The European Commission has approved nivolumab in combination with fluoropyrimidine- and platinum-based chemotherapy for the frontline treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma with a PD-L1 expression of 1% or higher on tumor cells.
The European Commission has approved nivolumab (Opdivo) in combination with fluoropyrimidine- and platinum-based chemotherapy for the frontline treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) with a PD-L1 expression of 1% or higher on tumor cells.1
The approval follows a positive opinion issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use, which had been based on data from the pivotal phase 3 CheckMate-648 trial (NCT03143153).2 In this subset of patients, the addition of nivolumab to chemotherapy (n = 158) resulted in a significant improvement in overall survival (OS) compared with chemotherapy alone (n = 157), at a median 15.44 months (95% CI, 11.93-19.52) vs 9.07 months (95% CI, 7.69-9.95), respectively (HR, 0.54; 95% CI, 0.37-0.80; P < .0001).3
In this population of patients with a tumor cell PD-L1 expression of 1% or higher, the median progression-free survival (PFS) was also significantly improved with the combination of nivolumab and chemotherapy vs chemotherapy alone, at 6.93 months (95% CI, 5.68-8.34) vs 4.44 months (95% CI, 2.89-5.82), respectively (HR, 0.65; 95% CI, 0.46-0.92; P = .0023).
The combination also improved objective response rate (ORR) over chemotherapy alone, at 53.2% (95% CI, 45.1%-61.1%) and 19.7% (95% CI, 13.8%-26.8%), respectively.
“This approval is an important advancement for patients in the European Union, especially given the highly aggressive nature of advanced ESCC,” Ian M. Waxman, MD, development lead of gastrointestinal cancers at Bristol Myers Squibb, stated in a press release. “[Nivolumab] with chemotherapy is now 1 of 2 newly approved [nivolumab]-based combinations to show superior OS benefit compared to chemotherapy alone, offering higher hopes for patients with unresectable advanced, recurrent or metastatic ESCC with tumor cell PD-L1 expression ≥1%.”
CheckMate-648 enrolled patients with unresectable, advanced, recurrent or metastatic ESCC who had measurable disease and an ECOG performance status of either 0 or 1. To participate, patients could not have received prior systemic therapy for advanced disease.
Study participants (n = 970) were randomized 1:1:1 to receive nivolumab at 240 mg every 2 weeks plus chemotherapy every 4 weeks (n = 321), nivolumab at 3 mg/kg every 2 weeks plus ipilimumab (Yervoy) at 1 mg/kg every 6 weeks (n = 325), or chemotherapy alone every 4 weeks (n = 324). Patients who received chemotherapy were given fluorouracil at 800 mg/m2 on days 1 through 5 and cisplatin at 80 mg/m2 on day 1 of a 4-week cycle. The immunotherapy was given for up to 24 months or until disease progression, unacceptable toxicity, or consent was withdrawn.
Key stratification factors included PD-L1 expression (≥1% vs <1%), region (East Asia vs rest of Asia vs rest of world), ECOG performance status (0 vs 1), and number of organs with metastases (≤1 vs ≥2).
The primary end points of the trial included OS and PFS in the population of patients with a PD-L1 expression of 1% or higher on tumor cells, and secondary end points included OS and PFS in the all-randomized population, as well as ORR in both populations.
Baseline characteristics between the 3 treatment arms were noted to be well balanced, and characteristics were consistent between the 2 populations analyzed. In the nivolumab/chemotherapy arm, the median age was 64 years (range, 40-90), 79% were male, 70% were Asian, 54% had an ECOG performance status of 1, and 97% had ESCC.
Moreover, 51% of patients had a PD-L1 expression of less than 1% and 49% of patients had an expression of 1% or higher. At study entry, 57% of patients had de novo metastatic disease, 22% had recurrent distant disease, 14% had unresectable advanced disease, and 7% had recurrent locoregional disease. Fifty-one percent of patients had 2 or more organs with metastases and the rest had 1 or fewer organs with metastases.
The median duration of treatment in the investigative arm (n = 310) was 5.7 months (range, 0.1-30.6), and 92% of patients discontinued treatment. The most common reason for discontinuation was progressive disease (59%), followed by treatment-related adverse effects (TRAEs; 11%), toxicities not associated with treatment (9%), patient request (5%), and other unspecified reasons (8%).
In the all-randomized population, nivolumab/chemotherapy (n = 321) produced a median OS of 13.2 months (95% CI, 11.1-15.7) vs 10.7 months (95% CI, 9.4-11.9) with chemotherapy alone (n = 324; HR, 0.74; 95% CI, 0.58-0.96; P = .0021). OS favored the immunotherapy regimen across the majority of prespecified subsets examined within this population.
The median PFS per blinded independent central review (BICR) in the investigative and control arms was 5.8 months (95% CI, 5.6-7.0) and 5.6 months (95% CI, 4.3-5.9), respectively, in the all-randomized population (HR, 0.81; 95% CI, 0.64-1.04; P = .03555). The PFS rates at 12 months in the nivolumab/chemotherapy and chemotherapy-alone arms were 24% and 16%, respectively. In the all-randomized population, the BICR-assessed ORRs with nivolumab/chemotherapy and chemotherapy alone were 47% (95% CI, 42%-53%) and 27% (95% CI, 22%-32%), respectively.
Moreover, the median duration of response (DOR) with the addition of nivolumab to chemotherapy in the population of patients with a PD-L1 expression of 1% or higher was 8.4 months (95% CI, 6.9-12.4) compared with 5.7 months (95% CI, 4.4-8.7) with chemotherapy alone (n = 31). In the all-randomized population, the median DOR with nivolumab/chemotherapy (n = 152) was 8.2 months (95% CI, 6.9-9.7) vs 7.1 months (95% CI, 5.7-8.2) with chemotherapy alone (n = 87).
Regarding safety, 96% of 310 patients who received nivolumab in combination with chemotherapy reported any-grade TRAEs and 47% of these effects were grade 3 or 4 in severity. Twenty-four percent of patients experienced serious TRAEs, 18% of which were grade 3 or 4 in severity. The any-grade TRAEs that were most frequently experienced in both arms included nausea, decreased appetite, and stomatitis.
Of those in the investigative arm, 34% of patients discontinued treatment due to any-grade TRAEs; 9% did so because of TRAEs that were grade 3 or 4 in severity. Five treatment-related deaths occurred.
In September 2021, the FDA accepted supplemental biologics license applications seeking the approval of nivolumab plus ipilimumab and nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy in the frontline treatment of adult patients with unresectable advanced, recurrent, or metastatic ESCC based on data from CheckMate-648.4 The agency is expected to decide on these applications by May 28, 2022.