Experts Discuss Groundbreaking Advances in EGFR-Mutant Lung Cancer

In a comprehensive discussion of EGFR-mutant non-small cell lung cancer at the American Society of Clinical Oncology (ASCO) annual meeting, a number of significant advancements were highlighted, particularly from the LAURA trial, which showed improved progression-free survival with osimertinib (Tagrisso) in patients with locally advanced disease.

MedPage Today brought together three expert leaders in the field for a roundtable discussion: Moderator Roy Herbst, MD, PhD, is joined by Anne Chiang, MD, PhD, and Sarah Goldberg, MD, MPH, all of Yale Cancer Center in New Haven, Connecticut. This third of four exclusive episodes delves into the LAURA trial’s impact and other promising EGFR-targeted therapies.

Click here to watch the other videos from this ASCO roundtable series.

Following is a transcript of their remarks:

Herbst: OK, next question. Let’s talk about EGFR. There was a plenary talk in EGFR, the LAURA trial, and then there were a couple of studies looking at other ways to target EGFR. Let’s start with the LAURA. Tell us about LAURA.

Goldberg: So LAURA was one of the trials that got the standing ovation at the plenary, and I think that people were really — and I was also really excited about the data. So the LAURA trial is looking at patients with locally advanced EGFR-mutant lung cancer who undergo chemoradiation, and then were randomized to either receive osimertinib or placebo. So this is the same population of patients that were included in the PACIFIC trial, but we know that those patients with EGFR mutations don’t do very well with immune therapy, whether it’s metastatic or in locally advanced disease.

So this was a really important trial. I’ve been waiting for the results of this trial for years, and it was incredible to see the results. I expected it to be a positive study based on the benefit of osimertinib in stage IV and the benefit in the ADAURA trial for resectable stage II and III. But this was really incredible. The progression-free survival or the disease-free survival was significantly improved with the addition of osimertinib. And I think what was really eye-opening to me was how poorly people did on placebo. So chemoradiation alone for EGFR-mutant lung cancer is just really pretty terrible. Most patients, the vast majority of patients, progressed within a few years or even a few months with just chemoradiation. So osimertinib really improved the disease-free survival.

Herbst: Yeah, those were stage IIIA, IIIB, IIIC.

Goldberg: That’s right.

Herbst: So some of those patients were pretty close to metastatic disease.

Goldberg: I think probably a lot of them had metastatic disease, whether it was micrometastatic and we didn’t see it on imaging. I think that’s basically what it’s telling us. And I guess we always knew that about stage III disease since so many of them recur. But I think this was really eye-opening to me that without consolidation therapy, so many of these patients were recurring and with osimertinib they were doing considerably better, although even so patients still there was progression now, fortunately years later.

The other thing I just want to mention about the design of the trial, different from ADAURA where patients got 3 years of adjuvant osimertinib. The lower trial, the osimertinib, kept going so patients could be on it indefinitely, which there was lots of discussion in the panel about whether that’s appropriate or not, but that’s how the study was designed. So that’s the way the patients were treated was they got indefinite.

Herbst: So what do you think Anne, new standard of care?

Chiang: I think so. I think so. I do think one of the points that Dr. Sequist made in the discussion is talking to your patient about cure or not, and that we need to be a little more pragmatic that many of these patients do have micrometastatic disease. I think that talking to your patient about indefinite therapy is something that — we need to introduce that concept. I think that patients who have been on [osimertinib] for 3 years and tolerated, they’re going to be happy to continue. Honestly, they’ve been living with it for 3 years and I think they’d be more anxious to stop.

Goldberg: Yeah, I agree. It’s that stopping after 3 years is sometimes harder than just saying, OK, let’s just keep going. I actually worry about the financial toxicity though sometimes that can really be a challenge that patients have these high copays. But I agree. I think a lot of times people are happy to stay on a drug that seems to be helping. Their cancer hasn’t returned and often it’s very well tolerated.

Herbst: What about cell-free DNA and looking at MRD [minimal residual disease]? Can that be used?

Chiang: Yeah. Well, actually it just came from the session from the ADAURA trial where they looked at MRD and using ctDNA [circulating tumor DNA] in terms of regularly longitudinal monitoring of whether or not ctDNA was showing up. And in this, it was pretty impressive that in the placebo arm there were a lot more red dots indicating presence of ctDNA that weren’t there in the osimertinib arm. So I think that that would be helpful potentially to deescalate.

