CheckMate 648 trial of Nivolumab Plus Ipilimumab or Chemo in ESCC Continues to Show Survival Benefit

Ken Kato, MD, PhD

The combination of nivolumab (Opdivo) with either chemotherapy or ipilimumab (Yervoy) continued to show a clinically meaningful overall survival (OS) benefit vs chemotherapy alone in patients with treatment-naïve advanced esophageal squamous cell carcinoma (ESCC), according to updated findings from the phase 3 CheckMate 648 trial (NCT03143153) ¹

Ken Kato, MD, PhD, chief of the department of head and neck, and esophageal medical oncology and gastrointestinal medical oncology at the National Cancer Center Hospital in Tokyo, Japan, said in a presentation at the 2023 ASCO Gastrointestinal Cancers Symposium that these data provide further support the use of these combinations as the new standard of care for first-line therapy in this patient population.

At a median follow-up of 28.8 months, the median OS in nivolumab/chemotherapy group (n = 321) was 12.8 months (95% CI, 11.1-15.7) compared with 10.7 months (95% CI, 9.4-12.1) for chemotherapy alone (n = 324) in the intent-to-treat (ITT) population (HR, 0.78; 95% CI, 0.65-0.93). The 24-month OS rate was 29% vs 19% in favor of the experimental arm.

For patients with a PD-L1 expression of 1% or higher, the median OS again favored the nivolumab arm (n = 158) at 15.0 vs 9.1 months in the chemotherapy arm (n = 157; HR, 0.59; 95% CI, 0.46-0.76). The 24-month OS rate was 31% compared with 12%, respectively.

“The PD-L1–positive population shows a 41% reduction in the risk of death and a 5.9-month OS improvement,” Kato said. “OS favored nivolumab plus chemo vs chemo across most subgroups in all randomized patients, consistent with [previously reported] results.”

He added that the OS benefit was consistent across most subgroups in both the ITT and PD-L1–positive populations.

For patients in the ITT population assigned to the immunotherapy doublet (n = 325), the median OS was 12.7 months (95% CI, 11.3-15.5) compared with 10.7 months (95% CI, 9.4-12.1) for those assigned to chemotherapy alone (n = 324; HR, 0.77; 95% CI, 0.65-0.92). For PD-L1–positive patients, the median OS was 13.1 months (95% CI, 11.2-17.4) for those assigned to the doublet (n = 158) vs 9.1 (95% CI, 7.7-10.0) for those assigned to chemotherapy (n = 157; HR, 0.62; 95% CI, 0.48-0.80).

The 24-month OS was 32% vs 19% in favor of the doublet in the ITT population and 34% vs 12% in favor of the doublet in the PD-L1–positive population.

In May 2022, the FDA approved nivolumab plus fluoropyrimidine- and platinum-containing chemotherapy and nivolumab plus ipilimumab as a first-line treatment for adult patients with unresectable advanced or metastatic ESCC irrespective of PD-L1 status based on previous results from CheckMate-648.²

In the all-randomized population, the median OS with nivolumab plus chemotherapy induced a 39% reduction in the risk of death compared with chemotherapy alone (HR, 0.74; 95% CI, 0.61-0.90; P = .0021). In the subset of patients with a PD-L1 expression of 1% or higher, nivolumab/chemotherapy reduced the risk for death by 46% (HR, 0.54; 95% CI, 0.41-0.71; P < .0001).³

In the all-randomized population, treatment with the dual immunotherapy combination reduced risk for death by 22% (HR, 0.78; 95% CI, 0.65-0.95; P = .0110). In the PD-L1–positive population, the dual immunotherapy combination resulted in 36% reduction in the risk for death (HR, 0.64; 95% CI, 0.49-0.84; P = .0010).

Eligible patients with unresectable advanced, recurrent, or metastatic ESCC were enrolled to the global, randomized, open-label phase 3 CheckMate-648 trial. They were required to have an ECOG performance status of 0 or 1 and measurable disease, and they could not have received prior systemic therapy for advanced disease.

