Roundtable Discussion: Sabari Evaluates Immunotherapy, Targeted Therapy Options in ES-SCLC

Joshua K. Sabari, MD

During a case-based roundtable event, Joshua K. Sabari, MD, an assistant professor in the Department of Medicine at NYU Grossman School of Medicine and medical director at NYU Langone Health/Perlmutter Cancer Center in New York, NY, discussed the case of a 73-year-old woman with extensive-stage small cell lung cancer (ES-SCLC).

KAPPEL: [In general], these patients present when they’re sick, and instead of giving the immunotherapy a chance, practitioners go to [palliative] care right from the very beginning.

There’s a line where they’ll treat vs not treat, but if [patients] get a response, it is quickly. So if you’re going to treat them, you’ve got to treat them and keep your fingers crossed.

SABARI: We’ve all been consulted on a newly diagnosed SCLC inpatient. What does that look like in your practice? Are you able to get immunotherapy in the inpatient setting?

KAPPEL: Yes, but that’s a great question, because 90% of the newly diagnosed patients you see in the hospital get discharged. You do their PET scans and work-up, and they’ll start their treatment 2 to 3 weeks later as an outpatient, and you don’t just have that luxury with these patients.

SABARI: Anyone else have issues up front? What are some common reasons for not getting immunotherapy in the frontline setting?

BLOKH: If they’re in the hospital, that’s how you meet them for the first time, and you just diagnose them in the hospital. One could give them 1 cycle of a platinum plus etoposide [Toposar] regimen, but after that cycle, they’re going to get out.

One could start giving them the immunotherapy. It shouldn’t really be an impediment at just 1 cycle, but that’s the only time they probably are missing immunotherapy in general.

SABARI: I agree with that. I have a hard time even getting into chemotherapy, [because it’s] a lift to get chemotherapy in the hospital through the administrators. We generally have a difficult time getting immunotherapy approved [by insurance], so I oftentimes will give 1 cycle of carboplatin [Paraplatin] and etoposide [to an] inpatient. And to your point, start cycle 2 in the outpatient setting. Any other barriers to using immunotherapy in the frontline setting?

MODI: A related contraindication, [such as] uncontrolled rheumatologic disorders or in HIV with very low CD4 count. Otherwise, I don’t encounter any significant barriers when we’re trying to use the immunotherapy [for patients with] ES-SCLC.

SABARI: We worry about contraindications to immunotherapy, [such as] rheumatologic conditions [or] lupus, which we more commonly see in the non–small cell lung cancer [NSCLC] population.

But Dr Modi brought up a great point about HIV, and there’s a lot of prospective data now to support the use of immune checkpoint inhibitors [ICIs], even in patients with HIV, even with low CD4 counts. Although these patients are generally excluded from our clinical trials, there is now prospective data that support safety of these agents in this patient population.

NIERODZIK: Well, the most important thing in these patients with ES-SCLC is [similar to patients with] lymphoma. Look at organ dysfunction, [don’t] use cisplatin [Platinol], then you have pretty much what you need to start the patient on chemotherapy.

SABARI: So, because of their burden of disease and how sick they are, what agents are you going to use?

WU: I agree with Dr Nierodzik. Usually we want to make sure the patient doesn’t have contraindications to certain therapy and make sure renal function is OK.

If a patient doesn’t have an autoimmune disease contraindication, immunotherapy will be preferred if they are treated as an outpatient.

SABARI: Agreed. What about PD-L1 expression or molecular testing? Is that important? Does it guide treatment? I know it’s been drilled into our heads multiple times, so is it something you look at in [patients with] SCLC?

WU: No, not in SCLC.

SABARI: I agree. I oftentimes will not wait for molecular testing here. We know it’s going to be TP53 and RB1 tumor suppressor loss. We don’t wait for PD-L1 expression because it doesn’t guide our treatment. That’s an important point. Immunotherapy is not guided by the PD-L1 expression as it is in NSCLC.

KAPPEL: Is there any value to looking at other markers after starting treatment? For NSCLC and other malignancies, do you wait for a FoundationOne panel to come back?

SABARI: I obtain tissue [and] plasma next-generation sequencing [NGS] on patients with SCLC. But if you ask me how often I act on it, it’s very low. It’s more of an academic pursuit.

