Treatments Emerging for ROS1-, BRAF-Driven Lung Cancers

Deepa S. Subramaniam, MBBS, MSc

Next-generation sequencing (NGS) should be used for all patients with newly diagnosed lung cancer to identify the most personalized treatment approaches, some of which are becoming available for patients with ROS1-positive disease, said Deepa S. Subramaniam, MBBS, MSc.

In ROS1-positive non—small cell lung cancer (NSCLC), crizotinib (Xalkori) is the only FDA-approved drug; however, others have shown promise in recent clinical trials.

For example, in the ongoing, phase I/II TRIDENT-1 study, repotrectinib (TPX-0005) demonstrated a clinically meaningful and durable benefit across multiple doses in patients with ROS1-positive NSCLC. Overall response rates (ORRs) were 80% (95% CI, 44%-97%) for TKI-naïve patients and 18% (95% CI, 4%-44%) for TKI-refractory patients, including 33% for those who received a dose of 160 mg once daily. A range of solid tumors were treated, with the most common being NSCLC (83%).

OncLive: Please provide an overview of your presentation.

In an interview with OncLive^® at the 2018 State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Subramaniam, director, Multidisciplinary Thoracic Oncology Clinic, director, Brain Tumor Center, MedStar Health, discussed the complex and evolving treatment paradigm of BRAF- and ROS1-driven NSCLC.Subramaniam: In ROS1-directed cancers, the only approved drug at this point is crizotinib. However, we have a lot of exciting new drugs in development, and there are 3, specifically, that are notable. Entrectinib, lorlatinib (Lorbrena), and repotrectinib are these drugs.

Entrectinib has already completed its basket trial of ROS1-positive cancers, and it does appear to have a superior duration of response and progression-free survival (PFS) to crizotinib. It is likely this drug will be approved for treatment-naïve patients with ROS1-positive NSCLC. However, this treatment is not particularly effective in those who have received prior crizotinib. I think this drug is going to be used as a frontline treatment. We are still waiting to hear data about repotrectinib.

What is the importance of performing a full-gene panel test in patients?

Could you share insight on some of the data with entrectinib and lorlatinib?

In BRAF-positive patients, there has not been a whole lot of movement in the field, but we do have a viable combination emerging: dabrafenib (Tafinlar) and trametinib (Mekinist). There is a 64% ORR in this patient population. There are not a lot of other combinations at this point. Therefore, we would probably have to treat these patients as if they do not have a driver mutation.Certainly, with the driver mutations that I mentioned, these are commonly in the panel of testing in most institutions. There are FDA-approved therapies for these targets. What is most important is targeting the mutations for which we do not have therapies. MET and RET fusions are among these. They are rare, but if you look at the greater scope of lung cancer, about 60% to 70% of patients have some sort of oncogenic driver. There are innumerable clinical trial options for these patients. It is crucial for all newly diagnosed patients to undergo NGS.With regard to entrectinib, we saw a median PFS of a little more than 2 years. With lorlatinib, there were only 34 patients tested. It was primarily a study focusing on ALK-positive NSCLC, and a heterogeneous cohort study of mostly treatment-naïve patients. Where I see the data going is that entrectinib might replace crizotinib as a frontline therapy for patients with ROS1-positive NSCLC. We do know that entrectinib is not very active in patients previously treated with a TKI.

How do you see treatment changing for these cancers with less common driver mutations?

What would be your advice to an oncologist treating patients with these rare drivers?

There may also be a role for cabozantinib (Cabometyx), which is approved in a few other cancers. This is a multikinase inhibitor that seems to have activity against the G2032R mutation in ROS1-positive NSCLC. As we learn more about these cancers and develop an optimal sequence, we might see there is a role for all of these agents.We just saw the first FDA approval for a targeted therapy directed to a molecular alternation rather than a disease-specific group. We will see more approvals of drugs like this. For example, the trial where entrectinib was tested included patients of all ROS1-positive cancers, not just lung cancer. We see multiple solid tumors enrolled in these studies. It does not seem that these drugs are effective only in specific diseases; the magnitude of the benefit may vary. We will see an explosion of approvals for targeted therapies for driver mutations, not specific diseases.The most important thing is to first look for FDA-approved drugs, if there are any. Clinical trial referral is the next most important thing. Even though there may be an approved drug already, there may be drugs in clinical trials that work better. I had a patient with newly diagnosed ROS1-positive NSCLC with brain metastases. I could give her a ROS1 inhibitor, but I know that that crizotinib is not a good central nervous system (CNS) drug. We would have to do brain radiation before starting crizotinib. Instead, I would enroll this patient on a trial with entrectinib because we believe entrectinib has good CNS activity.

Lin J, Kim D, Drilon A, et al. Safety and preliminary clinical activity of repotrectinib (TPX-0005), a ROS1/TRK/ALK Inhibitor, in advanced ROS1 fusion-positive NSCLC. In: Proceedings from the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract OA02.02.