Two nivolumab regimens outperform chemotherapy alone in advanced esophageal cancer
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The addition of nivolumab to chemotherapy or ipilimumab significantly improved OS compared with chemotherapy alone among patients with previously untreated advanced esophageal squamous cell carcinoma, according to phase 3 study findings.
Results of the CheckMate 648 study, scheduled for presentation during the virtual ASCO Annual Meeting, showed the greatest OS benefit among patients with PD-L1 expression of 1% or greater.
“Esophageal cancer carries a heavy global cancer burden, accounting for more than half a million deaths per year,” Ian Chau, MD, FRCP, consultant medical oncologist at Royal Marsden Hospital in Sutton, United Kingdom, said during a press conference. “First-line treatment for advanced esophageal squamous cell carcinoma carries a poor prognosis, with a median survival of around 10 months. CheckMate 648 is the largest randomized study conducted in this setting thus far.”
Nivolumab (Opdivo, Bristol Myers Squibb) is a PD-1 immune checkpoint inhibitor and ipilimumab (Yervoy, Bristol Myers Squibb) is a CTLA-4 inhibitor.
The randomized, open-label trial compared 240 mg nivolumab every 2 weeks plus chemotherapy (n = 321), 3 mg/kg nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks (n = 325) and chemotherapy alone (n = 324) as first-line therapy for 970 patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma. Chemotherapy consisted of fluorouracil and cisplatin every 4 weeks.
Treatment in the nivolumab groups continued for up to 2 years or until disease progression or unacceptable toxicity.
OS and PFS by blinded independent central review among those with tumor cell PD-L1 expression of 1% or greater (n = 473) served as co-primary endpoints. OS and PFS among all patients served as secondary endpoints.
Results showed significantly longer median OS with nivolumab plus chemotherapy vs. chemotherapy alone (15.4 months vs. 9.1 months; HR = 0.54; 99.5% CI, 0.37-0.8) and with nivolumab plus ipilimumab vs. chemotherapy alone (13.7 months vs. 9.1 months; HR = 0.64; 98.6% CI, 0.46-0.9) among patients with PD-L1 expression of 1% or greater.
In addition, researchers reported significantly longer PFS among patients with PD-L1 expression of 1% or greater who received nivolumab plus chemotherapy vs. chemotherapy alone (HR = 0.65; 98.5% CI, 0.46-0.92). Nivolumab plus ipilimumab did not meet the prespecified boundary for significance with regard to PFS vs. chemotherapy among these patients.
Among all patients, median OS was 13.2 months (95% CI, 11.1-15.7) with nivolumab plus chemotherapy, 12.8 months (95% CI, 11.3-15.5) with nivolumab plus ipilimumab and 10.7 months (95% CI, 9.4-11.9) with chemotherapy alone.
Researchers also observed higher objective response rates with nivolumab plus chemotherapy (53%; 95% CI, 45-61) and nivolumab plus ipilimumab (35%; 95% CI, 28-43) compared with chemotherapy alone (20%; 95% CI, 14-27) among those with PD-L1 expression of at least 1%. For all patients, objective response rates were 47% (95% CI, 42-53) with nivolumab plus chemotherapy, 28% (95% CI, 23-33) with nivolumab plus ipilimumab and 27% (95% CI, 22-32) with chemotherapy alone.
Median duration of response was longer with nivolumab plus chemotherapy (8.4 months) and nivolumab plus ipilimumab (11.8 months) vs. chemotherapy alone (5.7 months) among those with PD-L1 expression of 1% or more, as well as among all patients (8.2 months vs. 11.1 months vs. 7.1 months).
Researchers observed no new safety signals. Five treatment-related deaths occurred in each of the nivolumab groups compared with four in the group that received only chemotherapy.
“Of all front-line setting studies including cancer of the digestive system, this is the first study that showed an improvement with immunotherapy vs. chemotherapy,” Chau said. “Nivolumab plus chemotherapy and nivolumab plus ipilimumab represent a new potential first-line standard-of-care treatment for this patient population based upon the results of CheckMate 648.”
