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 me today are two of my colleagues. Dr. Heist, could you introduce yourself?
Dr. Rebecca Heist:
Hi, I'm Rebecca Heist. I'm a medical oncologist at Mass General Hospital in Boston.
Dr. Riely:
And Dr. Sabari. Welcome.
Dr. Joshua Sabari:
Hi. I'm Joshua Sabari, Thoracic Medical Oncology at NYU Langone Health, Perlmutter Cancer Center in New York.
Dr. Riely:
Welcome to you both. Today we'll be discussing the treatment and management of KRAS-mutant non–small cell lung cancer with three patient cases. Our third installment will focus on the management of unresectable locally advanced non–small cell lung cancer in a patient with a KRAS mutation.
Our case is a patient who's a 71-year-old man who presents with a left-sided lung mass. In addition to the primary tumor, there's a 3-cm subcarinal node and a 2.5-cm paratracheal node. Patient undergoes endobronchial ultrasound-guided biopsy of an N2 node, and that shows that this is in fact a lung adenocarcinoma, and the patient's tumor is PD-LI negative. Patient has molecular testing that shows that the tumor has a KRAS G12C mutation. Patient completes their staging evaluation with a PET scan and an MRI of the brain that show no additional sites of disease.
Maybe I'll begin, Dr. Sabari, with you. Patient who's come to see you with documented N2 disease in a couple different stations. What do you do with that patient?
Dr. Sabari:
Yeah, this is a classic tumor board patient, right, the stage IIIB, potentially maybe C, unresectable or borderline resectable. I think you need an opinion from your thoracic surgery colleague. You also need an opinion from your radiation oncologist. This is where tumor boards' multimodality team meetings are critical so that we can achieve the best outcome for patients. So both thoracic surgery and radiation oncology need to weigh in here.
Dr. Riely:
Okay, great. Now this patient ends up seeing a thoracic surgeon next before they meet with a radiation oncologist. The thoracic surgeon says that the patient's not a surgical candidate, and this is primarily due to the bulky multistation mediastinal nodes. So, Dr. Heist, for this patient who surgeon says is not appropriate for surgery, has stage III disease, take me through your thinking here.
Dr. Heist:
Yeah, so in that case, with surgery off the table for a stage III with bulky mediastinal nodes, we're thinking about definitive chemoradiation. Together with our radiation oncology colleagues, we would be seeing this patient and then thinking about what's the best plan, and typically we're doing concurrent chemotherapy with radiation.
I think your choice of chemotherapies in somebody who's got a lung adenocarcinoma, we sometimes will use cisplatin/pemetrexed in combination with radiation. There are many people who are not great candidates for cisplatin-based regimens, and in that setting we're very often using weekly paclitaxel and carboplatin with radiation. But really we would be trying to finish out a definitive course of chemoradiation, and then based on studies like PACIFIC, we're also thinking about adjuvant immunotherapy thereafter, so adjuvant durvalumab, for example, would be something we think about. I think there's with PD-L1 negative, there's various subgroup analyses that we can get into, but in general we are, unless somebody has a clear contraindication to immunotherapy, we are discussing and offering adjuvant immunotherapy after definitive chemoradiation.
Dr. Riely:
Now this patient had molecular testing at the beginning because it's certainly part of the initial evaluation, and if you're thinking about neoadjuvant therapy, molecular testing is pretty critical. Dr. Sabari, do you use the KRAS mutation that you know about here in your decision-making around concurrent chemoradiotherapy for this patient with locally advanced disease?
Dr. Sabari:
Yeah, so not necessarily. I mean, there are no approved KRAS G12C inhibitors in this space. But I do use the molecular testing. So, if a patient has an EGFR or an ALK fusion, that's a patient who I would not recommend giving durvalumab in the consolidation setting after completing chemoradiotherapy. So I think getting the results of the NGS back are important. But in the KRAS G12C space, they may be a candidate for a clinical trial, but unfortunately we don't have any standard of care therapies here. Greg, would you ever use a G12C inhibitor off-label in the neoadjuvant setting or unresectable setting?
