乌鸦传媒

Adjuvant chemotherapy has been the standard of care for patients with resectable non-small cell lung cancer (NSCLC), but newer therapies are entering the mix as well. At the American Society of Clinical Oncology (ASCO) annual meeting, findings from several trials on the role of adjuvant immunotherapy were presented.

乌鸦传媒 brought together three expert leaders in the field: Moderator , of Yale Cancer Center in New Haven, Connecticut, is joined by , of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, and , also of Yale Cancer Center, for a virtual roundtable discussion. This second of four exclusive episodes focuses on NSCLC treatment in the adjuvant setting.

Following is a transcript of their remarks:

Herbst: Topic two: Adjuvant therapy. So atezolizumab [Tecentriq] you mentioned was approved in the adjuvant setting only for stage II and III and for PD-L1 positive patients. But then we have KEYNOTE-091, which is FDA approved for all stages regardless of PD-L1 status. So biomarkers are important, but what's going on with biomarkers here? Julie, you worked on this PD-L1 biomarker at one time, if I recall, and still do. What's going on here?

Brahmer: Yes. I think the KEYNOTE study just in my mind is not making sense to me in the fact that patients with high PD-L1 did not seem to have the benefit compared to those patients with low or negative, which in the grand scheme of what we know, at least in metastatic disease, does not make any sense.

And then also where the atezolizumab data just seems to make more sense to me, so I think that that's kind of why I've still used PD-L1 in this space to kind of help me decide what to give. But I guess in some patients, maybe patients where the PD-L1 is zero but they have other factors that make me think immunotherapy may benefit them, then maybe I could use pembrolizumab [pembro; Keytruda] in that space as well.

Obviously, I think we would all love to have a minimal residual disease [MRD] assay to be able to say 'Hey this patient is more likely going to benefit from adjuvant therapy or needs adjuvant therapy compared to someone with an MRD assay that absolutely does not show any evidence of residual disease, so maybe that person doesn't need adjuvant therapy.' So it's coming, but for lung cancer, we're just not quite there yet to have an assay, either tumor informed or tumor uninformed, yet. But I don't know, what do you guys think?

Herbst: Yeah, Sarah, so your thoughts on biomarkers in the setting, and also do some patients need dual [immunotherapy]? What about adding an CTLA-4 there?

Goldberg: Yeah, I agree with what Julie was saying. I thought I understood it all with PD-L1. I was starting to understand PD-L1 and the adjuvant pembro study just confused me. I think we all know PD-L1 is not a great biomarker, but at least consistently in every study the higher the PD-L1, the greater the benefit; it just didn't seem that way with the adjuvant pembro study, which I just can't wrap my mind around.

But I still agree with what Julie said, and the way that I think about it is, I consider if someone didn't get neoadjuvant, I consider adjuvants -- or actually now even if they did -- but I consider adjuvant if someone didn't get neoadjuvant immune therapy regardless of PD-L1. But the higher the levels, I still think there likely is more benefit. So I'm still using it as a biomarker and someone who is maybe more borderline and has PD-L1 zero, I might skip it. But PD-L1-positive disease, I absolutely would give adjuvant immune therapy, either atezolizumab or pembro.

Combination adjuvant therapy, I'm not sure that we're there yet. I think there's more toxicity with combinations and is it clearly necessary? I almost know that we know that answer even in metastatic disease yet. And so I definitely don't know that answer in early-stage disease either.

Herbst: Okay. Very helpful. Julie, what's next? New biomarkers TMB [tumor mutational burden], is that a possibility? Where are we going with the adjuvant space and how do you decide who to do adjuvant therapy and who to do, again back to the other question, who to do perioperative with?

Brahmer: Yeah, I think upfront if a patient does not have a driver mutation and has lymph-node positive disease, we're pushing hard for neoadjuvant therapy. I really want to know, does this therapy actually work on the cancer? And it sure would be great to be able to see that that result at the time of surgery.

Obviously in those patients with the driver mutation, particularly those that we have TKIs [tyrosine kinase inhibitors] readily available [for], now with the durva [durvalumab; Imfinzi] data for those patients with EGFR TKI, then I want those patients to go to surgery, and then I can decide about therapy in the advent setting. Or if there's someone who I just think their tumor is just not behaving well, and I have a feeling like they may not end up going to surgery -- like they're borderline -- then maybe we just take them directly to surgery.

But it's really hard. You've got patients that want to get to surgery, but we know that having a tumor in place does seem to make a difference. And so, at least in lymph-node positive disease, I'm pushing hard to do neoadjuvant therapy.

Herbst: Yeah, that's been the experience with melanoma too. So it's very consistent. Sarah, they [in KEYNOTE-091] only treat with adjuvant for what about a year? Where did the year come from? Should it be more, could it be less? Is ctDNA [circulating tumor DNA] going to help us here?

Goldberg: Yeah, I think it's a bit arbitrary. Just like the 2 years for the metastatic patients and 3 years for adjuvant osimertinib [Tagrisso], right? I mean, there's maybe a bit of a rationale, but we don't really know the optimal timing. The trials used a year, and so I think that's what we will use in practice.

It sure would be nice to know if less is sufficient, right? I think most of these patients would be happy to have their surgery and be done with it and not even get adjuvant, especially if they got neoadjuvant. But we really don't know. So I think for now it's a year and at some point, and maybe there will be studies that help us fine tune that. I would love to see ctDNA or other assays to tell us if someone even needs adjuvant therapy, if they received neoadjuvant, but also to guide us with length of of therapy.

Herbst: And last question for you, Julie. Let's never forget that some patients probably shouldn't be resected, and we have the durvalumab data from PACIFIC. How do you adjudicate that at your tumor boards at Hopkins?

Brahmer: Well, it's easy when there's lymph nodes on the other side of the mediastinum where these patients obviously can't go to surgery. But if patients have bulky N2 disease, clearly that's where a little bit of a fight, or a slightly enlarged lymph node and is it multi-station or single station. So we arm wrestle about that on a weekly basis.

But I think now as time has gone by over the past year, we are becoming more and more comfortable to give neoadjuvant therapy in patients with N2 disease, even if it's multi-station. And as long as it's not huge, greater than 2 cm, but if some folks have borderline lymph nodes and we just know that they're positive, even if it's multi-station, we are considering neoadjuvant therapy.

Herbst: Great. It really speaks to the importance of getting profiling in advance, multimodality tumor boards, and cooperation. And making sure patients get to specialists for these types of diseases.

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