BRAF/MEK Combo New Standard for BRAF-Mutant NSCLC

David R. Gandara, MD

Targeted therapies are beginning to carve out a growing number of indications in non—small cell lung cancer (NSCLC), emphasizing the importance of precision medicine. The BRAF V600E mutations, which is present in 1% to 2% of NSCLC, was recently added to the list of potential targets, with an FDA approval for the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) in June 2017.

With new agents being introduced into the lung cancer paradigm, it becomes imperative for physicians to learn how to optimally use these medications, specifically when it comes to managing toxicities, according to David R. Gandara, MD, at the 18th Annual International Lung Cancer Congress.

"This is, I think, a major advance in the treatment of BRAF-mutated non—small cell lung cancer," said Gandara, an OncLive Giant of Cancer Care in lung cancer and the director of the University of California Davis Comprehensive Cancer Center's Thoracic Oncology Program. "If I identify a BRAF mutation in V600E, at least in California, insurance companies will approve this regimen."

In the phase II study that led to the approval, 57 previously-treated patients with NSCLC received dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily. The median age of patients was 64 years (range, 41-88) and 51% were female. All patients had nonsquamous histology and 73% were current or former smokers.

After a median follow-up of 16.2 months, the objective response rate (ORR) was 66.7% (95% CI, 52.9%-78.6%) and the median duration of response was 9.8 months (95% CI, 6.9-16.0). The median progression-free survival (PFS) was 10.2 months (95% CI, 6.9-16.7) and the 12- and 24-month PFS rates were 43% and 22%, respectively.

To illustrate the benefit seen with the combination, Gandara presented two case studies of excellent responses. The first example was a 59-year-old male who was a 70 pack years’ former smoker. The patient had adenocarcinoma with irradiated brain metastases and was treated in the second-line setting. Following treatment with the combination, the patient had a partial response at week 6 and a 70% reduction in tumor size that lasted for 12+ months.

In the second highlighted case, the patient was a 61-year-old female who had never smoked. She had adenocarcinoma with pleural effusion and liver metastases. The patient had previously received cisplatin plus pemetrexed, docetaxel, and gemcitabine. A partial response was observed at week 6 with a 54% reduction in tumor volume, which increased to a 73% tumor reduction for a duration of 9+ months.

The most common adverse events (AEs) of all grades with the combination were pyrexia (46%), nausea (40%), vomiting (35%), diarrhea (33%), asthenia (32%), dry skin (26%), decreased appetite (30%), chills (23%), peripheral edema (23%), rash (21%), and cough (21%). Serious AEs occurred in 56%, of which 7% (n = 4) were fatal but deemed unrelated to the medication.

"This is not a particularly easy combination to give," said Gandara. "I've treated quite a few patients, and there's quite a bit of pharmacodynamic variance from patient to patient. Some tolerate the combination quite well and others have intolerable GI or skin toxicity, primarily, and require dose reductions. Most patients can settle in at a 50% dose in my experience."

While Gandara implied that he reduced the dose for both medications simultaneously, others in the audience noted that reducing trametinib first may represent another option, as mechanistically the BRAF inhibitor dabrafenib may be more important for the efficacy seen with the combination. In either case, dose reductions appear not to dramatically impact efficacy, in anecdotal accounts, even when starting at a lower dose before AEs occur.

"I'm not sure we need to dose this regimen at the maximum tolerated dose for the individual drugs,” Gandara noted. “There's also inter-patient variability.”

The phase II study that led to the approval also contained an arm with single-agent dabrafenib (n = 78). In this group, the ORR was 32.1% (95% CI, 21.9%-43.6%). The median duration of response was 9.6 months (95% CI, 5.4-15.2). The median PFS was 5.5 months (95% CI, 2.8-7.3) and the 12- and 24-month PFS rates were 26% and 14%, respectively.

With the approval of the combination, the FDA also approved the Oncomine Dx Target Test, a next generation sequencing (NGS) test, which detects the presence of BRAF, ROS1, and EGFR gene mutations. As precision medicine continues to expand in NSCLC, NGS will continue to play an important role, although reimbursement for these tests remains a challenge, Gandara concluded.

Planchard D, Besse B, Kim TM, et al. Updated survival of patients (pts) with previously treated BRAF V600E—mutant advanced non-small cell lung cancer (NSCLC) who received dabrafenib (D) or D + trametinib (T) in the phase II BRF113928 study. J Clin Oncol. 2017;35 (suppl; abstr 9075).