Dr. Riely:
No, I wouldn't. For instance, if you're using, to go a little far afield from this case, if you're doing neoadjuvant therapy and you were giving concurrent chemo and immunotherapy, we know that those are both critically important components, both the chemotherapy, which we know improves overall survival in the perioperative space and immunotherapy, which we again know improves overall survival in the perioperative space. So I think if you add in targeted therapies here, you only reduce the tolerance of what we know to be curative therapies. So I don't use that in this space.
Dr. Sabari:
I would agree.
Dr. Riely:
All right, so this patient does in fact go on to receive concurrent carboplatin-paclitaxel and radiation therapy. That's followed by 7 months of consolidation durvalumab, patient's tolerating treatment well, and then the patient goes in for routine restaging scans that shows the patient now has one new liver metastasis. So, Dr. Heist, for you, when this patient now has gone through concurrent chemoradiotherapy in the midst of consolidation durvalumab, has a new liver lesion, what do you do next?
Dr. Heist:
Yeah. So this is too bad, and in the setting of new liver metastasis, I would just make sure first of all that we have complete staging everywhere and that includes looking at the brain again. Very often in the stage III setting, we're not often getting brain MRIs or if we are, they're kind of sporadic. So I would want to make sure with CTs of the whole body, possibly a PET as well as a brain MRI, that we really understand where the disease is. In a prior case, we talked about localized therapy to an oligometastatic site. I personally don't tend to think of the liver as a true oligometastatic site because I think very often there are other areas involved. But that'd be interesting to see if you have different opinions there.
Dr. Riely:
Yeah, I think that is an interesting thought. But I think we'll jump to this actual case what we did next in terms of imaging. So patient has a PET scan, and the PET scan confirms that this liver lesion is FDG avid, so supporting the idea that this is a site of metastasis. But the PET scan also shows new bone metastases, so we're kind of stepping away from the oligoprogression part. Then a patient has an MRI of the brain that shows two new brain lesions measuring up to 1.1-cm in size, and then there's a third lesion that's subcentimeter, it's new, radiologist isn't really calling it as a metastasis but says it's very suspicious. So, Dr. Sabari, you have this patient who's progressed on consolidation durvalumab, KRAS G12C mutant, has a couple spots in the brain and otherwise diffuse metastatic disease. What are you thinking?
Dr. Sabari:
Yeah, so this is a patient with a known KRAS G12C mutation. The thought of do we need to re-biopsy or re-profile here is always an important one depending how far out a patient is. I mean, you have the NGS upfront, most likely this is a recurrence. So we could talk about a biopsy, but to be honest, in tumor board we're biopsying, but in real life we're probably not. In a patient with a G12C mutation who's progressed on chemo, followed by consolidation durvalumab with brain metastasis, I would likely select adagrasib. As we've shown, all of us here on the call, have shown that this therapy has superior CNS penetration to some of the other KRAS G12C-GTPase inhibitors. Now 1.1 cm, Greg, makes me a little bit worried. So would you radiate this or would you start therapy upfront?
Dr. Riely:
Maybe I'll punt this one to Dr. Heist. What would you do? 1.1-cm lesion, would you go to the target therapy or would you take maybe what I might consider the more conservative approach and radiate the
Dr. Heist:
Yeah, I mean, I think both are reasonable. At 1.1 cm that starts to get to a size where I worry if it were to get larger that it could become symptomatic so I would tend to do focal radiation here. The nice thing about that is it can be just a 1-day procedure, and it's pretty straightforward and you can do that as you're starting the adagrasib. I think that one that was a little indeterminate, you would leave alone and follow. But I think for what could be targeted, I would tend to SRS there and move on, as you say to the adagrasib.
