PD-1 Inhibition in First-Line Treatment of Advanced Esophageal Squamous Cell Carcinoma: More to Come on New Paradigm

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Esophageal cancer is associated with significant morbidity and mortality worldwide, with more than 600,000 new cases and 540,000 deaths in 2020. The squamous cell histology comprises nearly 90% of cases globally, despite its steady decline in the United States over the past 40 years. Historically, the prognosis of metastatic esophageal squamous cell carcinoma (SCC) has been poor, with a median survival of less than 1 year and a reliance on cytotoxic chemotherapy regimens. Recently, a role for immunotherapy has emerged in previously treated advanced esophageal SCC based on four randomized studies showing improved survival with PD-1 inhibitor monotherapy compared with chemotherapy.

Jill Lacy, MD

Jill Lacy, MD

Michael Cecchini, MD

Michael Cecchini, MD

Implications of CheckMate 648 Findings

The findings of the CheckMate 648 study—reported by Doki et al in The New England Journal of Medicine and summarized in this issue of The ASCO Post—represent a significant and practice-changing advance in the treatment of advanced esophageal SCC.1 In this global study of patients with untreated metastatic or advanced esophageal SCC, the investigators compared the efficacy of chemotherapy alone (cisplatin and fluorouracil) with nivolumab plus chemotherapy vs nivolumab plus ipilimumab in patients with PD-L1–positive tumors and in the overall population. The key “take-away message” from this landmark study is that the incorporation of nivolumab into first-line therapy in combination with either chemotherapy or ipilimumab without chemotherapy prolongs the survival of patients with advanced esophageal SCC, without incurring excessive toxicity, compared with chemotherapy alone.

In the trial, the addition of nivolumab to chemotherapy increased median overall survival by an impressive 6.5 months (hazard ratio [HR] = 0.54) in patients with PD-L1–positive tumors and by 2.5 months (HR = 0.74) in the overall study population compared with chemotherapy alone. PD-L1 expression was assessed by the percentage of positive tumor cells (tumor proportion score [TPS]), with a TPS of at least 1% defined as PD-L1–positive for the primary analysis. Progression-free survival was increased in the PD-L1–positive subset (HR = 0.65), although not significantly increased in the overall population. Of note, given the morbidity of tumor burden in esophageal SCC, the response rate was both higher and more durable with the addition of nivolumab to chemotherapy in both populations, with an unprecedented complete response rate of 16% in patients with PD-L1–positive tumors.

These findings now give clinicians a chemotherapy-free option for those patients who are not candidates for cytotoxic agents.
— Jill Lacy, MD, and Michael Cecchini, MD

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The impressive benefit from the addition of nivolumab to chemotherapy in CheckMate 648 is consistent with the findings from four other randomized trials of PD-1 inhibitors combined with first-line platinum-based chemotherapy in esophageal SCC.2-5 The magnitude of survival benefit with the addition of PD-1 inhibitors to first-line chemotherapy in metastatic esophageal SCC is remarkably consistent across these studies (HRs = 0.58–0.72), despite the use of different PD-1 inhibitors and chemotherapy backbones. The consistency of benefit with PD-1 inhibitor therapy in esophageal SCC contrasts with gastroesophageal adenocarcinomas, where there have been conflicting findings regarding improvement in overall survival with first-line chemoimmunotherapy. The highly reproducible survival benefit of different PD-1 inhibitors with different chemotherapy doublets in esophageal SCC is reassuring and will facilitate individualized choice of regimens based on toxicity profiles, patient preferences, and cost.

The potentially transformational practice-changing finding from CheckMate 648 is that treatment with the chemotherapy-free regimen of nivolumab plus ipilimumab improved overall survival by 4.6 months (HR = 0.64) in the PD-L1–positive population and by 2.0 months (HR = 0.78) in the overall population compared with chemotherapy alone. The median response duration of nearly 1 year with nivolumab plus ipilimumab exceeded that of both chemotherapy alone and chemotherapy plus nivolumab. The notable durability of responses with nivolumab plus ipilimumab suggests the potential for long-term disease control and survival with dual checkpoint inhibitor therapy in a subset of patients with esophageal SCC. These findings now give clinicians a chemotherapy-free option for those patients who are not candidates for cytotoxic agents.

A Note of Caution

The cautionary note, however, is that the Kaplan-Meier curves reveal an early attrition in survival with nivolumab plus ipilimumab compared with chemotherapy, which is not seen with nivolumab plus chemotherapy. This phenomenon likely contributed to the absence of progression-free survival benefit with nivolumab plus ipilimumab compared with chemotherapy (HR = 1.02). The explanation for the early increase in deaths with nivolumab plus ipilimumab is unknown, but it may reflect the need for chemotherapy to mitigate the slower kinetics of checkpoint inhibitors in some patients. Of note, this observation does “raise a red flag” regarding the widespread use of nivolumab plus ipilimumab until we have a better understanding of the clinical and pathologic features predictive of early death with this combination.

There were no new safety signals with the nivolumab-containing regimens in this study. The spectrum of treatment-related adverse events differed predictably between the treatments, with more endocrinopathies and rash with nivolumab plus ipilimumab and more gastrointestinal and renal toxicity, fatigue, and cytopenias with chemotherapy alone. Notably, the regimen of nivolumab at 3 mg/kg every 2 weeks with “low-dose” ipilimumab (1 mg/kg every 6 weeks) used in this study was well tolerated, with a lower incidence of treatment-related adverse events compared with the chemotherapy regimens. Although treatment-related adverse events leading to drug discontinuation were highest in the nivolumab-plus-­chemotherapy arm, treatment-related deaths were rare and identical across the three arms (2% in each arm).

