Upfront Benmelstobart Added to Anlotinib and Chemo Prolongs Survival in ES-SCLC

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Results from the phase 3 ETER701 trial (NCT04234607) show that adding benmelstobart (TQB2450) to anlotinib (AL3818) and etoposide plus carboplatin (EC) led to significant improvement in progression-free survival (PFS) and overall survival (OS) compared with placebo plus EC when used in the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).¹

Data presented at the 2023 World Conference on Lung Cancer showed that in the intention-to-treat (ITT) population, the benmelstobart regimen (n = 246) resulted in a median PFS of 6.93 (95% CI, 6.18-8.25) months vs 4.21 months (95% CI, 4.17-4.24) with placebo plus EC (n = 247), translating to a 68% reduction in the risk of disease progression and death (HR, 0.32; 95% CI, 0.26-0.41; P < .0001). The 6-month PFS rates in the benmelstobart and placebo arms were 59.11% and 16.55%, respectively; the 12-month PFS rates were 27.91% and 2.29%, respectively.

The benmelstobart combination also reduced the risk of death by 39% vs placebo plus EC in this population. The median OS was 19.32 months (95% CI, 14.23-not evaluable) with benmelstobart vs 11.89 months (95% CI, 10.74-13.37) with placebo (HR, 0.61; 95% CI, 0.46-0.79; P = .0002). The 12-month OS rates were 64.12% vs 49.00%, respectively, and the 24-month OS rates were 41.83% vs 24.24%, respectively.

“The addition of [the] antiangiogenic agent to immunochemotherapy in the first-line treatment of ES-SCLC resulted in the historically longest PFS and OS, supporting the use of immunochemotherapy plus anlotinib as a new treatment option for [this] patient population,” said Ying Cheng, MD, a first-class professor, doctoral tutor, and postdoctoral supervisor, as well as chief physician in the Department of Thoracic Oncology at the JiLin Province Cancer Hospital in China, in a press briefing during the conference.

SCLC is known to be a recalcitrant malignancy, Cheng said. Although chemoimmunotherapy regimens have provided 2- to 4-month OS benefits to those with ES-SCLC, approaches that can boost long-term survival are needed. The limited benefit could be attributable to the tumor microenvironment, according to Cheng, one that is described by immunosuppression, angiogenesis, and vascularization.

“Considering the complexity and heterogeneity of the SCLC microenvironment, we made an advanced design to combine benmelstobart, a novel PD-L1 inhibitor, with anlotinib, an antivascular agent, plus standard chemotherapy, aiming to obtain improved efficacy, longer survival benefits, and manageable safety in ES-SCLC,” Cheng said.

The multicenter, placebo-controlled, randomized, phase 3 trial included patients with pathologically confirmed ES-SCLC who were between the ages of 18 years and 75 years and who had not previously received systemic treatment. They were required to have measurable disease by RECIST v1.1 criteria, an ECOG performance status of 0 to 1, and acceptable organ function. Those with asymptomatic or treated and stable brain metastases were allowed.

Study participants (n = 738) were randomly assigned 1:1:1 to receive induction treatment, comprised of four, 21-day cycles, of benmelstobart at 1200 mg on day 1 plus anlotinib at 12 mg on days 1 to 14, and EC followed by maintenance treatment with benmelstobart and anlotinib; placebo plus anlotinib at 12 mg on days 1 to 14 plus EC followed by maintenance placebo plus anlotinib; or placebo plus placebo plus EC followed by placebo in the maintenance setting.

Key stratification factors included performance status (0 vs 1), presence of brain metastases (yes vs no), and presence of liver metastases (yes vs no).

OS and PFS by RECIST v1.1 criteria served as the trial’s primary end points. In the study, a fixed-sequence test was utilized for comparisons between treatment groups. Secondary end points included investigator-assessed PFS by RECIST v1.1 and iRECIST criteria, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), 6- and 12-month PFS rate, 12- and 18-month OS rate, quality of life, and safety/tolerability.

The median age of patients who received the benmelstobart regimen was 62 years (range, 36-75) vs 63 years (range, 30-75) in the placebo arm. Most patients were male (85% vs 83.8%), had an ECOG performance status of 1 (80.9% vs 80.6%), were former smokers (62.6% vs 64%), had extensive-stage disease (99.6% vs 97.2%), and stage IV disease (87.8% vs 91.1%). In the benmelstobart arm, 10.2% of patients had brain metastases, 32.1% had liver metastases, and 28% had bone metastases; in the placebo arm, these rates were 10.5%, 32%, and 27.9%, respectively.

In all subgroups analyzed, PFS and OS favored benmelstobart plus anlotinib and EC vs placebo and EC.

