Applying the Heterogeneous Approach From NSCLC to SCLC

Anne Chiang, MD, PhD

As researchers begin to shift from a uniform approach in small cell lung cancer (SCLC) to a more targeted approach, the idea of transcriptomic or molecular subtypes has surfaced, with 4 main subtypes of SCLC identified and others gaining traction thus far.¹ Three subtypes of SCLC that have been identified include SCLC-A, which is defined by activation of the ASCL1 gene; SCLC-N by the NEUROD1 gene; and SCLC-P by the POU2F3 gene. Further, SCLC-I has been identified as a fourth major subtype, which is characterized by certain inflammatory characteristics^1,2 (Figure).¹

“We’re starting to understand more about the biology of SCLC. [Our] work over the years shows that there is heterogeneity, there are different ways to classify SCLC, and, more recently, this idea of transcriptomic or molecular subtypes [has emerged],” Anne Chiang, MD, PhD, associate professor of medicine and associate cancer center director, clinical initiatives, at Yale School of Medicine in New Haven, Connecticut, said in an interview with OncologyLive.

Figure

An analysis of the phase 3 IMpower133 trial (NCT02763579) revealed that a higher proportion of long-term survivors (LTS) vs non-LTS with extensive-stage SCLC (ES-SCLC) in both the atezolizumab (Tecentriq) plus carboplatin and etoposide arm and placebo plus carboplatin and etoposide arm had the SCLC-I subtype. Among patients with SCLC-I, a higher proportion of patients were LTS compared with non-LTS (28% vs 11%, respectively) in the atezolizumab arm, as well as the placebo arm (32% vs 18%). LTS were defined as patients who survived at least 18 months post random assignment. Notably, patients with the SCLC-P subtype experienced poor long-term survival.³

Investigators are also beginning to examine the YAP1 transcription regulator and its role in defining a SCLC subset with the proposed SCLC-Y subgroup.¹

“The idea of being able to subtype SCLC, and that different subtypes have therapeutic vulnerabilities, is interesting. Another example of a predictive biomarker for targeting the DNA damage response that looks promising is the SLFN11 protein,” Chiang said. “The phase 2 S1929 [study (NCT04334941)] in the maintenance setting took patients who had SLFN11-positive disease by immunohistochemistry and found that those patients, when treated with maintenance with a PARP inhibitor hitting the DNA repair pathway, seemed to do significantly better than patients who were SLFN11 negative.”

In S1929, maintenance atezolizumab plus talazoparib (Talzenna) improved progression-free survival (PFS) vs maintenance atezolizumab monotherapy in patients with SLFN11-positive ES-SCLC, meeting the study’s primary end point. Investigators noted that the study’s outcomes represent the feasibility of conducting biomarker selected trials in SCLC.⁴

Data from the trial demonstrated that the median PFS for patients treated with atezolizumab plus talazoparib (n = 54) was 4.2 months (80% CI, 2.8-4.7) vs 2.8 months (80% CI, 2.0-2.9) with atezolizumab alone (n = 52; HR, 0.70; 80% CI, 0.52-0.94; 1-sided log rank stratified P = .056).

Preliminary overall survival (OS) data revealed patients experienced a median OS of 9.4 months (80% CI, 8.1-14.2) in the doublet arm compared with 8.5 months (80% CI, 7.4-12.7) in the monotherapy arm (HR, 1.17; 80% CI, 0.80-1.71; 1-sided log rank stratified P = .30). Further, response rates in evaluable patients were 12% (80% CI, 5%-22%) in the doublet arm (n = 34) vs 16% (80% CI, 8%-27%) in the monotherapy arm (n = 32), respectively. Hematologic adverse effects were increased with the addition of talazoparib, occurring at rates of 50% vs 4%, respectively (P < .001).

“There’s no clear biomarker for SCLC, like PD-L1 status in NSCLC patients. In the past, we thought that high tumor mutational burden might predict response to immunotherapy, but it didn’t pan out. But we’re gaining more information to see that this myth that all SCLC should be treated the same may not be true,” Chiang said.

Tissue Samples Are Needed in SCLC to Further Elucidate
the Use of Biomarkers

“We need to understand the heterogeneity of SCLC and which patients may respond to a targeted therapy approach, and a key part of that is getting tissue,” Chiang explained. “Another myth is that there’s [not enough] tissue for SCLC because there’s crush artifact or because we often use fine-needle aspiration. But patients with SCLC often present with very bulky disease that is very accessible. For patients with non–small cell lung cancer [NSCLC], we require tissue for a biomarker, PD-L1 status, to guide treatment. If we had arequirement for a biomarker for SCLC, I believe we’d have no problem getting adequate tissue samples from patients with SCLC.”

