Quadruplet therapy for extensive-stage small cell lung cancer (ES-SCLC): does one size fit all in treatment for ES-SCLC?

First-line therapy for extensive-stage small cell lung cancer (ES-SCLC), an aggressive neuroendocrine cancer with poor outcomes, is a combination of chemotherapy and immunotherapy. Two pivotal trials, IMpower133 and CASPIAN, demonstrated improved overall survival (OS) of 12.3 and 12.9 months, respectively, with the addition of anti-programmed death-ligand 1 (PD-L1) agents atezolizumab or durvalumab to platinum-etoposide (EP), leading to Food and Drug Administration (FDA) approval of combination chemoimmunotherapy in 2019 and 2020 (1-4). More recently, the ASTRUM-005 and CAPSTONE-1 trials investigated the anti-programmed cell death 1 (PD-1) serplulimab with EP and anti-PD-L1 adebrelimab with EP, respectively, yielding similarly positive findings (5,6). Despite modest benefits with the addition of immunotherapy, most patients with ES-SCLC develop resistance and progress within 6 months, highlighting the need for additional therapeutics. The recent publication of the final progression-free survival (PFS) and interim OS data for the ETER701 trial of benmelstobart and anlotinib with etoposide/carboplatin (EC) holds promise for an addition to the repertoire of front-line treatment options for ES-SCLC (7). A crucial question, however, emerges: who would benefit from an upfront four-regimen approach?

Benmelstobart is a humanized monoclonal antibody targeting PD-L1 while anlotinib is an oral small-molecule multi-target tyrosine kinase inhibitor (TKI) with anti-angiogenesis effects targeting VEGFR1, VEGFR2/KDR, VEGFR3, c-Kit, PDGFR-α, FGFR1, FGFR2, and FGFR3 (8). ETER701 is a phase III multicenter, randomized, double blind, placebo-controlled trial that compared three first-line regimens for patients with ES-SCLC without prior systemic treatment: benmelstobart and anlotinib with EC (quadruplet therapy, n=246), placebo and anlotinib with EC (triplet therapy, n=245), or double placebo with EC (standard of care arm, n=247) followed by matching maintenance therapy (7). The co-primary endpoints of this trial were PFS and OS, with secondary endpoints that included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and safety.

ETER701 met both primary endpoints of PFS and OS in the quadruplet arm, while it met its PFS but not OS endpoint in the triplet arm. At a median follow up of 14.0 months, quadruplet therapy demonstrated a significant PFS benefit [6.9 vs. 4.2 months; hazard ratio (HR) =0.32; 95% confidence interval (CI): 0.26–0.41; P<0.0001] and OS benefit (19.3 vs. 11.9 months; HR =0.61; 95% CI: 0.47–0.79; P=0.0002). The triplet arm met only its PFS endpoint (5.6 vs. 4.2 months; HR =0.44; 95% CI: 0.36–0.55; P<0.0001), without a significant OS benefit (13.3 vs. 11.9 months; HR =0.86; 95% CI: 0.67–1.10; P=0.1723). In subgroup analyses, the OS and PFS benefit of quadruplet therapy appears to be consistent across subgroups, though with perhaps less significant benefit in patients with brain metastases and hepatic metastases for OS and brain metastases and limited stage at diagnosis for PFS.

For secondary endpoints, the quadruplet group and triplet group demonstrated an ORR of 81.3% and 81.2% respectively, compared to 66.8% in the control arm. Three patients in the quadruplet therapy arm and one patient in the triplet therapy arm attained a complete response, with no patients in the control arm. There were no differences in DCR between the quadruplet and control arms (90.7% vs. 87.0%, P=0.2003), but the triplet arm did demonstrate an improvement (92.7% vs. 87.0%, P=0.0378).

The results for the benmelstobart, anlotinib, and EC arm are exciting with an OS over 19 months, longer than what has previously been demonstrated in trials, and the quadruplet combination conferred an impressive survival benefit compared to the control arm with a HR of 0.61 and OS benefit of approximately 7 months. Prior to widespread adoption of any treatment that could carry a higher toxicity risk, however, it is essential to critically examine the study design and population. First, a major limitation to the study is the comparison control arm of chemotherapy alone, which is no longer standard of care. In addition, the impact of substituting different drugs within the same class with a similar mechanism of action—namely an anti-PD-L1 vs. an anti-PD-1—is unknown. The biological rationale of adding a fourth agent, a multi-target TKI with anti-angiogenesis properties, is sound and does appear to improve outcomes in this trial, notably at odds with trials utilizing another anti-angiogenesis agent, bevacizumab. With respect to study population, there are key differences including a higher proportion of never-smokers compared to global trials which may affect applicability to broader populations. Finally, weighing the risks of additional toxicity with the potential benefit of a fourth agent is necessary when considering a change in treatment paradigm, and a better understanding of the mechanisms of response will be essential for optimized patient selection.

