Applying Molecular Biomarkers in Treatment Decision Making in NSCLC

EP: 1.The Role of Molecular Testing In Metastatic NSCLC

EP: 2.Navigating Barriers to Molecular Testing and Role of Liquid Biopsy in NSCLC

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EP: 3.Applying Molecular Biomarkers in Treatment Decision Making in NSCLC

EP: 4.Clinical Insights on the Role of PD-1/PD-L1 Inhibitors in NSCLC

EP: 5.Treatment Approaches for NSCLC With Concurrent KRAS/STK11 or KRAS/KEAP-1 Mutations

EP: 6.Immunotherapy in NSCLC With Concurrent KRAS/STK11 or KRAS/KEAP-1 Mutations

EP: 7.NSCLC: Discussing Molecular Biomarkers and Treatment Decisions with Patients

EP: 8.Future Perspectives in Biomarker Testing and Targeted Therapy in NSCLC

EP: 9.Emerging Concepts on the Role of Immunotherapy in NSCLC

Transcript:

Meghan J. Mooradian, MD: We’re certainly learning so much about the mutations, and not only the common mutations that we’ve been so adept at treating, like EGFR and ALK. Now with KRAS, we know we have KRAS G12C, and we’re learning so much about these important coalterations. I’ll pivot a bit to that, thinking about KRAS and some of these important comutations like STK11, KEAP1, and TP53. How do these mutations impact your treatment of patients? How prevalent would you say you see these in the clinic?

Martin Dietrich, MD, PhD: That’s a good question and a challenging one, as you know. We’ve been struggling with biomarker guidance for the selection of immunotherapy, both from a predictive as well as a prognostic standpoint. We’re clearly living in a world that is much more complex than just the PD-L1 that has been utilized in most labels. We think of KRAS as probably a biological setup that is associated with smoking, with higher mutational burden. This is one that we typically think of as a better target background for immunotherapies. But what we’ve learned on large prospective trials in retrospective reviews is that we have other mutations that seem to be influencing this in a multidimensional setting. STK11 and KEAP1 were the ones that stood out the most in these large genomic analyses. We really think of this as an immunotherapy-relatable alteration, STK11 more in the setting of immunosuppression, and KEAP1 in more of a setting of therapy resistance, but independent of the mechanisms.

Obviously, a lot of these are patched together retroactively. We are thinking of them as negative prognostic markers. If we look at them in large studies, both in the real world as well as in clinical trials, they seem to be standardizing treatment back to more or less where we are with chemotherapy alone. They have a significant impact. Now, they’re not prospectively validated, so I’m not sure they can necessarily be utilized to rule against immunotherapy, but they certainly influence my prognostication for a patient. This is similar to, on the opposite end, concurrent KRAS and TP53 mutations in conjunction with an expectation of improved outcomes for immunotherapy responses. This is in these nondriver settings, or at least non–first-line driver settings, a combination we rely on very heavily on the long-term effect of immunotherapy.

For us, the idea of overcoming resistance in the secondary setting is particularly important. It is going to get more and more complicated in integrating all these mutations in a broader context for the selection of therapy into clinical practice. I think it will help us decide about therapies. We’ll dive into this a bit further to look at some of these parts. But it’s very clear that STK11, KEAP1, and TP53 in the context of KRAS comutations, as well as independently, seem to be having a prognostic impact that may be indicating to us that we might have to do more than just simple immunotherapies. Certainly, in my practice, if I see a patient with STK11 or KEAP1, I’m much more prone to intensify therapy in the direction of augmentation beyond the PD-1 backbone in the first-line setting of a nondriver mutation. I don’t know how your approach would be to interpret these mutations in your clinical context. I would love to hear it.

Meghan J. Mooradian, MD: It’s clear that immunotherapy, particularly PD-1 and PD-L1 inhibition, has revolutionized the way we treat lung cancer. These drugs are now approved in monotherapy, in combination with chemotherapy in the metastatic setting, the adjuvant setting, and now most recently the neoadjuvant setting. We’re learning more and more about the patients who are going to benefit the most from this approach. We’ve clearly seen from, as you point out, retrospective work that this backbone that we often lean on does not seem to be sufficient for these patients with co-occurring KRAS, STK11, or KEAP1 mutations. We have some burgeoning data, which we’ll talk about, in the setting of the POSEIDON trial that is looking at a dual ICI [immune checkpoint inhibitor] approach. This was initially seen in the CheckMate 227 and CheckMate 9LA trials. CheckMate 227 was the chemotherapy-sparing approach of IPI [ipilimumab] 1 mg/kg, nivo [nivolumab] 3 mg/kg. CheckMate 9LA expanded on this and looked at [ipilimumab] 1 mg/kg, [nivolumab] 3 mg/kg plus chemotherapy, albeit 2 cycles of chemotherapy.

What they found was the primary end point was improved in the dual ICI-chemotherapy group, which was overall survival, vs the chemotherapy group alone. Responses were seen in patients who typically have poor prognosis, including those with low PD-L1 expression of less than 1%, squamous cell histology. Then again with a retrospective scope, looking back, it did seem to have improvement in those patients with KRAS, STK11, and KEAP1. Subgroup analysis from POSEIDON also demonstrated the benefit of the addition of a CTLA-4 [inhibitor] to a PD-1, chemotherapy backbone in these hard-to-treat patients. Though prospective validation is needed, and thankfully ongoing, it will be necessary to see how these results play out. But with this improved efficacy we’ve seen to date, I’m encouraged by these data, and based on this, I discuss it and consider it in my fit patients who come in with these difficult-to-treat molecular signatures.

Transcript edited for clarity.