Benjamin Besse, MD, PhD
The multicenter phase III -CARMEN-LC03 trial did not meet its dual primary endpoints of progression-free and overall survival with the CEACAM5-directed antibody-drug conjugate tusamitamab ravtansine vs standard chemotherapy with docetaxel in previously treated patients with advanced nonsquamous non–small cell lung cancer (NSCLC), according to the final progression-free survival and first interim overall survival analyses.1 At the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer, Benjamin Besse, MD, PhD, of Gustave Roussy, Villejuif, France, and colleagues presented these findings, which led to the termination of the study in December 2023.
Dr. Besse reported trends toward improved overall survival in the overall population and improved progression-free and overall survival in the subgroup of patients with CEACAM5 expression levels of at least 80%, along with a favorable safety profile.
“CEACAM5 is a transmembrane glycoprotein, which is overexpressed in up to 25% of patients with nonsquamous NSCLC,” Dr. Besse explained. He noted that an exploratory analysis aiming to understand the high performance of the control arm, which was also presented during the conference, revealed a potential prognostic role for CEACAM5 expression.2
About CARMEN-LC03
In the CARMEN-LC03 trial, a total of 389 patients with advanced nonsquamous NSCLC who previously underwent platinum-based chemotherapy and immunotherapy (in combination or sequential) were randomly assigned in a 1:1 ratio to intravenously receive either 100 mg/m2 of tusamitamab ravtansine once every 2 weeks (n = 194) or 75 mg/m2 of docetaxel once every 3 weeks (n = 195; treated: n = 177). Those with high immunohistochemistry-assessed CEACAM5 expression (≥ 2+ intensity in ≥ 50% of tumor cells) were included in the study. At the data cutoff date (September 22, 2023), a total of 18.6% and 12.8% patients were still receiving tusamitamab ravtansine and docetaxel, respectively.
“The demographics and patient characteristics were well balanced between the two arms,” Dr. Besse commented, also noting that more than a quarter of the patients were randomly assigned to treatment in Asia, and more than half had a CEACAM5 expression level of at least 80%. Baseline brain metastases were documented in 16.5% of the patients who were treated with tusamitamab ravtansine and 13.3% of those who were assigned to receive docetaxel. Of these respective arms, 67.0% and 66.7% previously received concomitant chemotherapy and immunotherapy, and 33.0% and 33.3% were administered these therapies sequentially. A total of 17.5% of the tusamitamab ravtansine arm and 14.9% of the docetaxel arm were pretreated with taxanes, with an equal percentage having undergone prior tyrosine kinase inhibitor therapy (10.8% for both).
The dual primary endpoints were independent review committee–assessed progression-free survival and overall survival. The objective response rate, health-related quality of life, duration of response, and safety were evaluated as key secondary endpoints. Follow-up data were provided for a median of 7.4 and 18.1 months for progression-free and overall survival, respectively.
Dual Primary Endpoints Not Met
The median progression-free survival was 5.4 months with tusamitamab ravtansine and 5.9 months with docetaxel (hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 0.86–1.51; P = .8204). The median duration of overall survival was 12.8 vs 11.5 months, respectively (HR = 0.85, 95% CI = 0.64–1.11; P = .112). Dr. Besse highlighted that, across key subgroups, patients with expression levels of CEACAM5 of at least 80% demonstrated trends toward improved progression-free and overall survival with tusamitamab ravtansine.
The objective response rates were found to be similar between the treatment arms. Regarding health-related quality of life, the times to deterioration of disease-related symptoms (2.8 vs 1.9 months), physical functioning (7.5 vs 4.2 months), and role functioning (5.6 vs 4.2 months) were numerically prolonged with tusamitamab ravtansine vs docetaxel.
Safety Summary
The incidences of treatment-related adverse events of grade 3 or higher (14.9% vs 39.5%), serious treatment-related adverse events (6.2% vs 20.3%), and treatment-emergent adverse events leading to treatment discontinuation (7.7% vs 16.9%) and dose reduction (16.5% vs 36.2%) were lower with tusamitamab ravtansine than with docetaxel. However, dose delay was more frequently required with tusamitamab ravtansine (42.8% vs 28.2%).
The incidence and severity of ocular adverse events (corneal events: 25.8%; grade ≥ 3: 6.7%) were found to be consistent with those reported in previous studies of tusamitamab ravtansine. Peripheral neuropathy was observed in 14.4% of patients treated with tusamitamab ravtansine and 13.6% of those who received docetaxel. No treatment-related sudden death was documented.
