Expert Sheds Light on Lesser-Known Mutations in NSCLC

Raghava R. Induru, MD

Molecular subtyping through next-generation sequencing has revolutionized the treatment paradigm of lung cancer diagnosis and treatment, according to Raghava R. Induru, MD.

Common mutations, such as EGFR, ALK, and ROS1, have a pool of established therapeutic options; however, other mutations exist in the population of patients with non—small cell lung cancer (NSCLC) that are less frequent with, correspondingly, fewer treatment choices.

Patients with NSCLC who harbor BRAF mutations—a mutation commonly found in melanoma—have seen success with the combination treatment of dabrafenib (Tafinlar) and trametinib (Mekinist), which was approved by the FDA in June 2017 for patients with metastatic BRAF-mutant disease.

“We want to look at lung cancer as a puzzle with several pieces, rather than as a single entity,” said Induru. “We are moving away from histology-based treatment to more molecular-based treatment—which is actually the definition of precision medicine. There is a huge role for next-generation sequencing as we move forward. And, if we use the targeted treatments more effectively, they will become the standard of care.”

OncLive: Please provide an overview of your presentation.

These mutations were discussed in a lecture by Induru at the 2017 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer. In an interview during the meeting, Induru, a medical oncologist at the Levine Cancer Institute, shed light on lesser-known mutations in NSCLC, such as TRK and BRAF.Induru: The entire paradigm of treatment and testing in lung cancer has completely changed, and will continue to evolve over the next several years. From the common concept of lung cancer to molecular subtyping, the door has opened for newer and better treatments, which improve the quality of life of all patients with lung cancer.

The big 3 mutations are well known—EGFR, ALK, and ROS1—and there are several treatment options available for each. We want to continue to look at other mutations that open more treatment options. Some of them are evolving more rapidly and some are slower. Some of the clinical trials have been disappointing, while some have been very encouraging.

The 2 most important of the lesser-known mutations are BRAF, for which the combination of dabrafenib and trametinib has been FDA approved, as well as the role of a new targeted therapy called entrectinib in TRK1-, TRK2-, and TRK3-mutated lung cancers.

Let's zero in on BRAF. Can you discuss this mutation as a target?

We see [these advances] as a movement toward precision medicine, as we can subtype lung cancer as personalized as possible, and direct treatment accordingly. This will improve outcomes.BRAF is a well-known mutation in melanoma—that is where it first gained popularity—and V600E is the most common of that mutation found in lung cancer. It is found in about 3% of patients with NSCLC, and it is not exclusive to never-smokers, unlike what we see with EGFR, ALK, and ROS1 mutations. Instead, this is found in smokers—over 60% of smokers could harbor this mutation. Which means the actual number of patients with lung cancer who have this mutation could be much higher than patients with ALK or ROS1.

You mentioned entrectinib. Could you share some insight on that agent?

MSI is largely associated with colorectal cancer. What is its role as a target in lung cancer?

This has been studied in a few trials—initially with vemurafenib (Zelboraf)—which has shown a good response rate of about 42% in a phase II study. The combination of BRAF and MEK inhibitors showed good response rates and tolerability, and has gained FDA approval—just like in melanoma. Response rates were not as good as EGFR-mutated lung cancer when treated with EGFR inhibitors.Entrectinib is a new oral tyrosine kinase inhibitor that targets the TRK signal, but is also known to have responses to ALK, as well as ROS1. The initial phase I study revealed that there were complete responses in all of the 3 patients with TRK mutations, and a 70% response rate in ROS1-mutated patients, and it is being studied as a global basket trial at 134 centers. [This study] is looking at responsiveness of entrectinib in several cancers that could harbor TRK mutations. MSI is starting to gain more attention, especially with the recent evidence of MSI-high (MSI-H) tumors responding well to immunotherapy. Pembrolizumab (Keytruda) is approved in all of the solid tumors that exhibit MSI-H. Hence, MSI is a good marker, as well, although the instance of MSI in NSCLC is 0.8%, based on the limited data that we have. This was a study involving 480 patients with adenocarcinomas. Certainly, as we subtype more lung cancers, we may better understand the instances of MSI-H tumors in lung cancer.