Tusamitamab Ravtansine Misses Survival End Points in Advanced NSCLC Trial

Benjamin Besse, MD, PhD

Treatment with tusamitamab ravtansine, a CEACAM5-targeting antibody-drug conjugate (ADC), did not significantly improve progression-free survival (PFS) or overall survival (OS) when compared with docetaxel chemotherapy in patients with advanced nonsquamous non–small cell lung cancer who have CEACAM5 expression, according to findings from the phase 3 CARMEN-LC03 trial (NCT04154956) presented at the IASLC 2024 World Conference on Lung Cancer.¹

In the intent-to-treat (ITT) population, at a median follow-up date of 7.4 months, the PFS per independent review committee (IRC), as part of the final prespecified analysis, was 5.4 months (95% CI, 3.7-7.0) and 5.9 months (95% CI, 5.5-7.4) in the tusamitamab ravtansine (n = 194) and docetaxel (n = 195) arms, respectively (HR, 1.14; 95% CI, 0.86-1.51; P = .8204). At a median follow-up of 18.1 months, the OS during the first interim analysis was 12.8 months (95% CI, 11.8-14.2) and 11.5 months (95% CI, 8.9-15.2) in the respective arms (HR, 0.85; 95% CI, 0.64-1.11; P = .112).

“There was a dual primary endpoint of PFS, as per independent review committee and overall survival…These results led to the early study termination,” Benjamin Besse, MD, PhD, a medical oncologist and professor of medicine at Paris Saclay University, Institut Gustave Roussy, Villejuif, France, said during an oral presentation of the data.

The phase 3, open label, multicenter CARMEN-LC03 trial randomized 389 patients 1:1 to receive tusamitamab ravtansine at 100 mg/m2 every 2 weeks or docetaxel at 75 mg/m2 every 3 weeks.

The key eligibility criteria included patients with nonsquamous NSCLC who were previously treated with platinum-based chemotherapy and an immune checkpoint inhibitor (ICI), CEACAM5 expressions of an intensity of at least 2+ or higher in at least 50% or higher of tumor cells as assessed by immunohistochemistry (IHC), had at least 1 or more measurable lesions by RECIST v1.1 criteria, and an ECOG performance status of 0 or 1. Patients were stratified by ECOG performance status (0 vs 1); geographical region (Asia vs Western Europe, Australia, and North America vs rest of world); and prior ICI treatment (sequential vs combination with chemotherapy).

The dual primary end points were PFS per IRC and OS; secondary end points included objective response rate (ORR), duration of response (DOR), safety, and health-related quality of life (HRQoL).

Additional data showed that, across key subgroups, PFS per IRC as well as favored tusamitamab ravtansine patients with at least 80% of CEACAM5 expression. Specifically, those with an ICH CEACAM5 expression of 2+ or 3+ of 80% or higher favored tusamitamab ravtansine over docetaxel for PFS (HR, 0.866; 95% CI, 0.597-1.257) and OS (HR, 0.711; 95% CI, 0.492-1.028).

The time to deterioration in HRQoL in the ITT population demonstrated a positive trend for tusamitamab ravtansine. The median survival for disease-related symptoms was 2.8 months (range, 2.1-4.3) and 1.9 months (range, 1.5-2.8) in the tusamitamab ravtansine and docetaxel arms, respectively. Disease-related symptoms included cough, dyspnea, and chest pain. For role functioning, median survival was 5.6 months (range, 3.7-6.3) vs 4.2 months (range, 2.8-4.4) in the respective arms. The median survival for physical functioning was 7.5 months (range, 5.5-15.2) and 4.2 months (range, 3.0-4.6).

Regarding safety, there were fewer grade 3 or higher or serious adverse events (AEs) and treatment discontinuations in the tusamitamab ravtansine arm vs the docetaxel arm. All-grade treatment-emergent AEs (TEAEs) occurred in 186 patients (95.9%) and 168 patients (94.9%) from the tusamitamab ravtansine and docetaxel arms, respectively; grade 3 or higher TEAEs occurred in 79 patients (40.7%) and 102 patients (57.6%). All-grade treatment-related AEs (TRAEs) occurred in 141 patients (72.7%) and 152 patients (85.9%) in the respective arms; 29 patients (14.9%) and 70 patients (39.5%) experienced grade 3 or higher TRAEs. Of note, TEAEs leading to dose reductions occurred in 32 patients (16.5%) and 64 patients (36.2%); 15 patients (7.7%) and 30 patients (16.9%) experienced TEAEs the led to definitive treatment discontinuation.

“Around 90% of the patients had archived tissue [rather than fresh tissue], and we don't know what the role of chemotherapy and/or immunotherapy was on the potential change of the CEACAM5 expression,” Besse concluded. “CARMEN-LC03 was discontinued in December 2023, but patients benefiting from treatment could continue to receive tusamitamab ravtansine.”

Reference

1. Besse B, Lo Russo G, Lena H, et al. Tusamitamab ravtansine vs docetaxel in previously treated advanced nonsquamous NSCLC: results from phase 3 CARMEN-LC03 trial. Presented at:IASLC 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract OA08.05.