Clinical Labeling in Medicinal Products: An Interview With Dr. David Planchard About the Effects of BRAF Mutations on Non-small Cell Lung Cancer Outcomes and Therapeutic Selection

By David Planchard, MD, PhD

What was the rationale for conducting clinical research in BRAF mutationpositive NSCLC?
Recently, progress has been made in characterization of the oncogenic driver mutations that contribute to the molecular pathogenesis of lung cancers, including activating mutations in EGFR and ALK rearrangements. Moreover, lung cancer has one of the highest rates of genetic alterations when compared with other cancers. Some of the alterations are actionable via the administration of drugs that have already been approved, are available for off-label use for other indications, or are under investigation in clinical trials. Activating mutations in the BRAF gene, which are generally mutually exclusive from EGFR mutations or ALK rearrangements, act as an alternative oncogenic driver in NSCLC.

Most cancer cells harboring a BRAFV600 mutation display a critical dependence on the activity of this oncogene for their growth and survival, and these cells are exquisitely sensitive to selective BRAF and MEK inhibitors, irrespective of tissue of origin. Several studies have reported poor outcomes for patients with NSCLC who have BRAFV600E mutations, as well as a decrease in response to platinum-based chemotherapy for these patients.1-3

Dabrafenib and trametinib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway. Both dabrafenib and trametinib have demonstrated clinical benefit as monotherapies in randomized phase III studies when compared to chemotherapy for BRAFV600 mutation-positive metastatic melanoma.4,5 Preclinical research showed that the dabrafenib and trametinib combination was synergistic in enhancing cell-growth inhibition in the BRAFV600E mutation-positive NSCLC cell line. The combination of dabrafenib and trametinib was more effective in combination than either as single-agent therapy at inhibiting the MAPK pathway and inducing apoptosis. These effects in lung cancer cell lines were similar to those observed with the combination of dabrafenib and trametinib in BRAFV600E mutation-positive melanoma cells. Also, dabrafenib only inhibited ERK signaling in cells with mutant BRAF, whereas MEK inhibitors blocked the ERK pathway in both tumor and normal tissues.

These compelling clinical data for melanoma BRAFV600 and preclinical data for NSCLC BRAFV600 provided a rationale for conducting a study of BRAF and MEK inhibitors for patients with NSCLC.

How was France able to conduct and complete research on such a rare clinical entity?
The French National Cancer Institute funded a large-scale program in 28 molecular genetics centers and overseas entities for the systematic routine analysis of EGFR mutations and ALK rearrangements, as well as for HER2, KRAS, BRAF, and PIK3CA mutations in patients with advanced-stage nonsquamous NSCLC. In our phase II study with separate cohorts for treatment with dabrafenib alone or in combination with trametinib,6,7 BRAFV600E mutational status was ascertained based on local testing in Clinical Laboratory Improvement Amendments (CLIA)- approved laboratories or their equivalents outside of the US. Clinical correlative work with the French Cooperative Thoracic Intergroup (data from the 28 molecular genetics centers) indicated that from April 2012 to April 2013, a genetic alteration was recorded in approximately 50% of the NSCLC analyses. As part of this program, 13,906 patients were tested for BRAF mutations; of these, 262 (2%) were positive for a BRAF mutation (80% were BRAFV600E).3 In 2015, molecular screening was performed in France on roughly 26,000 patients with NSCLC. This systematic molecular screening program, which included BRAF mutation status, clearly helped us to identify a high number of patients with NSCLC who harbored a BRAF mutation and who were potentially eligible for clinical trials.

With approval of both dabrafenib and trametinib for NSCLC, what other kind of “label changes” occurred based on this research? What was the process for the regulatory changes?
We conducted a phase II study examining the clinical activity of the BRAF inhibitor dabrafenib as a single agent (Cohort A) and in combination with MEK inhibitor trametinib (Cohort B) in patients with advanced NSCLC and BRAFV600E mutations whose disease had relapsed or progressed after prior therapy.6,7 The third group (Cohort C) comprised treatment naïve patients who received the combination therapy in the first-line setting. The results demonstrated clinically meaningful antitumor activity with an objective response rate of 33.3% for Cohort A and 63.2% for Cohort B. The median progression- free survival was also longer for Cohort B when compared with Cohort A: 9.7 months vs. 5.5 months, respectively. This observation is consistent with those in metastatic melanoma studies. The most common adverse events (>20% incidence) were pyrexia, nausea, vomiting, peripheral edema, diarrhea, dry skin, decreased appetite, asthenia, chills, cough, fatigue, rash, and dyspnea.

Data from Cohort C for combination dabrafenib and trametinib in the first-line setting are not yet mature and will be presented in the near future.

