Immunotherapy Choices and High Attrition Rates in SCLC

Small cell lung cancer (SCLC) is a clinical paradox: it is famously sensitive to initial chemotherapy yet remains one of the most aggressive and difficult solid tumors to manage over the long term. For oncologists, the primary hurdle isn't just starting treatment but maintaining momentum as patient attrition rates climb sharply through subsequent lines of therapy.

During a live Community Case Forum^TM, Carl M. Gay, MD, PhD, assistant professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, provides a grounded perspective on the current systemic therapy landscape for SCLC.

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CASE SUMMARY

• A 73-year old woman presents with dyspnea on mild exertion, productive cough, chest pain, fatigue, anorexia, and a recent, unintentional 18-lb weight loss
• Hypertension is well controlled on candesartan/hydrochlorothiazide (Atacand HCT)
• 45 pack year smoking history and current smoker
• Staging: T3N3M1b — IV
  • Extensive-stage SCLC
• Initial diagnostic workup
  • ECOG performance status of 1
  • Left hilar mass and a 5.4-cm left upper lobe (LUL) opacity
  • Contrast chest CT reveals several masses with irregular margins in the LUL and contralateral hilar and mediastinal lymphadenopathy
  • 18F-FDG PET/CT demonstrates avid FDG uptake in LUL, hilum, mediastinal, and supraclavicular lymph nodes and several hepatic lesions
  • Brain MRI is negative
  • Percutaneous image-guided liver biopsy reveals histopathology consistent with SCLC: chromogranin and synaptohysin positive; Ki-67 90%

Targeted Oncology: What systemic therapy are you most likely to recommend to this patient?

Carl M. Gay, MD, PhD: There is a reason to prefer one over the other. But historically, atezolizumab [Tecentriq] was approved first,¹ but the data looks very similar for atezolizumab and durvalumab [Imfinzi]. Initially, durvalumab had an every-4-week dosing, which is a little bit more convenient, but atezolizumab very quickly took that on.²

One of the issues that comes up in a lot of the trials is the prognostic influence of liver metastases for patients that have SCLC. I generally tell my patients that there is some evidence that they might do a little bit worse, but I'm not sure that's such a helpful discussion at the beginning. You give everybody a fair shot with chemo-immunotherapy.

What do you see as the persistent challenges in SCLC?

I think one of the historically challenging things about SCLC, particularly extensive-stage SCLC, is the attrition that we see through the lines of therapy. I think there's the philosophy that everyone with SCLC deserves at least a shot at treatment. It's one of the few solid tumors where you'll see treatment in the intensive care unit for patients that have organ failure from the disease. It's an exquisitely chemo-sensitive disease, and so you can get some patients to rebound.

Most patients will receive frontline therapy—most of them with chemo-immunotherapy, a handful with chemotherapy alone. But as you go into maintenance therapy, let alone in the second line and third line, you lose most of these patients. By the time you get to the third line, you're down to about 13% of the patients that you started with.³ I think we've seen, and we are seeing in real time, a lot of major advances and options for patients with SCLC.

Can you discuss the NCCN guidelines in SCLC?

The preferred regimens are carboplatin-etoposide, and then the new addition here—not explicitly in the frontline, but adding into the maintenance setting—is the addition of lurbinectedin [Zepzelca].⁴

There are relatively equivalent data for frontline chemo-immunotherapy with atezolizumab and durvalumab. The initial approval here came with atezolizumab, and that came from the IMpower133 study [NCT02763579].¹ There is some nuance between the IMpower133 study and the CASPIAN study [NCT03043872]. The IMpower133 study enrolled patients with newly diagnosed extensive-stage SCLC and good performance status and allowed patients with some asymptomatic brain metastases but otherwise was fairly stringent on its inclusion criteria.⁵ Patients would get carboplatin-etoposide with atezolizumab or placebo 4 cycles, and they would get maintenance atezolizumab or placebo based on their initial treatment. This study had overall survival [OS] and progression-free survival [PFS] as the primary end points.

I think really what people care about here is the is the OS. There was some modest improvement in PFS with 5.2 months for the atezolizumab arm and 4.3 months in the placebo arm. I don't know if 0.9 months gets people really excited about PFS. It's a statistically significant, but perhaps not clinically meaningful, improvement in PFS but a 2-month improvement in OS, with 12.3 months vs 10.3 months. I think this really emphasizes how fallow things had been for SCLC. This came on the heels of a 30-year period without a positive phase 3 trial in SCLC. We see more so in the CASPIAN data that some of this survival is sustained. There is a small population of patients that have long-term durable disease control, and, dare I say, cure or remission with immunotherapy in SCLC. It's a small population, maybe 10% to 15% of patients, but it's not nothing.⁶

The adverse events [AEs] with chemo-immunotherapy you'll see are very similar between IMpower133 and CASPIAN. The chemotherapy AEs like cytopenias, nausea, and fatigue are all similar. There is some difference in the immune-related AEs. Initially, there was some concern that patients with SCLC may be especially prone to these because they have propensity for these paraneoplastic syndromes, including autoimmune paraneoplastic syndromes, but that hasn't borne out. The immune-related AE rate for SCLC seems to be about the same as it is for non–[SCLC].