Investigators randomly assigned patients to nivolumab at 240 mg every 2 weeks plus fluorouracil and cisplatin every 4 weeks (n = 321), nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks (n = 325), or fluorouracil plus cisplatin every 4 weeks (n = 324). Stratification factors included PD-L1 tumor cell expression (≥1% vs <1%), region (East Asia vs rest of Asia vs rest of the world), performance status (0 vs 1), and number of organs with metastases (≤1 vs ≥2).

The primary end points of the trial included OS and progression-free survival (PFS) in the subset of patients with a PD-L1 expression of 1% or higher. Key secondary end points include OS and PFS in the all-randomized population and objective response rate (ORR) in both populations.

Data presented in August 2022 at the ESMO World Congress on Gastrointestinal Cancer showed an ORR of 47% (95% CI, 42%-53%) with the nivolumab/chemotherapy combination in the ITT vs 27% (95% CI, 22%-32%) in the chemotherapy along arm. 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.^4,5

For patients who received the immunotherapy doublet, the ORR was 28% (95% CI, 23%-33%) vs 27% (95% CI, 22%-32%) with chemotherapy alone. The median DOR was 11.1 months (95% CI, 8.3-14.0) vs 7.1 months (95% CI, 5.7-8.2), respectively.

In the PD-L1–positive arm, the ORR was 53% (95% CI, 45%-61%) with was nivolumab plus chemotherapy compared with 20% (95% CI, 14%-27%) with chemotherapy alone. In the nivolumab/ipilimumab arm the ORR was 35% (95% CI, 28%-43%) vs 20% (95% CI, 14%-27%) with chemotherapy alone.

In these updated findings, the ORR was 47% (95% CI, 42%-53%) for nivolumab/chemotherapy vs 27% (95% CI, 22%-32%) for chemotherapy alone in the ITT population. The median DOR was 8.2 months (95% CI, 6.9-9.7) vs 7.1 months (95% CI, 5.7-8.2) in favor of the experimental arm.

Investigators did not record an ORR benefit the ITT population for nivolumab/ipilimumab vs chemotherapy (27% vs 27%). However, the doublet did improve median DOR, 11.1 months (95% CI, 7.1-14.3) vs 7.1 months (95% CI, 5.7-8.2).

In the PD-L1–positive population, the ORR was 35% (95% CI, 27%-43%) vs 20% (95% CI, 14%-27%) with the combination. The median DOR was 11.8 months (95% CI, 6.8-18.0) vs 5.7 months (95% CI, 4.4-8.7) in favor of the combination.

In her discussion, Jennifer Rachel Eads, MD, an associate professor of clinical medicine at the University of Pennsylvania’s Perelman School of Medicine, noted that ESCC is the sixth leading cause of cancer-related deaths worldwide. Historically, physicians used cytotoxic chemotherapy for this disease, but was never very successful. However, immunotherapeutic agents have demonstrated significant improvements in OS in the second-line setting, and these findings show immunotherapy may also have a role to play in first line.

“The take-home points that I got from this trial were that both combination chemotherapy and immune checkpoint inhibitor therapy and dual agent immunotherapy demonstrate superiority over chemotherapy alone,” she said. “However, these 2 regimens have not been compared against each other, so we don’t know if one is necessarily better than the other. However, they are both considered acceptable standard-of-care frontline treatment options, and in my personal practice, I'm most likely to probably choose a regimen based on response needs, toxicity profile, patient comorbidities, and patient preference.”

References

1. Kato K, Ajani JA, Doki Y, et al. Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): 29-month (mo) follow-up from CheckMate 648. J Clin Oncol. 2023;41(suppl 4; abstr 290). doi:10.1200/JCO.2023.41.3_suppl.290

2. FDA approves Opdivo in combination with chemotherapy and Opdivo in combination with Yervoy for first-line esophageal squamous cell carcinoma indications. News release. FDA. May 27, 2022. Accessed January 19, 2023. https://bit.ly/3WnT5kq

3. Chau I, Doki Y, Ajani JA, et al. Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): first results of the CheckMate 648 study. J Clin Oncol. 2021;39(suppl 15):LBA4001. doi:10.1200/JCO.2021.39.15_suppl.LBA4001

4. 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

5. 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