BRAF V600E Testing Necessary in NSCLC, but Experts Unsure of Optimal Setting With BRAF/MEK Combo

Christina S. Baik, MD, MPH

Upfront testing for BRAF V600E mutations is necessary for patients with non—small cell lung cancer (NSCLC), but if results are positive, physicians are unsure when to administer BRAF/MEK combination therapy—and they must be prepared to manage the associated adverse events (AEs).

“The key is to test these patients. A lot of times, by the time you’ve done EGFR/ALK/ROS1, there is not enough tissue to keep testing these patients,” said Christina S. Baik, MD, MPH, assistant professor at Seattle Cancer Care Alliance, and of the Department of Medicine, Division of Medical Oncology, at Fred Hutchinson Cancer Research Center. “I do think it’s important to test. Combination treatment is active, and the efficacy really does appear to be similar when you give it in the first-line or later-line settings. There are no real data to inform us when to use these drugs, but they should be used at some point during their treatment course.”

Baik highlighted new treatment approaches for patients with BRAF V600E—positive NSCLC that maximize efficacy and safety in a presentation during the 5th Annual Miami Lung Cancer Conference.

BRAF mutations make up 3% to 5% of all patients with NSCLC, with BRAF V600E mutations making up 1% to 2% of all patients with NSCLC, Baik explained. BRAF V600E mutations are most often seen in adenocarcinoma (98% of all cases) and have no clear association with age, gender, or smoking history.¹

While the options aren’t as varied for BRAF V600E-positive patients as they are for EGFR-mutant or ALK-rearranged patients with NSCLC, Baik says they can be treated with a combination regimen of BRAF and MEK inhibitors, now an FDA-approved option with dabrafenib (Tafinlar) and trametinib (Mekinist).

“BRAF is part of the RAS/RAF/MEK pathway and the most obvious target is BRAF, but we’ve learned from the melanoma studies that when we target BRAF, we really need to also target the downstream MET,” she said.

Data have demonstrated the efficacy of both BRAF monotherapy and combination approaches. A phase II clinical trial of 84 patients with stage IV metastatic BRAF V600E—positive NSCLC who were treated with dabrafenib demonstrated an investigator-assessed overall response rate (ORR) of 33% (95% CI, 25-45). Four of 6 previously untreated patients achieved an objective response.²

The BRAF inhibitor zemurafenib (Zelboraf) has also showed encouraging activity as a single agent in a phase II basket trial. In a cohort of 20 patients with BRAF V600 mutation—positive NSCLC treated with vemurafenib, the ORR was 42% (95% CI, 20%-67%) and the median progression-free survival (PFS) was 7.3 months (95% CI; 3.5-10.8).³

“It looks active, but the response and efficacy data are not as impressive as what were used to seeing for other targeted therapies,” said Baik on the monotherapy outcomes.

However, the BRAF/MEK combination strategy of dabrafenib and trametinib has shown efficacy for patients with BRAF V600E—positive advanced or metastatic NSCLC and was approved the FDA in June 2017. The European Union approved the combination in April 2017.

With the FDA’s approval, the agency also approved the Oncomine Dx Target Test, a next-generation sequencing (NGS) test, which detects the presence of BRAF, ROS1, and EGFR gene mutations. This is the first NGS oncology panel test the agency has approved for multiple companion diagnostic indications.

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

At an updated analysis with a median follow-up of 16.2 months, the 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 PFS was 10.2 months (95% CI, 6.9-16.7) and the 12- and 24-month PFS rates were 43% and 22%, respectively. Median overall survival was 12.7 months (95% CI, 7.3-16.3) with 57 deaths reported for those treated with dabrafenib monotherapy and 18.2 months (95% CI, 14.3-not estimable) with 33 deaths reported for patients treated with dabrafenib and trametinib.

“It looks active, but the toxicities can be quite challenging for our patients,” said Baik.

With the combination of dabrafenib and trametinib, 64% of patients reported grade 3/4 AEs including pyrexia (11%), vomiting (8%), and rash (3%). Baik added that other toxicities are usually mild, but ones such as fatigue and fever can significantly impact quality of life. Drug-related events include fever and cough with dabrafenib and decreased cardiac function with trametinib, while other AEs are likely due to the 2 drugs combined, she added.

Physicians should use clinical judgement when managing fever in patients on the combination to determine whether to investigate for infectious etiology. If no infection is suspected, Baik suggested that physicians should use anti-pyretic agents followed by holding treatment with dabrafenib if fever persists. Once resolved, patients should pre-medicate with an anti-pyretic agent and re-dose with dabrafenib. However, if fever recurs then dose reduction is necessary.

Additional toxicities that are rare with the combination of BRAF and MEK inhibitors, but notable, include ejection fraction decrease (8%-9%), hemoptysis (7%-9%), and squamous cell carcinoma of the skin (<5%).⁵

The optimal timing of administering dabrafenib with trametinib is a challenge, Baik said, as there are no head-to-head comparisons against chemotherapy or immunotherapy, and the activity of immune checkpoint inhibition therapy in BRAF V600-mutation—positive NSCLC is unknown.

“We really don’t have data to tell it, to inform us in terms of timing of treatment, but I do think it’s helpful to remember where the data exists and where it doesn’t so then we can make a sound decision.”

However, the efficacy of the combination is superior to what is expected with first- or second-line chemotherapy, she concluded, adding that NCCN guidelines leave the decision to administer dabrafenib and trametinib as frontline therapy up to treating physicians.

References

1. 1. Planchard D, Besse B, Groen HJM Souquet PJ, Quoix EA, Baik CS. An open-label phase II trial of dabrafenib (D) in combination with trametinib (T) in patients (pts) with previously treated BRAF V600E—mutant advanced non-small cell lung cancer (NSCLC; BRF113928). J Clin Oncol. 2016;34(15):107.
2. 1. 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. doi: 10.1016/S1470-2045(16)00077-2.
3. Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Eng J Med. 2015;373:726-736. doi: 10.1056/NEJMoa1502309.
4. 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).
5. Welsh SJ, Corrie PG. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol. 2015;7(2):122-136. doi: 10.1177/1758834014566428.