Perspective
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Julie Gralow, MD, FASCO
There have been very few treatment advancements to date for esophageal or upper gastrointestinal cancers. The CheckMate 648 study found two regimens that improved OS beyond the current standard of care. The addition of nivolumab to chemotherapy, as well as the combination of two immune checkpoint inhibitors without chemotherapy, significantly extended survival and should be considered superior first-line treatments of esophageal squamous cell carcinoma. The dual immunotherapy combination is the first chemotherapy-free first-line treatment showing benefit for these patients.
Perspective
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Victoria Villaflor, MD
We treat patients with metastatic cancer with an overall goal of improving survival and quality of life.
Recently, nivolumab received FDA approval for second-line treatment of esophageal squamous cell carcinoma based on results of the phase 3 ATTRACTION-3 trial. The study, which included 419 patients with esophageal squamous cell carcinoma unselected for PD-L1 combined positive score (CPS), showed a 2.5-month improvement in OS with nivolumab over taxane-based therapy as second-line therapy (median, 10.9 months vs. 8.4 months).
The FDA also approved pembrolizumab (Keytruda, Merck) for this indication, based on results of the phase 3 KEYNOTE-181 trial, which enrolled 628 patients with both squamous cell carcinoma and adenocarcinoma of the esophagus. Of these patients, 222 had a PD-L1 CPS of 10 or greater and 64% had squamous cell carcinoma. Results showed a 3.6-month improvement in median OS with pembrolizumab over investigator’s choice of second-line cytotoxic chemotherapy.
Squamous cell carcinoma of the lung and head and neck have properties similar to esophageal squamous cell carcinoma and are further along in development for immune therapy recommendations in the front-line metastatic setting. For patients with non-small cell lung cancer, squamous cell carcinoma treatment recommendations include platinum, taxane and pembrolizumab based on KEYNOTE-407, which demonstrated a 4.6-month improvement in OS (median, 15.9 months vs. 11.3 months), regardless of PD-L1 status, with the addition of pembrolizumab. For those patients with a PD-L1 tumor proportion score of 50% or greater, regardless of histology, pembrolizumab as a single agent demonstrated a doubling of median survival.
In KEYNOTE-048, investigators analyzed pembrolizumab with or without platinum plus 5-FU vs. the EXTREME regimen of platinum, 5-FU and cetuximab (Erbitux, Eli Lilly) among patients with recurrent or metastatic HNSCC. Results showed a 4.2-month OS improvement with pembrolizumab as a single agent over the EXTREME regimen among patients with a PD-L1 CPS of 20 or greater (median, 14.9 months vs. 10.7 months) and a 2-month OS improvement among patients with a CPS of 1 or greater (median, 12.3 months vs. 10.3 months).
There is a signal of immune responsiveness in esophageal squamous cell carcinoma; hence, CheckMate 648 was a logical and well-designed study to address how to optimize immune therapy. It is fitting that first-line nivolumab plus chemotherapy and, to a lesser extent, nivolumab plus ipilimumab appeared to extend PFS among patients with metastatic esophageal squamous cell carcinoma over chemotherapy alone. The benefit of PD-1/PD-L1 checkpoint inhibitors given in conjunction with chemotherapy has been demonstrated across multiple squamous cell carcinomas, as outlined above.
In conclusion, CheckMate 648 confirms that chemotherapy combinations with immune checkpoint inhibitors represent an innovative front-line treatment option for appropriate patients with advanced, metastatic esophageal squamous cell carcinoma, and there is a small OS benefit. This improvement is likely an additive effect as opposed to a synergistic effect, and more work needs to be done to better predict who will respond and to overcome immune resistance. Intense research should focus on better predictive biomarkers and newer immune therapy combinations to overcome tumor immune-resistance mechanisms.
References:
Burtness B, et al. Lancet. 2019;doi:10.1016/S0140-6736(19)32591-7.
Kato K, et al. Lancet Oncol. 2019;doi:10.1016/S1470-2045(19)30626-6.
Kojima T, et al. J Clin Oncol. 2020;doi:10.1200/JCO.20.01888.
Paz-Ares L, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1810865.
Reck M, et al. J Clin Oncol. 2019;doi:10.1200/JCO.18.00149.
Vermorken JB, et al. N Engl J Med. 2008;doi:10.1056/NEJMoa0802656.
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Chau I, et al. Abstract 4001. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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