First-Line Anlotinib Plus Etoposide and Carboplatin Improves PFS in ES-SCLC

Anlotinib in combination with etoposide, carboplatin, and a placebo for benmelstobart (TQB2450) elicited an improvement in progression-free survival (PFS) compared with etoposide and carboplatin in combination with placebos for anlotinib and benmelstobart in the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC), according to data from the phase 3 ETER701 trial (NCT04234607) presented at the 2024 European Lung Cancer Congress.¹

Findings showed that in the intent-to-treat (ITT) population, patients administered anlotinib plus etoposide, carboplatin and placebo (n = 245) experienced a median PFS of 5.62 months (95% CI, 5.55-6.83) vs 4.21 months (95% CI, 4.17-4.24) in patients treated with etoposide plus carboplatin and 2 placebos (n = 247; HR, 0.44; 95% CI, 0.36-0.55; P < .0001). The 12-month PFS rate was 12.61% (95% CI, 7.81%-18.60%) for the anlotinib arm vs 2.29% (95% CI, 0.56-6.38) for the double placebo arm.

Despite the PFS improvement, a statistically significant benefit in overall survival (OS) was not observed between the 2 arms. The median OS was 13.27 months (95% CI, 11.14-15.05) for the anlotinib arm vs 11.89 months (95% CI, 10.47-13.37) for the double placebo arm (HR, 0.86; 95% CI, 0.67-1.10; P = .1732). The 12-month OS rates were 54.63% (95% CI, 46.33%-60.39%) and 49.00% (95% CI, 41.66%-55.93%), respectively.

Previous data from ETER701 presented at the 2023 World Conference on Lung Cancer showed that the addition of benmelstobart to anlotinib, etoposide, and carboplatin significantly improved PFS and OS vs placebos plus etoposide and carboplatin in the first-line treatment of patients with ES-SCLC (HR, 0.32; 95% CI, 0.26-0.41; P < .0001).²

“[The] PFS improvement of anlotinib plus etoposide, carboplatin, [and placebo] did not translate into a statistically significant increase in OS. As anlotinib plus chemoimmunotherapy [etoposide, carboplatin, and benmelstobart] significantly improved PFS and OS, [this suggests] that anlotinib plus chemoimmunotherapy may have a more durable synergistic effect in ES-SCLC,” lead study author Ying Cheng, MD, and colleagues wrote in a presentation of the data. Cheng is a first-class professor, doctoral tutor, postdoctoral supervisor, and chief physician in the Department of Thoracic Oncology at the JiLin Province Cancer Hospital in China.¹

The multicenter, placebo-controlled, randomized ETER701 trial enrolled patients between 18 and 75 years of age who had pathologically confirmed ES-SCLC and did not previously receive systemic therapy. Furthermore, patients needed to have a measurable lesion per RECIST v1.1 criteria; an ECOG performance status of 0 or 1; and adequate organ function. Notably, patients with asymptomatic or treated and stable brain metastases were permitted.

Eligible patients were randomly assigned 1:1:1 to 1 of 3 treatment regimens, which consisted of 4 21-day induction cycles followed by a maintenance phase. In all three arms, etoposide was given at 100 mg/m² on days 1 to 3 in each induction cycle, and carboplatin was given at area under the curve 5 on day 1 of each induction cycle.

• Arm 1: 1200 mg of benmelstobart on day 1, 12 mg of anlotinib on days 1 to 14, and etoposide plus carboplatin as induction therapy; benmelstobart plus anlotinib as maintenance therapy
• Arm 2: 12 mg of anlotinib on days 1 to 14, placebo for benmelstobart, and etoposide plus carboplatin as induction therapy; placebo plus anlotinib as maintenance therapy
• Arm 3: Placebo for benmelstobart, placebo for anlotinib, and etoposide plus carboplatin as induction therapy; placebo plus placebo as maintenance therapy.

Patients were stratified by ECOG performance status (0 vs 1), brain metastases (yes vs no), and liver metastases (yes vs no).

The primary end point of the study were OS and independent review committee–assessed PFS per RECIST v1.1 criteria. Secondary end points again included investigator-assessed PFS; overall 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 and tolerability.

A total of 1,005 patients were assessed for eligibility; 267 patients were excluded, 217 did not meet eligibility criteria, and 50 withdrew consent, leaving 738 patients randomly assigned to 1 of the 3 treatment groups.