These results indicated that inhibition of a BRAF mutation defines a new class of patients with a specific oncogenic driver. This trial was the first assessment of combined BRAF and MEK inhibition in NSCLC. The results were particularly noteworthy in light of scarce pre-existing data and the clear unmet need for effective targeted therapy for patients with BRAF-mutated NSCLC.

Based on the results of this phase II trial, the Committee for Medicinal Products for Human Use adopted a positive opinion on February 23, 2017, and recommended a change to the terms of the marketing authorization for the medicinal products Tafinlar (Novartis, dabrafenib) and Mekinist (Novartis, trametinib), stating specifically that “Trametinib in combination with dabrafenib is indicated for the treatment of adult patients with advanced NSCLC with a [BRAFV600] mutation.” On April 3, 2017, the European Commission approved dabrafenib in combination with trametinib for the treatment of patients with BRAFV600-positive advanced or metastatic NSCLC.

Are the majority of patients with NSCLC and BRAFV600E mutations being treated on or off protocol in France at this point?
I would say that during the accrual periods for Cohort A (October 2010 to April 2014) and Cohort B (December 2013 to January 2015) most patients in France with BRAFV600E mutations were included in this phase II trial. Since the trial has closed, patients are now receiving combination dabrafenib and trametinib off label, or they have been enrolled in a French phase II basket study, “Phase 2 Study Assessing Secured Access to Vemurafenib for Patients With Tumors Harboring BRAF Genomic Alterations (AcSé).”8 This trial is ongoing for patients with a BRAFV600 mutation, regardless of histologic type. However, patients in the trial are treated with vemurafenib alone, which—based on the results from our phase II study—is not the optimal strategy in this setting. All reports of BRAFV600 mutation cases that we have at Gustave Roussy are systematically discussed during a monthly thoracic molecular tumor board to decide the best strategy for these patients; if they are not eligible to be included in a clinical trial, the offlabel use of combination dabrafenib and trametinib is often recommended.

Are similar processes being instituted for other uncommon mutations, such as the MET exon 14 skipping mutation?
For less common driver mutations such as the MET exon 14, RET, and NTRK mutations, it has become increasingly difficult to initiate and complete prospective trials. Multicenter registries might permit the generation of meaningful clinical data in a short time period, such as with patients with RET rearrangements who were treated with different multikinase inhibitors including cabozantinib, vandetanib, sunitinib, sorafenib, lenvatinib, nintedanib, ponatinib, and alectinib. However, prospective trials with larger sample sizes are needed, and collaboration among various investigators and centers around the world is crucial. In France, we are screening for these mutations in most centers, but we lack specific trials for these populations. Most inhibitors are used off label; crizotinib for patients with a MET exon 14 mutation is an example.

Are there other data on successful BRAF or MEK inhibitors, either alone or in combination, that might sway decision making regarding treatment?
I would say no because we do not have any data regarding combination vemurafenib and cobimetinib for BRAFV600E mutation-positive NSCLC. No prospective trials have been conducted in NSCLC that are similar to what has been done in BRAFV600 mutation-positive melanoma. The only prospective results we have for vemurafenib come from the histology-independent, phase II basket study of vemurafenib monotherapy for patients with non-melanoma cancers who harbor BRAFV600 mutations.9 In France we also have conducted the previously mentioned closed basket trial of single-agent vemurafenib.2 Final results are pending for both trials; however, neither trial specifically focuses on NSCLC, and no combination with a MEK inhibitor such as cobimetinib has been tested. To my knowledge, combination dabrafenib and trametinib is one of the best strategic options for patients with NSCLC who have BRAFV600 mutations. The next step in NSCLC BRAFV600 will be to test the benefit of immunotherapy treatments (anti-PD-1 or PD-L1) either alone or in combination with dabrafenib and trametinib as is currently done in melanoma.

References
1. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-smallcell lung cancer harboring BRAF mutations. J Clin Oncol. 2011;29:3574-3579.

2. Cardarella S, Ogino A, Nishino M, et al. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res. 2013;19:4532-4540.

3. Barlesi F, Mazieres J, Merlio JP, et al. Routine molecular profiling of patients with advanced non-smallcell lung cancer: Results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet. 2016;387:1415-1426.

4. Grob JJ, Amonkar MM, Karaszewska B, et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600- mutation-positive melanoma (COMBI-v): Results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015;16:1389-1398.

5. Long GV, Grob JJ, Nathan P, et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: A pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016;17:1743-1754.

6. 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;17:642-650.

7. Planchard D, Besse B, Groen HJ, 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;17:984-993

8. Blay JY, Labouret NH, Cropet C, et al. Biomarker driven access to vemurafenib in BRAF-positive cancers: Second study of the French National AcSé Program. J Clin Oncol. 2016;34(suppl):abstr TPS11620.

9. 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.