Tusamitamab Ravtansine Plus Pembrolizumab With or Without Chemo Elicits Responses in CEACAM5+ NSCLC

Luis Paz-Ares, MD, PhD

The combination of tusamitamab ravtansine (SAR408701) and pembrolizumab (Keytruda) with or without chemotherapy generated responses and was well tolerated when used as first-line treatment for patients with CEACAM5-positive nonsquamous non–small cell lung cancer (NSCLC), according to data from the phase 2 CARMEN-LC05 trial (NCT04524689).¹

Findings presented at the 2023 European Lung Cancer Congress showed that patients treated across all regimens and dose levels (n = 25) experienced an overall response rate (ORR) of 52% (95% CI, 31.3%-72.2%), with all responders achieving a confirmed partial response. The stable disease and progressive disease rates were 36% and 12%, respectively. The disease control rate (DCR) was 88% (95% CI, 68.8%-97.5%).

The T2 cohort explored tusamitamab ravtansine plus pembrolizumab alone, and in those given tusamitamab ravtansine at 150 mg/m² (n = 3), the ORR and DCR were both 100%. Those in this cohort who were treated with tusamitamab ravtansine at 170 mg/m² (n = 2) had an ORR of 0% and a DCR of 100% with both patients achieving stable disease.

Patients in the T3 cohort received tusamitamab ravtansine plus pembrolizumab and platinum-based chemotherapy, and those dosed at 150 mg/m² for tusamitamab ravtansine (n = 4) experienced an ORR of 50%; the stable disease rate was 50% and the DCR was 100%. One patient treated at the 170-mg/m² dose of tusamitamab ravtansine achieved stable disease.

The addition of pemetrexed to tusamitamab ravtansine plus pembrolizumab and platinum-based chemotherapy was explored in patients in cohort T4. Those treated with 150 mg/m² of tusamitamab ravtansine (n = 12) achieved an ORR of 50%, with a stable disease rate of 25%, a progressive disease rate of 25%, and a DCR of 75%. In patients treated at the 170-mg/m² dose of tusamitamab ravtansine in this cohort (n = 3), the ORR, stable disease rate, and DCR were 66.7%, 33.3%, and 100%, respectively.

“Responses were seen across all the doses, and, importantly, across all the PD-L1 levels,” lead study author Luis Paz-Ares, MD, PhD, said in a presentation of the data. Paz-Ares is chair of the Medical Oncology Department at the Hospital Universitario 12 de Octubre and associate professor at the Universidad Complutense de Madrid in Madrid, Spain.

The combination of immune checkpoint inhibition and chemotherapy is the standard of care for patients with newly diagnosed advanced/metastatic nonsquamous NSCLC who do not harbor EGFR, BRAF, or ALK/ROS aberrations. Notably 25% of patients with nonsquamous NSCLC have high expression of CEACAM5.

Tusamitamab ravtansine is a first-in-class CEACAM5-targeting antibody-drug conjugate, and in a prior phase 1/2 trial (NCT02187848), the agent elicited an ORR of 20.3% (95% CI, 12.27%-31.71%) in a cohort of patients with nonsquamous NSCLC and CEACAM5 expression of at least 50% (n = 64).²

The open-label CARMEN-LC05 trial enrolled adult patients with advanced/metastatic nonsquamous NSCLC who did not harbor an EGFR, BRAF, or ALK/ROS aberrations and had an ECOG performance status of 0 or 1.1 Patients were allowed to have any level of PD-L1 expression.

CEACAM5 positivity was evaluated by immunohistochemistry. Patients with at least 2+ intensity in 1% to 49% of tumor cells were considered to have moderate CEACAM5 expression, and those with at least 2+ intensity in 50% or more of tumor cells were defined as having high expression.

In all 3 cohorts, intravenous (IV) tusamitamab ravtansine was administered at 150 mg/m² or 170 mg/m² once every 3 weeks, and all patients received IV pembrolizumab once every 3 weeks. Patients in cohort T3 also received cisplatin or carboplatin, and those in cohort T4 were administered pemetrexed plus cisplatin or carboplatin.

Dose-limiting toxicities served as the trial’s primary end point. Secondary end points included treatment-emergent adverse effects (TEAEs), serious AEs, and ORR.

