimen with PD-1/PD-L1 inhibitors as single-agents or in combination with either chemotherapy or with a CTLA4 inhibitor is recommended for this population.
Q. What are some other trials of interest that you are watching?
A. Novel compounds are being generated that could allow effective targeting of the class 2 and class 3 BRAF non-V600E mutations. Previous work from our group has shown that the BRAF dimer inhibitors LXH254 and lifirafenib (BGB-283) seem to be effective BRAF dimer inhibitors14 and could potentially be active in treating patients with NSCLC harboring BRAF non-V600 mutations. Other BRAF dimer inhibitors have also shown activity for inhibiting BRAF non-V600 mutations. I look forward to the results of phase I/II studies evaluating BRAF dimer inhibitors as single-agents or in combination with MEK and ERK inhibitors for treatment of BRAF-mutant NSCLC.
- Yao Z, Torres NM, Tao A, et al. BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition. Cancer Cell. 2015;28(3):370-383.
- Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464(7287):427-430.
- Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med. 2015;373(8):726-736.
- Subbiah V, Gervais R, Riely G, et al. Efficacy of vemurafenib in patients with non–small-cell lung cancer with BRAF V600 mutation: an open-label, single-arm cohort of the histology-independent VE-BASKET Study. JCO Precis Oncol. 2019 Jun 27;3:PO.18.00266. doi: 10.1200/PO.18.00266. eCollection 2019.
- Mazieres J, Drilon A, Mhanna L, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic drive alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321-1328..
- Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248-60.
- Dreno B, Ascierto PA, McArthur GA, et al. Efficacy and safety of cobimetinib (C) combined with vemurafenib (V) in patients (pts) with BRAFV600 mutation–positive metastatic melanoma: analysis from the 4-year extended follow-up of the phase 3 coBRIM study. J Clin Oncol. 2018;36(15): 9522-9522.
- Robert C, Karaszewska B, Schachter J, et al. Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib. N Engl J Med. 2015;372(1):30-39.
- Planchard D, Besse B, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label multicentre phase 2 trial. Lancet Oncol. 2016;17(7):984-993.
- Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label multicentre phase 2 trial. Lancet Oncol. 2017;18(10):1307-1316.
- Planchard D, Kim TM, Mazieres J, et al. Dabrafenib in patients with BRAF V600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(5): 642–650).
- Negrao MV, Skoulidis F, Montesion M, et al. BRAF Mutations are associated with increased benefit from PD1/PDL1 blockade compared with other oncogenic drivers in non-small cell lung cancer. J Thorac Oncol. 2019;14(suppl):Abstr MA03.05.
- Dudnik E, Bar J, Kuznetsov T, et al. P2.06-14 BAP1 Mutant Malignant Pleural Mesotheliom (MPM): Outcomes with Chemotherapy, iCPi, and PARPi. J Thorac Oncol. 2019;14(10):S760.
- Negrao MV, Raymond VM. Lanman RB, et al. Molecular Landscape of BRAF-mutant NSCLC reveals an association between clonality and driver mutations and identifies targetable non-V600 driver mutations. J Thorac Oncol. 2020; 15(10):1611-1623.