Updates in Immunotherapy for Advanced Thoracic Malignancies - Episode 5

Understanding Immune Response in Non–Small Cell Lung Cancer

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Suresh Ramalingam, MD: Steve, as you talk about recurrence and second-line treatment options, we saw an interesting study at ESMO [the European Society for Medical Oncology 2020 meeting] called the PIONeeR trial, which looked at later lines used, but was a biomarker-focused trial. Tell us about that study.

Stephen Liu, MD: I like this study. It is important work, and this is not a therapeutic study. This was presented by our colleague, Fabrice Barlesi, MD, PhD, and is looking at patients who are receiving immunotherapy with either nivolumab, pembrolizumab, or atezolizumab in a second-line setting, or in combination with chemotherapy in the frontline setting. This was not an intervention study. Patients had a repeat biopsy and blood samples, trying to understand the science of immune responses and if we can understand better what’s happening. When we look at these drugs, they’re superior to chemotherapy. We see long-term survival and amazing results. People are startled to understand how little we understand about exactly how these drugs work and why they work in some and not others.

This is looking beyond PD-L1, and they saw some interesting things there. While PD-L1 did serve as one predictive marker of who’s benefitting, they saw an important role for tumor infiltration by cytotoxic lymphocytes, building on work done by our colleagues in melanoma, where if you have more immune cells within the tumor, those patients seemed to derive those antitumor immune-mediated responses, and high infiltration of regulatory T cells, coupled with weak PD-1, seemed to associate with worse outcomes. It’s not just activation through the PD-1/PD-L1 pathway. Those activated immune cells need to get to the tumor, infiltration into the tumor, and this type of biomarker-specific work is critical to increasing the sophistication of delivery for immunotherapy.

Suresh Ramalingam, MD: Yes, interesting, and it will be nice to know if you have a tumor that’s not responding, what can be done to increase the infiltration of T cells and to provide the right kind of microenvironment for those patients to respond better to therapy. This also brings up the importance of asking the question about the immune microenvironment and how that reflects the patient’s likely response to immunotherapy. We’re seeing some information here from various trials.

One study that I thought was informative is the subset analysis looking at the genomic characteristics of the tumor and how that relates to outcome. This was a subset analysis from IMpower150. This talked about the role of LKB1 and KEAP1 mutations. These are mutations we see in lung adenocarcinoma, and KEAP1 we see in squamous as well. It’s traditionally been thought that these mutations would be associated with poor outcomes with immune checkpoint inhibition, based on prior experience.

At the ESMO meeting, the IMpower150 investigators looked at the tumor samples in a subset of patients who had the KEAP1 and LKB1 mutations, and what was interesting is these mutations definitely have a prognostic impact, but the chemotherapy plus bevacizumab plus atezolizumab regimen was still better for STK11 and KEAP1 mutations compared to what they saw in degree of benefit in the wild-type population. There’s also something that we’ve seen with the pembrolizumab-based studies looking at the impact of STK11 and KEAP1. We’re still learning more about various genomic events that might either sensitize or portend a poorer outcome with immune checkpoint inhibition.

I couldn’t help but talk about TMB [tumor mutational burden] when we discuss biomarkers, and I want to turn this question to you, Christine. What do you think about TMB as a biomarker in this situation?

Christine Bestvina, MD: There have been a lot of challenges with using TMB as a biomarker, as I’m sure all of my colleagues on this panel have also appreciated. One of the biggest issues that we’ve had is standardization of TMB across platform and between institutions. It’s hard to know how to apply a nonstandardized biomarker to some of this information. We’d all been hoping that TMB was going to pan out as far as a complement to PD-L1, giving guidance and putting patients into buckets of high PD-L1, low TMB, what does that mean, how can we choose our therapy? But unfortunately, it doesn’t appear that we’ve had quite as much efficacy using TMB as a biomarker as with PD-L1.

Suresh Ramalingam, MD: Any other thoughts on the TMB issue? Steve?

Stephen Liu, MD: Part of the reason why we keep coming back to TMB and why we won’t let these negative studies put the issue to rest, is it just makes sense. It’s a rational biomarker. When we have more somatic mutations, you expect more neoantigens, and you’re just increasing the odds that you have a T-cell receptor that’s going to interact. It’s such a rational biomarker, that it seems like it should work despite evidence to the contrary, and we need to continue to refine that. But as of today, it doesn’t influence my treatment practice.

Transcript Edited for Clarity