Transcript: Benjamin P. Levy, MD: What’s the global perspective? Before we got here, I was learning that sometimes you can use triplet therapy; but for the most part, it’s not yet approved. Sanjay, maybe we can start with you. What’s going on in the United Kingdom?

Sanjay Popat, PhD, FRCP: It’s quite simple. The KEYNOTE-189 regimen has only recently been given the European label. There will be country-specific reimbursement discussions. It’s not routinely used in the United Kingdom because it’s not reimbursed. And so we’re very much looking forward to having this available and making this a treatment option for our patients.

Benjamin P. Levy, MD: Would your sequencing strategy for a patient in the United Kingdom who has advanced adenocarcinoma without an actionable mutation be carboplatin/pemetrexed followed by immunotherapy?

Sanjay Popat, PhD, FRCP: No. We have access to pembrolizumab as monotherapy in the 50%—PD-L1 expressers.

Benjamin P. Levy, MD: For the less-than—50%–PD-L1 expressers, though?

Sanjay Popat, PhD, FRCP: Yes. They’re getting a platinum doublet as standard and moving to immunotherapy at progression at the moment.

Benjamin P. Levy, MD: OK. Is it the same in France?

David Planchard, MD, PhD: This is where we are in France currently. There is not coverage for the combination in patients with lower than 50% PD-L1 expression, but for sure, it will be the standard of care in this population with low PD-L1 expression. We’ll keep pembrolizumab alone for the more-than-50% expressers, and lower-than-50% expressers will be treated with chemotherapy and pembrolizumab. It should become available shortly, but until now, it has not been covered.

Benjamin P. Levy, MD: And in Switzerland?

Solange Peters, MD, PhD: In Switzerland, it’s still not registered. But it’s going quite fast. We have access now through compassionate programs, so it’s now since the beginning of the year that we can use it, at least regarding the KEYNOTE-189 data. So we’re using it. But I’d like to address some nuance about negative, lower than, or even more than 50% PD-L1 expression. I had a second opinion by email from a colleague telling me that he had this BRAF-positive, never-smoker patient with PD-L1 expression of almost 95%. He was telling me, “The patient fears having toxicity, but he’s a never smoker with a BRAF mutation. Should I give targeted therapy? Monotherapy with pembrolizumab? Pembrolizumab plus chemotherapy?” So there’s still a gray zone where every option is right. We don’t know for these never smokers with low tumor mutational burden. If you have a threatening disease, a lot of disease, and a never-smoker status, maybe some chemotherapy might be a good idea. Maybe we should individualize the treatment strategy a bit more there.

On the other hand, if completely PD-L1 negative, I don’t like the PFS [progression-free survival] curves. The PFS curves are not good. Maybe here you should consider some other opportunities for checkpoints. There will be this debate, but it’s really instinct and opinions, right? I think there will be these marginal cases still opening a debate at the Chemotherapy Board, right?

Suresh S. Ramalingam, MD: What I would say is, Solange, I agree with you. These decisions are very difficult, and when the patient is sitting in front of you, the considerations are often unique and draw a lot on your experience. For patients with driver mutations, though, which we will talk about in the second part of this conversation, I feel that targeted therapies provide the best possible outcomes. We know that for EGFR, to a good extent. I would venture to say that even for BRAF- and ALK-positive patients, what we see with more and more exciting targeted agents coming down the road is that they should get targeted therapy. When we run out of targeted therapy options, we go with immune checkpoint inhibition, no matter how high the PD-L1 expression is.

Benjamin P. Levy, MD: I think there are a lot of unanswered questions about the role of immunotherapy and specific genotypes. I think we have good data with single-checkpoint blockade in the EGFR and ALK space. We’re learning more and more about these other actionable yet rare mutations that we’re finding, and I think there are a lot of unanswered questions about how to move forward. I agree, Suresh, that targeted therapy is the best chance for these patients, and it really speaks to the whole idea that we wrestle with in the United States of tissue stewardship. We send off the tissue, we get a PD-L1 test right back within a day, but the NGS [next generation sequencing] is taking 2 weeks, and you may be fooled on exactly what to do. I think it’s a real challenge. David?

David Planchard, MD, PhD: That’s right. For me, PD-L1 might be a good biomarker but not a good biomarker alone. If you don’t offer the other medical testing for EGFR, BRAF, ALK, and ROS1, I would never start an immune treatment alone, particularly in a never smoker. That’s why for me, PD-L1 is a good biomarker. The smoking status is probably the best biomarker. If you have a never smoker in front of you, you might fight to find a molecular alteration because you can find a molecular alteration, and this is a priority. In all the trials, in never smokers, you cannot prove completely that immune treatment does better than the other treatments, chemotherapy and so on.

That’s why in these cases, before I start any immune treatment, I try to find a molecular alteration. As you told Solange, clearly a BRAF-mutated never smoker will probably not benefit on an immune treatment alone and will have a major response in terms of PFS and response rate when started on targeted therapy. That’s why, for me, the smoking status is something quite important, particularly in first-line therapy now.

Solange Peters, MD, PhD: It’s even more fragile in EGFR, this story of really having the whole picture and needing to know of it. We know from a very recent publication in JCO [Journal of Clinical Oncology] that with monotherapies, the checkpoint inhibitor doesn’t work and is even risky for these patients. These patients die under single treatment. If you ignore an EGFR mutation or do not know about it and decide on the triplet, you go back to the old days where you give chemotherapy versus a TKI [tyrosine kinase inhibitor]. You give the chemotherapy, which is not a good decision.

On the other hand, Matt Hellmann from Memorial Sloan Kettering Cancer Center was telling me yesterday that sometimes he also has to catch up with a late discovery of an EGFR mutation. But now we give osimertinib frontline. You have a checkpoint inhibitor on board for your patient with a very long-acting pharmacokinetic, and then you have to give osimertinib on top of it, and nobody wants to do that because it creates pneumonitis. So get the full picture; then you have to make a decision, with some discussions with your patient, of course.

David Planchard, MD, PhD: I agree because even if you start the immune treatment and then stop it because the patient progressed after 2 or 3 cycles, you will start a targeted therapy. In fact, you will still have a huge amount of antibody in the blood of the patient, and they might develop some specific toxicity. That’s why it’s another issue.

Even if you think you have stopped the immune treatment, when you start an EGFR TKI, BRAF inhibitor, and so on, if there are some interactions with immune treatment, you will develop the toxicity. It’s at least 4 weeks or 6 weeks of half-life with an immune treatment. You cannot stop for 2 or 3 months before you start any specific targeted therapy. That’s why we have to take it into account. It’s something completely new, and we should also keep in mind this type of toxicity after the immune treatment, even if you stop the immune treatment early.

Benjamin P. Levy, MD: That’s a very good point.

Transcript Edited for Clarity