Very rarely—probably in less than 1% of cases—can one identify an EGFR mutation in this population, and this is generally in the never-smoking population, who had a de novo SCLC transformation.

LI: If the EGFR mutation was positive, are you treating with a targeted therapy or chemotherapy?

SABARI: [Now, in terms of ordering additional work-up], because of transformation, the EGFR inhibitor is not going to be effective, but we’re still going to use platinum and etoposide plus or minus immunotherapy. So NGS is academically helpful. If you’re thinking about the development of new agents in the next 5 to 10 years, protein expression [and] some other markers are going to be very helpful.

Charles Rudin, MD, PhD, has a beautiful paper that was published about 2 years ago from Memorial Sloan Kettering [Cancer Center], looking at 4 different subtypes of SCLC in animal models, but also in human patient–derived xenograft models.¹ We are looking at basketing these patients when we develop new clinical therapies.

There are some markers, [such as] protein and gene expression, that will help guide potential therapeutic development, but in 2022, molecular testing and PD-L1 expression are not useful in this setting. I would not wait for those results in SCLC; it does not generally change the patient outcomes.

BLOKH: I order [an] NGS panel on every patient with a solid malignancy I have, because I realize that even if it will not affect first-line therapy, maybe it will affect second-line therapy, or maybe they’ll eventually be a candidate for clinical trial. Now, what’s the point of doing NGS on certain malignancies, where it does not affect management?

Doesn’t it make much better sense on a practical level to do the NGS at progression, then do a send-off? What’s the point? One may get some evolution and some selective pressures from the treatments you’re giving, but you’re still going to do another NGS at progression, so why not just do [it] at progression for malignancies, where NGS has no effect on initial treatment?

SABARI: Again, in the frontline setting, there is no change in practice with NGS. It’s still done in academic practice. I don’t know [whether] there’s a great rationale, except for potential development of new strategies in the future. You’re right, maybe it would be more helpful [in the recurrent setting].

Generally, with immunotherapy or targeted therapy, you don’t have much selective changes or pressures for driver mutations, but it’s very different when you’re looking at protein expression. We have seen many different portfolios for SCLC post treatment with platinum and a PD-L1 inhibitor.

NIERODZIK: I have a question about doing both plasma and tissue NGS in these patients. I do it sometimes because I’m afraid that the samples are so small that we may not have enough for the tissue for FoundationOne, but what’s the rationale for doing both?

SABARI: For plasma NGS in SCLC, it’s helpful for heterogeneity, but again, it’s not going to change or drive management. Very rarely you get a [fine needle aspiration] when you don’t have enough tissue to make an accurate diagnosis, or there’s complete necrosis [that’s] very poorly differentiated and hard for the cytopathologist to give a diagnosis. In that case, it’s helpful to see RB1 and TP53 loss, which are the hallmarks of SCLC. It just drives our excitement here.

The other important reason is you see combined SCLC and NSCLC, either adenocarcinoma or squamous carcinoma, [approximately] 10% to 15% of the time. That’s where plasma and tissue NGS can help. It changes the prognosis. It also may help later down the road if patients have recurrence, but it does not generally change the frontline management. For the question of tumor heterogeneity, it is particularly useful in a combined picture, but again, it is not going to change management.

Most of us are treating patients in outpatient settings. It’s [uncommon] for us to be treating these patients in the inpatient setting. In the literature, especially from the SEER database literature, [approximately] 50% of patients get their first cycle in the inpatient setting. I agree, it’s [uncommon] in my practice—probably 1 or 2 of every 10 patients with SCLC are started on treatment as inpatients.

Now, for this patient case, how would you counsel this patient? What are you thinking about for her treatment regimen?

LI: I would start chemotherapy and immunotherapy, but I would do [gamma knife], because this is SCLC, and I am concerned a brain mass can progress even on the chemotherapy. The [gamma knife] is a 1-day treatment [and you are done]. I would then give a platinum plus etoposide plus atezolizumab [Tecentriq] as the regimen.

MODI: We usually use [platinum,] etoposide, and atezolizumab. I would do close monitoring for the brain mass and maybe reimage the brain in a couple weeks to make sure it’s not progressing while on the chemotherapy.

CHEUNG: [I would give] etoposide/cisplatin/atezolizumab.

SABARI: Interesting. Dr Cheung is the first to mention cisplatin. Dr Blokh, what are you using in the frontline?

