Expanded Safety Analysis from CheckMate 648 Shows Tolerability with Frontline Nivolumab Combinations in ESCC


Data from the CheckMate 648 trial informed the FDA’s recent approval of 2 nivolumab combinations for esophageal squamous cell carcinoma. A 1-year follow-up analysis highlighted key safety and time-to-event data surrounding immune-related toxicities.

Ken Kato MD, PhD

Ken Kato MD, PhD

An expanded safety analysis of CheckMate 648 (NCT03143153) illustrated a manageable safety profile with nivolumab (Opdivo) plus chemotherapy, and nivolumab plus ipilimumab (Yervoy), as frontline treatment for esophageal squamous cell carcinoma (ESCC).The analysis, which was presented during the 2022 ASCO Annual Meeting, also highlighted key differences in median onset and resolution times between the dual immunotherapy and chemotherapy combinations, as well as the number of patients receiving immune modulating medications (IMM) at a 1-year follow-up.

The FDA recently approved nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy or ipilimumab for unresectable advanced or metastatic ESCC based on findings from CheckMate 648. Overall, the study demonstrated that these frontline combinations may be a viable method of extending overall survival in all-randomized patients with ESCC as well as those with a tumor cell PD-L1 score of at least 1%, compared with chemotherapy alone.

In addition, the nivolumab plus ipilimumab and nivolumab plus chemotherapy regimens, yielded superior time to second disease progression (PFS2) and demonstrated greater efficacy in prolonging duration of response compared with chemotherapy, regardless of tumor cell PD-L1 score. Deep responses were reported across all 3 treatment regimens.

Safety Data

The updated data confirmed the adverse event (AE) profiles were consistent with previously reported safety outcomes of the individual components at similar doses. Further, 2% or less of patients treated with nivolumab plus chemotherapy and 6% of less of patients treated with nivolumab pus ipilimumab developed grade 3/4 TRAEs with potential immunologic etiology.

Across the 3 treatment arms, the percentage of patients who experienced a TRAE of any-grade in the nivolumab/chemotherapy (n = 310), nivolumab/ipilimumab (n = 332), and chemotherapy alone arms (n = 304) were 96%, 80%, and 90%, respectively. Among these, the percentage of grade 3/4 TRAEs was 47%, 32%, and 36%.

The percentage of TRAEs leading to treatment discontinuation across the 3 arms was 34%, 18%, and 19%, respectively, and the number of treatment-related deaths was 5 (2%), 8 (2%), and 6 patients (2%), respectively.

Data on TRAEs with potential immunologic etiology showed that any-grade endocrine-related toxicities occurred in 12%, 27%, and fewer than 1% of patients receiving nivolumab/chemotherapy, nivolumab/ipilimumab, and chemotherapy alone, respectively. The rates of any-grade gastrointestinal-related toxicities were 21%, 12%, and 15%; hepatic toxicities were 10%, 13%, and 4%; pulmonary toxicities were 6%, 8%, and fewer than 1%; and renal toxicities were 24%, 2%, and 19%, respectively. Skin-related toxicities were the most common, the rate of these toxicities in the nivolumab/ipilimumab arm (34%) and occurred at rates of 17% and 4% in the nivolumab/chemotherapy and chemotherapy alone arms, respectively.

Time-to-Event Analysis

Among patients who received nivolumab plus chemotherapy and experienced a non-endocrine TRAE with potential immunological etiology, most were resolved (57%-91% across organ categories). The median time to resolution had a range of 1.5 to 17.1 weeks.

Similarly, among patients receiving received nivolumab plus ipilimumab who experienced a non-endocrine TRAE with potential immunological etiology, most were resolved (63%-95%) and the median time to resolutions were between 2.9 to 12.1 weeks.

In an interview with Oncology Nursing News®, CheckMate 648investigator Ken Kato MD, PhD, medical oncologist at the National Cancer Center of Tokyo, said the median onset time differed between the chemotherapy/immunotherapy and dual immunotherapy combinations.

“Time-to-onset was [accelerated] in the IO [immunotherapy] arm,” Kato said. “For example, with endocrine-related toxicities, the median onset time was 13.0 weeks [range, 5.0-100.0] with the nivolumab/chemotherapy combination. On the other hand, in the nivolumab/ipilimumab combination [arm], the median onset time was 8.2 weeks [range, 1.9-72.9].”

This trend was also observed across other immune-related toxicities. Hepatic toxicities, for example, had a median onset time of 5.0 weeks (range, 1.0-5.0) in the ipilimumab combination arm vs 7.9 weeks (range, 0.3-84.1) in the chemotherapy combination arm. For pulmonary toxicity, the median onset time between the 2 arms was 11.9 weeks (range, 1.9-72.3) vs 31.2 weeks (range, 5.0-85.1), respectively; for renal toxicities, median onset time was 7.1 weeks (range, 1.1-47.1) vs 10.1 weeks (range, 0.7-60.7); and skin-related toxicities had a median onset time of 3.9 weeks (range, 0.1-54.3) vs 5.9 weeks (range, 0.1-61.1).

Gastrointestinal toxicities were the exception in this data set. The median onset time with dual immunotherapy was 9.1 weeks (range, 0.6-50.3) nearly doubling that of the nivolumab/chemotherapy combination at 5.1 weeks (range, 0.3-53.1).

Resolution Analysis + Immune Modulating Therapy

Although the median resolution time for TRAEs among patients in both nivolumab combination treatment arms was not reached, most other immune-related TRAEs did resolve by the data cutoff.

Among those treated with nivolumab plus chemotherapy, 91% of gastrointestinal toxicities were resolved (n = 58/64) at a resolution time of 1.5 weeks (range, 0.1-65.9); 90% of hepatic toxicities were resolved (n = 28/31) at a median resolution time of 2.4 weeks (range, 0.4-24.0); 67% of pulmonary were resolved (n = 12/18) at a median time of 12.1 weeks (range, 1.0-39.9); 57% of renal were resoled (n = 42/74) at a median of 17.1 weeks (range, 0.4-128.1); and 76% of skin toxicities were resolved (n = 41/54) at a median resolution time of 7.1 weeks (range, 0.1-157.0).

The percentage of patients receiving IMM, including corticosteroids, with gastrointestinal, hepatic, pulmonary, renal, or skin TRAEs was 11%, 6%, 50%, 70%, 7%, and 43%, respectively. The percentage of patients with endocrine-related toxicity receiving an IMM was 22%.

Among those treated with nivolumab plus ipilimumab, 95% of gastrointestinal toxicities were resolved (n = 36/38) at a resolution time of 2.9 weeks (range, 0.3-79.1); 88% of hepatic toxicities were resolved (n = 37/42) at a median resolution time of 5.1 weeks (range, 1.1-30.9); 65% of pulmonary were resolved (n = 17/26) at a median time of 12.1 weeks (range, 1.0-119.3); 63% of renal were resoled (n = 5/8) at a median of 9.6 weeks (range, 0.7-142.3); and 70% of skin toxicities were resolved (n = 77/110) at a median resolution time of 11.4 weeks (range, 0.3-146.6).

The percentage of patients receiving IMM among these organ groups was 26%, 31%, 35%, 50%, and 51%, respectively. The percentage of patients with endocrine-related toxicity on IMM was 39%.

Overall, no new safety developments were identified, and the immunological responses were deemed manageable by investigators. These data, in combination with the promising survival data, support the combinations’ role in treating ESCC.


Chau I, Doki Y, Ajani JA, et al. Nivolumab + chemotherapy or ipilimumab vs chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma: 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

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