One of the most prominent limitations to this study is the lack of a benmelstobart with EC arm in ETER701. The authors do make note that the control arm of EP was standard of care at the time of design of the study, as immune checkpoint inhibitor (ICI) had not been approved for combination with EP in China. Without a benmelstobart and EC arm and no published studies of benmelstobart with chemotherapy in ES-SCLC, it is difficult to determine the contribution of each agent in the quadruplet therapy, as well as the effect of using an anti-PD-1 vs. an anti-PD-L1. It is possible that benmelstobart is the primary driver of survival benefit as it is a novel anti-PD-L1, or that the quadruplet therapy may not demonstrate the same degree of benefit when compared to an approved chemoimmunotherapy regimen.

Secondly, the exact impact of different drugs within the same class is unclear, but do appear to yield disparate outcomes. KEYNOTE-604, a phase III study which evaluated the anti-PD-1 pembrolizumab plus EP, did not meet its OS endpoint leading to withdrawal of the drug’s indication for ES-SCLC (9). In comparison, studies of anti-PD-L1 agents, durvalumab and atezolizumab, did demonstrate a survival benefit and are currently approved for first-line treatment. More recently, both ASTRUM-005 and RATIONALE-312 met their primary endpoints and demonstrated improved OS with the combinations of the anti-PD-1 serplulimab or tislelizumab with chemotherapy, respectively (6,10). It remains unclear if the benefit seen in the quadruplet arm is due to the specific drug or a class effect of anti-PD-L1 compared to anti-PD-1, though it appears that both anti-PD-1 and anti-PD-L1 have demonstrated efficacy in ES-SCLC. Notably, with the lack of OS benefit from the triplet arm with anlotinib and EC, it is difficult to determine if the bulk of benefit from quadruplet therapy is derived from benmelstobart or if the combination of an anti-PD-L1 and anti-angiogenic agent is synergistic.

There is certainly biological justification for use of a PD-1/PD-L1 inhibitor and an anti-angiogenesis agent based on the pathways involved in tumor invasion and growth in SCLC (11). Potential mechanisms for a synergistic effect include alterations in the tumor microenvironment and differences in the vasculature mediated by VEGF. Hypoxia and aberrant intratumor vasculature are hallmarks of SCLC, with upregulation of VEGF via hypoxia and aberrant vasculature that can hinder ICI penetration and effector T-cell trafficking and infiltration (12,13). In addition, VEGFA can enhance expression of alternate inhibitory receptors such as TIM-3 leading to an exhausted T-cell phenotype, which can be reversed with the addition of an anti-angiogenic agent to an anti-PD-1 (11).

Another question that is yet unanswered is if the OS benefit in ETER701 is due to utilization of a multi-target TKI rather than an anti-VEGF monoclonal antibody as was the case in BEAT-SC, a phase III trial evaluating the combination of bevacizumab with atezolizumab and chemotherapy as first-line treatment in ES-SCLC (14). Results from the second interim analysis of BEAT-SC demonstrated a median PFS and OS of 5.7 and 13.9 months respectively for the bevacizumab arm compared to 4.4 and 16.4 months in the control arm. Although OS data were immature at time of abstract presentation, it is intriguing to note the longer median OS for the control arm which is counter to the results of the ETER701 trial. The reported rates of treatment-related adverse events appeared similar between the groups in the first interim analysis, though overall number of deaths in each group was not available in the abstract. It is possible that the anti-angiogenesis agent potentiates the effect of the immunotherapy to improve durability of response in a subset of patients, which will not be apparent until longer follow-up. Of note, prior studies of bevacizumab with chemotherapy in ES-SCLC, IFCT-0802 and GOIRC-AIFA FARM6PMFJM, have not yielded significant OS benefit, suggesting that the addition of an anti-angiogenesis agent by itself may not be sufficient (15,16). Lastly, the addition of an anti-angiogenesis agent could be more beneficial in certain subgroups rather than all-comers. The BEAT-SC study population had a lower rate of never smokers at 12.4% compared to ETER-701, although both trials recruited from a Chinese population. As never smokers tend to have a less impressive response to immunotherapy, perhaps a higher proportion of never smokers contributes to a more significant survival benefit.

The external validity of the results and applicability to a global population is an important discussion point when considering widespread adoption. In the United States, FDA approval for a drug based solely on foreign clinical data must meet several criteria including “(1) The foreign data are applicable to the U.S. population and U.S. medical practice” (17). ETER701 enrolled from an Asian population, with a higher percentage of never smokers (21.9%, 24.1%, and 24.0% in the EC alone, triplet, and quadruplet arms, respectively) compared to CASPIAN (6% and 8% in the placebo and durvalumab arms, respectively) and IMpower133 (1.5% and 4.5% in the placebo and atezolizumab arms, respectively). The rate of never smokers in ASTRUM-005 and CAPSTONE-1 were more comparable to the patients in ETER701, ranging from 17.8% to 23%. As ASTRUM-005 and CAPSTONE-1 recruited from a similar geographic region in Asia as ETER701 while CASPIAN and IMpower133 included North America and Europe, the difference may reflect baseline heterogeneity in the study population (Table 1). The authors discuss this difference and make note of the higher prevalence of EGFR mutations in the Chinese population, though molecular testing is not yet available to confirm. As small cell transformation is a known resistance mechanism in this population, it will be key to characterize the genomic landscape in this population and perform subgroup analysis based on molecular subtypes.

