Considerations for Immunotherapy Duration in NSCLC: Dr Heather Wakelee

The topic of immunotherapy was repeatedly explored throughout the 2024 World Conference on Lung Cancer (WCLC) meeting. A particular session held on Sunday, September 8, featured 2 points of view that weighed the pros and cons of indefinite or limited immunotherapy durations. In one respect, Lecia Sequist, MD, MPH, Massachusetts General Hospital, discussed a “marathon” approach and the implications that an unspecified immunotherapy duration can have for patients with non-small cell lung cancer (NSCLC). On the other hand, Heather Wakelee, MD, professor of medicine, chief of the division of oncology, Stanford University, and deputy director, Stanford Cancer Institute, spoke to an immunotherapy duration “sprint” and the outlooks for patients with NSCLC who experience a more limited treatment duration.

In her interview, Wakelee provided further insights into this conversation, touching on the data supporting and informing different immunotherapy duration, as well as the possibility for patient-specific care to address the unique and variable needs of patients with NSCLC.

This transcript has been lightly edited.

Transcript

What key evidence supports the view that limited immunotherapy duration is sufficient for NSCLC?

When we think about using immune therapy in non–small cell lung cancer, we have the data in early stage and the data in metastatic [stage]. And so, with early stage, we have questions of giving it with chemotherapy before surgery—neoadjuvant—or giving it after surgery or adjuvant, and then kind of doing both approaches. And the trials with the adjuvant component have all given that 1 year. And so there hasn't been a lot of question about the duration of the 1 year, but it's whether or not we need the adjuvant component at all.

We know adjuvant alone works. We've got EMPOWER-ONO with 5-year data at ASCO, with some further updates at the WCLC that just happened in September of 2024. So we know adjuvant—pure adjuvant—works, and we know that pure neoadjuvant works, and we think that the combination is perhaps even better, but it's not clear. But there are some patients where that adjuvant piece is actually bringing in more toxicity and not clearly bringing in benefits. So that's one of our big questions: “Who needs adjuvant at all?”

Then in metastatic, most of the trials gave 2 years and stopped. We have very limited data. There was 1 trial that looked at 1 year versus indefinite, where the indefinite was definitely better than the 1 year. That was the 153 trial with nivolumab. But many of the studies that continued to 2 years stopped, and we know from that that maybe half the patients never have recurrence, but the other half do. And when they do, and you rechallenge with immune therapy, about half respond, but the other half don't. So, a quarter of patients, if you stop, eventually have a recurrence, it's no longer responsive to immune therapy. We don't know if that would have happened if you'd continued or not.

Lots of questions. And really we try to weigh: what's the benefit of continuing indefinitely? What's the benefit of stopping? Benefits of stopping: you potentially reduce toxicity. You definitely reduce financial toxicity. And we know that some patients do well without the continuation. Benefits of continuing: psychological safety of continuing on the drug; we know it seems that more patients continue to have that benefit and a few other factors, and so we're really not sure. We need to do the trials to ask that question. We need better biomarkers to help us know, for whom is it safe to potentially give that break? So, lots of work to do, and no clear answers on that question.

Do you see a future where the duration of immunotherapy could be individualized based on patient-specific factors? What evidence is needed to confidently tailor therapy duration for patients with NSCLC?

Well, we know that there are a lot of patient factors and tumor factors that weigh into having that immune response. So, some of the person factors are things like the microbiome, which there's a lot of work [but] we don't fully understand it. I saw some interesting data that high-fiber diet maybe is helpful in keeping a better microbiome and improving that immune response. We know that certain co-mutations can reduce the likelihood of having a good immune response, things like KEAP1, SDK11. We also have things like ctDNA [circulating tumor DNA], circulating tumor RNA, and other liquid biopsies that might be able to tell us who's responding and who isn't, certain other immune cell factors, and being able to really study: what are the immune cells getting into a tumor? What's circulating? What are different inflammatory markers?

So, there's a lot of research trying to get us to a point where we can figure out: “this patient’s going to have a great response, has now had that great response, and doesn't need additional ongoing therapy." "This patient may or may not have response. Oh, look, they did, but they need to continue it,” and “this patient is never going to respond to a checkpoint inhibitor and needs something else.” So we're trying to get there. But which of those—and it is probably not going to be simple, it's going to be a combination of things—are going to help us make those determinations. That's some really critical ongoing research right now.