Frontline BMS-986012 Plus Nivolumab/Chemotherapy Shows Promise in ES-SCLC

The addition of BMS-986012 to nivolumab (Opdivo) plus chemotherapy provided a modest progression-free survival (PFS) benefit but signals of overall survival (OS) improvement over nivolumab plus chemotherapy alone when used in the frontline treatment of patients with extensive-stage small cell lung cancer (ES-SCLC), according to data from the interim analysis of the phase 2 CA001-050 study (NCT04701880) presented during the 2024 ESMO Congress.¹

At a data cutoff date 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) by blinded independent central review (BICR) vs 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). At a later cutoff of February 26, 2024, and with a median follow-up of 17.2 months, the median PFS with the respective regimens was 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% (95% CI, 12%-33%) and 19% (95% CI, 9%-31%), respectively.

At the later cutoff date with the 17.2-month medium follow-up, the median OS with BMS-986012 and nivolumab/chemotherapy was 15.6 months (95% CI, 12.5-not applicable) vs 11.4 months (95% CI, 9.3-16.6) with nivolumab/chemotherapy alone (HR, 0.71; 95% CI, 0.44-1.16).

“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,” Ewa Kalinka, MD, PhD, of the Instytut Centrum Zdrowia Matki Polki-Klinika Onkologil, in Lödź, Poland, said in an oral presentation of the data. “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.”

Although Fuc-GM1 is highly expressed in the majority of SCLC cases, the expression of this marker is limited in normal tissues. BMS-986012 is a first-in-class, fully human IgG1 monoclonal antibody that was designed to bind Fuc-GM1 with high affinity and specificity; the agent elicits antibody-dependent cell-mediated cytotoxic­ity (ADCC)–, complement-dependent cytotoxicity–, and antibody-dependent cellular phagocytosis–mediated cancer cell death. Moreover, because this is a non-fucosylated agent, it is hypothesized to boost antibody binding to FcγRs on natural killer cells and boosts ADCC, Kalinka explained.

Previous data from a phase 1/2 trial (NCT04702880) indicated BMS-986012 plus nivolumab (n = 29) led to an objective response rate (ORR) of 38% (95% CI, 20.7%-57.7%) in patients with relapsed/refractory SCLC and responses proved to be durable, with a median duration of response (DOR) of 26.4 months (95% CI, 4.4-not reached). Moreover, the 24-week PFS rate with the doublet in this population was 39.3% (95% CI, 21.7%-56.5%).²

At the congress, Kalinka shared interim results from the randomized, open-label, phase 2 CA001-050 study, which enrolled patients with histologically or cytologically confirmed ES-SCLC who had not previously received therapy and had at least 1 measurable lesion.1 Patients were at least 18 years of age and had an ECOG performance status of 0 or 1.

Study participants were randomly assigned 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 or until disease progression, intolerable toxicity, or death. Chemotherapy consisted of IV carboplatin on day 1 at area under the curve 5 mg/mL/min and IV etoposide at 100 mg/m² on days 1, 2, and 3.

The primary end points of the study were PFS by BICR and RECIST 1.1 criteria as well as safety. Secondary end points included OS; ORR, DOR, and time to response (TTR) by BICR and RECIST 1.1 criteria; investigator-assessed PFS by RECIST 1.1 criteria; and immunogenicity. Investigators also examined OS according to baseline brain metastases.

“The prespecified analysis took place when about 75% of PFS information was available, which happened about a year ago,” Kalinka said. “But an additional analysis took place after a longer follow-up of 17 months to allow for a more meaningful assessment of OS early this year.”

Baseline characteristics of the two groups were balanced, according to Kalinka. However, she added that there were more patients with an ECOG performance status of 1 (76% vs 74%) and central nervous system (CNS) metastases (31% vs 26%) in the BMS-986012 arm vs the nivolumab/chemotherapy alone arm. The median patient age was 67 years in both arms (range, 41-80); 9% vs 18% of patients in the experimental and control arms, respectively, were aged 75 years or older. Most patients were White (90% vs 91%) and from Europe (70% vs 76%). Moreover, 42.5% of patients across the arms had liver metastases.

“What was very interesting was our findings in two subgroups of patients with brain metastases with or without baseline brain metastases,” Kalinka said. In those with brain metastases at baseline, the median OS with the BMS-986012 regimen (n = 19) or nivolumab/chemotherapy alone (n = 15) was 16.3 months (95% CI, 10.5-NA) and 8.7 months (95% CI, 6.6-23.1), respectively (HR, 0.59; 95% CI, 0.24-1.49). The 12-month OS rates in the respective arms were 74% and 34%.

