Shields Spotlights Lessons Learned in Limited-Stage SCLC and Areas Ripe for Further Research

Recent breakthroughs in the management of limited-stage small cell lung cancer (LS-SCLC), particularly the December, 2024 FDA approval of durvalumab (Imfinzi) consolidation after chemoradiation, have transformed standard of care (SOC) and offered hope for longer survival, but additional efforts are needed to address relapse, refine existing strategies, and explore new approaches which could mean leveraging bispecific antibodies.1

“[The treatment paradigm in] SCLC has rapidly changed over the past 4 decades, particularly in the past 5 years,” Misty Dawn Shields, MD, PhD, said in a presentation during the 22nd Annual Winter Lung Cancer Conference®, an event held by Physicians’ Education Resource, LCC.“As medical oncologists, it’s devastating to tell a patient who has been diagnosed with LS-SCLC that we’re going to do everything we can to cure [them], but there’s still a risk within the first 2 years of this cancer coming back and being extensive stage and ultimately leading to [their] demise. How do we reconcile this gap in care?”

Shields is an assistant professor of clinical medicine in the Department of Medicine of the Division of Hematology/Oncology at Indiana University (IU) School of Medicine and an associate member of Experimental and Developmental Therapeutics at IU Melvin and Bren Simon Comprehensive Cancer Center.

Setting the Stage: Taking a Look at the Current Treatment Landscape

Relapse is common among patients with LS-SCLC, with the most likely area being the thorax, although the disease can also spread to extra-thoracic sites, such as the cranium.

“[To have this come back,] can be quite devastating for patients who have done everything possible to get to an area of cure, including chemoradiation with intensity, losing their hair, etc.,” Shields stated.

For patients with stage II disease plus lymph node involvement or stage III disease, concurrent chemoradiation is leveraged for curative intent, with twice-daily radiation serving as the “gold standard for most,” she added. Under 5% of patients with stage I or II disease without lymph node involvement can potentially be resected and cured by surgery followed by adjuvant chemotherapy.

“I do believe that with the implementation of lung cancer screening, we’re going to see this number increase,” Shields noted.

What Is the Role of Immunotherapy?

Shields highlighted 4 studies that were launched to further investigate the role of immunotherapy in patients with LS-SCLC: the phase 2 STIMULI study (NCT02046733), the phase 3 ADRIATIC study (NCT03703297), the phase 3 NRG-LU005 study (NCT03811002), and the phase 3 KEYLYNK-013 study (NCT04624204).

In STIMULI, patients (n = 153) received consolidation combination immunotherapy comprised of 4 cycles of nivolumab (Opdivo) at 1 mg/kg every 3 weeks (Q3W) plus ipilimumab (Yervoy) at 3 mg/kg Q3W followed by single-agent nivolumab at 240 mg every 2 weeks for up to 12 months (n = 78) vs observation (n = 75) after chemoradiation plus prophylactic cranial irradiation (PCI).2

“This study was very slow to accrue and saw lots of toxicity which ultimately led to switching of the primary end point to progression-free survival [PFS],” Shields said.1

At a median follow-up of 22.4 months, no improvement in PFS (HR, 1.02; 95% CI, 0.66-1.58; 2-sided P = .93) or overall survival (OS; HR, 0.95; 95% CI, 0.59-1.52; P = .82) was observed.2

"Adding more did not seem to provide benefit, and we saw that toxicities were severe, with 62% of grade 3 or 4 adverse effects [AEs] with ipilimumab/nivolumab, including 4 fatal toxicities,” she said.1

In ADRIATIC, patients (n = 730) were randomized to receive durvalumab at 1500 mg every 4 weeks (Q4W; n = 264), placebo Q4W (n = 266), or durvalumab at 1500 mg Q4W plus tremelimumab at 75 mg Q4W for 4 doses followed by durvalumab at 1500 mg Q4W (n = 200).3 Consolidation durvalumab after concurrent chemoradiation was found to significantly boost PFS and OS in these patients. At a median follow-up of 37.2 months (range, 0.1-60.9) in censored patients, the median OS was 55.9 months (95% CI, 37.3-not evaluable) with durvalumab alone vs 33.4 months (95% CI, 25.5-39.9) with placebo (HR, 0.73; 95% CI, 0.57-0.93; P = .0104). The median PFS in the respective arms was 16.6 months (95% CI, 10.2-28.2) vs 9.2 months (95% CI, 7.4-12.9; HR, 0.76; 95% CI, 0.61-0.95; P = .0161).