Clinical Challenge Centers on Treatment Decisions

The challenging question for clinicians now is how to incorporate PD-L1 expression into treatment decisions for their patients with esophageal SCC. The CheckMate 648 investigators provided a preplanned comprehensive subgroup analysis using both TPS and CPS (combined positive score) methodologies, with cutoffs of 1%, 5%, and 10%. Of note, the hazard ratio for death did not exceed 1 in any of the subgroups, providing reassurance that the use of nivolumab in the first-line setting does not appear to negatively impact overall survival based on PD-L1 expression.

In patients with PD-L1–positive tumors by TPS (≥ 1%), the survival benefit with the nivolumab-containing regimens was greatest in the TPS ≥ 1% subgroup, with no apparent incremental benefit at higher TPS cutoffs. In the PD-L1–negative subgroup by TPS (< 1%), representing 51% of the population, there was no difference in overall survival between the three treatment arms for the nivolumab-containing regimens compared with chemotherapy (HR = 0.98 for nivolumab plus chemotherapy and HR = 0.96 for nivolumab plus ipilimumab). However, the percentage of patients with a sustained response of at least 12 months’ duration was higher with nivolumab-containing regimens compared with chemotherapy alone, and thus a survival benefit may emerge with longer follow-up in the tumor-cell PD-L1–negative subgroup.

Overall, the PD-L1 subgroup analysis in CheckMate 468 confirms that PD-L1 expression plays a role in predicting survival for nivolumab-containing regimens in esophageal SCC and indicates that not all patients will derive benefit. However, it is difficult to draw definitive conclusions regarding the utility of PD-L1 expression in clinical decision-making in esophageal SCC, given the nuances related to the preferred scoring method (TPS or CPS), ideal cutoffs, and the dynamic nature of this biomarker. Thus, at present, the use of PD-L1 scores to exclude patients from first-line PD-1 inhibitor treatment should be undertaken with circumspection and caution.

At present, the use of PD-L1 scores to exclude patients from first-line PD-1 inhibitor treatment should be undertaken with circumspection and caution.
— Jill Lacy, MD, and Michael Cecchini, MD

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The findings from CheckMate 648, as well as the other studies of PD-1 inhibitors with chemotherapy in the first-line treatment of metastatic esophageal SCC, represent a true paradigm shift in our approach to this disease. Given the limitations of PD-L1 as a predictive biomarker, treatment decisions should be individualized in those patients with PD-L1–negative tumors, and all patients can be considered for inclusion of a PD-1 inhibitor in their initial treatment. In addition, the trial gives us a new and well-tolerated chemotherapy-free treatment option of nivolumab plus ipilimumab for select patients who may not be candidates for cytotoxic chemotherapy. However, the caveat is there is increased death in the first 6 months in the absence of chemotherapy, and thus careful patient selection for dual checkpoint inhibition is critical.

The U.S. Food and Drug Administration (FDA) accepted an application for nivolumab plus ipilimumab and nivolumab plus chemotherapy as initial treatment for advanced esophageal SCC. A decision is expected by the FDA in May 2022. With this paradigm shift, the role and utilization of PD-1 inhibitors in later lines of therapy in esophageal SCC will diminish. There now emerges a compelling need to identify novel agents for PD-1 inhibitor–refractory disease as well as to improve upon these results with incorporation of novel agents into the emerging first-line chemoimmunotherapy regimens for esophageal SCC. 

Dr. Lacy is Professor of Medicine (Medical Oncology), Yale School of Medicine, and Dr. Cecchini is Assistant Professor of Medicine (Medical Oncology) and Co-Director of the Colorectal Program in the Center for Gastrointestinal Cancers at Yale School of Medicine and Smilow Cancer Hospital Care Center, New Haven, Connecticut.

DISCLOSURE: Dr. Lacy has served as an advisor or consultant to Aptitude Health, ASCO, Deciphera Pharmaceuticals, Equinox, First World, Guidepoint, Ipsen, Novartis, and Techspert. Dr. Cecchini owns stock or other ownership interests in Parthenon Therapeutics; has received honoraria from Agios, AstraZeneca, and Eisai; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca and Eisai.


1. Doki Y, Ajani JA, Kato K, et al: Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med 386:449-462, 2022.

2. Sun JM, Shen L, Shah MA, et al: Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study. Lancet 398:759-771, 2021.

3. Luo H, Lu J, Bai Y, et al: Effect of camrelizumab vs placebo added to chemotherapy on survival and progression-free survival in patients with advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st randomized clinical trial. JAMA 326:916-925, 2021.

4. Xu R, Wang F, Cui C, et al: JUPITER-06: A randomized, double-blind, phase III study of toripalimab versus placebo in combination with first-line chemotherapy for treatment naive advanced or metastatic esophageal squamous cell carcinoma. ESMO Congress 2021. Abstract 1373M0. Presented September 17, 2021.

5. Shen L, Lu Z, Wang J, et al: Sintilimab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced or metastatic esophageal squamous cell cancer: First results of the phase III ORIENT-15 study. ESMO Congress 2021. Abstract LBA52. Presented September 17, 2021.


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