In those without these metastases at baseline who received the BMS-986012 combination (n = 48) or nivolumab/chemotherapy (n = 51), 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). The respective 12-month OS rates were 64% and 51%. “Patients without brain metastases also had a slightly longer median OS of 15.5 months, but what was very interesting is that they reached a plateau at about 50% surviving,” Kalinka explained.

The BMS-986012 regimen elicited an ORR of 73% (95% CI, 61%-83%) in evaluable patients vs 68% (95% CI, 56%-79%) with nivolumab/chemotherapy. Among the responders in the experimental arm, 7% achieved a complete response, 66% experienced a partial response, and 13% had stable disease; this information was not determined for 13% of patients. 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. The median TTR in the experimental (n = 58) and control (n = 60) arms was 1.5 months (range, 1.3-3.0) and 1.6 months (range, 1.2-5.2).

Regarding safety, any-grade adverse effects (AEs) occurred in all evaluable patients who received the BMS-986012 regimen (n = 66) vs 98% of evaluable patients in the control arm (n = 64); these effects were grade 3 or 4 for 53% and 56% of patients, respectively. Any-grade serious AEs were reported in 53% and 49% of patients, respectively; they were grade 3 or 4 in 32% and 30% of patients, respectively. Treatment-related AEs (TRAEs) occurred in 92% of those in the experimental arm vs 94% of those in the control arm; they were grade 3 or 4 for 50% and 45% of patients, respectively. In the experimental arm, any-grade AEs and TRAEs led to discontinuation for 17% and 8% of patients, respectively. Two treatment-related deaths occurred in the BMS-986012 arm (febrile neutropenia, n = 1; multiorgan failure, n = 1).

Those who received the BMS-986012 regimen experienced more pruritus events than those who did not, at incidence rates of 61% and 16%, respectively. However, these events were predominantly low grade, according to Kalinka, who added that most cases resolved with 1 to 2 treatment cycles. The median duration of these events in the respective arms was 54 days and 36 days. Select skin (65% vs 23%) and hepatic (21% vs 8%) AEs also occurred more frequently in the experimental arm vs the control arm.

The most frequent grade 3/4 TRAEs experienced in the experimental arm were neutropenia (27%), pruritus (6%), thrombocytopenia (3%), anemia (2%), nausea (2%), rash (2%), and increased alanine aminotransferase (2%).

“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.

Disclosures: Dr Kalinka has served as an invited speaker for Amgen and received personal, clinical trials, and lectures honoraria. She is on the advisory board; received personal, advisory role, clinical trials and lectures honoraria; is a local principal investigator; and has personal and institutional financial interest with AstraZeneca and Bristol Myers Squibb. She is an invited speaker; received personal, advisory role, clinical trials and lectures honoraria; is a local PI; and has personal and institutional financial interest with Gilead. For GlaxoSmithKline, she is an invited speaker, on the advisory board, and has received personal and lectures honoraria. For Merck Sharp and Dohme, she is an invited speaker; received personal, lectures and clinical trials honoraria; serves in an advisory role; is a local PI; and has personal and financial interest. For Regeneron, she is an invited speaker; has received personal, lectures honoraria; and has a writing engagement. For Roche, she is an invited speaker; received personal, lectures, and clinical trials honoraria; is a local PI; and has personal and institutional financial interest. For Sanofi, she is an invited speaker; has received personal and lectures honoraria; and has a writing engagement. Finally, for Instytut MSF Sp. Z. O. O, she has ownership interest and personal interest.

References

1. Kalinka E, Bahce I, Navarro A, et al. BMS-986012 (anti-fucosyl-monosialoganglioside-1 [fuc-GM1]) with carboplatin + etoposide + nivolumab (CE/NIVO) as first-line (1L) therapy in extensive-stage small cell lung cancer (ES-SCLC): Interim analysis (IA) of a randomized phase II study. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation 1786O.
2. Chu Q, Leighl NB, Surmont V, et al. BMS-986012, an anti-fucosyl-GM1 monoclonal antibody as monotherapy or in combination with nivolumab in relapsed/refractory SCLC: Results from a first-in-human phase 1/2 study. JTO Clin Res Rep. 2022;3(11):100400. doi:10.1016/j.jtocrr.2022.100400