Interim results from a phase 2 trial indicate that the addition of BMS-986012 to nivolumab and chemotherapy yields a slight progression-free survival (PFS) benefit and promising overall survival (OS) signals in patients with extensive-stage small cell lung cancer (ES-SCLC). The CA001-050 study (NCT04701880), presented at the 2024 European Society for Medical Oncology Congress, suggests a potential new first-line treatment option for this aggressive cancer.
Improved Survival Signals with BMS-986012
At a data cutoff of August 28, 2023, and a median follow-up of 11.2 months, the median PFS with the BMS-986012 regimen (n = 66) was 5.8 months (95% CI, 5.0-7.9) compared to 5.2 months (95% CI, 4.8-6.6) with nivolumab/chemotherapy alone (n = 66; HR, 0.89; 95% CI, 0.57-1.40; P = .61). A later cutoff on February 26, 2024, with a median follow-up of 17.2 months, showed median PFS of 5.8 months (95% CI, 5.0-7.9) and 5.1 months (95% CI, 4.8-6.6), respectively (HR, 0.81; 95% CI, 0.53-1.23; P = .32). The 12-month PFS rates were 22% and 19%, respectively.
The median OS with BMS-986012 and nivolumab/chemotherapy was 15.6 months (95% CI, 12.5-not applicable) versus 11.4 months (95% CI, 9.3-16.6) with nivolumab/chemotherapy alone (HR, 0.71; 95% CI, 0.44-1.16) at the 17.2-month follow-up.
Insights from the Investigator
Ewa Kalinka, MD, PhD, of the Instytut Centrum Zdrowia Matki Polki-Klinika Onkologil, stated, "The combination of BMS-986012, the anti-Fuc-GM1, plus nivolumab and chemotherapy shows promising OS signals vs nivolumab and chemotherapy in the first-line treatment of patients with ES-SCLC. Also, the benefit in PFS was modest. We see numerical improvements in patients with and without brain metastases at baseline. The new compound with nivolumab and chemotherapy had a manageable safety profile similar to that of nivolumab plus chemotherapy, with the exception of pruritus although that was not a big clinical problem."
Mechanism of Action
BMS-986012, a first-in-class, fully human IgG1 monoclonal antibody, is designed to bind Fuc-GM1 with high affinity and specificity. Fuc-GM1 is highly expressed in the majority of SCLC cases but limited in normal tissues. The agent elicits antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis-mediated cancer cell death. Its non-fucosylated nature is hypothesized to boost antibody binding to FcγRs on natural killer cells, enhancing ADCC.
Study Design and Patient Population
The randomized, open-label, phase 2 CA001-050 study enrolled patients with histologically or cytologically confirmed ES-SCLC who had not previously received therapy and had at least 1 measurable lesion. Patients were randomized 1:1 to receive induction treatment with 360 mg of intravenous (IV) nivolumab every 3 weeks plus chemotherapy with or without 420 mg of BMS-986012 for four 21-day cycles, followed by maintenance treatment with 480 mg of nivolumab with or without 560 mg of BMS-986012 for up to 2 years. Chemotherapy consisted of IV carboplatin and IV etoposide.
The primary end points were PFS by BICR and RECIST 1.1 criteria, as well as safety. Secondary end points included OS; ORR, DOR, and TTR by BICR and RECIST 1.1 criteria; investigator-assessed PFS; and immunogenicity.
Impact on Brain Metastases
In patients with brain metastases at baseline, the median OS with the BMS-986012 regimen (n = 19) was 16.3 months (95% CI, 10.5-NA) compared to 8.7 months (95% CI, 6.6-23.1) with nivolumab/chemotherapy alone (n = 15; HR, 0.59; 95% CI, 0.24-1.49). The 12-month OS rates were 74% and 34%, respectively.
In those without brain metastases at baseline, the median OS was 15.5 months (95% CI, 11.3-NA) and 13.8 months (95% CI, 9.7-16.6), respectively (HR, 0.72; 95% CI, 0.41-1.28).
Response Rates and Safety Profile
The BMS-986012 regimen elicited an ORR of 73% (95% CI, 61%-83%) vs 68% (95% CI, 56%-79%) with nivolumab/chemotherapy. The median DOR in the experimental arm was 6.4 months (95% CI, 4.2-7.2) vs 4.5 months (95% CI, 3.5-5.5) in the control arm.
Any-grade adverse effects (AEs) occurred in all evaluable patients who received the BMS-986012 regimen vs 98% in the control arm. Those who received the BMS-986012 regimen experienced more pruritus events (61% vs 16%).
Next Steps
"Planning for the phase 3 study of BMS-986012 plus nivolumab and chemotherapy vs standard of care as first-line treatment in patients with ES-SCLC is underway to confirm these findings," Kalinka concluded.
