What’s New in Targeted Lung Cancer Treatment?

Derick Alison
Derick Alison
11 Min Read

MedPage Today brought together three expert leaders for a virtual roundtable discussion on lung cancer: Moderator Roy Herbst, MD, PhD, is joined by Anne Chiang, MD, PhD, and So Yeon Kim, MD, all from the Yale Cancer Center in New Haven, Connecticut.

This first-of-four exclusive episodes focuses on new data on targeted drugs for non-small cell and small cell lung cancer that may affect how patients are treated.

Following is a transcript of their remarks:

Herbst: Hi, I am Dr. Roy Herbst from the Yale Cancer Center where I’m the deputy director and the assistant dean for translational research. I’m thrilled to be joined by some of my colleagues today on this MedPage Today program where we’re going to talk about some very exciting and new topics in non-small cell and small cell lung cancer. I’m joined by Dr. Anne Chiang and Dr. So Yeon Kim.

It’s wonderful to be here, I feel like we’re in the clinic at a tumor board and we can discuss interesting cases. So number one, let’s talk about EGFR. What’s new with EGFR right now? Anne, we were just in Singapore, I’m not sure if you were there, but you probably saw it, but there was this FLAURA2. What is FLAURA2? Is that going to have any impact on our practice?

Chiang: FLAURA2 is really exciting. It’s a phase III trial for osimertinib [Tagrisso] and chemo versus osimertinib alone for first-line therapy, and that was a positive trial. It showed that the median PFS [progression-free survival] was improved by about almost 9 months with the [osimertinib]/chemo combination and the PFS was somewhere around 25 [months], so that was 25 versus 16 months or so, and it really decreased the risk of disease progression by around 40%. So hazard ratio of 0.60.

I think this is really exciting. We’ve always talked about using our best guns upfront and I think this is saying, well, maybe we can do better than what we’ve been doing already. I just think that we’ll have to talk about the effects on the patients and the toxicities of that additional therapy, but this looks really good. I think it’ll be practice changing.

Herbst: What do you think, So Yeon, you were there, you saw the presentation. It’s a bit more inconvenient for patients and has toxicities. Will you use it?

Kim: Yeah, so I believe that that was a great plenary session and I think there’s a couple of things that we have to think about. So we have osimertinib, which is a very good first-line drug, and there’s other third-line TKIs [tyrosine kinase inhibitors] that have demonstrated good efficacy. For example, lazertinib, which is very good CNS [central nervous system] efficacy as well. Of course we can’t really do cross-trial comparisons, but I think with the better CNS efficacy possibly with lazertinib, and the MARIPOSA trials that are coming out that combine lazertinib with also amivantamab [Rybrevant], there’s different options that we have to think about for first-line therapies.

As far as whether I would use it for my patients in the first-line treatment, many patients with EGFR therapies come to us to be off of chemotherapy, so there is a PFS benefit, but until we really know for sure that there is an OS [overall survival] benefit, I think I would possibly really save it for patients with CNS metastases at baseline.

Herbst: Right. And you mentioned the MARIPOSA, at the time of this filming it’s not out yet. It will be at the ESMO [European Society for Medical Oncology] meeting, which is coming up. Any thoughts on that? Is amivantamab less toxic than chemotherapy in a combination? And again, we have to wait and see what the hazard ratio is and the results, but is that something that could take off and how toxic and how convenient is that for patients?

Kim: So I think MARIPOSA and MARIPOSA-2 will be a very interesting as far as understanding the results. So MARIPOSA is looking at the combination of amivantamab and lazertinib versus [osimertinib] alone and also versus lazertinib alone, and that’s in the first-line setting. And then MARIPOSA-2 is actually looking at the combination of amivantamab, lazertinib and chemotherapy versus chemotherapy versus a combination of amivantamab and chemotherapy to really understand the effects of lazertinib. So it’s a trial that’s looking at it in the second line. So I’m very excited for those results at ESMO.

And of course amivantamab has its own toxicities, for example, infusion reactions, so how that plays into account versus chemotherapy side effects, we’ll have to take a better look.

Herbst: Yeah, it’s an exciting time. A lot of new data. What about something new? We’re talking about chemotherapy, a dual EGFR-MET antibody. Is there anything from precision medicine, Anne, that can help us to even be more precise in what we do in EGFR-resistant disease?

Chiang: Yeah, I think there’s a lot out there, especially around antibody-drug conjugates [ADCs]. I’ll say just one more comment about MARIPOSA and amivantamab. There are trials looking at a subcutaneous version of that and I think that might be really interesting to stay abreast of because it may actually help the decrease the CRS, the cytokine release syndrome potentially, I don’t know. Or it might be easier for patients to tolerate. So I think that just thinking about subcutaneous versions of anti-cancer treatment I think is really interesting to highlight and to look out for.

But you asked me about precision medicine and I think that one way — we’ve always thought about biomarkers and certainly that leads us back to the EGFR story, and we can talk about ADAURA and things like that. But if we think about antibody-drug conjugates that are targeted and precisely towards certain tumor cells by the expression of proteins on their services, I think that thinking about the DLL [delta-like ligand] story for small cell is really interesting.

DLL3 is often expressed on the surface of small cell proteins. There have been other approaches looking at antibody-drug conjugates direct against DLL3, but I think one of the most exciting compounds or agents in small cell is the bispecific antibody with one head directed towards DLL3 and the other a T-cell engager with CD3. And so tarlatamab is the Amgen bispecific and at ASCO [American Society of Clinical Oncology] we also heard about the BI compound [BI 764532], and both of those are very exciting because you’re looking at small cell patients who’ve progressed on multiple other regimens and are still having really robust responses there.

The other ADC I think to keep an eye on is TROP2, and both in small cell and in non-small cell that looks like a very interesting compound with some robust responses.

Herbst: Are those for EGFR-mutated disease though?

Kim: Yeah, so they actually looked at Dato-DXd [datopotamab deruxtecan] in subcohort of patients with EGFR [mutations] and there was some efficacy of overall response, about 33%, so I think there is a little bit of signal there as well for Dato-DXd.

Herbst: OK. But they’re looking at those in small cell, there are some data coming. A phase II trial of that DLL3 in small cell is soon to report, correct?

Chiang: Yeah. The tarlatamab trial, that first in-human trial was recently published, and that’s a drug that has pretty significant cytokine release syndrome symptoms, about 50% to 80%. And so it’s a drug you have to be hospitalized for, but we are trying to look at whether you can do that in the outpatient setting. We treated our first patient at Yale, the 8-hour monitoring, and she was unfortunately hospitalized. But I think again, we’re trying to push the envelope there.

Herbst: Beautiful. Well, a lot going on and new data that are coming down the pike that clinicians are going to have to assimilate in their practice. My take on all this is that we do have some new options in EGFR-mutated disease, which we’ve been treating now for about 25 years. We know that we can do quite well in patients with EGFR mutations, but we don’t cure anyone except perhaps in the earliest stages, adjuvant, neoadjuvant. So new combinations are going to be critical. The question is at what cost and then what do you do next after you’ve given that combination. But the discussion will continue and thank you both. That was great.

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