Of further note, the OS of 11.9 months in the control group in ETER701 is comparable to the control cohorts in CAPSTONE-1 (12.8 months) and ASTRUM-005 (10.9 months), but does appear to be longer than in IMpower133 (10.3 months) and CASPIAN (10.5 months). This raises the question of whether the patients in ETER701 were healthier or have a better prognosis at baseline. In general, inclusion and exclusion criteria were consistent with similar studies. Of note, however, patients with arterial or venous thrombosis within 6 months of randomization were excluded. Venous thromboembolism (VTE) is associated with a higher risk of death for patients with SCLC, so the starting population in this trial arguably was in general at a lower risk of death (18). The exclusion of patients with thrombosis is consistent with prior trials of anti-angiogenesis agents, but warrants further investigation for safety considerations and impact on outcomes given evidence for elevated rates of thromboembolism in SCLC patients (18).

With increasing recognition that SCLC is a heterogeneous entity with multiple subtypes, it will be critical to characterize the genomic and transcriptomic features of the patients in this trial and impact on treatment response (19-21). For example, patients with high MHC I expression may be associated with more durable responses to ICI (19). Analyses of molecular data from CASPIAN and IMpower133 demonstrated associations with outcomes to immune checkpoint blockade based on SCLC subtype, PD-L1 expression, and tumor mutation burden (TMB), but a reliable predictor of benefit has yet to be identified (21-23). Biologically, certain subtypes of SCLC (24) may overexpress markers of epithelial-mesenchymal transition (EMT) and hypoxia and angiogenesis (HIF1A, VEGFA, and FOXO3), which could predispose these patients to a better response with an anti-angiogenesis agent. Correlative studies examining the mechanism leading to survival benefit will aid in understanding of the mechanisms of immunotherapy response. The protocol makes note of pre-treatment biopsies and ctDNA that were collected during this trial, and the results of these studies are highly anticipated (7).

Adverse events in the quadruplet and triplet arms were similar but still higher than the control arm, with several deaths. The toxicity profile of the quadruplet therapy reflects the challenges of more intensive regimens, with higher rates of grade 3 or more treatment-emergent adverse events (TEAEs) in the quadruplet and triplet groups (94.3% and 95.9%, respectively) compared to the control arm (89.0%). There were several deaths associated with TRAEs, at a rate of 4.5%, 2.5%, and 1.6% in the quadruplet, triplet, and EC alone groups. While the adverse event profile is acceptable and the quadruplet therapy does appear to be generally tolerated, there was a higher rate of grade 3 or higher serious adverse events in the quadruplet (46.7%) and triplet (43.4%) groups compared to the EC alone group (34.1%), which is not inconsequential. Moreover, the potential for financial toxicity with the addition of another therapeutic to the regimen, including maintenance, will need to be considered. These results emphasize the importance of identifying patients for whom benefits of the quadruplet therapy outweigh the increased risk of toxicity.

A final consideration for future studies that will become increasingly relevant is the effect of prior exposure to a PD-1/PD-L1 agent, given the recent publication of ADRIATIC demonstrating significant OS and PFS benefit with consolidation durvalumab after concurrent chemoradiotherapy in patients with limited-stage SCLC (25). Patients with prior immunotherapy targeting PD-1 and PD-L1 were excluded in ETER701. There will be significantly more patients with exposure to prior anti-PD-L1 in the limited stage setting, so it is unclear how this will impact choice of treatment regimen if those patients recur with ES-SCLC. As these patients may have developed resistance to ICI with prior exposure, adding an anti-angiogenesis agent with an alternate mechanism of action may confer additional benefit.

Overall, the OS of 19.3 months is impressive, clinically significant with a solid biological rationale, and is an exciting step forward for patients with ES-SCLC. Prior to widespread implementation of this combination, however, it is imperative to understand how it compares to the current standard of care of chemoimmunotherapy in a wider population. There is likely a subset of patients for whom an aggressive regimen is more beneficial, such as never smokers, patients with prior immunotherapy exposure, or a better performance status able to tolerate increased risk of toxicities. Further correlative studies will help elucidate which patients should be placed on a more aggressive quadruplet regimen if the differences are due to identifiable molecular heterogeneity. These results highlight the necessity for biomarker-driven trials designed with this goal in mind.

ETER701 provides promising evidence for the combination of benmelstobart, anlotinib, and EC for first-line therapy in ES-SCLC, but perhaps quadruplet therapy is not ideal for every patient—one size does not fit all and further studies are needed to understand for whom the fit is right.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-243/coif). A.C.C. reports grants or contracts from Amgen, AbbVie, AstraZeneca, Genentech, and BMS; payments or honoraria from Jazz Pharmaceuticals and GNE; participation in the advisory boards for AstraZeneca, GNE, Zai Lab, Amgen, Fosun, Janssen, Daichi, and Jazz Pharmaceuticals; and a leadership or fiduciary role in SWOG. The other author has no conflicts of interest to declare.

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