Second- & Third-line options after Chemotherapy or I/O



Naiyer A. Rizvi, MD: I think this does segue nicely into a discussion on the relapsed setting. We’re hopeful our patients will do great with first-line chemotherapy, and atezolizumab with durvalumab, but unfortunately the majority of these patients will still progress on this treatment. Jamie, we’ll start with you. What’s your second-line and your third-line therapy for this population?

Jamie E. Chaft, MD: After chemoimmunotherapy?

Naiyer A. Rizvi, MD: Yeah.

Jamie E. Chaft, MD: We’re in a bit of a pickle. I think it depends a bit on their disease burden. For patients with CNS [central nervous system] metastases, I still do lean toward temozolomide. I know the data are quite limited, but perhaps it’s institutional bias. They attempt to be well tolerated and have great CNS penetration. I echo what’s been said before. We all have moved away from topotecan. However, we can, whether it’s clinical trials or standard other agents such as irinotecan or paclitaxel. CAV [cyclophosphamide-Adriamycin-vincristine] rarely. We have a plethora of options that are really selected based on bone marrow reserve and disease distribution.

Naiyer A. Rizvi, MD: And third-line?

Jamie E. Chaft, MD: It’s the same argument again if they get there.

Naiyer A. Rizvi, MD: Yeah. So the question I’m leading to is, would you go back to I/O [immuno-oncology]?

Jamie E. Chaft, MD: I would not, so I didn’t even grasp that question.

Naiyer A. Rizvi, MD: Because Taofeek, you know, does something a little differently.

Jamie E. Chaft, MD: Yeah. I think an I/O failure is an I/O failure, so I would—if someone was robust enough to reconsider a rechallenge—most likely seek out a clinical study. I don’t think I would clinically represcribe immunotherapy with just limited confidence, but we would really see efficacy in that population.

Naiyer A. Rizvi, MD: Right. I think that’s right. I think third-line approvals really were in the pre-I/O era. You know, first-line I/O. But if somebody had really high TMB [tumor mutational burden], you may want to think about other options.

Jamie E. Chaft, MD: TMB?

Naiyer A. Rizvi, MD: Yeah. Your tumor TMB. You know, a trial or an I/O combination. Like bring the CTLA4, maybe something like that.

Jamie E. Chaft, MD: Right. I think the combination arm of the CASPIAN trial will be really interesting, and I think we’ll learn a lot from that. And particularly, to ask ourselves that question, so when that reads out if there’s a greater signal, if our patients who have failed a PD-1 [programmed cell death protein 1] agent, should we be challenging them with combination? I don’t think we’ve seen any promise there in non—small cell lung cancer.

Naiyer A. Rizvi, MD: But we see that a lot in the community. People progress after first-line chemotherapy I/O and then do go to second-line I/O, and it’s just kind of a data-free zone right now. Ticiana, what are your second- and third-line therapies?

Ticiana Leal, MD: Can I go back to the rechallenge question? What about rechallenging with the platinum-etoposide alone? You’ve failed the I/O, and the I/O stopped working. And you can say, “OK, this is I/O refractory.” But depending on the interval, if there’s still platinum sensitivity, I actually go back to the platinum etoposide. And we’ve seen retrospective data in the non—small cell lung cancer scenario, where there are reports that perhaps after I/O, patients respond better to docetaxel. And will we see something like that in the small cell population? I actually go back to the platinum-etoposide if I can. If that patient is still platinum sensitive and can tolerate a platinum again, that’s what I would try first.

My second-line option if they’re not platinum eligible, or if they have been challenged with a platinum already, would be to go with probably irinotecan on a weekly basis. It’s been well tolerated, there are fewer cytopenias, and there’s activity based on phase II data. It’s kind of, again, trying to avoid the toxicities of topotecan and trying to still identify patients who are motivated enough to get chemotherapy and who we think will benefit from these agents.

As you can see, if NCCN [National Comprehensive Cancer Network] has multiple options, it’s really choosing based on toxicities they’re trying to avoid. Signally, JAK activity is very similar between a lot of these agents. Certainly a clinical trial really is what we’re focusing on and trying to consider: how do we move the field forward in the second- and third-line setting? I agree that I wouldn’t go back to an I/O in the third line if they’ve unfortunately already had their disease progress on immunotherapy.

Naiyer A. Rizvi, MD: Do you think there’s a difference between PD-L1 [programmed death-ligand 1] and PD-1 antibodies? If you progress on a PD-L1, do you think they should get a PD-1 afterward?

Ticiana Leal, MD: Not really. When we saw the second-line data for atezolizumab, the response rate is 2.3%. That study is the smaller study, but in that second-line setting, the atezolizumab study, didn’t meet the overall response rate at 6 weeks, which was primary endpoint. I don’t have any reason to believe that PD-1 versus PD-L1 would make a significant difference that would change the clinical decision to try 1 versus the other.

Taofeek K. Owonikoko, MD, PhD: Yeah, I’m of the same opinion that rechallenge outside a well-designed biologically based clinical trial is the right strategy here. When a patient goes on chemotherapy I/O, if they don’t progress immediately, we can conclude that they did not respond to the chemotherapy because we know that’s what is driving the initial response. However, if they do respond and then you have that durable response that translates into survival advantage, I would agree with Ticiana: there are opportunities there for redefining what our platinum-sensitive relapsed strategy should be.

The French study helped answer that question a little. There were 2 patient cohorts with platinum-sensitive relapsed small cell lung cancer and randomized to nab-paclitaxel versus I/O. Not surprisingly, the progression-free survival of that study is miles apart when you look at the nab-paclitaxel arm compared with the I/O, which I know is much better.

Eventually the overall survival did not look different. But it would suggest that if you have a patient who has actively progressed, you want to address that progression. You’re really better off with cytotoxic agents rather than I/O. I don’t want us to lose sight of the fact that when we have patients who are chemotherapy-sensitive patients progress, re-treating them with a platinum doublet if they meet the requirement will still be a reasonable option.

The question is, do you rechallenge them along with the I/O or do you not? We don’t know. It’s all, at this point, data-free. I hope the data are there before the practice gets set, so we don’t all get set in our ways, and then you can no longer answer the question in a systematic manner.

Transcript Edited for Clarity

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