BLOKH: I would not attack that brain lesion, as I think it’s asymptomatic and small. I would give a platinum, etoposide, and immunotherapy. In terms of which platinum, I remember they’d traditionally say if it’s extensive, it’s not curable, so why give cisplatin?

But if cisplatin has better activity and someone has good performance status, is relatively young, their kidneys are young, and everything else is fine, I don’t see any negatives [for] trying it to see [whether] you can maximize response.

BRAUNSTEIN: I agree—atezolizumab, carboplatin, [and] etoposide. The question is where you are sequencing the radiation. I would probably start the systemic therapy, then radiation afterward.

DAI: I would start a systemic chemotherapy with etoposide, carboplatin, [and] atezolizumab. I would postpone radiation, because the brain mass is small and the patient is asymptomatic.

WU: I probably would do carboplatin, etoposide, durvalumab [Imfinzi]. I thought the data for durvalumab included more patients with asymptomatic brain metastasis.

SABARI: That’s the first durvalumab response we’ve heard tonight, which is interesting. Again, it’s controversial and we’ll have that discussion.

VIVEKANANDARAJAH: I also would use carboplatin, etoposide, [and] durvalumab in these patients. I thought that [because] the patient has brain metastasis, it probably means durvalumab has better response in these patients. As far as the brain metastasis, I would watch it and see how the patient is progressing.

NIERODZIK: [Because of the brain metastasis], I would use durvalumab if I could get it. I always time the gamma knife, but I usually wind up giving [chemoimmunotherapy] first and getting another image. Unless they’re progressing, then [I will do the gamma knife] a little further down the line.

SABARI: We talked about a platinum agent—whether to use cisplatin or carboplatin. The patient has a brain metastasis— whether to deal with it up front or not. We talked about atezolizumab vs durvalumab; are there any differences here?

KAPPEL: For the brain metastasis, I would see how symptomatic or [asymptomatic] they are and discuss with my radiation oncologist, then observation.

SABARI: The newest National Comprehensive Cancer Network guidelines for systemic primary therapy in [ES] disease recommend 4, not 6, cycles [because of] toxicity.

The preferred regimens are carboplatin, etoposide, atezolizumab, followed by atezolizumab maintenance, or carboplatin, etoposide, durvalumab, followed by durvalumab maintenance.² Cisplatin is controversial, but I agree with Dr Blokh. If you have someone who has an ECOG performance status of 0 or 1, it does make sense.

Outside the United States, there is significantly more use of cisplatin in the frontline setting. In our patient population, there’s been head-to-head studies of cisplatin, etoposide vs carboplatin, etoposide, and there haven’t been any real differences. Some of the studies—for example, the atezolizumab one—did not allow for cisplatin, whereas the durvalumab regimen did, so there were some slight differences.

I think it’s inferior in 2022 to not offer a PD-L1 inhibitor in the frontline setting. There are regimens that do not use etoposide but use irinotecan [Camptosar], [which is] generally not something we commonly use in the frontline setting here in the United States.

ALI: I use [carboplatin] because it’s easier to administer and easily tolerated. I try to do outpatient.

SABARI: Are people looking at the performance status of patients and their renal function and toxicity issues, saying, “Oh, this patient is young, fit, [and] healthy. Let’s use cisplatin vs carboplatin.” Or is everybody just using carboplatin in the frontline setting?

KAPPEL: To be honest, I don’t even think about it anymore. I guess carboplatin comes off my tongue like acetaminophen [Tylenol].

SABARI: I think cisplatin is a better drug, but it’s more poorly tolerated and more difficult to administer for patients. Because of that, we’re commonly seeing carboplatin used in the frontline. I would say 9 of 10 of my patients with SCLC are treated with carboplatin in the frontline setting.

BLOKH: In most of the other cancers, if you have oligometastasis or low volume of disease and cisplatin is an active drug, you would say, “Well, let me give the most potentially lethal drug against the tumor because I want to see [whether] I can still cure the patient.”

But what’s unique in my mind with SCLC is it is a systemic disease, even when localized. Seeing the way it acts, how aggressive it is, and how it spreads all over the body…the use of cisplatin, in my mind, is going to be very limited, because there’s very few patients you’re going to be able to cure once they already have extensive disease.

