Roundtable Discussion: Iams Considers Platinum Rechallenge or Other Therapy for Relapsed ES-SCLC

Wade T. Iams, MD (Moderator)

Assistant Professor of Medicine

Division of Hematology-Oncology

Vanderbilt University Medical Center

Nashville, TN

IAMS: It is a pretty even split among participants over prophylactic cranial irradiation. I will cite a couple components. I do usually have the patients have a conversation with a radiation oncologist. One unique thing about this case that jumped out at me was that it did not seem like the patient had high disease burden overall, with predominantly intrathoracic disease.

Potentially, there’s a case there, to [increasing] the time to brain metastasis. But there are phase 3 randomized data of a lack of survival benefit in ES-SCLC with [prophylactic cranial irradiation]¹ that are being reevaluated in the SWOG S1827 study [NCT04155034]. We will have additional data commenting on those results [soon].

DISCUSSION QUESTION

• What is your approach to follow-up, specifically regarding frequency of scans?

IAMS: This is something that comes up in the NCCN [National Comprehensive Cancer Network] guidelines.² This is a patient with ES-SCLC who had a good response; but [frontline treatment in this setting] has clifflike Kaplan-Meier curves for progression-free survival [PFS]. So how frequently are you doing scans for these patients with ES-SCLC?

ROSENFELD: I typically scan every 2 months. It is such an aggressive disease that I do 2 months instead of 3 months.

FLEISCHMAN: [Could this depend on] what you see in his partial remission PET scan?

IAMS: Potentially, depending on the depth of response, that could help guide frequency. Guidelines are currently allowing that 2-month interval for ES-SCLC.²

NAKHOUL: I scan every 2 months.

FLEISCHMAN: I think it's fine, but we do not know [whether] more frequent scanning is going to change overall survival [OS].

IAMS: We will touch on that bit tangentially, with timing of relapse and decisions on therapy.

KHASAWNEH: I would consider them platinum sensitive if they progressed more than 6 months from their last platinum therapy.

IAMS: Absolutely. The NCCN guidelines have the 6-month interval noted. One of the tensions in the data and the guidelines is a lot of the data come out attempting to define it as a 3-month interval, so it can be a struggle to interpret the guideline of 6 months, [whereas] the data we have is at 3 months.

IAMS: We will revisit the NCCN guidelines quickly.² There is a laundry list of options for relapsed SCLC. We are focusing on the guidelines for patients with relapse 6 months since last platinum. The preferred regimen within the guidelines is the original regimen, or platinum rechallenge. Lurbinectedin [Zepzelca] is among the list of other recommended regimens, with no specific downgrading, so to speak.

What I mean by that is that nivolumab [Opdivo] and pembrolizumab [Keytruda] have been downgraded but preserved within the guidelines. As immune checkpoint inhibitors [ICIs] have gotten to first line, some of the companies have been withdrawing indications. When we look at the options for relapse at less than 6 months since last platinum, topotecan [Hycamtin] or lurbinectedin are both standard-of-care options. Lurbinectedin was approved in 2020, and topotecan was approved in 1996.^3,4

GALLAGHER: Unfortunately, the PFS may be half as long [for platinum rechallenge].

IAMS: Yes.

MAHESHWARI: Can we combine the platinum with irinotecan [Camptosar] in these situations?

IAMS: For the platinum rechallenge, I think that would be reasonable. The platinum backbone would be the main intended component, so I think so.

IAMS: When you are thinking about platinum rechallenge, do you feel like a longer time since the last platinum makes a stronger case to do the rechallenge? Or if they are right at the 6-month interval, for example, would you be more likely to choose a different agent?

MAHESHWARI: I think the longer the disease-free interval, the more likely the patient is going to respond to the cisplatin backbone treatment, along with the irinotecan. I prefer irinotecan in situations where the patient already got [etoposide]. I give it day 1 and day 8, every 21 days.

IAMS: I do not have specific data to comment on that question. What would be the significance of a complication that would preclude platinum rechallenge, in your opinion?

MAHESHWARI: If we have used a cisplatin-based treatment initially and they have significant hearing issues, neuropathy, or even renal insufficiency, that will impact the decision. On the other hand, if you give carboplatin-based treatment and the patient has significant thrombocytopenia or blood issues, that can definitely change.

IAMS: The question of performance status and frailty [relates to] the tolerance of lurbinectedin vs a platinum rechallenge. For a patient with a performance status of 2, which many of these patients are at relapse, do you have more comfort with a certain regimen?

