In the Journals

Dabrafenib plus trametinib shows promise for BRAF–mutated NSCLC

Combined treatment with dabrafenib and trametinib demonstrated robust antitumor activity and tolerable safety for patients with BRAFV600E–mutated non–small cell lung cancer, according to phase 2 study results.

“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,” Bruce E. Johnson, MD, professor of medicine at Harvard Medical School, chief clinical research officer at Dana-Farber Cancer Institute, and ASCO president-elect, and colleagues wrote. “Although prognostic implications of BRAFV600E mutations are unclear, several studies have associated BRAFV600E with poor outcomes and with a lower proportion of patients achieving a response to platinum-based chemotherapy in patients with NSCLC compared with patients with NSCLC without BRAF mutations.”

Bruce E. Johnson, MD

Bruce E. Johnson

Dual inhibition of BRAF and MEK has led to improved outcomes in patients with BRAFV600E–mutated metastatic melanoma compared with BRAF inhibition alone. A preclinical study of dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, GlaxoSmithKline) inhibited cell growth in a BRAFV600E–mutated lung carcinoma cell line.

Johnson and colleagues sought to observe the safety and efficacy of the combination in patients with BRAFV600E–mutated NSCLC.

The researchers conducted an open-label, nonrandomized study that included data from 57 patients (median age, 64 years; range, 58-71; 51% men) with metastatic, pretreated stage IV BRAFV600E–mutated NSCLC. All patients had documented progress after platinum-based chemotherapy and treatment with no more than three prior anticancer systemic therapies.

Patients received 150 mg oral dabrafenib twice a day and 2 mg of oral trametinib once a day for continuous 21-day cycles. Treatment continued until progression, withdrawal of consent, unacceptable toxicity or death.

Investigator-assessed overall response rate served as the primary endpoint. The researchers assessed safety at least once every 3 weeks.

Thirty-six patients responded for an ORR of 63.2% (95% CI, 49.3-75.6). Two patients (4%) achieved a complete response and 34 (60%) achieved a partial response. Nine patients (16%) had stable disease, whereas seven patients (12%) had progressive disease.

The disease control rate was 78.9% (95% CI, 66.1-88.6).

Median PFS of 9.7 months (95% CI, 6.9-19.6), with a median duration of response of 9 months (95% CI, 6.9-18.3).

OS data were immature at the time of the analysis. The researchers reported that 82% (n = 47) of patients remained alive at 6 months, with 23 deaths (40%) recorded at data cutoff.

The median duration of treatment for both agents was 10.6 months (interquartile range, 4.2-12.2), and 32 patients (56%) experienced serious adverse events.

Frequently observed adverse events included pyrexia (n = 9; 16%), anemia (n = 3; 5%), confused state (n = 2; 4%), decreased appetite (n = 2; 4%), hemoptysis (n = 2; 4%), hypercalcemia (n = 2; 4%), nausea (n = 2; 4%) and cutaneous squamous cell carcinoma (n = 4; 7%).

Grade 3 or worse adverse events included neutropenia (n = 5; 9%), hyponatremia (n = 4; 7%) and anemia (n = 3; 5%).

Four patients died while on treatment. The researchers judged the causes of death — which included retroperitoneal hemorrhage, subarachnoid hemorrhage, respiratory distress and severe disease progression — to be unrelated to treatment.

The trial remains ongoing, although new patients are no longer being enrolled.

“To the best of our knowledge, this report is the first to show a highly effective targeted therapy combination strategy in this patient population, which has few treatment options that can achieve more than 50% overall response and median PFS longer than 9 months,” Johnson and colleagues wrote. “The emergence of optimized sequencing strategies and targeted agents, including dabrafenib plus trametinib, will continue to broaden personalized therapy in NSCLC and improve patient outcomes.”

Additional trials are needed to further validate targeted treatments in this patient population, Gareth Rivalland, BHB, MBChB, FRACP, and Paul Mitchell, BHB, MBChB, MD, FRACP, GAICD, both of Olivia Newton-John Cancer and Wellness Centre and University of Melbourne in Victoria, Australia, wrote in an accompanying editorial.

“Diagnosis and treatment of rare lung cancer subtypes requires a coordinated approach to tissue collection and comprehensive molecular diagnosis, as has been achieved by several cancer centers and the national program established in France,” Rivalland and Mitchell wrote. “Well-organized international collaborations, such as the Thoracic Alliance for Cancer Trials — a recently established umbrella organization of national trial groups — are increasingly needed to do timely trials in rare lung cancer subtypes, especially multimodality studies. As our ability to screen for rare and actionable mutations improves, so must our ability to bring effective treatment strategies to the clinic.” – by Cameron Kelsall

Disclosure: GlaxoSmithKline funded this study. Johnson reports personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Chugai, Clovis, Genentech, KEW Group, Merck and Novartis, as well as post-market revenue for an EGFR genotyping patent. Please see the full study for a list of all other researchers’ relevant financial disclosures. Rivalland reports personal fees from AstraZeneca and nonfinancial support from Pfizer for research outside the submitted work. Mitchell reports personal fees or nonfinancial support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene and Roche.

