Choosing Appropriate Patients for Dual Immunotherapy/Chemotherapy in NSCLC

Sandip P. Patel, MD (Moderator)

Professor of Medicine

UC San Diego Health

San Diego, CA

DISCUSSION QUESTIONS

• In which patients with non–small cell lung cancer (NSCLC) have you considered using nivolumab (Opdivo) plus ipilimumab (Yervoy) plus 2 cycles of chemotherapy?​
• What clinical and disease characteristics influenced your decision to use this regimen?

SANDIP PATEL, MD: For what patient populations would you consider this regimen? Does anyone have any initial thoughts?

SAM YEH, MD: I will use nivolumab/ipilimumab with 2 cycles of chemotherapy, [based on] CheckMate 9LA [NCT03215706] in someone with PD-L1 expression less than 1%.

PATEL: For PD-L1 0%, I do the same. I consider it in patients who have PD-L1 expression of 0%. Are there any other characteristics for this patient or more broadly?

ANDY JANG, MD: For patients with squamous histology, definitely. Also, it is probably getting more popular since the shortage of carboplatin, so physicians might [choose this].

PATEL: You nailed it. Remember in the CheckMate 227 trial [NCT02477826] of nivolumab/ipilimumab without any chemotherapy, because of the way the statistical plan was done, PD-L1 less than 1% was not tested formally.¹ That was not part of the FDA approval. Many of us who use nivolumab/ipilimumab or CTLA-4/PD-1 in a PD-L1 negative population, use it with 2 cycles of chemotherapy because of that approval.

We talked about [patients who are] PD-L1 negative, we talked about squamous histology. I consider it in patients with brain metastasis. There are stronger data in melanoma, but there are reasonable retrospective data in NSCLC that patients with brain metastasis may benefit from anti–CTLA-4 blockade.^2,3 My other angle on those patients is that if…patients with brain metastases…progressed in the brain, you’re probably not going to get to the second line. So you want to use your best drugs first, if you think CTLA-4 is part of that. Last but not least, for patients with adenocarcinoma who may have STK11/KEAP1 coalterations, those are patients who may benefit from a secondary immunologic. Dr Wang, do you have a thought on when you consider this or if you don’t, what regimen would one use instead?

HENGBING WANG, MD: I think [we] use this a little bit more, especially with our carboplatin shortage. It only uses 2 cycles of carboplatin. I think it’s a very good alternative now [when] you couldn’t have carboplatin for most of the practices.

PATEL: It’s a great point during the carboplatin shortage, using less, especially in the metastatic setting is relevant, especially when you’re treating as many patients with lung cancer as we are.

What regimen would one use instead in this specific scenario? Probably the alternative most people would tell me would be chemotherapy plus PD-1, something like the KEYNOTE-407 [NCT02775435] regimen of [chemotherapy plus pembrolizumab (Keytruda)] or chemotherapy plus cemiplimab [Libtayo]; because they’re PD-L1 negative, you’re generally going to give chemotherapy with PD-1 [inhibition].

ESHA SACHDEV, MD: Are there a lot of toxicities in this regimen with the nivolumab and ipilimumab together with the chemotherapy?

PATEL: The toxicities when you add a CTLA-4 agent—this is 1 mg/kg every 6 weeks continuous, so it’s different than the melanoma dosing which is 3 mg/kg, a much higher dose. In renal cell carcinoma, it’s 1 mg/kg that’s every 3 weeks.⁴ This is given every 6 weeks and it’s the lower dose. You do get toxicities. The main toxicities [of concern] are colitis, [but] it’s at a much lower rate…than what you expect with the higher dose ipilimumab. There is a higher rate of endocrinopathies as well but not of pneumonitis, which is nice.⁵

SACHDEV: Would you give this regimen to an elderly patient? Because ipilimumab’s [given every] 6 weeks and at a lower dose, would you recommend it for someone who’s older and maybe their…ECOG performance status [PS] is not 0 but it’s maybe 2.

PATEL: We don’t have a ton of data for patients with ECOG PS of 2. I would [ask] how did they get to ECOG PS 2? If it’s because of their cancer, and you think they have a good shot and this is their best shot on goal then you try, like with patients with lymphoma [where] you’ll bite the bullet and give them R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone].

But the point is well taken. If someone is above 75 years old with ECOG PS 2, we don’t have a lot of data on what to do. It becomes an individualized discussion, both precision medicine on the molecular side, but also, on the toxicity side. Is this a 78-year-old who’s going to the mall, or is this someone who’s bedbound? Is this a patient who can tolerate diarrhea? Are they going to call you or they are they able to come in? Those are the main points I’d use.

Typically, with lung cancer, you sadly will not get as many shots on goal. This isn’t like ER [estrogen receptor]-positive breast cancer where we can cycle through multiple therapies, or even more indolent colon cancer. This is more like pancreatic or aggressive ovarian cancer where typically, I use most of my options in the first 2 rounds. It depends on the individual patients and their goals. Do they want to be aggressive [or] are they interested in palliation?

The majority of the benefit does come from the PD-1 inhibitor, but if we are getting a benefit from the CTLA-4, it’s probably on the order about 5%. Maybe you can stretch it to 10% at most. That’s a great question, and we don’t have any definitive answers. Those are just my thoughts when I’m thinking about these regimens, and when I introduce the CTLA-4.

XINTING FU, MD: I do use this for PD-L1 negative [disease]. I have wanted to use this regimen for patients who cannot handle chemotherapy, like for 80-year-olds. My experience is that the adverse events [AEs] came up later. After about 4 to 6 cycles into the treatment, that’s the time where I would watch for serious AEs. At the beginning, they’re fine without the chemotherapy, and they responded pretty well. For patients who respond, they last a really long time and they are already several years on the regimen.

PATEL: I would agree that the chemotherapy AEs [are reduced]—you’re only giving 2 cycles of carboplatin/pemetrexed, you don’t get into the asthenia, fatigue, cytopenias of pemetrexed. Then with taxanes, part of the reason I like it in squamous [cell carcinoma] is I typically start hitting neuropathy around cycle 2, 3, or 4. So 2 cycles of taxane benefit me from that standpoint but there are reasonable points to be made about using a chemotherapy/PD-1 backbone. It’s extremely reasonable to want to use a chemotherapy/PD-1 regimen as well. It’s worked in many other settings.

_References:

_{1. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231}

_{2. 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}

_{3. Carbone D, Ciuleanu T, Cobo M, et al. First-line nivolumab + ipilimumab + chemo in patients with advanced NSCLC and brain metastases: Results from CheckMate 9LA. J Thorac Oncol. 2021;16(suppl_10):S862. doi:10.1016/j.jtho.2021.08.061}

_{4. Yervoy. Prescribing information. Bristol-Myers Squibb; 2023. Accessed August 24, 2023. https://tinyurl.com/yxymszcm}

_{5. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):198-211. doi:10.1016/S1470-2045(20)30641-0}