FLEISCHMAN: One of the things I sometimes go on is whether they have to travel and whether they would rather have an oral regimen or [intravenous]. I mean at this point, you are buying months of survival. You do not want to make a patient terribly ill or take away their quality of life [QOL] to do that.

IAMS: Yes. As they proceed in the course of SCLC, what you are gaining in QOL is declining, so the attention to QOL is escalating, for sure.

MAHESHWARI: With a performance score of 1 or 2, you still can rechallenge it based on the toleration. On the other hand, if a patient is [declining], I still prefer combination drugs if they have more than 6-month times [of response]. The reason why is because it is SCLC. I have not seen a great response from topotecan, so there is another reason. When we reach [for] the topotecan, pancytopenias can be challenging.

FLEISCHMAN: [This is true of] lurbinectedin, as well.

IAMS: Yes, we will continue to discuss individual thoughts on lurbinectedin. The febrile neutropenia was not too bad for the [overall] rates of neutropenia, but the rate of neutropenia alone was quite prominent [From the Data⁵].

FLEISCHMAN: It depends on your patient population. Once they get severe enough neutropenia, they say there were not that many febrile ones. But I wait until I have my patients, [and I expect] they are all going to be febrile.

FLEISCHMAN: Why couldn’t they improve PFS, though?⁵ It looks exactly the same.

IAMS: I think that comes back to there being a subgroup of patients who have any degree of treatment sensitivity. I could launch into a bit of a tangent about the SCLC subtypes. A lot of [National Cancer Institute]–funded research is going into delineating the 4 subtypes of SCLC. These are defined by unique transcription factor profiles. What I can offer is: the cohort that is benefiting in OS—maybe they are a particular predominant subtype that is a minority subtype. So, the median PFS is still bad, but there is some subgroup of individuals, or within an individual, where there is an intratumoral subtype that is manageable.

FLEISCHMAN: But we have to go back and reanalyze all the patients for transcriptome analysis.

IAMS: The best guess is the short answer, and that being impossible is the implication. Tumors are so hard to come by to do in-depth analyses like that, so we are going to need more blood-based monitoring in SCLC.

FLEISCHMAN: Can you do that based on the blood-based circulating tumor DNA [ctDNA]? Don’t you need real tissue?

IAMS: That is one of the main areas on the horizon. I think this comes back to clinical meaning, hopefully within the next 5 to 10 years. With methylation profiling, there is some interesting validation work going on right now.

Nothing has been published yet, but I know there are [studies] aimed at high-impact publications to RAI2 [retinoic acid-induced 2]-link subtype by ctDNA methylation profiling, which could provide some delineation of what transcription factor programs are activated. Anyway, there is more to come on that. That would be a bit of a Rosetta Stone of the issue.

KHASAWNEH: I've used it in a couple patients. Two of the 4 or 5 patients had stable disease, and the data seemed to be comparable with my personal experience. From a tolerance standpoint, I find myelosuppression and fatigue are the most common adverse events [AEs], but I did not see any significant AEs causing discontinuation of the drug.

IAMS: I have had a similar experience, where it is fatigue predominantly, and certainly cytopenias. We had debated whether to administer G-CSF [granulocyte colony-stimulating factor] as primary prophylaxis in the use of the treatment, but we had had opted toward the secondary prophylaxis, so it is not necessarily primary prophylaxis for lurbinectedin.

FLEISCHMAN: Although the percentages are high enough that, based on the old criteria for G-CSF, you could justify it because it is already greater than 40%.⁵

IAMS: The grade 3 or higher rate of neutropenia is [46%].⁵

FLEISCHMAN: In lymphoma, we would say that is high enough that you can get primary prophylaxis.

IAMS: The hypothesis of selection bias of trials is probably the primary driver of why their febrile neutropenia rate was so low, despite the severe neutropenia.⁵

FLEISCHMAN: They are all study patients. They are always going to be better than patients I am going to get, a lot of whom would probably not even get into a clinical trial.

IAMS: Exactly. Any additional comments on the use of lurbinectedin or just relapsed SCLC, in general?

MAHESHWARI: I would probably use it in the third-line setting.

FLEISCHMAN: I think so, yes.

IAMS: That would align with the guidelines we reviewed.

TIAN: Are you going to comment on the trilaciclib [Cosela] for use in the frontline setting?

IAMS: As a new alternative to G-CSF for myelopreservation...it is an interesting point. I have not used it, but I am curious [whether] others use it. There was a FDA approval of trilaciclib.⁶ It induces cellularsenescence to preserve from cytopenias, particularly during SCLC regimens. Has anyone used trilaciclib?

TIAN: I have used it once. The patient ended up getting transfusion support, so I just wanted to find out what other physicians are doing.