Chiang was the principal investigator of a phase 2 study (NCT03670056) conducted at Yale Cancer Center, which found that dual checkpoint blockade using nivolumab (Opdivo) plus ipilimumab (Yervoy) has a prominent immunomodulatory role in ES-SCLC. Investigators obtained biopsies of patients enrolled (n = 22) at baseline, week 4, and progression, and a genomic analysis revealed that patients with progressive disease had more deleterious HLA-A gene mutations at baseline compared with those who experienced clinical activity with the combination.⁵

“Having those paired biopsies allowed us to look at which patients responded after 2 cycles of treatment and correlate what was happening in the tumor microenvironment,” Chiang noted.

Further, 40% of evaluable patients (n = 15) experienced clinical activity in the form of partial responses or stable disease; all these patients had the SCLC-A subtype. Increased local adaptive immune responses, such as T-cell activation and PD-1 signaling, were associated with treatment sensitivity or resistance to dual checkpoint blockade.

“To push the field forward, we need to be able to get tissue [from] patients so we can understand what’s going on and [determine] which patients might be able to respond to targeted therapies,” Chiang added. “Understanding the biology of these tumors is important—especially for SCLC—to get tissue, be able to understand what subtypes there are, and see whether we can target our therapies to those subtypes.”

Chiang is leading development of a key new biomarker-driven trial through the Southwest Oncology Group, the phase 2 multicohort PRISM study (S2409). The study is examining durvalumab (Imfinzi) vs biomarker-directed novel agents in combination with durvalumab in patients with different subtypes of ES-SCLC.⁶

Parsing out Further Data in NSCLC and SCLC: What’s Next?

“For NSCLC, we’re starting to understand the heterogeneity of the comutational landscape,” Chiang said. In the phase 3 POSEIDON trial (NCT03164616), she added that “if you look at the patients in the trial with STK11 or KEAP1 mutations, which are more associated with a worse prognosis, they actually do better with the chemotherapy plus combination immunotherapy (durvalumab plus tremilimumab) than with durvalumab alone. Piecing out the mutational landscape and understanding which patients might do better with combinations vs [monotherapy] is important.”

According to updated OS data from the POSEIDON trial, patients with KEAP1-mutated stage IV NSCLC who received tremelimumab (Imjudo) plus durvalumab and chemotherapy (n = 22) achieved a median OS of 13.7 months (95% CI, 7.2-26.5) vs 8.7 months (95% CI, 5.1-not evaluable) for those treated with chemotherapy alone (n = 6; HR, 0.43; 95% CI, 0.16-1.25). The median OS for patients who received durvalumab and chemotherapy (n = 23) was 8.1 months (95% CI, 4.0-12.9) for a HR of 0.77 (95% CI, 0.31-2.15).⁷

The phase 3b TRITON study (NCT06008093) will continue to examine genetic mutations and is currently recruiting patients with nonsquamous NSCLC who have mutations and/or comutations in STK11, KEAP1, or KRAS. Patients will be randomly assigned to receive tremelimumab plus durvalumab vs pembrolizumab (Keytruda) with platinum-based chemotherapy in the first-line setting in this multicenter, open-label study.⁸

Moreover, agents currently generating conversations in SCLC include bispecific antibodies such as tarlatamab.

“SCLC is often described as a ‘desert’ or ‘cold’ immune-exclusive environment, without much T cell infiltration—that’s why bispecific antibodies that bring and engage the immune system to the immune environment are very exciting,” Chiang said. “For SCLC, the bispecific antibody tarlatamab targeting DLL3 on the surface of the cancer cell and with CD3 engaging the T cells has shown very impressive [data].”

In December 2023, the FDA accepted and granted priority review to the biologics license application seeking the approval of tarlatamab for the treatment of patients with advanced SCLC based on data from the phase 2 DeLLphi-301 study (NCT05060016).⁹ In the trial, patients with advanced SCLC and disease progression on or after platinum-based chemotherapy treated with tarlatamab achieved a median PFS of 4.9 months (95% CI, 2.9-6.7) in the 10-mg cohort (n = 40) and 3.9 months (95% CI, 2.6-4.4) in the 100-mg cohort (n = 28).¹⁰ Notably, 40% of patients (97.5% CI, 29%-52%) and 32% (97.5% CI, 21%-44%) experienced an objective response, respectively; 59% of patients who achieved an objective response had a duration of response extending at least 6 months.

