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Nivolumab Plus Fluoropyrimidine and Platinum-Based Chemotherapy and Nivolumab Plus Ipilimumab Approved for Esophageal Squamous Cell Carcinoma

Squamous cell carcinoma tumor.

The FDA has approved nivolumab (Opdivo®, Bristol Myers Squibb) in combination with fluoropyrimidine with platinum-based chemotherapy, and nivolumab in combination with ipilimumab (Yervoy®, Bristol Myers Squibb) for treatment of patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC).

"Esophageal cancer causes more than half a million cancer-related deaths worldwide each year, with squamous cell carcinoma accounting for approximately 85% of cases," wrote Yuichiro Doki, MD, Professor at Osaka University Graduate School of Medicine in Japan, and colleagues, in their published results of the CheckMate-648 trial (NCT03143153), on which the approval was based. "Treatment with the anti–PD-1 monoclonal antibody nivolumab has been reported to result in significantly longer overall survival than chemotherapy in previously treated patients with advanced ESCC and is approved for this indication, irrespective of programmed death ligand 1 (PD-L1) expression status."

This phase 3, open-label, three-arm trial enrolled 970 patients with previously untreated advanced, recurrent, or metastatic ESCC in a 1:1:1 ratio to receive nivolumab 240 mg via intravenous infusion (IV) every six weeks in combination with chemotherapy, consisting of fluorouracil 800 mg/m2 IV on Days 1 through 5 and cisplatin 80 mg/m2 IV on day 1 of a four-week cycle; nivolumab 3 mg/kgIV every two weeks in combination with ipilimumab 1 mg/kg IV every six weeks; or chemotherapy. The primary end points were overall survival and progression-free survival, measured via blinded independent central review, with a key secondary end point of overall response rate. All end points were to be assessed first in patients with tumor cell PD-L1 expression of 1% or more, and then in patients in the overall randomized population.

At a minimum follow-up of 13 months, overall survival was significantly extended in patients with tumor cell PD-L1 expression ≥1% being treated with nivolumab plus chemotherapy in comparison with chemotherapy alone (15.4 months versus 9.1 months). This significance was also reflected in the overall population with 13.2 months compared with 10.7 months. Progression-free survival was also found to be significantly longer in patients with tumor cell PD-L1 expression ≥1% being treated with nivolumab plus chemotherapy in comparison with chemotherapy alone (6.9 months versus 4.4 months). In the overall population, progression-free survival did not reach significance, with 5.8 months compared with 5.6 months, respectively. Overall response rate was significantly different as well in patients with tumor cell PD-L1 ≥1% (53% versus 20%, respectively), as well as the overall population (47% versus 27%, respectively).

In the comparison of nivolumab plus ipilimumab versus chemotherapy alone, overall survival, again, was significantly longer for the nivolumab plus ipilimumab group compared with the chemotherapy group in patients with tumor cell PD-L1 ≥1% (13.7 months versus 9.1 months), as well as in the general population (12.7 months versus 10.7 months). Progression-free survival did not reach significance in the tumor PD-L1 ≥1% population, so it was not measured in the overall population. The overall response rate was significantly higher for the nivolumab plus ipilimumab group as well for those with tumor cell PD-L1 ≥1% (35% versus 20%), but not for the overall population (28% versus 27%).

The most common adverse events occurring in ≥20% of patients treated with nivolumab and fluoropyrimidine with platinum-containing chemotherapy were nausea, decreased appetite, fatigue, constipation, stomatitis, diarrhea, and vomiting. The most common adverse events occurring in ≥20% of patients treated with nivolumab and ipilimumab were rash, fatigue, pyrexia, nausea, diarrhea, and constipation.

"First-line treatment of advanced ESCC with either nivolumab plus chemotherapy or nivolumab plus ipilimumab resulted in a significant overall survival benefit and durable responses as compared with chemotherapy alone," concluded Dr. Doki and colleagues in their report. "The safety profiles of each treatment were consistent with the known safety profiles of the individual components in each regimen."

The recommended dose for patients being treated with nivolumab is 240 mg every 2 weeks or 480 mg every 4 weeks plus fluoropyrimidine and platinum-containing chemotherapy. The recommended dose of nivolumab with ipilimumab is nivolumab 3 mg/kg every 2 weeks or 360 mg every 3 weeks and ipilimumab 1 mg/kg every 6 weeks.

For More Information

Doki Y, Ajani JA, Kato K, et al (2022). Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med, 386(5):449-462. DOI:10.1056/NEJMoa2111380

Clinicaltrials.gov (2022). A study to evaluate efficacy in subjects with esophageal cancer treated with nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin (CheckMate 648). NLM identifier: NCT03143153.

Opdivo® (nivolumab) prescribing information (2022). Bristol Myers Squibb. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125554s106lbl.pdf

Yervoy® (ipilimumab) prescribing information (2022). Bristol Myers Squibb. Available at: https://packageinserts.bms.com/pi/pi_yervoy.pdf

US Food and Drug Administration (2022). FDA approves Opdivo in combination with chemotherapy and Opdivo in combination with Yervoy for first-line esophageal squamous cell carcinoma indications. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-opdivo-combination-chemotherapy-and-opdivo-combination-yervoy-first-line-esophageal

Image Credit: Nephron. Licensed under CC BY-SA 3

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