Combined treatment with dabrafenib and trametinib demonstrated robust antitumor activity and tolerable safety for patients with BRAFV600E–mutated non–small cell lung cancer, according to phase 2 study results.

“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,” Bruce E. Johnson, MD, professor of medicine at Harvard Medical School, chief clinical research officer at Dana-Farber Cancer Institute, and ASCO president-elect, and colleagues wrote. “Although prognostic implications of BRAFV600E mutations are unclear, several studies have associated BRAFV600E with poor outcomes and with a lower proportion of patients achieving a response to platinum-based chemotherapy in patients with NSCLC compared with patients with NSCLC without BRAF mutations.”

Bruce E. Johnson, MD

Bruce E. Johnson

Dual inhibition of BRAF and MEK has led to improved outcomes in patients with BRAFV600E–mutated metastatic melanoma compared with BRAF inhibition alone. A preclinical study of dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, GlaxoSmithKline) inhibited cell growth in a BRAFV600E–mutated lung carcinoma cell line.

Johnson and colleagues sought to observe the safety and efficacy of the combination in patients with BRAFV600E–mutated NSCLC.

The researchers conducted an open-label, nonrandomized study that included data from 57 patients (median age, 64 years; range, 58-71; 51% men) with metastatic, pretreated stage IV BRAFV600E–mutated NSCLC. All patients had documented progress after platinum-based chemotherapy and treatment with no more than three prior anticancer systemic therapies.

Patients received 150 mg oral dabrafenib twice a day and 2 mg of oral trametinib once a day for continuous 21-day cycles. Treatment continued until progression, withdrawal of consent, unacceptable toxicity or death.

Investigator-assessed overall response rate served as the primary endpoint. The researchers assessed safety at least once every 3 weeks.

Thirty-six patients responded for an ORR of 63.2% (95% CI, 49.3-75.6). Two patients (4%) achieved a complete response and 34 (60%) achieved a partial response. Nine patients (16%) had stable disease, whereas seven patients (12%) had progressive disease.

The disease control rate was 78.9% (95% CI, 66.1-88.6).

Median PFS of 9.7 months (95% CI, 6.9-19.6), with a median duration of response of 9 months (95% CI, 6.9-18.3).

OS data were immature at the time of the analysis. The researchers reported that 82% (n = 47) of patients remained alive at 6 months, with 23 deaths (40%) recorded at data cutoff.

The median duration of treatment for both agents was 10.6 months (interquartile range, 4.2-12.2), and 32 patients (56%) experienced serious adverse events.

Frequently observed adverse events included pyrexia (n = 9; 16%), anemia (n = 3; 5%), confused state (n = 2; 4%), decreased appetite (n = 2; 4%), hemoptysis (n = 2; 4%), hypercalcemia (n = 2; 4%), nausea (n = 2; 4%) and cutaneous squamous cell carcinoma (n = 4; 7%).

Grade 3 or worse adverse events included neutropenia (n = 5; 9%), hyponatremia (n = 4; 7%) and anemia (n = 3; 5%).

Four patients died while on treatment. The researchers judged the causes of death — which included retroperitoneal hemorrhage, subarachnoid hemorrhage, respiratory distress and severe disease progression — to be unrelated to treatment.

The trial remains ongoing, although new patients are no longer being enrolled.

“To the best of our knowledge, this report is the first to show a highly effective targeted therapy combination strategy in this patient population, which has few treatment options that can achieve more than 50% overall response and median PFS longer than 9 months,” Johnson and colleagues wrote. “The emergence of optimized sequencing strategies and targeted agents, including dabrafenib plus trametinib, will continue to broaden personalized therapy in NSCLC and improve patient outcomes.”

Additional trials are needed to further validate targeted treatments in this patient population, Gareth Rivalland, BHB, MBChB, FRACP, and Paul Mitchell, BHB, MBChB, MD, FRACP, GAICD, both of Olivia Newton-John Cancer and Wellness Centre and University of Melbourne in Victoria, Australia, wrote in an accompanying editorial.

“Diagnosis and treatment of rare lung cancer subtypes requires a coordinated approach to tissue collection and comprehensive molecular diagnosis, as has been achieved by several cancer centers and the national program established in France,” Rivalland and Mitchell wrote. “Well-organized international collaborations, such as the Thoracic Alliance for Cancer Trials — a recently established umbrella organization of national trial groups — are increasingly needed to do timely trials in rare lung cancer subtypes, especially multimodality studies. As our ability to screen for rare and actionable mutations improves, so must our ability to bring effective treatment strategies to the clinic.” – by Cameron Kelsall

Disclosure: GlaxoSmithKline funded this study. Johnson reports personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Chugai, Clovis, Genentech, KEW Group, Merck and Novartis, as well as post-market revenue for an EGFR genotyping patent. Please see the full study for a list of all other researchers’ relevant financial disclosures. Rivalland reports personal fees from AstraZeneca and nonfinancial support from Pfizer for research outside the submitted work. Mitchell reports personal fees or nonfinancial support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene and Roche.