Additional data showed that benmelstobart plus anlotinib and EC elicited an ORR of 81.30% (95% CI, 75.86%-85.97%) vs 66.80% (95% CI, 60.55%-72.64%) with placebo plus EC (P = .0001). The DCR in the benmelstobart arm was 90.65% (95% CI, 86.30%-93.98%) vs 87.04% (95% CI, 82.21%-90.97%) in the placebo arm (P = .2003). The median DOR with the benmelstobart regimen was 5.75 months (95% CI, 5.52-7.20) vs 3.09 months (95% CI, 2.89-4.11) with placebo/EC (HR, 0.31; 95% CI, 0.24-0.41; P < .0001).

Of the 738 patients who underwent randomization, 246 were assigned to the benmelstobart arm, 245 were assigned to the anlotinib plus EC arm, and 247 were assigned to the placebo/EC arm; 246, 244, and 246 of patients, respectively, received at least 1 dose of their assigned treatment, and thus comprised the safety population of the trial.

In the benmelstobart arm, 29 discontinued induction treatment due to withdrawn consent (n = 10), progressive disease (n = 5), toxicity (n = 5), death (n = 3), protocol deviation (n = 1), loss to follow-up (n = 1), or other reasons (n = 4). A total of 217 patients completed induction treatment but 3 withdrew. A total of 214 patients received maintenance therapy; 160 of these patients discontinued due to progression (n = 133), adverse effects (AEs; n = 12), withdrawn consent (n = 9), death (n = 5), or other reasons (n = 1).

At the time of the data cutoff of May 14, 2022, 54 patients in the benmelstobart arm were still receiving treatment vs 9 patients in the placebo arm. Moreover, 47.6% and 74.8% of patients, respectively, received subsequent therapy, with 13% and 21.5% of patients, respectively, receiving subsequent immunotherapy.

“The safety profile [of the benmelstobart regimen] is tolerable and manageable,” Cheng noted.

Any-grade treatment-related AEs (TRAEs) were experienced by all safety-evaluable patients who received the benmelstobart regimen (n = 246) vs 99.6% of safety-evaluable patients who were given placebo/EC (n = 246); grade 3 or higher TRAEs were experienced by 93.1% and 87.0% of patients, respectively. In the benmelstobart arm, any-grade TRAEs resulted in dose reduction or interruption for 50.4% of patients, any discontinuation in 8.5%, and death in 4.5%; in the placebo arm, these rates were 23.2%, 2.8%, and 1.6%, respectively.

Any-grade immune-related AEs (irAEs) were reported in 42.7% of those who received the benmelstobart combination vs 19.1% of those given placebo/EC); grade 3 or higher irAEs were experienced by 16.7% and 6.9% of patients, respectively. In the benmelstobart arm, irAEs led to dose reduction, discontinuation, or death for 6.5%, 8.1%, and 2.0% of patients, respectively; these rates were 2.0%, 1.6%, and 0.4%, respectively, in the placebo arm. Serious AEs (SAEs) were observed in 54.9% of those who received the benmelstobart regimen vs 41.1% of those given placebo plus EC.

The most common any-grade TRAEs experienced by 10% or more of patients in the benmelstobart and placebo arms, respectively, included decreased neutrophil count (91.1% vs 90.7%), decreased platelet count (89% vs 81.7%), decreased white cell count (90.7% vs 91.5%), increased alanine aminotransferase (27.6% vs 29.7%), increased aspartate aminotransferase (26.8% vs 24.4%), weight loss (18.3% vs 6.9%), increased thyroid hormone levels (13.4% vs 3.3%), positive occult blood (11.8% vs 6.9%), decreased lymphocyte count (11.8% vs 9.8%), increased total bilirubin (11.8% vs 6.9%), and increased γ-GT (11% vs 11.4%).

“As you all know, seeing separation of survival curves in SCLC like that is quite remarkable and simply something we don’t see often in lung cancer, so hopefully this presentation will be robustly discussed,” Brendon M. Stiles, MD, moderator and chair of the IASLC Communications Committee said during the briefing. Stiles is also professor and chief of Thoracic Surgery and Surgical Oncology in the Department of Cardiothoracic & Vascular Surgery at Montefiore-Einstein, and associate director of Surgical Services in the Montefiore-Einstein Cancer Center.

_Reference

_{Cheng Y, Yang R, Chen J, et al. Benmelstobart with anlotinib plus chemotherapy as first-line therapy for ES-SCLC: a randomized, double-blind, phase III trial (ETER701). Presented at: 2023 World Lung Cancer Conference; September 9-12, 2023; Singapore, Republic of Singapore. OA01.03.}