Maxing out with chemoimmunotherapy in extensive-stage small cell lung cancer
Kubra Canaslan1
, Lu Xiao2
, Ticiana Leal3
Keywords: Small cell lung cancer (SCLC); anti-programmed cell death-1 (anti-PD-1); chemoimmunotherapy; anti-programmed death-ligand 1 (anti-PD-L1)
Submitted Jan 09, 2025. Accepted for publication Mar 18, 2025. Published online Apr 24, 2025.
doi: 10.21037/cco-25-5
For decades, platinum-based first-line chemotherapy had been the standard of care in the treatment of patients with extensive-stage small cell lung cancer (ES-SCLC), yielding high initial response rates but with short-lived efficacy. The 5-year survival rate remained approximately 5%, highlighting the need for improved therapies (1). Chemotherapy with platinum and etoposide in combination with immune check point inhibitors has become the new standard of care based on landmark clinical trials, with the CASPIAN study in 2022 (2) showing a tripling of the three-year survival rate and the IMbrella. A study reported in 2024, extension study of IMpower133 in 2021 (3), showing 5-year overall survival (OS) estimate of 12% (4).
In the article that accompanies this editorial, Dr. Cheng et al. report on the final OS analysis of RATIONALE-312 (5). This was a randomized, placebo-controlled, phase 3 clinical trial conducted to evaluate the efficacy of tislelizumab, an anti-programmed cell death-1 (PD-1) inhibitor, in combination with platinum and etoposide as first-line therapy in patients with ES-SCLC conducted in 51 centers in China. Patients were randomized to receive four cycles of tislelizumab 200 mg intravenous (IV) or placebo IV every 3 weeks, in combination with etoposide 100 mg/m2 IV days 1–3 every 3 weeks plus investigator’s choice of carboplatin area under the plasma or serum concentration-time curve 5 or cisplatin 75 mg/m2 IV every 3 weeks followed by tislelizumab 200 mg IV or placebo IV every 3 weeks as maintenance. Maintenance therapy was continued until disease progression, loss of clinical benefit, unacceptable toxicity, or withdrawal of informed consent. The study met the primary endpoint of OS. Tislelizumab in combination with platinum and etoposide led to improved OS, with a median of 15.5 months compared to 13.5 months in the placebo group [hazard ratio (HR) =0.75, P=0.004]. Progression-free survival (PFS) was also superior in the tislelizumab arm, with a median PFS of 4.7 vs. 4.3 months for placebo (HR =0.64, P<0.0001). The adverse events were primarily hematologic and considered manageable.
Patient recruitment for RATIONALE-312 occurred between 2019 and 2021, a period during which treatment paradigms for ES-SCLC were rapidly evolving. The landmark IMpower133 trial demonstrated that the addition of atezolizumab to platinum and etoposide significantly improved OS in first-line treatment for ES-SCLC, regardless of programmed death-ligand 1 (PD-L1) status (6). As a result, in 2019 and 2020, the Food and Drug Administration (FDA) and the State Food and Drug Administration of China, respectively, approved atezolizumab in combination with platinum and etoposide. Subsequently, durvalumab was approved in 2020 and 2021 by the FDA and the State Food and Drug Administration of China, respectively, based on the CASPIAN trial results that also showed improved OS (7).
Both atezolizumab and durvalumab have achieved a median OS of approximately 12 months with tolerable safety profiles. In contrast, pembrolizumab, an anti-PD-1 antibody, failed to demonstrate statistically significant benefit in OS when combined with platinum and etoposide chemotherapy (8). In a more recent study conducted in China, adebrelimab, an anti-PD-L1 agent, combined with carboplatin and etoposide, showed a median OS of 15.3 months in patients with ES-SCLC (9). Similarly, serplulimab, an anti-PD-1 inhibitor, also showed a median of 15.4 months in a similar patient population (10). First-line chemoimmunotherapy clinical trials in ES-SCLC are summarized in Table 1.