SABARI: So, this patient is started on carboplatin, etoposide, [and] atezolizumab and completes 4 cycles, then goes on to get maintenance atezolizumab. Now, has anyone used the IMpower133 [NCT02763579] regimen?

SABARI: Any experiences, negative or positive, with the durvalumab regimen? Do you think it’s helping patients? Is it doing much more than what we saw with standard carboplatin plus etoposide?

LI: I would say yes. I have a patient who now [has] used it for 2 years, so [using] chemotherapy alone would not have lasted as long.

KAPPEL: I don’t go past 4 cycles all that much. It’s also because atezolizumab has the advantage of being the first drug out. The other drugs in the CASPIAN study have got to show significant improvement, which they don’t.

For both studies, and correct me if I’m wrong, if you have brain metastasis, there is no significant improvements with immunotherapy. Is that correct?

SABARI: Sarah Goldberg, MD, MPH, at Yale School of Medicine has shown data for NSCLC with pembrolizumab [Keytruda], for example, showing CNS [central nervous system] activity.³ But in SCLC, we don’t have much prospective data.

These patients all had treated brain metastasis, so it’s hard to say. But it does look like, in the subset analyses, patients did better with durvalumab than with atezolizumab. But honestly, it is hard to make that conclusion based off the small numbers we have.

CHEUNG: I have a question about the CASPIAN trial: Is the control group better?

SABARI: It’s interesting, as the control arm seems like the atezolizumab arm. It is a good question, and to me, the response rate was a little lower. It was below 60% in the control arm for the CASPIAN study, whereas [it was a little higher] in the IMpower133 study. [However], the 1 thing I think is different is the long-term data we have.

It’s hard to compare data we don’t have, right? We don’t have the data for atezolizumab past 23 months, but we do have that for durvalumab, so it’s hard to compare them.

CHEUNG: Have they differentiated response rates between cisplatin and carboplatin in the CASPIAN trial?

SABARI: Interestingly, when you look at prospective studies, the response rate to cisplatin does not seem to be all that much different from carboplatin. Then you could also argue that maybe healthier patients are getting cisplatin vs carboplatin.^4-6 It’s a double-edged question.⁵

This patient went on to develop diarrhea—so immune-mediated colitis—3 to 4 times a day, [as well as] nausea after the second cycle. Diarrhea is not all that uncommon, right? Again, thinking broadly outside of SCLC, we use PD-1 and PD-L1 inhibitors routinely.

BRAUNSTEIN: It depends on the grade of the diarrhea. Was this patient admitted? It sounds like it was low grade, so I would just rechallenge and monitor the diarrhea.

SABARI: If it’s grade 1 or 2 and you’re able to treat with low-dose steroids, for example, or holding 1 or 2 cycles and then they recover, I oftentimes will retreat. But for grade 3 or 4 adverse events [AEs], I would stop therapy.

We’ve all seen our patients, particularly those who get a CTLA-4 inhibitor, for example, in combination with a PD-1 or PD-L1 inhibitor, who have grade 3 or 4 AEs where you need to use high-dose steroids, infliximab [Remicade], and other agents down the road. I would not feel comfortable retrying [those patients], but I agree with you. Immune-related AEs have become a common scenario in our clinical practice.

_REFERENCES:

_{1. Rudin CM, Poirier JT, Byers LA, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.Nat Rev Cancer. 2019;19(5):289-297.Publishedcorrection appears in Nat Rev Cancer. 2019 Jun 7.}

_{2.NCCN.Clinical Practice Guidelines in Oncology. Small cell lung cancer,version 2.2022. Accessed June 6, 2022. https://bit.ly/3miiU5L}

_{3.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}

_{4.Paz-Ares L, Dvorkin M, Chen Y, et al; CASPIAN Investigators. Durvalumab plus platinum-etoposide versusplatinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6}

_{5.Paz-Ares LG, Dvorkin M, Chen Y, et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): updated results from the phase III CASPIAN study. J Clin Oncol. 2020;38(suppl 15):9002. doi:10.1200/JCO.2020.38.15_suppl.9002}

_{6.Goldman JW, Dvorkin M, Chen Y, et al; CASPIANInvestigators. Durvalumab, with or without tremelimumab, plus platinum-etoposide versusplatinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):51-65. doi:10.1016/S1470-2045(20)30539-8}