Expanded Efficacy Data Underscore Nivolumab Combinations Role as Standard of Care for ESCC

Recent data highlight the value of the newly approved indications for nivolumab (Opdivo) plus ipilimumab (Yervoy) and nivolumab plus chemotherapy for patients with advanced esophageal squamous cell carcinoma (ESCC). In a presentation at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer 2022 (World GI), investigators presented additional objective response rate (ORR) data for the combinations in the overall and PD-L1–stratified cohorts from the phase 3 CheckMate 648 trial (NCT03143153).¹

In the intention-to-treat population, those who received nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy (n = 321) the ORR was 47% (95% CI, 42%-53%) vs 27% (95% CI, 22%-32%) in the chemotherapy along arm (n = 324). The median duration of response (DOR) was 8.2 months (95% CI, 6.9-9.7) vs 7.1 months (95% CI, 5.7-8.2), respectively. Among responders, 39% (95% CI, 30%-47%) and 23% (95% CI, 13%-34%) had a response lasting at least 12 months, respectively.^1,2

For patients who received the immunotherapy combination (n = 325), the ORR was 28% (95% CI, 23%-33%) vs 27% (95% CI, 22%-32%) with chemotherapy alone (n = 324). The median DOR was 11.1 months (95% CI, 8.3-14.0) vs 7.1 months (95% CI, 5.7-8.2), respectively, with 48% (95% CI, 36%-58%) and 23% (95% CI, 13%-34%) of responders having a response of lasting at least 12 months.^1,2

In a presentation of the additional data at World GI, investigators noted that regarding ORR both nivolumab-based combinations were effective regardless of PD-L1 expression except for the cohort of patients with a PD-L1 tumor proportion score (TPS) of less than 1%. Additionally, they added that nivolumab plus chemotherapy outperformed nivolumab plus nivolumab plus ipilimumab in terms of ORR, but not in terms of DOR where a more durable benefit was reported with nivolumab/ipilimumab. These comparisons were not powered in the original protocol of the trial and is for observation purposes only.

Among those who had PD-L1 TPS of at least 1% and received nivolumab plus chemotherapy (n = 158) the ORR was 53% (95% CI, 45%-61%) compared with 20% (95% CI, 14%-27%) with chemotherapy alone (n = 157). The median DOR was 8.4 months (95% CI, 6.9-12.4) vs 5.7 months (95% CI, 4.4-8.7), respectively. A pronounced benefit in durability was reported in this cohort with responses of at least 1 year reported among 40% (95% CI, 28%-51%) of responders in the nivolumab/chemotherapy arm vs 13% (95% CI, 2%-33%) of patients in the chemotherapy alone arm.

In the nivolumab/ipilimumab arm (n = 158) the ORR was 35% (95% CI, 28%-43%) vs 20% (95% CI, 14%-27%) with chemotherapy alone (n = 157). The median DOR was 11.8 months (95% CI, 7.1-27.4) vs 5.7 (95% CI, 4.4-8.7) with responses of at least 12 months reported in 49% (95% CI, 35%-62%) vs 13% (95% CI, 2%-33%) of responders, respectively.

Finally, among patients with PD-L1 TPS less than 1%, the ORR for those who received nivolumab plus chemotherapy (n = 163) was 42% (95% CI, 34%-50%) vs 34% (95% CI, 27%-42%) with chemotherapy alone (n = 166). The median DOR was 6.9 months (95% CI, 5.8-14.6) in the nivolumab/chemotherapy arm with 38% (95% CI, 25%-50%) of responders having a response of at least 12 months. The median DOR was 7.2 months (95% CI, 5.7-9.7) in the chemotherapy alone arm with 27% (95% CI, 14%-41%) of responders having a response lasting at least 1 year.

For this patient population, the ORR for patients who received chemotherapy was superior to the nivolumab/ipilimumab combination (n = 164). The ORR with the immunotherapy combination was 20% (95% CI, 14%-27%). However, the DOR and percentage of responders were both superior in the combination arm vs chemotherapy alone. The median DOR was 11.1 months (95% CI, 5.7-14.3) with 47% (95% CI, 28%-64%) of responders having a response of at least 12 months.

The nivolumab-based combinations were approved on May 27, 2022, for the treatment of patients with unresectable advanced or metastatic ESCC, irrespective of PD-L1 status based on previously reported overall survival (OS) data from the trial.³

Expanded data for OS were presented during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting for the intention-to-treat population of patients who received nivolumab plus ipilimumab.²

The median OS with nivolumab plus chemotherapy was 13.2 months (95% CI, 11.1-15.7) vs 10.7 months (95% CI, 9.4-11.9) with chemotherapy alone (HR, 0.74; 95% CI, 0.61-0.90; P = .0021).^2,3 Among patients who received the immunotherapy combination, the median OS was 12.7 months (95% CI, 11.3-15.5) with the regimen (HR, 0.78; 95% CI, 0.65-0.95; P = .0110).

According to investigators, the largest magnitude of benefit was observed among patients with a PD-L1 TPS 1% or higher. The median OS with nivolumab/chemotherapy was 15.4 months (95% CI, 11.9-19.5) vs 9.2 months (95% CI, 7.7-10) with chemotherapy alone (HR, 0.55; 95% CI, 0.41-0.71; P < .0001). The median OS with nivolumab and ipilimumab was 13.7 months (95% CI, 11.2-17.0) translating to a 37% reduction in the risk of progression or death vs chemotherapy alone (HR, 0.63; 95% CI, 0.49-0.84; P = .0010).

During the World GI presentation, investigators noted that the nivolumab plus ipilimumab demonstrated a delayed benefit relative to nivolumab chemotherapy or chemotherapy alone.¹ The Kaplan Meier curves for all randomized patients showed that the nivolumab/chemotherapy separates from the chemotherapy group at the early in treatment, but that nivolumab/ipilimumab overlaps chemotherapy until approximately 7 months where the curve begins to separate. The chemotherapy and ipilimumab combination arms have almost overlapping long-tail effects.

Investigators said that further investigations are required to characterize the early mortality cases of nivolumab/ipilimumab to better stratify patients with ESCC to the appropriate nivolumab-based combination.

Investigators also noted that previously reported safety data show earlier signs of immune-related adverse effects with nivolumab/ipilimumab vs nivolumab/chemotherapy except for gastrointestinal (GI) toxicities. The median time to onset of endocrine, hepatic, pulmonary, renal, and skin toxicities was 13.0, 7.9, 31.2, 10.1, and 5.9 weeks, respectively, for nivolumab/chemotherapy. These times were 8.2, 5.0, 11.9, 7.1, and 3.9 weeks with nivolumab/ipilimumab. For GI-related toxicities, the median time to onset was 5.1 weeks with nivolumab/chemotherapy vs 9.1 weeks with nivolumab/ipilimumab.²

References

1. Chau I, Ajani JA, Doki Y, et al. Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): expanded efficacy and safety analyses from CheckMate 648. Ann Oncol. 2022;22(suppl 4):S379-S380. doi:10.1016/j.annonc.2022.04.444
2. Chau I, Ajani JA, Doki Y, et al. Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): expanded efficacy and safety analyses from CheckMate 648. J Clin Oncol. 2022;40(suppl 16):4035. doi:10.1200/JCO.2022.40.16_suppl.4035
3. FDA approves Opdivo in combination with chemotherapy and Opdivo in combination with Yervoy for first-line esophageal squamous cell carcinoma indications. FDA. Updated May 31, 2022. Accessed August 12, 2022. bit.ly/3MEZtit