Among all patients, the median age was 65.0 years (range, 38-83), and 48% were female. Fifty-six percent of patients had an ECOG performance status of 0, and 44% had a performance status of 1. Notably, all patients in the T2 and T3 cohorts had a high CEACAM5 expression. In the T4 cohort, half of patients given 150 mg/m² of tusamitamab ravtansine and all 3 patients treated with 170 mg/m² of tusamitamab ravtansine had moderate CEACAM5 expression.

Overall, 12% of patients had a PD-L1 expression of less than 1%, 64% had a PD-L1 expression between 1% and 49%, and 24% had a PD-L1 expression of at least 50%.

“Even patients treated with low expression of PD-L1 responded,” Paz-Ares said. “For example, 2 patients [with a PD-L1 expression between 1% and 49%] treated in the T2 cohort [with 150 mg/m² of tusamitamab ravtansine] responded.”

As of the data cutoff of January 10, 2023, the median treatment duration was 24 weeks (range, 3-93), and 7 patients received treatment for at least 12 months. Eleven patients (44%) were still receiving study treatment. One patient did not have a post-baseline tumor assessment following early death due to progressive disease.

Regarding safety, 1 dose-limiting toxicity of increased aspartate aminotransferase was reported in a patient in the T4 cohort who was treated at 170 mg/m² of tusamitamab ravtansine. All patients experienced at least 1 TEAE of any grade, and grade 3 or higher TEAEs occurred in 68.0% of patients. Any-grade serious TEAEs were reported in 44.0% of patients.

Four patients (16%) experienced grade 5 TEAEs; notably, all 4 patients were in the T4 cohort and treated with 150 mg/m² of tusamitamab ravtansine. All grade 5 events were unrelated to tusamitamab ravtansine. “Importantly, all cases [of grade 5 TEAEs] were not drug related,” Paz-Ares said. “Those were 2 disease progressions, 1 pulmonary embolism, and 1 sudden death.”

TEAEs led to permanent discontinuation of all treatments in 20% of patients, although only 1 patient stopped all treatment due to TEAEs outside of the T4 cohort. Corneal TEAEs were observed in 24.0% of all patients and were manageable with dose modification. One grade 3 corneal event occurred in a patient in the T2 group who was treated with 150 mg/m² of tusamitamab ravtansine. No grade 4 corneal events were reported.

The most common any-grade TEAEs included nausea (44%), diarrhea (36%), and asthenia (32%). Any-grade pneumonitis/interstitial lung disease (ILD) was reported in 16% of patients, with 4% who experiencing grade 3 pneumonitis/ILD. Twenty-eight percent of patients had peripheral neuropathy, although all events were grade 1/2.

Editor’s note: Dr Paz-Ares reported serving in a consulting or advisory role for Roche, Merck Sharp & Dohme (MSD), EMD Serono, Bristol Myers Squibb, AstraZeneca, Lilly, Pfizer, PharmaMar, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati Therapeutics, BeiGene, Daiichi Sankyo, Medscape, and PER; receiving speaker fees from Roche, MSD, Bristol Myers Squibb, AstraZeneca, Lilly, PharmaMar, BeiGene, Daiichi Sankyo, Medscape, and PER; and being an invited speaker for Amgen.

He also reported other relationships with GENOMICA, Altum Sequencing, AACR, ASCO, AECC, ASEICA, ESMO, OncoSur, and Small Cell Lung Cancer Group; and his institution was an invited speaker for Daiichi Sankyo, AstraZeneca, Merck, Bristol Myers Squibb, Janssen, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfrizer, and PharmaMar.

References

1. Paz-Ares L, Nagy T, Ravoire M, et al. Safety and efficacy of tusamitamab ravtansine in comination with pembrolizumab ± chemotherapy in patients with CEACAM5-positive nonsquamous NSCLC (CARMEN-LC05 phase 2 study). Presented at: 2023 European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Abstract 13MO.
2. Gazzah A, Ricordel C, Cousin S, et al. Efficacy and safety of the antibody-drug conjugate (ADC) SAR408701 in patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5). J Clin Oncol. 2020;38(suppl 15):9505. doi:10.1200/ JCO.2020.38.15_suppl.9505