The Evolving Landscape of Molecular Alterations in NSCLC: Optimizing Testing and Treatment to Improve Outcomes - Episode 16

I/O Therapy in KRAS-Mutant NSCLC With Concomitant STK11 or KEAP1 Mutations

Insight on the potential role of immunotherapy in patients with NSCLC and concomitant KRAS/STK11 or KRAS/KEAP1 mutations.


John V. Heymach, MD, PhD: We know for patients with driver oncogenes like EGFR and ALK,immunotherapy shouldn’t be the first-line therapy. An exception to this is KRAS. For KRAS, we still use immunotherapy as first-line therapy. Recent data from our group and others have suggested that if KRAS occurs in the setting of the second mutation in a tumor suppressor like STK11 or KEAP1, those tumors seem to respond less well to immunotherapy. In fact, there seems to be little or no benefit from PD-1 inhibitors in patients who have KRAS and a concurrent STK11 or KEAP alteration.

Those data were based on retrospective analyses. We initially reported on patients treated with PD-1 monotherapy who had STK11 alterations with KRAS. Patients who did have KRAS with STK11 mutations had only a 7% response rate to immunotherapy. But if they had KRAS with the TP53 alteration, they had more than a 35% response to immunotherapy. This told us that for KRAS, what helped drive the decision of whether they responded to immunotherapy was the second mutation. The STK11 or KEAP or TP53 was the key determinant of whether they responded to immunotherapy.

These findings have largely been reinforced by a recent publication by [Biagio] Ricciuti and colleagues from Dana-Farber [Cancer Institute] as part of a collaborative group. They confirmed that if you have a KRAS, STK11, or KEAP mutation, there was a limited benefit, but that effect seemed to be strongest only when it was KRAS with the second mutation. If you had STK11 or KEAP by itself, it was a much less strong effect.

Does this impact what we do day-to-day? First, these were all based on retrospective studies. There are some prospective studies that are ongoing to test whether we should select patients prospectively based on these biomarkers. Right now, if somebody has an STK11 or a KEAP mutation, I don’t deprive those patients of immunotherapy, but I try to include chemotherapy in the up-front regimen. For example, using a chemotherapy-plus-immunotherapy regimen is what I’ll typically take with these patients. Sometimes that’s a combination immunotherapy, like PD-1 and CTLA4 in the CheckMate 9LA regimen, or chemotherapy with tisotumab and bevacizumab, which is the IMpower150 regimen. Retrospective data presented from that study suggest that patients who are treated with that 4-drug combination get benefit if they have STK11 or KRAS mutations.

The bottom line is that patients with STK11 or KEAP appear to derive less benefit from immunotherapy. My recommendation is to use chemotherapy-immunotherapy combinations, and there are a few choices to choose from. But there are prospective studies going on to try to determine the optimum therapy for these patients because we’re basing this on retrospective analyses or cross-trial comparisons, which are fraught with potential confounders.

STK11 and KEAP mutations can be detected by next-generation sequencing, but only if it’s a broad panel that includes those genes; some do, and some don’t. In fact, at [The University of Texas] MD Anderson [Cancer Center], for a long time until recently, we were using a panel that didn’t include KEAP1 mutations. That’s something to consider if you’re choosing a next-generation sequencing panel. Many of the common larger panels do include both of these oncogenes.

The FDA label for immunotherapy does not include guidance with STK11 or KEAP mutations. If you look at the approval for these drugs, STK11 or KEAP don’t factor in there, but a number of prospective clinical studies do incorporate these. In some cases, KRAS G12C inhibitor trials are using these biomarkers. In other cases, immunotherapy trials are using these markers. If a patient has 1 of these alterations, I’d certainly recommend considering clinical trials for these patients or using combination chemotherapy with immunotherapy. These are just 2 of the genomic subgroups where we’re looking for better therapies for these patients going forward, so keep your eyes posted, and always consider clinical trials if they’re available.

One type of trial incorporating STK11 and KEAP mutations is the studies of KRAS G12C inhibitors. For example, in the KRYSTAL studies being done with adagrasib, for some of those cohorts, we’re looking specifically for those with STK11 and KEAP mutations. There are data that suggest that STK11 and KEAP may influence the response to KRAS G12C inhibitors. These are early data from modestly sized cohorts. But data suggest that with both sotorasib and adagrasib, the patients with KEAP1 alterations may have a reduced response to KRAS G12C inhibitors. There’s at least a suggestive trend that they may respond better in the setting of STK11 alterations. In the future, with KRAS G12C inhibitors like adagrasib and sotorasib, we’ll use combination regimens that will likely be tailored at least in part based on the co-occurring alteration like STK11 or KEAP1.

Transcript edited for clarity.