The other part of that that was notable to me was that most of the patients, or actually all of the patients who progressed were pretty much after they stopped their therapy. So within the next year, everybody progresses. So again, supporting this idea of micrometastatic disease.

Herbst: No, absolutely. So there are also, Sarah, in the session you shared there were several abstracts with amivantamab [Rybrevant] + lazertinib [Leclaza] and MARIPOSA updates. Tell us about that and how that fits in, and subQ [subcutaneous] versus IV [intravenous].

Goldberg: Yeah, those were some, I think also other really exciting abstracts and presentations that hopefully will change our practice in the next couple of months to years.

So there was a study that was presented at ASCO this year that I thought was really important where they compared subcutaneous to intravenous amivantamab. And that’s really important because IV amivantamab, which is what’s approved right now, has a really high rate of infusion-related reactions. I actually tell my patients they’re very likely to get a reaction. Most often it’s low-grade reactions and they do OK with stopping, slowing the rate, supportive measures. But sometimes there are high grade reactions, but it is definitely challenging. The other thing is it takes hours to give the first dose. You have to give it on days 1 and 2. So IV amivantamab is really challenging logistically. And then for the patients when they have a reaction.

But this study basically compared subcutaneous versus IV and showed that the rates of infusion reactions were significantly lower. It took 5 minutes versus something like 5 hours to give. And the clinical outcomes were the same and actually maybe even a little better with the subcutaneous form, which I don’t know that I can quite explain, but they weren’t inferior. They looked the same or maybe even better with subQ. So this is not approved yet, but I hope that it will be. And then maybe that will be an option for use for our patients.

Herbst: Make it a lot easier for patients in terms of compliance and quality of life.

Goldberg: I agree.

Herbst: OK. Is there anything else on the horizon, Sarah, for EGFR-mutant disease?

Goldberg: I think what’s so important in this space right now is figuring out the best first-line regimen. So we’ve had first-line osimertinib for several years now, and I think that that’s really the universal practice is that we use that when we make a diagnosis of metastatic EGFR lung cancer.

But now there’s a few regimens that look potentially better. So the FLAURA2 regimen, this wasn’t at ASCO, but it’s in the last year or so. I think this has really emerged. FLAURA2 regimen of chemotherapy, carboplatin plus pemetrexed, with osimertinib has an improvement in progression-free survival. And then amivantamab plus lazertinib also improves progression-free survival compared to osimertinib. And the FLAURA2 regimen is approved. So those are potential options for our patients.

I think what the challenge is is figuring out which patients need those regimens and who can get away with single-agent osimertinib. We already talked about how single-agent [osimertinib] is so tolerable, and some patients do incredibly well for years and years, but unfortunately some patients don’t do as well and they progress in a year or two. And so trying to figure out which of those patients need the combination is so key and I hope that we’re going to figure that out.

Herbst: Absolutely. It’s so exciting. We first started using EGFR inhibitors in 1996. Mutations were published, I think 2004, now 20 years later, we’re using these best drugs earlier. We have accurate approaches now in stage I, II, and III disease, ADAURA, and stage III chemoradiation, LAURA, we have a neo-ADAURA going on in neoadjuvant. It just is great to have this. And then what about extrapolation to ALK or MET or RET? What do you think?

Goldberg: Yeah, I think going back to the LAURA data, I think the benefit with consolidation osimertinib after chemoradiation in stage III disease was so great that I think we maybe can think about extrapolating to other subsets. We don’t have data on this. Maybe one day we will, I don’t know. But I think we can extrapolate to ALK and ROS1, maybe RET.

We can’t do it to everything because I think sometimes the drugs get somewhat toxic and also the benefit even in the metastatic setting is lower. So for example, I wouldn’t extrapolate to KRAS, but I think we can start to think about extrapolating.

One of the other presentations I’ll just highlight is that one of our residents at Yale actually had a presentation yesterday in the mini oral session for early-stage locally advanced lung cancer, looking at a retrospective data set of ALK-positive locally advanced disease patients, and basically consolidation ALK TKI [tyrosine kinase inhibitors] also looked better than either durvalumab [Imfinzi] or placebo or surveillance. So I think we can start to extrapolate from some of these subsets based on the lower data.

Herbst: Absolutely.

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