Discussions to Come Following ASCO at ILCC Conference

Coming off the heels of the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, the 25th Annual International Lung Cancer Congress^® in Huntington Beach, California, will serve as an opportunity for clinicians to discuss the latest data in the lung cancer field. Biomarkers and testing strategies, the application of recent clinical data, discussions on novel agents, and overcoming disparities in care will be the focuses at the meeting, which will be held July 25-27, 2024, along with multidisciplinary case-based tumor boards.¹¹

Chiang will be among the clinicians presenting lectures at the meeting and noted discussions on SCLC, especially limited-stage SCLC (LS-SCLC), will be of interest to her. “The phase 3 ADRIATIC trial [NCT03703297] is a large trial, and a press release has shown it’s positive. It’s looking at immunotherapy after consolidation chemoradiation with durvalumab or durvalumab/tremelimumab. This approach mimics what is already approved in NSCLC with the phase 3 PACIFIC trial [NCT02125461] regimen—consolidation immunotherapy after chemoradiation. I believe that’s going to be practice-changing. We’re going to hear about that at the 2024 ASCO [meeting], then we’ll be able to talk about how we utilize that [regimen]. That’s going to be a fantastic step forward.”

A press release revealed that in ADRIATIC, treatment with durvalumab resulted in a statistically significant and clinically meaningful improvement in PFS and OS for patients with LS-SCLC who did not progress following concurrent chemoradiotherapy vs placebo after concurrent chemoradiotherapy. Durvalumab’s manufacturer, AstraZeneca, noted that data will be presented at an upcoming medical meeting and that the second experimental arm of tremelimumab plus durvalumab remains blinded and will continue to the next planned analysis.¹² Notably, durvalumab is the first and only immunotherapy to demonstrate a survival benefit in a global phase 3 trial in this patient population.

References

1. Solta A, Ernhofer B, Boettiger K, et al. Small cells - big issues: biological implications and preclinical advancements in small cell lung cancer. Mol Cancer. 2024;23(1):41. doi:10.1186/s12943-024-01953-9
2. Study defines small-cell lung cancer subtypes and distinct therapeutic vulnerabilities for each type. News release. The University of Texas MD Anderson Cancer Center. January 21, 2021. Accessed April 25, 2024. bit.ly/4dhK9qz
3. Liu SV, Mok TSK, Nabet BY, et al. Clinical and molecular characterization of long-term survivors with extensive-stage small cell lung cancer treated with first-line atezolizumab plus carboplatin and etoposide. Lung Cancer. 2023;186:107418. doi:10.1016/j.lungcan.2023.107418
4. Karim NFA, Miao J, Reckamp KL, et al. SWOG S1929: phase II randomized study of maintenance atezolizumab (A) versus atezolizumab + talazoparib (AT) in patients with SLFN11 positive extensive stage small cell lung cancer (ES-SCLC). J Clin Oncol. 2023;41(suppl 16):8504. doi:10.1200/JCO.2023.41.16_suppl.8504
5. Chiang AC, Asghari H, Ashley K, et al. Molecular predictors and immunomodulatory role of dual checkpoint inhibitor blockade using ipilimumab/nivolumab in patients with extensive stage small cell lung cancer. J Clin Oncol. 2023;41(suppl 16):8597. doi:10.1200/JCO.2023.41.16_suppl.8597
6. VA committee. Southwest Oncology Group. October 12, 2023. Accessed April 25, 2024. bit.ly/3Ql7TQG
7. Peters S, Cho BC, Luft A, et al. LBA3 - durvalumab (D) ± tremelimumab (T) + chemotherapy (CT) in first-line metastatic (m) NSCLC: 5-year overall survival (OS) update from the POSEIDON study. Ann Oncol. 2023;20(suppl 1):100535. doi:10.1016/iotech/iotech100535
8. A study to investigate the efficacy of durvalumab plus tremelimumab in combination with chemotherapy compared with pembrolizumab in combination with chemotherapy in metastatic non-small cell lung cancer (NSCLC) patients (TRITON). ClinicalTrials.gov. Updated March 20, 2024. Accessed April 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06008093
9. FDA grants priority review to Amgen’s tarlatamab application for advanced small cell lung cancer. Press release. Amgen. December 13, 2023. Accessed April 25, 2024. bit.ly/4bbGEzT
10. Paz-Ares L, Ahn MJ, Felip E, et al. Tarlatamab for patients (pts) with previously treated small cell lung cancer (SCLC): primary analysis of the phase II DeLLphi-301 study. Ann Oncol. 2023;34(suppl 2):1333-1334. doi:10.1016/j.annonc.2023.10.094
11. 25th Annual International Lung Cancer Congress. Physicians’ Education Resource. Accessed April 25, 2024. bit.ly/44klLQP
12. Imfinzi significantly improved overall survival and progression-
    free survival for patients with limited-stage small cell lung cancer in ADRIATIC phase III trial. News release. AstraZeneca. April 5, 2024. Accessed April 25, 2024. bit.ly/3UfPSED