She noted that benefit was observed with this approach irrespective of whether patients received PCI.1 Moreover, there was no increase in radiation tinnitus in those who received consolidation durvalumab. These data supported the December 2024 FDA approval of durvalumab for adults with LS-SCLC whose disease has not progressed after concurrent platinum-based chemotherapy and radiation.4

“I think the majority of the audience is well aware of these exciting data…We saw this transformational change for LS-SCLC, which led to the FDA approval that established this as the new SOC for [these] patients,” Shields said.1 “So why does immunotherapy benefit patients with LS-SCLC more than those with extensive-stage disease (ES-SCLC)? The short answer is that nobody knows. This is a clear area of unmet translational need, and as physician scientists, this is something we would love to understand more. What drives this response?”

In NRG-LU005, patients (n = 544) who received 1 cycle of chemotherapy before registration were randomized 1:1 to receive concurrent chemoradiation (n = 270) vs concurrent chemoradiation plus atezolizumab (Tecentriq) given at 1200 mg Q3W for a maximum of 17 cycles (n = 274).5

“The data presented, unfortunately, fell flat,” Shields said.1 “This was a negative study, with no improvement in PFS or OS across this patient population.” The respective hazard ratios were 1.00 (95% CI, 0.80-1.25; P = .9542) and 1.11 (95% CI, 0.85-1.45; P = .7640).5 Moreover, there was no benefit observed with the addition of immunotherapy across patient subsets, except for a signal with twice-daily thoracic radiation, she noted.1

“There is disappointment with the role of concurrent immunotherapy and concurrent chemoradiation, whether it is non–small cell lung cancer (NSCLC) or SCLC, putting a stamp that this should not be a strategy that is pursued by additional studies or treatment options,” Shields said.

Lastly, KEYLYNK-013 enrolled 672 patients who were randomized 1:1:1 to 1 of the following 3 arms:6

1. Platinum doublet chemotherapy plus 200 mg of pembrolizumab (Keytruda) Q3W for cycle 1 followed by platinum doublet chemotherapy plus 200 mg of pembrolizumab Q3W plus radiotherapy for cycles 2 to 4 followed by PCI and then pembrolizumab at 400 mg every 6 weeks (Q6W) for 9 cycles plus placebo twice daily for 12 months/cycles 5 to 13
2. Platinum doublet chemotherapy plus 200 mg of pembrolizumab Q3W for cycle 1 followed by platinum doublet chemotherapy plus 200 mg of pembrolizumab Q3W plus radiotherapy for cycles 2 to 4, followed by PCI and then 400 mg of pembrolizumab Q6W for 9 cycles plus 300 mg of olaparib (Lynparza) twice daily for 12 months/cycles 5 to 13
3. Platinum doublet chemotherapy plus placebo Q3W for cycle 1 followed by platinum doublet chemotherapy plus placebo Q3W and radiotherapy for cycles 2 to 4 followed by PCI and then placebo Q6W for 9 cycles plus placebo for 12 months/cycles 5 to 13

“This is a complex schema, with 3 groups looking at the role of platinum doublet plus pembrolizumab, as well as the consolidation of olaparib with concurrent chemoradiation overlaying the pembrolizumab administration,” Shields noted.1 “This is anticipated to be completed in October 2027, and I do hold personal concerns about lymphodepletion, that we have seen in NSCLC and SCLC, and myelosuppression potentially playing a role here with the addition of the PARP inhibitor and consolidation.”

What’s Next in SCLC?

When looking toward the future, Shields posed several questions she would like to see answered with ongoing research efforts. For example, after concurrent chemoradiation, would a DLL3-targeted bispecific T-cell engager (BiTE) lead to better outcomes than immunotherapy? She noted that the phase 3 DELLphi-306 study (NCT06117774) is examining tarlatamab vs observation, not SOC durvalumab consolidation, in LS-SCLC.

“We will be able to see what the role of a DLL3-targeted BiTE is in this cohort,” Shields said. “We’re not able to cross-trial compare with immunotherapy, but perhaps there are patients who would be better off served with BiTE vs immunotherapy if they potentially have a condition that would prohibit that opportunity. We’ll see this read out in the next few years.”

She added that the phase 3 IMforte trial (NCT05091567) is seeking to answer the question of whether the addition of lurbinectedin (Zepzelca) to maintenance atezolizumab in ES-SCLC could lead to a survival benefit. A press release issued in October 2024 indicated that the combination led to a significant OS and PFS benefit over atezolizumab alone when used as frontline maintenance in this population.7

"This was an exciting press release…hopefully soon we will hear [more about] these data,” she said. “But what is the role of moving lurbinectedin earlier? Is there a particular subtype or biomarker that might help improve response? Is there a role for lurbinectedin and durvalumab consolidation post-chemoradiation for LS-SCLC?”

