Dr. Gregory Riely:
Welcome to The ASCO Post Roundtable Series, Clinical Perspectives on KRAS-Mutant Lung Cancer. I'm Dr. Greg Riely. I'm a medical oncologist at Memorial Sloan Kettering Cancer Center. Joining today are two of my colleagues. Dr. Heist, can you introduce yourself?
Dr. Rebecca Heist:
Hi, I'm Rebecca Heist. I'm a medical oncologist at Mass General Hospital in Boston.
Dr. Riely:
Dr. Sabari?
Dr. Joshua Sabari:
Hi, I'm Josh Sabari, thoracic medical oncology at NYU Langone Health Perlmutter Cancer Center in New York.
Dr. Riely:
Well, welcome to you both. Today, we'll be discussing the treatment and management of KRAS-mutant non–small cell lung cancer with three patient case studies. Our second installment will focus on the second-line treatment of KRAS G12C–mutant lung cancer.
For our second case, this is a 67-year-old woman that's initially diagnosed with lung adenocarcinoma. Initial imaging shows metastatic disease involving lung, mediastinal lymph nodes, adrenal gland, and a sclerotic pelvic bone tumor. The patient's tumor PD-L1 testing shows 10%, so 10% PD-L1. Molecular testing of the tumor shows a KRAS G12C mutation, and the tumor also shows an STK11 mutation and KEAP1 alteration.
So this patient receives initial therapy with chemotherapy and dual checkpoint inhibition. After 8 cycles of therapy, the patient has evidence of progression of disease in one lung mass. Patient has a PET scan and MRI that show no other sites of disease. So the question is, and I guess we'll go with Dr. Heist, what's your recommendation? Again, this is a patient with newly diagnosed... I'm sorry, they no longer are newly diagnosed. They've actually completed 8 cycles of therapy. So KRAS-mutant lung cancer, they've gone through 8 cycles of therapy, and they're just beginning to have some progression at a single site. PET scan and MRI show no other sites of disease. What are you thinking about at this point?
Dr. Heist:
Yeah. In this situation with oligoprogressive disease, you're really thinking about, "Okay, should I switch treatment entirely now, or can I still get something out of the treatment we're on?" And so we shouldn't switch right away. And so having the PET scan and the brain MRI is really helpful. You get a really complete look at everything. And if it really is just one site, we are more and more thinking about localized treatment for that one-sided disease. So the techniques with stereotactic radiation have improved greatly. So that's something we would think about. And I think, here, we are always balancing, "Can we go after this one site and still control disease for a long period of time with our current regimen, or is this a harbinger of a lot of disease to come and we should switch sooner rather than later?" But in general, as somebody who is feeling quite well, if we've really proven there's only this one site, we do try to get some more time out of the therapy that they're on and do some local treatment here if it's a feasible thing.
Dr. Riely:
Dr. Sabari, do you agree? Is this the approach you take for this sort of patient?
Dr. Sabari:
Yeah, I would agree. I think for oligoprogressive disease, I do try to radiate, but I really try to explain to the patient that we're only going to know if what we're doing is successful 3 months out, so on the next scan. And if a patient wants to change the systemic therapy, meaning I look for reasons, "Are they not tolerating it?" Or generally, I would change systemic therapy, especially in a patient with a KRAS alteration. If we take a patient with an EGFR driver alteration, for example, or an ALK fusion, or a RET fusion, there where we think we could get many months to years off of the targeted therapy, even after local therapy, I'm much more willing to radiate an oligoprogressing site. So, really, it's a discussion with the patient. But yeah, it's not wrong here to do local therapy to an oligoprogressive site. I just want to contextualize it for the patient.
Dr. Riely:
All right, great. I think that's exactly the right approach that I take in this situation as well. So this particular patient then went on to radiation therapy. She completed radiation therapy to that progressing lung lesion. She got one of these sorts of focused radiation, SBRT type approaches, so she was able to have the radiation done after three doses. And given that there were no other sites of progression, we didn't continue with the maintenance immunotherapy that she had been on prior and completed an additional 6 cycles. So, after the 6 additional cycles, the patient developed multiple small new lung masses, and I think we talked about this notion of oligoprogression and treating single sites of disease. This patient now has more disease than we can think about with a local therapy type approach. So, Dr. Sabari, what's your next therapy in a patient like this who has KRAS G12C mutant lung cancer and they've progressed after initial chemotherapy and immunotherapy?
Dr. Sabari:
Yeah. So, clearly here, I'd want to restage MRI, brain PET scan again. So I want to know where the disease is. But in someone that has a KRAS G12C alteration, I would offer a KRAS GTPase inhibitor in the second-line setting, and there are two FDA-approved therapies here with adagrasib, as well as sotorasib. And historically, prior to these KRAS G12C GTPase inhibitors, we had docetaxel or docetaxel and ramucirumab. And there, we're seeing response rates in the 10%, maybe combo, 20% range, and they're not durable, right? 3 to 4 months in combination with ramucirumab. So, if we can move the needle forward for a patient, particularly using a targeted therapeutic keeping chemotherapy or conventional chemotherapy in our back pocket, I'm generally offering one of the GTPase inhibitors in this setting. Becca, what are you doing in your practice?
Dr. Heist:
I completely agree. I think this is a time when you're really glad you had that tumor NGS from the outset so you know where you want to go when you're having progression on the first-line setting. And I agree, with the KRAS G12C mutation, one of the approved G12C inhibitors would be my standard go-to here.
