During a Targeted Oncology case-based roundtable event, Rafael Santana-Davila, MD, discussed with participants which patients are candidates for chemoimmunotherapy for advanced non–small cell lung cancer. This is the second of 2 articles based on this event.
RAFAEL SANTANA-DAVILA, MD: Because I consider the standard of care to be full dose chemotherapy and immunotherapy in my practice, I still don't know who is a patient I should give the CheckMate 9LA regimen [and] who we should throw the kitchen sink at; I don't know what the right answer is. I think a patient who has a PD-L1 of less than 50%, a large burden of disease, and who I know, when they progress, are unlikely to receive second-line chemotherapy—those are the patients I would reserve the CheckMate 9LA regimen for. Does anybody have another opinion aside from that one?
MICHAEL HARRIS, MD: A few years ago, when ipilimumab/nivolumab was first shown to be fairly active in NSCLC in one of the earlier CheckMate studies, in patients who had absent PD-L1 levels, there was a benefit, albeit a very small benefit.1 That's the area where everybody was considering it. But it was unclear if, since the FDA hadn't approved it as yet, that you were ever going to be able to give it, because the insurance companies wouldn't pay for it.
SANTANA-DAVILA: You’re right; in CheckMate 227 [NCT02477826] it was for all patients regardless of PD-L1 status.1 When it was presented, it was endorsed by the National Comprehensive Cancer Network [NCCN] for all comers, but to everybody's surprise, the FDA said to only give it for patients with a PD-L1 of more than 1%,2 and I never understood the rationale as to why the FDA said that, but it's what they said. I think that if you're using it for a Medicare patient where patients are typically treated by what the NCCN says, it is OK to use that in that setting, but the patients who have private insurance, because you're not following FDA criteria, will not be allowed to use it. The CheckMate 9LA regimen, regardless of PD-L1 standing, is approved for all comers.3
Another question that we ask is, are patients typically able to tolerate 4 cycles of chemotherapy? My answer is, in the majority of cases, they are. What I tell patients is typically cycles 3 and 4, they are going to have more adverse events [AEs] from it. Does anybody know what the value of cycles 3 and 4 are? [No], but that is the standard of care. Does anybody have a different experience?
MUJAHID RIZVI, MD: In my experience, they usually tolerate it OK.
FENGTING YAN, MD: The fourth cycle is when I have issues, typically. In the first and second cycles, usually no one has issues, but when it's the third or fourth, that's when I see cytopenia and other AEs. Oftentimes, I have to reduce the dose or delay the cycle.
SANTANA-DAVILA: I have the same experience. I agree that with most patients, the majority tolerated the 4 cycles well, but when I ran into problems, it's typically in the third and fourth cycles.
RIZVI: Before immunotherapy, chemotherapy was all we gave. I remember docetaxel and [other chemotherapy], and patients used to [go on more frequently to] second line therapy for lung cancer, but the 4 cycles have been pretty easy to tolerate.
SANTANA-DAVILA: It was not unusual, then, that we would push on, because that was the only thing we had. We would push them to 6 cycles, but that's [now] when you would dose reduce.
SANTANA-DAVILA: The [CheckMate 9LA] study only allowed patients with brain metastases who had previously been treated with radiation. Since then, we have learned from data both from melanoma and NSCLC that patients treated with immunotherapy can do well and have ongoing responses to the brain.4,5 There was initially some concern that you would have some degree of pseudo-progression or immune infiltration into the brain that would cause more symptoms, [but] I think that issue has been somewhat quelled now that we have more experience. In my experience, patients who have had symptomatic brain metastases can be safely treated with immunotherapy without any problems.
MICHAEL HARRIS: I'd be interested in your take on whether you should give radiosurgery concurrently with immunotherapy.
SANTANA-DAVILA: Typically, I've encountered that situation in patients who have been treated with chemoimmunotherapy, and now [receive] the maintenance immunotherapy alone, or patients treated with nivolumab/ipilimumab and then develop a single brain metastasis…and there is really no right or wrong answer. That has never been studied, to my knowledge, but what I typically do is tell the radiation oncologist, “Let me do the next cycle of immunotherapy, and you can do the [stereotactic radiosurgery] or the radiation therapy in between cycles.” This drug is our antibody drug, so they stay in the system forever, and my experience has not been that they increased the AEs of radiation, so I feel pretty safe doing that.
Another question is, what do you do when patients present with brain disease, need steroids, and you have a problem getting them off steroids because of their brain edema? We know that those patients may not respond that well to immunotherapy, so that will be an indication for me—I will still give it, but I would not give, for example, combination immunotherapy to the patients [who are receiving] steroids for brain disease.
HARRIS: My corollary is that in stage III disease, where we now use durvalumab [Imfinzi], after combined chemoradiation, it was generally recommended that you start the durvalumab soon after finishing the radiation therapy because the radiation may make the tumor more immunogenic. Therefore, you get a better response to the durvalumab, and you may not have such a good response if you wait too long. That's why I was thinking, “Should we do radiosurgery first, then come back with immunotherapy?”
SANTANA-DAVILA: That is a question that nobody knows the right answer to. There have been many clinical trials looking at the abscopal effect of immunotherapy. I remember [hearing at a conference] discussion…that the abscopal effect is something that you see more in slides [presented at] investigational meetings, than what you see [in practice].
You're right that in the PACIFIC study [NCT02125461], there was an exploratory analysis [of those who started durvalumab] within 2 weeks of radiation, and those patients did better.6 The theory is that maybe by the destroying of the tumor, you are seeing more uptake, more antigen running around, [which] is seen by the immune system. A lot of that is theoretical, and we don't know if it really happens. Patients who are able to start within 2 weeks are probably just doing better, and that's why they [responded better to immunotherapy]. I'm not saying that we should not do that. I think that we should still aim to study starting patients early on, on durvalumab or [other] immunotherapy, but I think a lot of that analysis is biased.
1. Hellmann MD, Paz-Ares L, Caro RB, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019; 381:2020-2031. doi:10.1056/NEJMoa1910231
2. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). FDA. May 15, 2020. Accessed November 28, 2022. https://bit.ly/3ENTBBg
3. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. FDA. May 27, 2020. Accessed November 28, 2022. https://bit.ly/3GPjd3y
4. Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med. 2018;379(8):722-730. doi:10.1056/NEJMoa1805453
5. Goldberg SB, Schalper KA, Gettinger SN, et al. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2020;21(5):655-663. doi:10.1016/S1470-2045(20)30111-X
6. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308