Selecting Optimal Treatment for NSCLC With KRAS/STK11, or KRAS/KEAP1 Mutations

Transcript:

Melissa Johnson, MD: Josh, are there other data looking at STK11 mutations and managing them with a CTLA4 inhibitor that might help us feel good about making that choice?

Joshua Sabari, MD: We know that this is a difficult-to-treat patient population, [those with] KRAS coaltered with STK11 and KEAP1. We looked at the subset on another prospective trial called CheckMate-9LA [NCT03215706], which looked at ipilimumab (Yervoy), a CTLA4 inhibitor plus a PD1 inhibitor, nivolumab (Opdivo), plus chemotherapy. This trial is slightly different, it only gives 2 cycles of chemotherapy up front, whereas the POSEIDON study [NCT03164616] gives the standard 4 cycles of chemotherapy. The CheckMate-9LA also gave indefinite CTLA4 inhibitor ipilimumab until progression of disease. What’s interesting, is when you pull out a subset of patients with KRAS/STK11 or KRAS/STK11/KEAP1, that patient population seems to also benefit from the addition of a CTLA4 inhibitor. Here, there are now 2 large prospective studies where we looked at retrospective sets of data. I think we need a prospective validation set for this patient population. Given the approval of the POSEIDON regimen and of the 9LA regimen, this is a really difficult-to-treat patient population. Dr Johnson, how are you approaching a patient who is PD-L1 negative, KRAS/STK11, and KEAP1 in your clinical practice now?

Melissa Johnson, MD: These are often the patients where I am worried that our current standards of care may not be enough. In particular, these patients who are PD-L1-0, I’m worried that their immune system may not be able to generate an adequate immune response. I always have this nagging doubt that maybe there might be something more. These are patients who I will think about the addition of an anti- CTLA4. Prior to this, CheckMate-9LA was a regimen that I would absolutely prefer for these patients, and I’ll consider it now. I’ll also consider the POSEIDON regimen. Both of these trials are interesting in that they are evaluating the addition of CTLA4 to the PD1 chemo backbone a little differently. It’s a little bit of chemo and a lot of IO [immuno-oncology], or a little bit of CTLA4 and a little bit more chemo? I can see that there are advantages to both. Josh, what is your preference? When you vote in your clinic this week, will you use 2 cycles or 4 cycles of chemotherapy?

Joshua Sabari, MD: My preference right at this moment is the 4 cycles of therapy, particularly for patients who present with large visceral amounts of disease, I feel more comfortable using the 4 cycles of chemotherapy. We know that immunotherapy, both PD1 and PD-L1 inhibitors, as well as CTLA4 inhibitors take time to work. We don’t commonly see response until 9 or maybe even 12 weeks, so using the 4 cycles of chemotherapy for me is an opportunity to debulk disease to allow patients to become less symptomatic, but we know that chemotherapy is not durable. I think that’s where the utilization of the PD-L1 inhibitor and the CTLA4 inhibitor come in. One of my concerns about CTLA4 inhibitor on the back end of lifelong [treatment] or until progression is toxicity. We know that CTLA4 inhibitors have increased rates of immune-related adverse events. As a thoracic medical oncologist, I’m a little skittish. You talk to the renal cell doctors or other melanoma doctors and they feel far more confident with the use of a CTLA4 inhibitor. In our field, we’re just getting used to it. The heavy chemotherapy up front followed by the limited the CTLA4 inhibitor, tremelimumab (Imjudo), on the back end, is what I prefer. I’m curious, why the fifth dose? A lot of people ask me that question, why the fifth dose of the CTLA4 inhibitor once we complete chemotherapy?

Melissa Johnson, MD: At the time that we designed this trial, we didn’t know whether chemotherapy and PD1 and CTLA4 would be a good idea. I think we were evaluating both sides of the coin. Was the toxicity going to be prohibitive? In fact, we found that patients who got DURVA-TREME-chemo [durvalumab (Imfinzi), tremelimumab, chemotherapy], their adverse effects profile looked about the same in the trial as those patients who got DURVA-chemo. We’re just getting accustomed to what those combinations look like together. Also, was the addition of chemotherapy that is immunosuppressive going to counteract the immunostimulant that was being provided by the PD-L1 and the CTLA4? That fifth dose of tremelimumab with 1 dropped. It’s after the 4 cycles of chemotherapy and so the idea is even if there was some immune suppression during the 4 cycles of induction chemotherapy, we’d give 1 more dose of CTLA4 after that, in case that was relevant or necessary.

Transcript edited for clarity.