Dr. Riely:
Now, both these drugs, adagrasib and sotorasib, received their initial accelerated approvals based on their phase I/II trials, and so we saw response rate in that 30% to 40% range. Dr. Heist, after those initial accelerated approvals, have they gone on to do frank comparison trials against standard therapies?
Dr. Heist:
Yeah, both of them have done comparison trials against docetaxel, which is the FDA-approved, second-line treatment that we use very often in second-line lung cancer. So, for both sotorasib and adagrasib, in general, we see higher response rates compared to docetaxel. We see longer PFS compared to docetaxel. I think we haven't seen OS improvement per se with the G12C inhibitor. My personal interpretation of this is response rate matters to me. And in somebody who is progressing, having a higher rate of getting responses, partial responses, even minor responses, is meaningful because, very often, people are symptomatic from the disease, and so the response rate matters. And so I do use the G12C inhibitors before I use docetaxel because I do think the higher response and PFS is clinically meaningful to me.
Dr. Riely:
Now, I think the response rate focus is a good one. Dr. Sabari, in addition to response rate, I think another difference between these RAS-targeted therapies and docetaxel comes in toxicity. How do you think about the toxicity? What's your impression of toxicities of these agents?
Dr. Sabari:
Yeah. First off, I agree with the response rate. I think the small molecules have far better response rates than chemotherapy, but the counter argument to that is the progression-free survival maybe didn't pan out as well as we'd hoped it to. But still, to me, clearly better than chemotherapy. Now, whether we have full overall survival data, we need to see that in order to have a better understanding and better discussions with our patients. But when it comes to toxicity, it's a no-brainer. I think that both, adagrasib and sotorasib, have far better toxicity profiles than conventional chemotherapy. Remember, these GTPase inhibitors are causing some GI side effects, abdominal discomfort, bloating, maybe some diarrhea, some nausea. But when you think about chemotherapy, chemotherapy, you worry about things like neutropenia, neutropenic fever, profound fatigue at times. And most of my patients on docetaxel have a really rough go. So, I'd much prefer to use a targeted therapeutic option with a better toxicity profile over docetaxel.
Dr. Riely:
Yeah, I think looking at toxicity and response are definitely key. Now, Dr. Heist, when you're thinking about this patient who has completed, who has been on immune checkpoint inhibitor and you're making the decision to switch from immune checkpoint inhibitor to a targeted therapy, do you use that information? Does that matter to you?
Dr. Heist:
Yeah, I think one of the things we think about as we switch is we do have to be cautious because there has been observed higher rates of some toxicities with that switch from immunotherapy to a targeted treatment, and we clearly saw it in the TKI world and it wasn't so clear we were going to see it with drugs like sotorasib and adagrasib. But I do think in the KRAS G12C world, we do see some of that as well. In particular, we know based on actually combination studies that the combination of sotorasib with immunotherapy has been tricky with liver toxicities in particular being an issue. Adagrasib at a lower dose than the monotherapy dose has been combined with immunotherapy with reasonable toxicity rates. And so I think all of those things are things I think about as I think about the G12C inhibitor that I'm using next, and I'm thinking about also close monitoring as we start because I think that immunotherapy to a targeted therapy transition can be a time when we do see heightened toxicities.
Dr. Riely:
Great. And now, Dr. Sabari, going back to our last case, and also in this particular case, the patient has STK11 and KEAP1 mutations, does that matter when you think about second-line therapy options?
Dr. Sabari:
Yeah. So we know, for frontline, as we mentioned earlier, that it does predict poor prognosis with response to immunotherapy as a single agent, and therefore dual checkpoint inhibitors may be worthwhile. In the second-line setting with the KRAS GTPase inhibitors, the G12C inhibitors, it does not matter. Actually, patients respond equally as well whether they have a STK11 or KEAP1 co-alteration or not. So, I think this is a group or a population, especially if they're not deriving much benefit from immunotherapy, I think is worthwhile to use one of the KRAS G12C inhibitors in this space.
Dr. Riely:
I completely agree. And I think when I look at those STK11, KEAP1 mutations, we talk about these things a lot. But ultimately, they're not boiling down to something I use when I make my decisions. And for instance, there doesn't seem to be a difference in response rate for STK11, KEAP1 mutants if you compare between the two drugs that are available, sotorasib and adagrasib. And so, ultimately, really isn't getting into my decision-making.
All right. Well, I think this has been a great discussion about this particular case. I guess I just emphasize a few key clinical takeaways. I think, first, local therapies can play a role in localized progression of disease on initial systemic therapy. One thing that we did in this case is the patient had a PET scan and MRI. I think that's pretty important to do prior to taking that approach of treating localized progression. You want to make sure that is all you are treating. We know that KRAS G12C–targeted therapies have efficacy after initial chemotherapy, and the efficacy of these drugs is superior to docetaxel when we look at progression-free survival and response rate endpoints. Notably, there can be interactions between KRAS G12C–targeted therapies in prior immune checkpoint inhibitors. These might be slightly more common with sotorasib. And then, finally, STK11, KEAP1 mutations are negative prognostic factors in patients with KRAS mutant lung cancer, but their role in picking treatments today remains unclear.
So that brings us to the end of this case. Please see the other segments for further discussion about the latest research in lung cancer, or visit ascopost.com.