Dr. Riely:
Right, and so actually that's what I did for this patient. I recommended referral to the radiation oncologist, of course, the patient already seeing one from the beginning. Based on what we talked about, the patient did receive stereotactic radiation to the two larger lesions, and then the patient began a KRAS G12C–targeted therapy, in this case adagrasib. So, Dr. Sabari, so when you're starting a patient on one of these new KRAS G12C–targeted therapies, how do you do it? What do you talk about with the patient? How often do you see them, that kind of stuff?
Dr. Sabari:
Yeah, so some of the targeted therapies historically we've started, see a patient in 2 weeks and they can come back in 3 months. This is one of the drugs where I do want to see them back in the office 7 to 10 days after initiating therapy. I do a lot of education on explaining the side effects, maybe some of the GI, nausea, as well as the diarrhea side effects up front. We're also monitoring liver function tests. You heard from Becca earlier that we do want to make sure patients are tolerating these therapies well, and if they are, I bring them back in another week and if they're still doing well, that's when I start to extend the visits. But a lot of times for the first cycle or so, first 4 weeks or more, patients need to be seen a little bit more frequently until we get the patient on the right dose and make sure we're achieving response. So despite this being a targeted therapy, I do want to hold their hand a little bit more in the early days.
Dr. Riely:
Yeah, I find these patients, if you use that analogy to other targeted therapies and things like osimertinib or alectinib or something like that, these patients are not sort of that front-line patient. So they're somebody who's gone through chemotherapy, sometimes checkpoint inhibitor, and frankly they're having a little bit harder time tolerating all of it. I do feel like, I agree completely, they need a little bit more close watch than a patient who's starting up on osimertinib or something like that. I bring the patients in again in the first week or two, and then you end up typically seeing them once a month thereafter to keep a closer eye on things like LFTs and some of the other toxicities.
Now, Dr. Heist, for this patient, the patient comes in 2 weeks later and reports some grade 2 diarrhea for the past week. How do you think through diarrhea, and how do you manage that?
Dr. Heist:
Yeah, so diarrhea is one of the potential side effects of these G12C inhibitors so it's definitely something to pay attention to. I would one, make sure that there's not an infectious cause. You want to make sure that it's not something viral or infectious. Two, you also want to make sure that they're using the antidiarrheals appropriately. You want to be aggressive with the use of antidiarrheals and make sure that they're staying hydrated. Grade 2 diarrhea is bad diarrhea. It is hard to live with. Your quality of life with grade 2 diarrhea is really tough, and so I will very often hold drug and let that diarrhea settle down, get to grade 1 or less before I consider restarting it and very often with a slight dose reduction.
Dr. Riely:
Yeah. I'm often surprised by how patients with diarrhea seem to think they can tough it out and are a little bit slow to take advantage of the agents that we've provided them. And so really that, as Dr. Sabari highlighted, that anticipatory counseling, if you will, talking through what may happen and what we want them to do, I think is pretty critical.
Dr. Heist:
Yeah.
Dr. Riely:
All right, so for this patient, 8 weeks in, the patient has a repeat CT scan that shows a slight reduction in liver metastases, stability of bone metastases, and resolution of the subcentimeter brain lesion, the one that wasn't radiated, as well as improvement of the two radiated lesions. So I think that CNS efficacy that, Dr. Sabari, you mentioned, we're seeing a hint of that here because the nontreated lesion has gone away. So I think that's a reassuring sign.
All right. So some key clinical takeaways for this case. For patients with locally advanced non–small cell lung cancer, initial therapy does not target the KRAS alteration, and instead we use our known approaches based on chemotherapy radiation as well as immune checkpoint inhibitor. I'd highlight that there's demonstrated CNS efficacy with KRAS G12C targeted therapies. But if stereotactic radiation is possible, particularly for lesions that are greater than a centimeter in size, it's reasonable to give radiation prior to using KRAS G12C targeted therapies. Then as always, with any of our therapies, anticipatory management of adverse events is critical, and close contact with our patients is also important.
So we'll close there. This 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.
