Poor Outcomes With IO Therapy in NSCLC With Concomitant KRAS/STK11 or KRAS/KEAP1 Mutations

Expert perspective on the poor outcomes observed with immunotherapy in NSCLC with STK11 or KEAP1 mutations, alone or in combination with KRAS alterations.


Meghan J. Mooradian, MD: I think there’s an important question of, is there a role for PD-1 or PD-L1 inhibitors and the treatment of non–small cell lung cancer in patients with STK11 or KEAP1 mutations when they occur alone, specifically when they are not occurring in the context of a KRAS mutation? What we’ve seen is though STK11 and KEAP1 commonly occur with KRAS, these mutations, which are mutations and tumor suppressor genes, can occur independently. They have been associated with poor clinical outcomes, regardless of the treatment that these patients receive. At this point, though we again know that these can be prognostic, it really shouldn’t dissuade us from using our most effective therapy in the first-line setting, which is chemotherapy plus immunotherapy [IO]. There was an exploratory analysis in KEYNOTE-189. Although the overall response rates of chemotherapy plus pembrolizumab were lower, and progression-free survival and overall survival shorter in patients vs those without STK11 or KEAP1, the pembrolizumab plus chemotherapy arm was associated with better outcomes than chemotherapy alone. Again, this is cementing that chemotherapy plus IO should be the first-line standard of care for these patients, particularly if there’s no clinical trial available.

One additional question that we’re confronted with in the clinic is, is there a role for immune checkpoint inhibition in the treatment of non–small cell lung cancer with concomitant KRAS/STK11 and/or KEAP1? What we’ve seen, particularly in large retrospective series, is that patients with these co-occurring mutations do tend to do less well than patients without. One specific retrospective study tried to break patients down into those with KRAS mutations alone vs KRAS mutations with KEAP1 and/or STK11. What they found is that the presence of STK11 and/or KEAP1 was associated with inferior response rates in comparison to KRAS-mutated lung cancer, with response rates of less than 10% when we were looking at the co-occurring mutations vs about 20% to 25% in patients with KRAS-mutated lung cancer without STK11 or KEAP1.

Chemotherapy plus immunotherapy is still considered a first-line standard of care for these patients primarily because we don’t have another fantastic first-line option. Though there are several clinical trials underway looking at agents such as glutaminase inhibitors and mTOR inhibitors to see if we can overcome some of these tumor-suppressive qualities that STK11 and KEAP1 confer, we do think that a lot of the inhibition or resistance to immunotherapy with these agents is driven by noninflamed or cold tumors. So many of the clinical trials are trying to look at how to make a cold tumor hot and/or target some of the unique pathways that STK11 and KEAP1 engage.

It’s important that we understand that STK11 and KEAP1 mutations can be detected through our next-generation sequencing panel. This really drives home the importance of obtaining broad-based testing. Though it is important to understand the presence of some of the most common mutations, such as KRAS, EGFR, and ALK, having broad-based testing to understand what co-occurring mutations may be present and how they may impact both patient prognosis and predict therapeutic efficacy, is an important aspect of clinical care.

In prior studies, KRAS/STK11 and KEAP1, the presence of these concomitant mutations was not often included in stratification factors. I think as trials move forward in the immunotherapy space, it is something that the investigators will have to keep in mind, understanding that these mutations do seem to confer immunotherapy resistance. We’re in a time where several different clinical trials are trying to look at therapeutic strategies to overcome this resistance or target these drugs by a different mechanism. Some of these trials include agents such as glutaminase inhibitors or mTOR inhibitors. The hope is that when these agents are used alone or in combination with other treatment modalities, such as chemotherapy or immunotherapy, we’ll be able to confer better antitumor outcomes for these patients.

Transcript edited for clarity.

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