Exploring the CARMEN-LCO3 Trial: Tusamitamab Ravtansine vs Docetaxel in Advanced Non-Squamous NSCLC

Pharmacy Times interviewed Benjamin Besse, MD, PhD, director of clinical research, Institut Gustave Roussy and professor of medical oncology, Université Paris-Saclay, on the results of the phase CARMEN-LCO3 trial (NCT04154956), which Besse presented at the 2024 World Conference on Lung Cancer (WCLC) in San Diego, California. The focus of his presentation at WCLC was tusamitamab ravtansine (SAR408701; Sanofi) vs docetaxel in patients with previously treated advanced non-squamous non–small cell lung cancer (NSCLC).

Pharmacy Times: What was the focus of the phase 3 CARMEN-LCO3 trial presented at the 2024 World Conference on Lung Cancer?

Benjamin Besse, MD, PhD: Tusamitamab ravtansine that I will call tusa-rav, is an [antibody drug conjugate (ADC)] against [carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)]. CEACAM5 is a transmembrane protein that is overexpressed in roughly 25% of non-squamous NSCLC, so it's a logical target for an ADC. CARMEN-LCO3 is a study in which we have enriched the population, selecting only the patients with another expression of CEACAM5. The payload of tusa-rav is DM4, its microtubule inhibitor.

Pharmacy Times: What were the key efficacy findings from the phase 3 CARMEN-LCO3 trial?

Besse: The study has randomized tusa-rav vs docetaxel in 389 patients; 450 were planned, but the study was discontinued early because of the negative results on the dual primary end point of [progression-free survival (PFS)] by independent review committee and [overall survival (OS)]. So the population is, as I said, patients with positive tumors for CEACAM5. It was defined by a 2+ or 3+ staining in at least 50% of the cancer cells. Patients with oncogene addicted tumor could be enrolled if previously treated by a [tyrosine kinase inhibitor].

All the patients should have received chemotherapy and immunotherapy, either combined or sequential, [since] it's a second-line study. The median PFS is 5.4 months for the tusa-rav arm vs 5.9 months for the docetaxel arm, leading to another ratio of 1.14, so on this primary end point, the study is negative. In the OS, there is a trend of benefit for the tusa-rav arm. The median OS on docetaxel arm is 11.5 months vs 12.9 months for the tusa-rav arm. The surprise of the study is the very good, and I would say too good, performance of the docetaxel arm. The response rate in the docetaxel arm is 24.7%, which is higher than tusa-rav at 21.7% for tusa-rav. We explored why there is such good results in the docetexal arm and the poster showed at this conference that there is a prognostic value of CEACAM5 expression, and the more CEACAM5 is expressed, the better the prognosis of the patient.

Pharmacy Times: What were the safety findings of the phase 3 CARMEN-LCO3 trial?

Besse: So overall, the safety profile favored tusa-rav over docetaxel. In terms of a grade 3 plus adverse event related to the study drug, it was 14.9% for tusa-rav, and 33% for docetaxel, so there were twice less treatment discontinuation in the tusa-rav [arm] related to the adverse events, but a bit more treatment delay.

Pharmacy Times: What are next steps following this research?

Besse: So, Sanofi decided to stop the tusa-rav program. So, for this specific drug, there is no clear future, but there are other drugs in phase 1 exploring the same target, 2 of them being linked to a payload that is a [topoisomerase I] inhibitor. So, let's say probably for this drug, there is no future, but for the target, there might be a future.

Speakers discuss the trajectory of World Conference on Lung Cancer meetings. Image Credit: © Jon Benjamin Photography

Pharmacy Times: What were some notable presentations at the 2024 World Conference on Lung Cancer?

Besse: I was surprised by the presentation of the CheckMate 816 and CheckMate 770 where there was a comparison of the value of the adjuvant compound of the perioperative strategy with immunotherapy. So, these 2 studies were compared to look if there is a benefit to give adjuvant immunotherapy when in the pre-operative setting, and you already gave 3 to 4 cycles of chemo plus immunotherapy. This presentation does not give a response, although the curves favor adjuvant nivolumab (Opdivo; Bristol Myers Squibb) after neoadjuvant nivolumab, because the population that were presented are really different in the first study, the neoadjuvant chemo nivolumab [study], they take all the patients that got surgery. in [CheckMate 770], which there is an adjuvant component of nivolumab, they have selected only the patients that receive nivolumab, taking out all the patients with probably a poorer prognostic, maybe early progression or surgery complication that led to not to give nivolumab in this population. So, you compare 2 different population, and I don't think that the curves that we see really clarify the role of this adjuvant setting, which is one of the burning question we have in early stages today.