Table 1
| Items | IMPower133 | CASPIAN | KEYNOTE-604 | ECOG-ACRIN-EA5161 | ASTRUM-005 | CAPSTONE-1 | RATIONALE-312 |
|---|---|---|---|---|---|---|---|
| Study drug | Atezolizumab (anti-PD-L1) | Durvalumab (anti-PD-L1) | Pembrolizumab (anti-PD-1) | Nivolumab (anti-PD-1) | Serplulimab (anti-PD-1) | Adebrelimab (anti-PD-1) | Tislelizumab (anti-PD-1) |
| Chemotherapy backbone | Carboplatin + etoposide | Carboplatin or cisplatin + etoposide | Carboplatin or cisplatin + etoposide | Carboplatin or cisplatin + etoposide | Carboplatin + etoposide | Carboplatin + etoposide | Carboplatin or cisplatin + etoposide |
| Median PFS (mo.)† | 5.2 vs. 4.3 | 5.1 vs. 5.4 | 4.5 vs. 4.3 | 5.5 vs. 4.6 | 5.7 vs. 4.3 | 5.8 vs. 5.6 | 4.7 vs. 4.3 |
| Median OS (mo.)† | 12.3 vs. 10.3 | 12.9 vs. 10.5 | 10.8 vs. 9.7 | 11.3 vs. 8.5 | 15.4 vs. 10.9 | 15.3 vs. 12.8 | 15.5 vs. 13.5 |
| Treatment-related AE (grade 3–4)† | 56.6% vs. 56.1% | 46% vs. 52% | 63% vs. 61% | 77% vs. 62% | 33.2% vs. 27.6% | 86% vs. 85% | 86% vs. 86% |
| Immune-related AE (any grade)† | 39.9% vs. 24.5% | 20% vs. 3% | 24.7% vs. 10.3% | NG vs. NG | 37% vs. 18.4% | 28% vs. 17% | 38% vs. 18% |
†, study drug plus chemotherapy backbone vs. placebo plus chemotherapy backbone (only chemotherapy backbone for CASPIAN and EA5161 studies). AE, adverse events; ES-SCLC, extensive-stage small cell lung cancer; mo., months; NG, not given; OS, overall survival; PD-1, programmed cell death protein-1; PD-L1, programmed cell death-ligand 1; PFS, progression-free survival.
The most noteworthy outcome of RATIONALE-312 is the significantly longer OS in both arms, with the placebo arm in this study having similar survival to the intervention arms of other chemoimmunotherapy trials. In this regard while we agree with the authors of RATIONALE-312, this could be explained in part by patient selection. To this effect, in this study, the proportion of patients who were never-smokers (24.5%) was higher than global estimates (2.5%), but this is consistent with the observed higher prevalence of never-smoking patients with SCLC in Asia, as well as a previous phase 3 trials of SCLC conducted in China (20% in ASTRUM-005; 22% in CAPSTONE-1) (9,10). As the major risk factor for SCLC is smoking, residential radon exposure, air pollution, occupational exposures (e.g., diesel engine emissions, polycyclic aromatic hydrocarbons, heavy metals), and second-hand smoking have been found to play a role in SCLC. Molecular alterations as found non-small cell lung cancer are not yet characterized in SCLC (11). Also, the inclusion of patients with brain metastases in both arms was quite low and represents a group of patients with better prognosis. Notably, the safety profile was favorable with no safety signals.
Of note, the authors cite that there is a lack of survival benefit in the Chinese population observed in the IMpower133 study. The fragment crystallizable (Fc) region of the tislelizumab antibody is engineered to avoid T-cell depletion caused by antibody-mediated phagocytosis. Given this unique feature and the low prevalence of treatment-associated adverse effects, tislelizumab was hypothesized to have better innovation potential than the other immune checkpoint inhibitors. However, it is unlikely there is a clear superiority in the anti-PD-1 inhibitor vs. an anti-PD-L1 inhibitor, based on the current body of evidence (12).
