Targeted Therapy Benefit for Actionable Mutations


Shirish M. Gadgeel, MD, MBBS:I need to state that at the present time we don’t have specific RET inhibitors approved by the FDA, though there are clinical trials ongoing with these RET inhibitors.

I would not necessarily use drugs such as cabozantinib and vandetanib as first-line therapies, based on the response rate and PFS [progression-free survival] observed in RET translocated non–small cell lung cancer. We still rely on chemotherapy or chemotherapy and immunotherapy in these patients.

But we anticipate, based on the results that are available, that these RET-specific drugs will be available very shortly, and therefore, in anticipation of that approval I would highly encourage that RET translocations be specifically assessed in patients with advanced non–small cell lung cancer, specifically patients with adenocarcinoma of the lung.

Consistently, what we have observed is targeted therapy in patients who have genetic alterations that can be targeted for therapeutic benefit provides the best response rate and generally the longest progression-free survival, at least compared with cytotoxic chemotherapy. And in general in these patients, single-agent immunotherapy has not been as efficacious. Finally, at least with certain targeted drugs, if used after initial use of immunotherapy, there is a higher incidence of certain toxicities. And so for all those reasons, but particularly the fact that you’re most likely to get the best response rate and progression-free survival with targeted therapy, I would consider targeted therapy as the initial option for patients whose tumors have genetic alterations.

Robert Doebele, MD, PhD: The rationale for broad next-generation sequencing testing in non–small cell lung cancer really comes from the remarkable efficacy of many of our targeted therapies. Prior to the advent of oncogene targeted therapy, the standard of care was chemotherapy, which is very effective in most patients. However, for those patients who have a targetable alteration, for example, those with FDA approved targets such as EGFR or ALK, we now know from multiple randomized studies of targeted agents vs. chemotherapy that the targeted agents are always superior to chemotherapy.

And they're really superior in multiple facets. They are more effective in terms of response rate, PFS, or progression-free survival. They also tend to have far fewer adverse effects. This is really a win-win for the patients. They get better efficacy with fewer adverse effects. The other thing that is, I think, important in this modern era of immunotherapy is that we are learning that…many of the patients with targetable oncogenes are not as responsive to immunotherapy and may actually have rapid progression. And so I think it's very important to identify these patients to give them the most effective therapy first.

Transcript Edited for Clarity

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