Would you consider ever giving more than 4 cycles of the chemotherapy backbone?

When I first started treating SCLC, it was fairly typical to push out 6 cycles in patients that were doing well. IMpower133 and CAPSIAN focused on this 4-cycle regimen that gives you an excuse to stop when AEs are starting to get a little bit challenging. But I think that's a very fair strategy, and I think it has interesting implications for some of the discussion about maintenance therapy and continuing the cytotoxic therapy a little bit further than we're used to.

How do you approach consolidation in SCLC?

I approach the consolidation for SCLC much at a higher threshold. In my own practice, we have often administered thoracic consolidated radiation in our practice. Some data from Slotman et al that predates the use of immunotherapy in this setting where patients showed a very slight OS benefit at 2 years with 13% in patients who received radiotherapy vs 3%. But a very select group of patients had a complete response outside of the chest and residual disease inside of the chest.⁷ When I run into a patient like that, I send them to my radiation oncologist.

Can you discuss the use of circulating tumor (ct)DNA in SCLC?

There are some interesting data with SCLC ctDNA velocity and dynamics out there, and they speak to the limitations in our ctDNA tests. In the CASPIAN study, if you look between cycles of platinum-etoposide, patients cleared their ctDNA based on our tests, and they look to be cured.⁸ Then you check again before they go to the next cycle, and ctDNA has bounced back even higher than it was before. Clearly, our tests aren't sensitive enough.

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DISCLOSURES: Gay reports having speaking engagement for ACHL, Dava Oncology, IDEOlogy, IDR, Impact Education, MJH, OncLive, PeerView, Physicians’ Education Resource (PER), and Targeted Healthcare; serving on the advisory board/steering committee of Abdera, Amgen, AstraZeneca, BeOne, BioNTech, Boehringer Ingelheim, Daiichi Sankyo, G1 Therapeutics, Jazz Pharmaceuticals, Merck, OncoHost, and Roche/Genentech; providing paid consulting for Axiom, Boehringer Ingelheim, Cantor Fitzgerald, Catalyst, and Pontifax.

REFERENCES

1. FDA approves atezolizumab for extensive-stage small cell lung cancer. News release. US FDA. March 18, 2019. Accessed February 24, 2026. https://tinyurl.com/383nc5de

2. Aleem A and Shah H. Atezolizumab. National Library of Medicine. Updated October 29, 2024. Accessed February 24, 2026. https://tinyurl.com/3f6pnrkm

3. Sankar K, Unni S, Eberl M, et al. Real-world treatment patterns and clinical outcomes in patients with extensive-stage small cell lung cancer treated with first-line platinum-based chemotherapy and ≥ 2 subsequent lines of therapy in the United States. Adv Ther. 2026 Jan;43(1):214-230. doi: 10.1007/s12325-025-03408-z. Epub 2025 Nov 12. PMID: 41222788; PMCID: PMC12858494.

4. NCCN Guidelines in SCLC, version 2.2026. National Comprehensive Cancer Network. Accessed February 24, 2026. https://tinyurl.com/4pap95m5

5. Horn L, Mansfield AS, Szczęsna A, et al. First-Line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018 Dec 6;379(23):2220-2229. doi: 10.1056/NEJMoa1809064. Epub 2018 Sep 25. PMID: 30280641.

6. Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-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 Jan;22(1):51-65. doi: 10.1016/S1470-2045(20)30539-8. Epub 2020 Dec 4. PMID: 33285097.

7. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet. 2015 Jan 3;385(9962):36-42. doi: 10.1016/S0140-6736(14)61085-0. Epub 2014 Sep 14. Erratum in: Lancet. 2015 Jan 3;385(9962):28. PMID: 25230595.

8. Paz-Ares L, Garassino MC, Chen Y, et al. Durvalumab ± tremelimumab + platinum-etoposide in extensive-stage small cell lung cancer (CASPIAN): outcomes by PD-L1 expression and tissue tumor mutational burden. Clin Cancer Res. 2024 Feb 16;30(4):824-835. doi: 10.1158/1078-0432.CCR-23-1689. PMID: 37801329; PMCID: PMC10870117.