The combination of nivolumab and ipilimumab and nivolumab plus chemotherapy resulted in a statistically significant overall survival benefit compared with chemotherapy alone in patients with unresectable advanced or metastatic esophageal squamous cell carcinoma.
The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) and nivolumab plus chemotherapy resulted in a statistically significant overall survival (OS) benefit compared with chemotherapy alone in patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC), according to topline data from the phase 3 CheckMate-648 trial (NCT03143153).1
Nivolumab plus chemotherapy was found to yield a significant benefit for both the primary and secondary end points of OS in patients with PD-L1–positive tumors and in all randomized patients at the time of the prespecified interim analysis. The combination also resulted in a significant benefit in progression-free survival (PFS) in those with PD-L1 positivity per blinded independent central review (BICR), meeting another primary end point.
Moreover, the dual-immunotherapy combination of nivolumab/ipilimumab was also found to meet primary and secondary end points in that the regimen significantly improved OS in the subgroup of patients with PD-L1 expression, as well as the all-randomized population. However, this regimen did not meet its other primary end point of improving PFS per BICR in the subgroup of patients with PD-L1 positivity.
The toxicity profile of nivolumab alone and in combination with ipilimumab proved to be consistent with prior data reported with these approaches.
“The results for these [nivolumab]-based combinations represents a significant advancement for patients with esophageal cancer who are often diagnosed after their disease has spread and would benefit from new therapeutic options,” Ian M. Waxman, MD, development lead of gastrointestinal cancers at Bristol Myers Squibb, stated in a press release. “This study further demonstrates our commitment to pursue combination strategies that improve outcomes for patient with high unmet need, such as those with gastrointestinal [GI] cancers.”
In the phase 3 CheckMate-648 trial, investigators set out to examine nivolumab plus ipilimumab or nivolumab plus fluorouracil and cisplatin vs fluorouracil/cisplatin in patients with unresectable advanced or metastatic esophageal squamous cell carcinoma.
To be eligible for enrollment, patients needed to have histologically confirmed squamous cell carcinoma or adenosquamous cell carcinoma of the esophagus, be at least 18 years of age, and have disease that is deemed inoperable, cannot be treated with definitive chemoradiation with curative intent, or is advanced.2
If they had tumor cells present in the brain or spinal cord that are symptomatic and necessitate treatment, active known or suspected autoimmune disease, a serious or uncontrolled medical disorder or active infection, or a known history of human immunodeficiency virus or hepatitis B or C, they were excluded.
Study participants in the dual-immunotherapy arm received nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks for up to 24 months or until progressive disease or intolerable toxicity.
In the nivolumab/chemotherapy arm, participants were given nivolumab at 240 mg/kg on days 1 and 15, fluorouracil at 800 mg/m2 on days 1 through 5, and cisplatin at 80 mg/m2 on day 1 of a 4-week treatment cycle. Participants in this arm were given nivolumab for up to 24 months or until progressive disease and intolerable toxicity; chemotherapy was administered until disease progression or unacceptable toxicity.
The primary end points of the trial were OS and PFS per BICR in patients with PD-L1 positivity for both of the nivolumab-based combinations compared with chemotherapy. Key secondary end points included OS and PFS per BICR in the all-randomized patient population.
These data build on those yielded from the CheckMate-649 trial (NCT02872116), which demonstrated that nivolumab in combination with leucovorin, 5-fluororacil, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CapeOX) resulted in a significantly improvement in survival in treatment-naïve patients with PD-L1–positive advanced gastric cancer, gastroesophageal junction (GEJ) cancer, and esophageal adenocarcinoma vs chemotherapy alone.3
At a minimum follow-up of 12 months, the nivolumab/chemotherapy combination resulted in a 29% reduction in the risk of death. The median OS with the nivolumab-based regimen was 14.4 months (95% CI, 13.1-16.2) vs 11.1 months (95% CI, 10-12.1) with chemotherapy alone in patients who had a PD-L1 combined positive score of 5 or greater (HR, 0.71; 98.4% CI, 0.59-0.86; P <.0001). Nivolumab/chemotherapy also resulted in a 32% reduction in the risk of disease progression or death vs chemotherapy alone (HR, 0.68; 95% CI, 0.56-0.81; P <.0001).
These data supported the submission of a supplemental biologics license application to the FDA for nivolumab plus a fluoropyrimidine- and platinum-containing chemotherapy in patients with advanced or metastatic gastric cancer, GEJ cancer, or esophageal adenocarcinoma, which was granted priority review in January 2021. The regulatory agency is expected to make a decision on the application by May 25, 2021.
Collectively, the data from CheckMate-648 and CheckMate-649 show that nivolumab is the first and only PD-1/PD-L1 inhibitor to show superior survival in the frontline setting in patients with upper GI cancers across histologies and tumor locations like the stomach, GEJ, and the esophagus, according to Bristol Myers Squibb.
The pharmaceutical company plans to complete an assessment of the data from CheckMate-648 and to share the results at an upcoming medical meeting, as well as with health authorities.