Optimizing the Selection of Novel Therapy for Patients With Advanced NSCLC

Closing out their panel on immunotherapy in non–small cell lung cancer, expert oncologists share key takeaways on the selection of novel therapy in this setting.

Balazs Halmos, MD, MS:
We’ve been talking about at least 15 different molecular alterations and 10 treatment choices that oncologists will need to decide about. Do you have any advice for community oncologists? How can they optimize the care of their patients with this rapidly evolving and very complicated scenario?

Martin Dietrich, MD, PhD: Institutionally, we’ve bought into our own molecular program. We have in-house NGS [next-generation sequencing] testing. We have molecular pathologists. We have molecular geneticists who are helping with the interpretation of the data. It’s simply impossible to treat every disease state and be an expert on every subset of non–small cell lung cancer. That’s a fair statement. If we’re including external help, whether it’s from a reference laboratory or in house, that’s inevitable for an appropriate recommendation. This isn’t just a targeted therapy, yes-or-no decision. It’s much broader.

With regard to the reports, they need to balance the simplicity and durability with the complexity of the genomic findings, especially in these smoking populations where immunotherapy is particularly important. If a patient gets sick once and they’ve had a smoking history, we’re going to see dozens of mutations—most often an elevated tumor mutation burden—to correlate to this, adding to the complexity of interpretation. There’s an intrinsic challenge and disadvantage to practicing lung cancer in the community. Without help, it’s not competitively doable.

When I think about our standard approach in a PD-1–centric world, even in the best scenarios within preselected adenocarcinoma PD-L1–high subsets, we’re seeing long-term survival of about 30% in 5 years. That means 70% of patients don’t survive in the long term, so by no means is it a state where we can feel comfortable or particularly optimistic for the majority of our patients.

For me, it doesn’t take a lot for me to think about escalation or combination immunotherapy approaches, either on trial or with the available options for treatment. We use a multitude of markers, but they’ll never have a good scoring system based on prospective data. Even though we always talk about subgroups and insufficiencies, if we see them repeated and confirmed in larger trials and subsets, they can guide therapy and practice. Our starting point is not high enough to feel comfortable and not consider escalation.

Regarding the discussion about the POSEIDEN regimen, we don’t use more CTLA4 because of toxicity concerns. We’ve had long discussions about this. CTLA4, unlike PD-1, has a very dose-dependent response and adverse effect curve. We used to come from 10 mg/kg body weight in ipilimumab to 3 and now 1 mg/kg body weight. The reputation of the 3 and 10 mg/kg lingered and was maintained. There was certainly an increase. On the other hand, we have to accept an intensification of the immune responses that comes with adverse effects in a nonepitope-directed setting. Even in an epitope-directed setting, with CAR [chimeric antigen receptor] T cells and bispecifics, we have to get better at managing immunotherapy adverse effects if we want to augment the long-term feel of the curve. That’s where the CTLA4 impact is seen. We see 6% to 8% improvement across the different phase 3 trials. If we look at adverse effects in a bispecific or in a CAR T-cell setting, they’re much more willing to use not only steroids but IL-6 inhibitors and other medications to manage them. We have to get there to provide similar outcomes, as our colleagues in hematology do. I think we will eventually. CTLA4 is a good step in that direction. For the properly selected patients, it’s certainly an issue.

You mentioned KEYNOTE-598. It’s a small phase 2 study that looked at pembrolizumab plus or minus ipilimumab. It may not be easy to show in a PD-L1–high context, but in PD-L1 low we have prospective phase 3 data that see the differentiator. It’s not a revolution. I want to be clear that the percentages are palpable between chemotherapy–I/O [immuno-oncology] and dual I/O, and we should capitalize on what we have rather than always trying to look for the future.

Balazs Halmos, MD, MS: Thank you all for this rich and informative discussion. Before we conclude, I was hoping we could go around for some closing thoughts. Kristen, anything that you could share with our audience?

Kristen A. Marrone, MD: This conversation shows how exciting this area is and how many questions we have. For every step forward, we’re trying to push the needle. We’re excited about the 5-year survival data, but now we’re excited on behalf of our patients and want to double it. How can we do that in the metastatic setting? Hopefully, we can learn a lot in the neoadjuvant space, maybe from the tumor itself. We can think about different tumor microenvironments and bimolecular subsets of tumors and then think about how we can move it into the metastatic setting to individualize treatment decisions. That’s an exciting area. In the perioperative space, thinking about duration of I/O and agent in combination is going to be keeping us on these topics for many months and years to come.

Balazs Halmos, MD, MS: Fabulous thoughts. Josh, anything to add?

Joshua Reuss, MD: We’re very excited to see 5-year survivals in the 20%-to-30% range, but we’re still talking about 5-year survival in the 20%-to-30% range. This means the majority of patients aren’t alive and don’t reap long-term benefits of these treatments. It’s an improvement from where we were, but there’s still a long way to go. But I agree with Dr Marrone: there’s a lot of excitement. We didn’t even talk about the exciting antibody-drug conjugates. Do we replace chemotherapy? Do we augment that with chemotherapy? Then we get into cellular therapies. It’s an exciting time to be in the field. I feel fortunate to be entering and involved in the field during this exciting time, but there’s still a long way to go.

Balazs Halmos, MD, MS: That’s a fantastic summary. Thank you, Kristen, Josh, and Martin. We hope you found this OncLive® Peer Exchange® discussion to be useful and informative, and we hope to see you soon.

Transcript edited for clarity.

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