IAMS: Some of the data showed not only decreased severity of neutropenia but also decreased red blood cell–transfusion requirements with trilaciclib.⁷ There are some interesting data. We ultimately did not add it to our formulary [at Vanderbilt University Medical Center].

IAMS: We are discussing the platinum-sensitive setting, so it is going all the way back to 7 months since last platinum-based therapy. What if this patient had brain metastases? Would your selection of platinum rechallenge, lurbinectedin, topotecan, or CAV [cyclophosphamide, doxorubicin, and vincristine] differ based on brain metastasis?

ROSENFELD: Are there data on lurbinectedin cross-comparison trials? Do you feel like one agent is better with brain metastases, whether it is topotecan or CAV?

IAMS: No.

FLEISCHMAN: Temozolomide [Temodar] has CNS [central nervous system] penetration. Of course, it is oral, so that is also sometimes convenient. But are you talking about uncontrolled brain metastases or ones that have been pretty well treated with Gamma Knife [stereotactic radiosurgery], or [otherwise] controlled? It makes a difference.

IAMS: Let us say uncontrolled, with any hope for CNS efficacy. But I do agree with temozolomide, for sure. There are some interesting data—not relevant to relapse, because most of them have received ICIs, as well—but there is a subgroup of patients whose data sets are being put together, more so in non–small cell lung cancer, of ICI efficacy for patients with CNS metastases. But I have not seen that as much in SCLC.

IAMS: What do you view as the most critical unmet need?

ROSENFELD: Everything.

IAMS: [We need to] help them live longer and better.

MAHESHWARI: Yes, we have not had [many] breakthroughs, as long as we have been treating SCLC.

FLEISCHMAN: [We also need] better prediction. The 25% or 20% that are going to do well with immunotherapy are going to be [longer-term survivors]. But we do not have to treat everybody; we already know ahead of time they are not going to do well. I think that would be good. I do not know [whether] the patients would appreciate it, but it would be helpful.

MAHESHWARI: I had a patient who had a significant skin rash, [and] I had to stop the treatment. He had ES-SCLC. He is almost 1.5 years out. He is doing remarkably well. I still believe patients who get a lot of AEs may have a better response.

IAMS: Yes. There are intriguing and well-replicated data sets along those lines, regarding immune-related AEs, except in the setting of pneumonitis with lung cancer, which is typically very bad prognostically and very difficult to manage. Besides that, there are some compelling data sets displaying improved antitumor efficacy for basically any other immune-related AE.

To cite the major studies going on in the field, novel ICIs outside of PD-1 and CTLA-4 are being added. Anti-TIGIT [T-cell immunoglobulin and ITIM domain] antibodies is a big first-line trial [SKYSCRAPER-02; NCT04256421]. I am not sure we are going to be able to gain much more from the PD-1/platinum-etoposide backbone, but we will see.

Adding PARP inhibitors to that ICI maintenance is being assessed [in a study; NCT04790955]. Another interesting [ongoing] study is lurbinectedin being added to checkpoint inhibitor maintenance [IMforte; NCT05091567]. Is there a cohort of patients within that maintenance group who could achieve further benefit by adding lurbinectedin to the checkpoint inhibitor?

Those are the big trials I am aware of in ES-SCLC, at least in the first-line setting. Then we have a lot of phase 1 trials, with no clear leader of the pack, for the relapsed setting. Some interesting work is being done for antibody-drug conjugates, bispecific T-cell engagers, and immune effector cells, like [chimeric antigen receptor] T-cell therapies. Those are all being evaluated but nothing has demonstrated breakthrough data, that I have seen so far.

FLEISCHMAN: The antigen is unique to those cells. I would be surprised if you could find one.

IAMS: There is an interesting case for DLL3 [delta-like ligand 3]. The main cross-reactivity of DLL3 is neural, which is problematic. But interestingly, the main toxicities that were seen when an anti-DLL3 antibody-drug conjugate was assessed were severe pericardial and pleural effusions.⁸ The reasons are unclear as to why that happened, but there is a lot of investment in trying to use bispecific T-cell engagers for DLL3. That is the lead antigen I am aware of, but there has not been a breakthrough yet.

The other complicating factor when we think about the paradigm of SCLC subtypes is that DLL3 does not consistently track with subtypes, so it is going to be hard to link attempts at going after that specific antigen with subtypes. But there are interesting data that 1 subtype could be particularly immunogenic, and it is a little too good to be true. It looks like it is [approximately] 15% of the patients, a similar cohort you would hypothesize has that clear benefit with immune therapy. We will see how that could play out clinically, if that can be replicated.

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