Nivolumab Combination Therapy in Advanced Esophageal Squamous Cell Carcinoma

Esophageal cancer is the eighth most common cancer worldwide, with squamous cell carcinoma being the most common subtype. During the last 60 years, the 5-year survival rate for esophageal cancer has increased from 5% to 20% with the implementation of platinum-based therapy and radiotherapy; yet both esophageal adenocarcinoma and squamous cell carcinoma continue to be associated with high mortality rates, especially in patients with locally advanced and distant disease. In fact, esophageal cancer is the sixth most deadly cancer worldwide.

Checkpoint inhibitors, such as programmed death receptor 1/programmed death receptor ligand 1 (PD-1/PD-L1), are a promising therapeutic target for several solid tumor malignancies (e.g., non-small cell lung cancer, melanoma), with ever-expanding indications (e.g., urothelial cancer, breast cancer).  Moreover, PD-L1 targeted immunotherapy confers a survival benefit in previously treated patients with advanced esophageal squamous cell cancer (ESCC). Now, a study published in NEJM provides the first evidence for this type of immunotherapy in advanced ESCC in treatment-naïve patients. 

In this international study, researchers randomized 970 patients with untreated, unresectable, advanced ESCC to receive standard chemotherapy, ipilimumab plus nivolumab, or nivolumab plus chemotherapy. At 13 months, treatment with nivolumab plus chemotherapy or in combination with ipilimumab resulted in a significant overall survival benefit, as compared with chemotherapy alone. In both the overall population and among patients with tumor-cell PD-L1 expression of  ≥1%, median overall survival exceeded 1 year, with patients surviving 2.0 to 6.3 months longer with a nivolumab-containing regimen, compared with chemotherapy alone. In patients with PD-L1 expression ≥1%, nivolumab plus chemotherapy was associated with a progression-free survival benefit, as compared with chemotherapy alone, and the addition of nivolumab to chemotherapy or ipilimumab was associated with higher and more-durable response rates.

Subgroup analysis of the 50% of patients with tumor cell PD-L1 expression ≤1% did not show a survival benefit with nivolumab-containing therapy, as compared to chemotherapy. Grade 3–4 adverse effects were more common in the nivolumab plus chemotherapy group (47%) and least common in the nivolumab plus ipilimumab group (32%); adverse events with nivolumab plus ipilimumab were even lower than with standard chemotherapy (36%).

Given that nivolumab-containing regimens extended overall survival by 2 to 6 months in treatment-naïve patients with advanced ESCC and tumor cell PD-L1 expression >1%, this trial will certainly change practice. However, the trial was not designed to help clinicians decide which nivolumab regimen to use (with chemotherapy or with ipilimumab). Further studies are needed to help discern whether one regimen is more efficacious for certain patient subgroups. For now, oncologists will have to use principles of shared decision making with patients to decide which nivolumab regimen might be the best first-line option for each patient with advanced ESCC.

The following NEJM Journal Watch summary provides more details of the trial.

David H. Ilson, MD, PhD, reviewing Doki Y et al. N Engl J Med 2022 Feb 3

Immune checkpoint inhibitors targeting tumor-cell PD-L1 have been approved to combine with first-line chemotherapy in advanced esophagogastric cancer and esophageal squamous cell cancer. Alternative checkpoint inhibitors are also yielding positive results in first-line trials. Investigators now report results from CheckMate 648, an open-label, industry-sponsored, phase 3 trial of first-line immune checkpoint inhibitor therapy in advanced squamous cell carcinoma of the esophagus. A total of 970 patients received one of three regimens: a 4-week cycle of chemotherapy alone (intravenous fluorouracil/cisplatin), chemotherapy plus nivolumab, or nivolumab plus ipilimumab. Patients' median age was 64, 70% were treated in Asia, half had PD-L1 expression ≥1%, and half had two or more sites of metastatic disease.

At a minimum follow-up of 13 months, overall survival was superior for nivolumab plus chemotherapy compared to chemotherapy alone in patients with PD-L1 expression ≥1% (15.4 vs. 9.1 months; hazard ratio, 0.54; P<0.001) and in all treated patients (13.2 vs. 10.7 months; HR, 0.74; P=0.002). However, there was no survival benefit in patients with PD-L1 expression >1%. Overall survival was also superior for nivolumab/ipilimumab compared with chemotherapy in patients with PD-L1 expression ≥1% (13.7 vs. 9.1 months; HR, 0.64; P=0.001) and in all treated patients (12.7 vs. 10.7 months; HR, 0.78; P=0.01). Again, there was no survival benefit in patients with TPS score <1% or CPS score <1%. Progression-free survival was superior for nivolumab plus chemotherapy compared with chemotherapy only in patients with TPS score >1% (6.9 vs. 4.4 months, HR 0.65, P =0.002). Response rates were higher for nivolumab plus chemotherapy than chemotherapy alone in patients with PD-L1 expression ≥1% (53% vs. 20%) and in all patients (47% vs. 27%), as was response duration (8.2 vs. 5.7 months and 8.2 months vs. 7.1 months). Improved response was seen for nivolumab/ipilimumab versus chemotherapy only in patients with PD-L1 expression ≥1% (rate, 35% vs 20%; duration, 11.8 vs 5.7 months). No new safety signals were observed.

Comment: This landmark trial in squamous cell cancer of the esophagus indicates a survival benefit over chemotherapy alone for nivolumab added to first-line chemotherapy and for the combination of nivolumab and ipilimumab. The benefit, not clearly stated by the authors but evident from review of data in the supplement, is limited to patients with PD-L1 expression ≥1%. Nivolumab added to chemotherapy or with ipilimumab will likely gain regulatory approval for this indication.

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Roma Bhatia, MD, is a 2021–2022 NEJM Editorial Fellow.