Targeting ROS1, RET, and BRAF in NSCLC

Alexander Drilon, MD

Today, we are speaking with Dr. Alexander Drilon, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City who specializes in treating patients with lung cancer. Dr. Drilon recently spoke at the New York Lung Cancer Symposium held on November 12th on three relatively new molecular drug targets for lung cancer.

-Interviewed by Anna Azvolinsky, PhD

OncoTherapy Network: There are therapies for EGFR-mutated and ALK-rearranged lung cancer. What are some of these more newly discovered molecular abnormalities in lung cancer that researchers are trying to target and maybe you can talk about their frequencies among lung cancer patients?

Dr. Drilon: Thanks. We found over the last few years that non-small cell lung cancers are really rich in several targets that are clinically actionable, meaning that these are gene changes that are either mutations or recurrent gene rearrangements for which we have targeted therapies that are either currently approved for other indications or in clinical testing or approved by the FDA [US Food and Drug Administration] for lung cancer.

Specifically, ROS1 rearrangement lung cancers are present in 1% to 2% of all non-small cell lung cancers. RET-rearranged lung cancer which are also present in about 1% to 2% of all non-small cell lung cancers and other events that include mutant lung cancers that serves as drivers of lung cancer growth, such as BRAF-mutant lung cancers that make up about 4% of non-small cell lung cancers. The druggable alterations for BRAF mutants are the V600E alterations, similar to what we see with melanoma. And lastly, I would like to mention also that recently MET exon 14 splicing alterations are a clinically actionable driver for which targeted therapies are currently being explored.

OncoTherapy Network: Maybe we can start with the BRAF mutations. So there are BRAF-targeting oral drugs now approved, as you mentioned, for V600-mutated metastatic melanoma. Can you talk about the development of these types of drugs for BRAF-mutated lung cancer?

Dr. Drilon: The paradigms that we see for targeting BRAF V600E-mutated lung cancer are not very different from what we see for melanoma. There is single-agent activity of BRAF tyrosine kinase inhibitors [TKI], so specifically vemurafenib [Zelboraf] and dabrafenib [Tafinlar] have been tested in advanced non-small lung cancer with V600E BRAF mutations. And the dabrafenib data specifically, which was published in Lancet Oncology, the response rate with a single agent is approximately 33%. And while this seems low compared to EGFR and ALK tyrosine kinase inhibition, it certainly exceeds the historical response rate of about 10% that we see for cytotoxic chemotherapy.

What is interesting is that similarly to what we have observed for BRAF V600-mutated melanomas, that when you add a second drug, you get better efficacy. So in a paper also published in Lancet Oncology, where investigators gave patients with advanced BRAF V600E-mutated lung cancers dabrafenib and trametinib [Mekinist], the response rate went from 33% with single-agent dabrafenib to almost double that to about 63%. So here we are seeing the synergy of these two agents, a BRAF inhibitor and a MEK inhibitor, and certain adverse events such as skin toxicity we also see with melanoma, was also lower with the combination. So this looks to be a very active treatment with this driver mutation.

OncoTherapy Network: Rearrangements in the ROS1 gene have also been recently uncovered. Can you talk about whether these overlap with other driver mutations in lung cancer and what are the therapeutic approaches there?

Dr. Drilon: ROS1 rearrangements are thought to be mutually exclusive with other major lung cancer drivers. This is the same pattern we see with ALK-rearranged lung cancers and EGFR-mutated lung cancers. As I mentioned, ROS1-rearranged lung cancers are found in about 1% to 2% of non-small cell lung cancers. However, these are highly druggable. The ROS1 inhibitor that has been tested in phase I expansion cohorts is crizotinib [Xalkori], a multikinase inhibitor with activity against ALK, MET, and ROS1 and specifically, for advanced ROS1-rearranged lung cancers, the overall response rate was in the order of 70% with a median progression-free survival of approximately 20 months, which is more than what we have seen in terms of median progression-free survival with the same drug in ALK-rearranged lung cancer. So we are seeing very durable responses to TKI therapy in ROS1-rearranged lung cancers and crizotinib has been approved by the FDA for the treatment of these patients recently.

OncoTherapy Network: RET rearrangements in lung cancer are also being pursued as a therapeutic target. Could you talk about that approach?

Dr. Drilon: RET-rearranged lung cancers have been a focus of my research. These are similar in incidence to ROS1 overally, found in 1% to 2% of non-small cell lung cancers and are also mutually exclusive to other lung cancer driver mutations for the most part. We had a phase II trial of cabozantinib that was presented at ASCO [American Society of Clinical Oncology] last year which showed that the response rate with the drug, a multikinase inhibitor with activity against RET, is approximately in the 30% range, which again, much less than we have seen than with EGFR and ALK, but similar to what we see with single-agent BRAF inhibition, specifically dabrafenib for BRAF-mutated non-small cell lung cancers.

Now, several other phase II trials have been reported out in the last few months. There is a Japanese trial with vandetanib [Caprelsa], also a multikinase inhibitor with activity against RET and a Korean trial, both are phase II trials where the response rates were about 50% and 16%, respectively. Other drugs being explored include lenvatinib [Lenvima] which reported out recently at ESMO [European Society for Medical Oncology] and also had about a 16% response rate. So, you’ll see that across the board, the response rates are lower for RET-rearranged lung cancers and I think we have a long way to go for this subset of patients. There are newer RET inhibitors that are currently in preclinical development that are more specific for RET and it’s possible that those will be both better tolerated and may have better activity once they hit the clinic.

OncoTherapy Network: And just lastly, these molecular targets make up a small proportion of the patients with lung cancer tumors as you mentioned. Is this a hurdle for the development of drugs for these patient subpopulations?

Dr. Drilon: I think as we get down to smaller and smaller slices of the pie, it certainly gets more difficult. And so, we have to lean more heavily on trials that are cooperative and involve multiple centers across the globe, especially for very rare subsets. But the incidence of lung cancer overall is relatively high compared to other cancers. In the US, the incidence is about 200,000 cases per year so if you have a 1% event you can still find a substantial proportion of patients. But more and more, we need to consider how to design clinical trials for these rarer subsets as we discover smaller slices of the pie.

OncoTherapy Network: Thank you so much for joining us today, Dr. Drilon.

Dr. Drilon: You’re welcome.