In the anlotinib/placebo arm, the median age was 60.0 years (range, 32-75); 83.3% of patients were male; 80.8% of patients had an ECOG performance status of 1; 24.1% of patients were never smokers; 60.4% and 15.5% of patients were former or current smokers, respectively; 98.8% of patients had extensive-stage disease; 10.6% and 89.4% of patients had stage III or IV disease, respectively; and 9.0%, 31.8%, and 30.2% of patients had brain, liver, or bone metastases, respectively. Prior therapy included surgery (2.0%), chemotherapy (1.2%), radiotherapy (2.0%), or traditional Chinese medicine (4.1%).

In the double placebo group, the median age was 63.0 years (range, 30-75); 83.8% of patients were male; 80.6% of patients had an ECOG performance status of 1; 21.9% of patients were never smokers; 64.0% and 14.2% of patients were former or current smokers, respectively; 97.2% of patients had extensive-stage disease; 0.4%, 8.5% and 91.1% of patients had stage II, III, or IV disease, respectively; and 10.5%, 32.0%, and 27.9% of patients had brain, liver, or bone metastases, respectively. Previous therapy included surgery (2.4%), chemotherapy (2.8%), radiotherapy (2.4%), or traditional Chinese medicine (5.7%).

The data cutoff was May 14, 2022, and the median follow-up was 14.0 months (range, 12.8-15.5).

Additional data demonstrated that patients in the anlotinib/placebo arm experienced an ORR of 81.22% (95% CI, 75.76%-85.91%) vs 66.80% (95% CI, 60.55%-72.64%) for the double placebo arm (P = .0003). Patients in the experimental arm achieved a complete response rate of 0.41%; a partial response (PR) rate of 80.82%; a stable disease (SD) rate of 11.43%; and a progressive disease (PD) rate of 1.22%. Notably, 6.12% of patients were not evaluable for response. Conversely, in the double placebo arm, the PR rate was 66.8%; the SD rate was 20.24%; the PD rate was 6.48%; and 6.48% of patients were not evaluable for response.

Notably, the DCR was 92.5% (95% CI, 88.64%-95.59%) in the investigational group and 87.04% (95% CI, 82.21%-90.97%) in the placebo group (P = .0378).

The anlotinib/placebo regimen elicited a median DOR of 5.49 months (95% CI, 4.27-5.59) compared with 3.09 months (95% CI, 2.89-4.11) for the double placebo.

Regarding safety, 94.3% of patients in the anlotinib/placebo arm experienced grade 3 or higher treatment-related adverse effects (TRAEs), which included grade 3 or higher TRAEs led to any dose reduction/interruption (57.4%), discontinuation (8.6%), or death (2.5%). Furthermore, 43.4% of these patients experienced a grade 3 or higher serious AEs. Grade 3 or higher serious AEs led to a dose reduction/interruption in 32.4% of patients, any discontinuation in 8.2% of patients, and death in 6.1% of patients.

In the double placebo group, 87.0% of patients had grade 3 or higher TRAEs, which led to any dose reduction/interruption in 41.9% of patients, any discontinuation in 4.1% of patients, and death in 1.6% of patients. Additionally, 34.1% of patients experienced a grade 3 or higher serious AE. Serious AEs of grade 3 or higher in severity led to a dose reduction/interruption in 24.0% of patients, any discontinuation in 5.3% of patients, and death in 6.9% of patients.

The most common grade 3 or greater TRAEs included decreased neutrophil count (anlotinib/placebo group, 73%; double placebo group, 68.7%), decreased platelet count (53.7%; 35.8%), decreased white cell count (30.7%; 34.6%), anemia (26.6%; 23.6%), hypertriglyceridemia (8.2%; 0.8%), hypertension (11.9%; 1.6%), increased alanine aminotransferase (0.8%; 2.0%), and increased aspartate aminotransferase (1.2%; 0.4%).

References

1. Cheng Y, Yang R, Chen J, et al. Anlotinib plus etoposide/carboplatin (EC) versus placebo plus EC in first-line therapy for extensive-stage small cell lung cancer (ES-SCLC): A randomized, double-blind, parallel controlled, phase III trial (ETER 701). Ann Oncol. 2024;9(suppl 3):1-11. doi:10.1016/esmoop/esmoop102577
2. 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.