“A potential limitation of the study was using archived rather than fresh tissue to evaluate CEACAM5 in most participants,” commented Dr. Besse. He added that “it remains unclear how prior immunotherapy and/or chemotherapy may have affected CEACAM5 expression before the administration of tusamitamab ravtansine or docetaxel.”
Dr. Besse concluded: “CARMEN-LC03 did not meet its primary objective of independent review committee–assessed progression-free survival but showed a positive trend on the primary objective of overall survival at this interim analysis. Subgroup analyses suggested a trend of improved relative progression-free and overall survival for tusamitamab ravtansine vs docetaxel among patients with very high CEACAM5 expression. Tusamitamab ravtansine demonstrated a safety profile that is favorable compared with docetaxel.”
EXPERT POINT OF VIEW
Saiama N. Waqar, MD, MSCI
Invited discussant of the session entitled “The New Generation of Cytotoxics,” Saiama N. Waqar, MD, MSCI, of the Washington University School of Medicine, St. Louis, stated that docetaxel and docetaxel-based combinations have remained the standard of care in the second-line setting since the first U.S. Food and Drug Administration (FDA) approval of the agent over 20 years ago. However, several potential new “challengers” have recently emerged, including tusamitamab ravtansine, plinabulin plus docetaxel, datopotamab deruxtecan, and sacituzumab govitecan-hziy.
Dr. Waqar reiterated that the CARMEN-LC03 trial did not meet its primary endpoints of progression-free and overall survival with tusamitamab ravtansine vs docetaxel. “The docetaxel arm had better progression-free [5.9 vs 2.0–4.2 months] and overall [11.5 vs 5.7–9.6 months] survival than we have seen with historical studies of docetaxel,” she further emphasized.
Dr. Waqar briefly discussed the nonsignificant trends toward improved progression-free and overall survival with tusamitamab ravtansine in the subgroup of patients with CEACAM5 expression levels of at least 80%. She believes this underscores the need for further refinement of biomarker cutoffs.
Prognostic Role for CEACAM5?
Although Dr. Waqar expressed that tusamitamab ravtansine is “not ready for prime time,” she noted that CEACAM5 is still being examined as a target in the phase I/II study of NEO-201 (an anti-CEACAM5/6 monoclonal antibody) and various phase I studies of antibody-drug conjugates targeting CEACAM5, with different payloads (including M9140, PF-08046050/SGN-CEACAM5C, and EBC-129). In accordance with Dr. Besse’s interpretation of the data from the exploratory analysis, which revealed improved overall survival with increasing terciles of CEACAM5 expression for both treatment arms, Dr. Waqar acknowledged a potential prognostic role for CEACAM5 in the CARMEN-LC03 study.
Upon review of all the abstracts presented during the session, she concluded: “Docetaxel-based therapy remains hard to beat. We need more cytotoxic agents with fewer toxicities, and we need to define and refine our patient populations that will derive benefit from them.”
DISCLOSURE: Dr. Besse has served on an advisory board for AbbVie, BioNTech SE, Bristol Myers Squibb, Chugai Pharmaceutical, CureVac AG, Daiichi Sankyo, F. Hoffmann–La Roche Ltd, PharmaMar, Regeneron, Sanofi Aventis, and Turning Point Therapeutics; has served as a consultant for AbbVie, Eli Lilly, Ellipse Pharma Ltd, F. Hoffmann–LaRoche Ltd, Genmab, Immunocore, Janssen, MSD, Ose Immunotherapeutics, Owkin, and Taiho oncology; has served on a steering committee for AstraZeneca, BeiGene, GENMAB A/S, GlaxoSmithKline, Janssen, Ose Immunotherapeutics, PharmaMar, Roche-Genentech, Sanofi, and Takeda; and has served as a speaker for AbbVie, AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Hedera Dx, Janssen, MSD, Roche, Sanofi Aventis, and Springer Healthcare Ltd. Dr. Waqar has served on advisory boards for AstraZeneca, Gilead Sciences, Janssen, Boehringer Ingelheim, Pfizer, and Daiichi Sankyo.
REFERENCES
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. 2024 World Conference on Lung Cancer. Abstract OA08.05. Presented September 9, 2024.
2. Cho BC, Cadranel J, Chadjaa M, et al: Exploratory analyses of tusamitamab ravtansine vs docetaxel in previously treated non-squamous NSCLC patients: CARMEN-LC03. 2024 World Conference on Lung Cancer. Abstract P2.10B.01. Presented September 8, 2024.