During her presentation, Shields also posed the question of whether there is a role for antibody-drug conjugates in LS-SCLC, or if these agents are too toxic to add after concurrent chemoradiation.

“I would propose, potentially, to hold off on this opportunity given the risk those AEs may be too great, but that’s just my personal opinion,” she said. She added that trilaciclib (Cosela) has proven to reduce myelosuppression in ES-SCLC, “so why not use it in the area that we see the most myelosuppression?” Could trilaciclib be used during concurrent chemoradiation for LS-SCLC?

Trials to Watch

Shields highlighted 4 additional active trials that she is looking forward to hearing more information from:

1. A phase 3 trial (NCT05353257) evaluating the safety and efficacy of the PD-1 inhibitor serplulimab with concurrent chemoradiation followed by 1 year of maintenance in LS-SCLC. This is approximated to read out in December 2026.
2. The phase 3 MAVERICK trial (NCT04155034) examining MRI given every 3 months as surveillance vs PCI in LS-SCLC or ES-SCLC. This is projected to read out in November 2027.
3. A phase 2 study (NCT06140407) examining pembrolizumab after concurrent chemoradiation in LS-SCLC. This is anticipated to read out in May 2029.
4. A phase 3 study (NCT06095583) evaluating the PD-1 inhibitor toripalimab (Loqtorzi) alone or paired with tifcemalimab, a humanized antibody that targets BTLA, as consolidation treatment after concurrent chemoradiation in LS-SCLC. Shields noted she is “excited to see this one,” which is approximated to read out in July 2029.

Closing Thoughts

“Relapse is, unfortunately, way too common for LS-SCLC and new regimens are desperately needed to help prevent relapse and help our patients live longer,” Shields reiterated, adding that, “We saw with ADRIATIC that durvalumab consolidation following concurrent chemoradiation is the new SOC for LS-SCLC and there is no role for concurrent immunotherapy with concurrent chemoradiation for SCLC or NSCLC. Dual immunotherapy with ipilimumab and nivolumab, unfortunately, was just too toxic.”

Shields closed out her presentation by emphasizing the importance of exploring alternative avenues for reducing the risk of relapse in SCLC. “Are there other avenues we can pursue? Is PCI necessary, or can we start doing MRIs every 3 months and help [avoid] this toxicity in patients who are living longer? Can DLL3-targeted BiTEs improve outcomes post-chemoradiation, or is that an opportunity that should be saved for later? How can we better support patients with SCLC who are now living longer?” she concluded.

References

1. Shields MD. Updates in the management of limited-stage small cell lung cancer. Presented at: 2025 Winter Lung Conference; January 31-February 2, 2025; Hollywood, FL.
2. Peters S, Pujol J-L, Dafni U, et al. Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy - results from the randomised phase II ETOP/IFCT 4-12 STIMULI trial. Ann Oncol. 2022;33(1):67-79. doi:10.16/j.annonc.2021.09.011
3. Spigel DR, Cheng Y, Cho BC, et al. ADRIATIC: durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). J Clin Oncol. 2024;42(suppl 17):LBA5. doi:10.1200/JCO.2024.42.17_suppl.LBA5
4. FDA approves durvalumab for limited-stage small cell lung cancer. FDA. December 4, 2024. Accessed February 1, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-limited-stage-small-cell-lung-cancer
5. Higgins K, Hu C, Ross HJ, et al. Concurrent chemoradiation ± atezolizumab (atezo) in limited-stage small cell lung cancer (LS-SCLC): Results of NRG Oncology/Alliance LU005. Int J Radiat Oncol Biol. 2024;120(suppl 2):LBA02. doi:10.1016/j.ijrobp.2024.08.013
6. Rimner A, Lai W-CV, Califano R, et al. Rationale and design of the phase 3 KEYLYNK-013 study of pembrolizumab with concurrent chemoradiotherapy followed by pembrolizumab with or without olaparib for limited-stage small-cell lung cancer. Clin Lung Cancer. 2022;23(5):e325-e329. doi:10.1016/j.cllc.2022.04.005
7. Jazz Pharmaceuticals announces statistically significant overall survival and progression-free survival results for Zepzelca (lurbinectedin) and atezolizumab combination in first-line maintenance therapy for extensive-stage small cell lung cancer. News release. Jazz Pharmaceuticals plc. October 15, 2024. Accessed February 1, 2025. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-statistically-significant-overall