Tusa Rav Not Better Than Docetaxel for NSCLC

SAN DIEGO — The novel antibody-drug conjugate tusamitamab ravtansine (tusa rav, Sanofi) did not demonstrate greater efficacy than docetaxel in treating advanced nonsquamous non–small cell lung cancer (NSCLC), according to the final results of a study.

These findings, which were presented at the World Conference on Lung Cancer (WCLC) 2024 on September 9, led to the discontinuation of the CARMEN-LC03 study in December. But patients benefiting from tusa rav were able to continue using the drug.

The current phase 3 study “did not meet its primary objectives,” said presenter Benjamin Besse, MD, PhD, director of clinical research at the Gustave Roussy and professor of medical oncology at Université Paris-Saclay, Paris, France.

A subgroup of patients with high CEACAM5 expression did nevertheless show a trend toward survival benefit with the novel drug, and it had a “favorable safety profile compared to docetaxel,” Besse underlined.

Furthermore, an exploratory analysis seeking to understand the high performance of the docetaxel control arm, which was also presented at the conference, revealed that CEACAM5 expression may have a potential prognostic role in this patient population.

Tusa rav targets CEACAM5, a transmembrane glycoprotein highly expressed in up to 25% patients with nonsquamous NSCLC. Previous phase 1 data presented at ASCO 2020 suggested that the drug has promising antitumor activity in heavily pretreated advanced patients with high CEACAM5 expression.

Moreover, compared with standard chemotherapy, tusa rav was found to be well tolerated, with minimal hematological toxicity.

Study Methods

The CARMEN-LC03 phase 3 trial enrolled patients with nonsquamous NSCLC who had undergone prior platinum-based chemotherapy and immune checkpoint inhibitor immunotherapy and had CEACAM5 expression in at least 50% tumor cells.

They were randomized to tusa rav every 2 weeks or docetaxel every 3 weeks, with progression-free survival (PFS) and overall survival selected as dual primary endpoints.

Besse noted that the current analysis presents the final PFS and interim overall survival results, which led to the early termination of the study.

He said that the demographics and patient characteristics were well balanced between the two study arms and pointed out that just over 25% participants were randomized in Asia.

CEACAM5 expression in at least 80% tumor cells was seen in just over half of the participants, and approximately 50% had brain metastases at study entry. One third had previously received sequential chemotherapy and immunotherapy, while two thirds had undergone concomitant chemoimmunotherapy. Around 15% were pretreated with taxanes, and 10% had previously received a tyrosine kinase inhibitor.

At the cutoff date of September 22, 2023, 389 patients were randomized, and 36 in the tusa rav arm and 25 of those assigned to docetaxel were still on therapy. The mean duration of drug exposure was 24.9 and 16.4 weeks, respectively.

Primary Endpoints Not Met

Besse reported that the study did not meet the dual primary endpoints.

The median PFS with tusa rav was 5.4 months vs 5.9 months with docetaxel, at a hazard ratio for progression of 1.14 (P = .8204). The median overall survival was 12.8 months vs 11.5 months, at a hazard ratio for death of 0.85 (P = .112).

Subgroup analysis revealed that having at least 80% CEACAM5 expression was associated with a trend toward a PFS benefit, with a hazard ratio for progression of 0.866 (95% CI, 0.597-1.257) seen with tusa rav vs docetaxel.

A similar result was seen for overall survival, with patients with high-expressing tumors experiencing a trend toward a survival benefit with a hazard ratio of 0.711 (95% CI, 0.492-1.028) for the antibody-drug conjugate vs docetaxel.

Besse also noted that there was a positive trend in favor of tusa rav in terms of the time to deterioration of health-related quality of life for disease-related symptoms, physical functioning, and role functioning.

The safety analysis showed that tusa rav was associated with fewer grade ≥ 3 treatment-related adverse events than docetaxel, seen in 14.9% vs 39.5% patients, and fewer treatment-emergent serious adverse events, in 28.4% vs 38.4%.

Treatment-related adverse events leading to dose reductions or definitive treatment discontinuation were also far less common in the experimental arm, although there were more events leading to dose delays vs docetaxel.

Corneal adverse events were seen in 25.8% tusa rav patients, with 6.7% grade ≥ 3 events, vs 1.7% and no grade ≥ 3 events with docetaxel. Peripheral neuropathy, on the other hand, was equally common in the two study arms, occurring in just under 15% patients.

Control Arm ‘Exceeded Expectations’

Besse said that a “potential limitation of the study was using archived rather than fresh tissue to evaluate CEACAM5 in most participants.”

It also remains “unclear how prior immunotherapy and/or chemotherapy may have affected CEACAM5 expression before administration of tusa rav or docetaxel.”

Saiama Waqar, MD, MSCI, professor of medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, who was not involved in the study, underlined that the control arm in the current study “exceeded expectations.”

The trend toward improved survival outcomes in high–CEACAM5-expressing tumors also suggests, in her opinion, the need to further refine biomarker cutoffs.

Waqar said that tusa rav is “not ready for prime time but pointed out that CEACAM5 is still being examined as a target in the phase 1/2 study NEO-201, the phase 1 studies PROCEADE-CRC-01 and SGN-CEACAM5C, and the phase 1 trial of EBC-129.”

She also agreed with Besse that the protein “may have a prognostic role,” given that median overall survival improved with increasing tertiles of CEACAM5 expression in the exploratory analysis.

The study was funded by Sanofi. Besse declared relationships with AbbVie, BioNTech SE, Bristol Myers Squibb, Chugai pharmaceutical, CureVac AG, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, PharmaMar, Regeneron, Sanofi Aventis, Turning Point Therapeutics, Eli Lilly, Ellipses Pharma Ltd, Genmab, Immunocore, Janssen, MSD, Ose Immunotherapeutics, Owkin, Taiho Oncology, AstraZeneca, BeiGene, GENMAB A/S, GSK, Roche-Genentech, Takeda, Hedera Dx, Roche, and Springer Healthcare Ltd. Waqar declared relationships with AstraZeneca, Gilead Sciences, Janssen, and Daiichi-Sankyo.