The authors also hypothesized that improved survival may be attributed to use of anlotinib, an antiangiogenic multi-target tyrosine kinase inhibitor, in subsequent lines of therapy. In Alter-1202 conducted in China, anlotinib showed superior PFS [4.1 vs. 0.7 months, HR =0.19 (95% CI: 0.12–0.32), P<0.0001] and OS [7.3 vs. 4.9 months, HR =0.53 (95% CI: 0.34–0.81), P=0.0029] compared to placebo in third-line in ES-SCLC (13). To that effect, there is an ongoing open-label, single arm, prospective phase 2 trial investigating the efficacy and safety of combination of tislelizumab and anlotinib as maintenance therapy following induction chemotherapy with tislelizumab as first-line therapy for ES-SCLC in China (NCT05896059).
Despite recent advancements, SCLC remains a disease with poor prognosis. Although SCLC shares similar histopathological and radiological characteristics, its clinical behavior can vary significantly. These differences in clinical outcomes may be attributed to underlying subtype variations, which could play a crucial role in influencing disease progression, response to therapy, and overall prognosis. Identification of predictive biomarker has been challenging. Expression of PD-L1 was initially hypothesized to be an important criterion for determining the responsiveness to anti-PD-1 therapy, however, exploratory analyses of the IMpower133 and CASPIAN trial showed no significant impact of PD-L1 expression on the effect of treatment (2,3). Furthermore, PD-L1 expression was low (22% of specimen exhibiting ≥1% PD-L1 expression). Similarly, in the KEYNOTE-604 study, tumor PD-L1 expression did not correlate with outcomes (8). Most SCLC cases, given high association with smoking, display high tumor mutation burden, which is another critical indicator of immunotherapy responsiveness (need responsiveness) (14). In the RATIONALE-312 study, no predictive biomarker was reported.
Given the benefits of tislelizumab in ES-SCLC and the positive results of the ADRIATIC trial demonstrating the survival advantage of durvalumab as consolidation therapy after chemoradiation in limited-stage disease (15), ongoing studies aim to integrate immune check point inhibitors into earlier treatment stages. Two phase 2 trials are currently evaluating the efficacy of neoadjuvant tislelizumab in combination with chemotherapy for resectable limited-stage SCLC (NCT06375109, NCT04542369).
As the treatment landscape continues to evolve, the need for continued research into novel therapeutic approaches and biomarker-driven strategies remains critical. While the RATIONALE-312 trial marks a significant milestone, global efforts must continue to refine and expand treatment options beyond combinations of chemotherapy and immune checkpoint inhibitors, ultimately improving survival and quality of life for patients with SCLC.
Acknowledgments
None.
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.
Peer Review File: Available at https://cco.amegroups.org/article/view/10.21037/cco-25-5/prf
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.org/article/view/10.21037/cco-25-5/coif). T.L. reports receiving institutional research grants from AstraZeneca, Advaxis, Synthekine, 23&Me, Daiichi-Sankyo, Pfizer; consulting for Roche, AstraZeneca, Regeneron, Novocure, Takeda, Merck, Jazz Pharmaceuticals, Catalyst, Amgen, Janssen, Genentech, Novartis, AbbVie, Pfizer, Gilead, and Boehringer Ingelheim; receiving payments or honoraria for presentations or educational events from OncLive, Medscape, UpToDate, Peerview, Curio, Aptitude Health, Ideology, CME Outfitters, BioAscend, GASCO, Targeted Oncology, GRACE, and SITC; receiving support for travel, accommodations, and other expenses from Regeneron and Sanofi, participating on advisory boards for Roche, AstraZeneca, Regeneron, Novocure, Takeda, Merck, Jazz Pharmaceuticals, Catalyst, Amgen, Janssen, Genentech, Sanofi, BMS, Pfizer, Black Diamond, Boehringer Ingelheim, and Synthekine; serving on the data safety monitoring board for OncoC4. The other authors have no conflicts of interest to declare.
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