Second- and Third-Line Treatment for ES-SCLC

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Transcript:

Mark Socinski, MD: The same time that we had these data, we also had third-line indication for immuno-monotherapy in this disease setting, and I wanted to get the perspective. Dr Liu, clinically, how many patients get to second-line [therapy]? How many patients get to third-line? It’s a tough population, but what’s your experience there?

Stephen Liu, MD: There’s a lot of attrition with small-cell lung cancer, much more than with other cancers. We have published data in this setting. If you look at a group of patients who received first-line treatment, the data will tell us about half would get second-line and less than a quarter would eventually get third-line [treatment]. The approvals of nivo [nivolumab] monotherapy [and] pembro [pembrolizumab] monotherapy in the third-line are important approvals. But for a potentially transformative drug, they would have much less impact because patients wouldn’t survive long enough to receive third-line treatment. That’s why the front-line treatment with atezo/durva [atezolizumab/durvalumab] has the chance to make a much bigger impact.

Mark Socinski, MD: What is your standard second-line [treatment] following first-line chemo-immunotherapy?

Stephen Liu, MD: It’s a setting where I look for a trial if we can. Trials are my preference. If I’m taking a board exam, my answer is topotecan, but if I’m in practice, that’s a drug that I’m disappointed with. I find it very toxic; quality of life is not so great with topotecan. It’s a tough drug to receive and the responses are fairly limited. There are many other agents that are equally good or bad. Taxanes, irinotecan, temozolomide, if there’s CNS [central nervous system] efficacy. It’s an area where we have an unmet need for more potent agents.

Mark Socinski, MD: Roy, any thoughts there?

Roy S. Herbst, MD, PhD:No. Topotecan—I hate using it. I have. We sometimes use taxanes here, but that’s where we send them over to phase 1. I still remember a patient I sent over to phase 1 years ago for an immunotherapy who is alive 7, 8 years later. Now, we’re in the post–I-O [immune-oncology] world. I think we look at I-O combinations if a patient is strong enough. Some of the ADCs [antibody drug conjugates], I think are worth exploring there, but it’s a tough area. At least, we’ve elevated from where we were in the past [by] having immunotherapy to begin with.

Mark Socinski, MD: We are seeing patients that get a fair durability to their responses on immuno-maintenance therapy. Is there a cut point in which you would think about going back or adding platinum/etoposide back in at some point?

Roy S. Herbst, MD, PhD: In the absence of data, it’s hard to say. If someone becomes resistant, add back some chemotherapy, and if chemotherapy is helping in the first place, probably knocking down some immune-resistant cells or regenerating some neoantigen [is a good idea]. It’s something to try and if someone is not having any issues with clinical progression, or if they’re just progressing radiographically, it’s worth a try.

Mark Socinski, MD: Any role for nivo/ipi [ipilimumab] in the refractory setting following first-line I-O? You mentioned I-O combinations earlier.

Roy S. Herbst, MD, PhD: We’ve done that and we’ve had trials. I’m a little disheartened in the fact that durvalumab/tremelimumab didn’t seem to have any effect up front because it’s a different situation. But nivo/ipi has phase 2 experiences, but you’re just giving the patient a lot of toxicity and the absence of any real data; I’ve not used it that much.

Mark Socinski, MD: Any experience with lurbinectedin?

Stephen Liu, MD: I haven’t used it but the data look interesting. Lurbinectedin is a transcription inhibitor; it binds onto the DNA promotor region that prevents transcription. It also has an effect on tumor-associated macrophages, which may alter the microenvironment and help facilitate some immune responses. In a single- arm study of over 100 patients, it gave a response of about 35%. In [patients who were] platinum sensitive, that was up to 45%, and in [those who were] platinum resistant, 22%. It’s impressive for [patients who are] platinum resistant. We don’t have any drugs that are active in that setting. We’re waiting for the randomized data. We need a control arm there, and the ATLANTIC trial is looking at lurbinectedin with doxorubicin versus topotecan or CAV [cyclophosphamide, doxorubicin, and vincristine], and I think when we see those data, we’ll know more about just how active this drug is, but there is promise in that area.

Roy S. Herbst, MD, PhD: I would agree. When those data were presented at ASCO [American Society of Clinical Oncology], it was almost too good to be true; we were all very impressed and we’re waiting for the randomized trials. That could have a real mixture especially given our current paradigm using immunotherapy up front.

Mark Socinski, MD: Any appetite for PARP inhibition in this setting? There’s been some work, although I must say the data that I’ve seen have had a modest impact in this disease setting from my perspective. I don’t know if either of you have a different feeling.

Stephen Liu, MD: I find them exciting. When we think of PARP inhibitors throughout oncology, we often think of tumors that have defects and BRCA or a homologous repair, but these drugs also have some activity in small-cell [lung cancer]. Monotherapy didn’t really get us there. We remember the STOMP trial looking at maintenance PARP that didn’t really show much activity. I think there’s a lot more promise in combinations. It makes sense to combine a PARP inhibitor with a drug that will induce single-strand DNA breaks. Olaparib is a bit of a stronger PARP trapper than veliparib and in combinations with temozolomide for example, I think there’s some promising activity there. PARP inhibitors have more promise and maybe in combination with immunotherapy. We know from work that our colleagues have done that inhibition of PARP using PARP inhibitors, using CHK1 [checkpoint kinase 1] inhibitors will drive up PD-L1 expression and will induce T-cell infiltration. A CHK1 inhibitor will have an antitumor effect in small-cell lung cancer models, but if you deprive that model of CD8-positive T cells, it has no effect showing that its efficacy is medicated through the immune system.

Transcript Edited for Clarity

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