Treatment Options Expand for ROS1, BRAF, and NTRK Alterations in NSCLC

Lisa Astor
Published: Saturday, Jan 26, 2019

Christina S. Baik, MD, MPH
Christina S. Baik, MD, MPH
The scope of targeted therapies has extended more in non–small cell lung cancer (NSCLC), especially with the recent FDA approval of larotrectinib (Vitrakvi) for patients with NTRK gene fusions irrespective of the primary tumor type. A growing focus on smaller oncogenic drivers in lung cancer has opened up new treatment options and many potential drugs in development for patients with less common alterations.

During a presentation at the 16th Annual Winter Lung Cancer Conference, Christina S. Baik, MD, MPH, discussed several existing and emerging treatment options for ROS1, BRAF, and NTRK genetic aberrations.

ROS1-Targeted Therapy

ROS1 translocations or rearrangements occur in about 1% to 2% of patients with NSCLC, and usually only in those with a nonsquamous histology. Baik explained that ROS1-rearranged NSCLC usually occurs in younger patients who are never smokers.

Currently, only crizotinib (Xalkori) is FDA-approved for the treatment of patients with ROS1-positive NSCLC. However, Baik said that patients with ROS1 will eventually develop resistance to crizotinib and progress, requiring further treatment. The reasons for disease progression on crizotinib are typically either central nervous system (CNS) failure or acquired resistance, which develops in about 50% to 60% of patients.

A phase II East Asian study looking at the efficacy of crizotinib in patients with ROS1-altered NSCLC demonstrated an overall median progression-free survival (PFS) of 15.9 months. When PFS was reviewed in patients with and without CNS disease at baseline, the median PFS was 18.8 months in those without CNS disease and 10.2 months in patients with CNS disease.1

Several next-generation TKIs are in development for treating patients with ROS1-altered NSCLC. Baik pointed out 2 agents that are active against CNS disease but are not reliably active against resistance mutations: ceritinib (Zykadia) and entrectinib. Ceritinib has already been approved for the treatment of patients with ALK alterations and also shows activity against ROS1.

In a phase II study of 32 patients with ROS1 rearrangements performed in Korea, ceritinib induced an objective response rate (ORR) of 67% in patients who did not receive prior treatment with crizotinib.2 The study had previously looked at patients who had received prior treatment with crizotinib but no responses were seen in pretreated patients, Baik explained. The median PFS in the overall population was 9.3 months, but in crizotinib-naïve patients, the median PFS was 19.3 months.

“That’s one more important distinction that you should keep in mind, that ceritinib is active after crizotinib in ALK-positive patients, but not in ROS1-positive patients,” Baik said. “The situation where I can think about using this drug are those patients who are crizotinib naïve who have enough CNS disease where we might be thinking about whole brain radiation unless the patient wants to postpone whole brain radiation.”

Entrectinib is a TKI that is active against ALK, ROS1, and NTRK, while it is not yet FDA approved, Baik noted that it will likely be approved in the near future.

In the cohort of patients with ROS1-positive NSCLC, entrectinib demonstrated a median PFS of 19.0 months (95% CI, 12.2-36.6). Patients with CNS disease at baseline had a median PFS of 13.6 months (95% CI, 4.5-not evaluable) and those without CNS disease had a median PFS of 26.3 months (95% CI, 15.7-36.6). The ORR was 77% with an ORR in CNS disease of 55%.3

Lorlatinib, a third-generation ALK/ROS1 inhibitor with broad activity against resistance mutations, was recently FDA approved for the treatment of patients with ALK-positive NSCLC who have previously received treatment with a second-generation ALK TKI. Baik noted that in ROS1-rearranged NSCLC, lorlatinib is active against both CNS disease and resistance mutations.

In the ROS1 cohort of a phase II trial, lorlatinib induced an ORR of 26.5% (95% CI, 12.9%-44.4%) among 34 crizotinib-pretreated patients, with stable disease also seen in 47.1% of patients.4 The median PFS was 8.5 months (95% CI, 4.4-18.0), and the median duration of response was not yet reached. Additionally, the intracranial ORR was 52.6% among 19 patients with CNS disease. Baik also pointed to repotrectinib, DS-6051b, brigatinib (Alunbrig), and cabozantinib (Cabometyx), all of which have shown preclinical activity for treating patients with ROS1 rearrangements.

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