Two new regimens, a dual immunotherapy regimen and a single immunotherapy agent added to chemotherapy, significantly improve overall survival (OS) for patients with advanced esophageal squamous cell carcinoma (ESCC) compared to standard-of-care chemotherapy, particularly in patients who express the immune checkpoint protein programed death-ligand 1 (PD-L1). ESCC carries a heavy cancer burden, leading to more than half a million deaths each year globally. About 90 percent of patients diagnosed with the disease will die. First-line treatment for advanced ESCC with cisplatin plus 5-fluorouracil chemotherapy has a poor prognosis, with a median survival of about 10 months.
Treatment advances for recurrent or metastatic ESCC or upper gastrointestinal cancers have been slower than for other cancers. The programmed death-1 inhibitor nivolumab has been shown to improve survival in patients with advanced ESCC that is refractory or intolerant to previous chemotherapy. The combination of nivolumab with the cytotoxic t-lymphocyte-associated protein 4 inhibitor ipilimumab has demonstrated significant clinical activity across several tumor types, leading investigators to examine the combination for the treatment of ESCC.
About the Study
CheckMate 648 (LBA4001) is the largest randomized, controlled trial conducted in this setting so far, assessing dual immunotherapy options along with an immunotherapy plus chemotherapy option. The Phase III trial enrolled 970 patients with previously untreated, unresectable advanced, recurrent or metastatic ESCC. Patients were randomly assigned to receive treatment with nivolumab 240 mg every 2 weeks plus chemotherapy (5-fluorouracil and cisplatin) every 4 weeks (321 patients); nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (325 patients); or chemotherapy alone every 4 weeks (324 patients). Patients randomized to the investigational arms were allowed to receive treatment up to 24 months or until disease progression or unacceptable toxicity.
Primary endpoints were OS and PFS in a biomarker-defined patient population who expressed tumor cell levels of (PD-L1) >= 1 percent. Secondary endpoints included OS and PFS in all randomized patients. The patient populations were well-balanced; just over half of patients had expression of PD-L1 >= 1 percent.
Key Findings
"In the first treatment comparison of nivolumab plus chemotherapy versus chemotherapy, in our primary population with expression of PD-L1 of 1 percent or more, we observed a highly significant statistical improvement in OS, with a hazard ratio (HR) of 0.54. This translated into an improvement of median OS of 6 months (15.4 months nivolumab plus chemotherapy versus 9.1 months for chemotherapy)," said lead author Ian Chau, MD, a consultant medical oncologist at the Royal Marsden Hospital in Sutton, U.K., at a press briefing during the 2021 ASCO Annual Meeting. He added that more patients had prolonged OS with the combination.
In the all-randomized population, the researchers found the same trend in OS benefit in favor of nivolumab plus chemotherapy, and PFS was also improved in the primary population with the combination. Objective response rate was also higher by adding nivolumab to chemotherapy in both populations. The proportion of patients who achieved a complete response was 3 times higher in the combination arm, he pointed out.
Comparing nivolumab plus ipilimumab versus chemotherapy, in the primary population, "again we saw a significant survival advantage for nivolumab plus ipilimumab, with HR of 0.64, with more patients with longer OS," said Chau. In the all-randomized population, OS also favored the combination.
"In frontline studies of all cancers of the digestive system, this is the first study to show an improvement of immunotherapy alone versus chemotherapy," he said. "Importantly, the responses with immunotherapy were much longer compared to those achieved with chemotherapy alone."
Adverse events and serious adverse events grade 3 or higher were comparable between the three groups. The most common treatment-related adverse events in the nivolumab plus chemotherapy or chemotherapy arms were nausea, decreased appetite, and stomatitis. In the nivolumab plus ipilimumab arm, they were rash, pruritis, and hypothyroidism. Discontinuations due to any component of a regimen were more likely for patients receiving nivolumab plus chemotherapy.
"Encouragingly, treatment-related deaths were low among all three groups of patients," said Chau. "With OS benefits seen in both patient populations, nivolumab plus chemotherapy and nivolumab plus ipilimumab each represent a new potential first-line standard of care for patients with advanced ESCC based on the results of CheckMate 648."
ASCO Chief Medical Officer and Executive Vice President Julie R. Gralow, MD, the Jill Bennett Endowed Professor of Breast Medical Oncology and Professor of Global Health at the University of Washington School of Medicine, shared her thoughts on the study.
"Today, there are very few advancements for esophageal or upper GI cancers. The CheckMate 648 study found two regimens that improved OS beyond the standard of care, which is chemotherapy alone, for recurrent or metastatic ESCCs, particularly those that express PD-L1," she noted. "The addition of nivolumab to chemotherapy, as well as the combination of two checkpoint inhibitors without chemotherapy, both significantly extended survival and should be considered superior treatments as first-line treatments for ESCC. This dual immunotherapy treatment without chemotherapy is the first chemo-free first-line treatment showing benefit for these patients."
Mark L. Fuerst is a contributing writer.