Major Advances in RET Inhibition for NSCLC and MTC - Episode 7

Importance of Frontline RET Inhibition in NSCLC


Jared Weiss, MD: Now, for EGFR and ALK certainly, when we see these response rates of roughly two-thirds, PFS [progression-free survival] of 10 to 20 months, these kind of toxicity profiles, what we've done there has moved the drugs to the front line. If you look at the FDA approval of these 2 agents, the FDA “forgot” to mention line of therapy. These are both indicated for RET-rearranged lung cancer. In your practice, are you planning on using these as frontline agents?

Benjamin P. Levy, MD: Yes, you get 1 chance to get it right for lung cancer. You mentioned early in our conversation how unforgiving of a disease it can be, so you need to identify these up front and give your best drug first. This is a call for testing. This means that you must identify it. This means you need to pick an optimal platform and consider plasma as well, so that you can deliver the drug first. Every line of therapy that a patient gets, you lose an opportunity. We know there is drop-off and patients, unfortunately, when their tumors progress, some of them are not candidates for treatments. For all those reasons, I tend to try to give this drug first. I don't know what your thoughts are on this.

Jared Weiss, MD: Absolutely. Even in the absence of direct data, I would be doing it, with this kind of toxicity, response rate, and durability. But we actually do have data. The selpercatinib patients who were treated as their first treatment, the response rate was a whopping 85%, and you’re not even out of the box. The FDA has let you out of that. In my opinion, everyone should be tested at diagnosis, and if an activating RET fusion is found, one of these drugs should be used in the first line.

Benjamin P. Levy, MD: I couldn't agree more. It's again, it's a call for testing. You can't give the drug unless you do it. And what I hear providers say is that this is only 1% to 2% of patients. But the conversation and the outcome that goes down when you identify this fusion and deliver these types of drugs is different than the conversation that goes down and the outcome that may happen when you're just delivering nonselective chemotherapy or, dare I even say, immunotherapy.

Jared Weiss, MD: We should touch on that at least briefly. There are some data on immunotherapy in RET positive patients.

Benjamin P. Levy, MD: These data come out of France. It's a retrospective analysis. It’s been published in the Annals of Oncology. It was presented 2 years back at ASCO [the American Society of Clinical Oncology annual meeting], the immuno-targeted data. The bottom line is they looked at multiple different genotypes, not only RET but others, and the single-agent activity of immunotherapy for RET-altered or RET-fused non–small cell lung cancer is very low, and the response rates aren't durable and the PFS [progression-free survival] is somewhere between 3 and 4 months. I don't know if those are the data you're alluding to or if there are others….

Jared Weiss, MD: Yes, that's 1 of the 3. There are 3 retrospective case series I'm aware of. Two of them looked absolutely horrible. One looked like about a 30% response rate, if I remember right. If you sum them all together, it's about a 10% response rate, as you say, not great durability. And as well, there is anecdotal experience that the toxicities of the TKIs [tyrosine kinase inhibitors] may be worse after PD-1s. When considering both the opportunity cost in terms of drugs like pralsetinib and selpercatinib, as well as just the lack of efficacy, I wouldn't say I would never offer a PD-1 drug to a RET-rearranged patient, but it wouldn't be my first- or second-line treatment. It would be a deep salvage that I would have to have a conversation with the patient about. 

Benjamin P. Levy, MD: Yes, I think the single-agent activity, if I'm going to give it, it may have to be in combination with chemotherapy. But I would agree a consideration for immunotherapy in this case would have to be at a salvage, no trial or anything else going on for that patient, in which we were fourth, fifth line; it certainly may be something to consider.

Transcript Edited for Clarity