Esophageal and gastroesophageal cancers remain aggressive malignancies with poor long-term outcomes, even when diagnosed at a potentially curable stage. The phase II PROCEED trial, titled “Pembrolizumab, Radiotherapy, and Chemotherapy in Neoadjuvant Treatment of Malignant Esophago-gastric Diseases,” was designed to address the limitations of standard neoadjuvant chemoradiotherapy (CRT) in this setting.
Published in Cancer, the peer-reviewed journal of the American Cancer Society, on December 11, 2025, the PROCEED study evaluated whether adding pembrolizumab to standard neoadjuvant CRT could deepen pathologic responses and improve outcomes in patients with locally advanced esophagogastric malignancies.
Authors (original publication): Pooja Karukonda MD, Brian G. Czito MD, Eileen Duffy RN, BSN, Hope E. Uronis MD, Thomas A. D’Amico MD, John H. Strickler MD, Donna Niedzwiecki PhD, Christopher G. Willett MD, Manisha Palta MD
Methods and Endpoints
PROCEED was a prospective, single-institution, single-arm phase II trial (NCT03064490) conducted over five years. Eligible patients had locally advanced esophageal or gastroesophageal malignancies considered appropriate for neoadjuvant CRT followed by surgical resection.
Patients received three cycles of pembrolizumab (200 mg every three weeks) administered concurrently with neoadjuvant CRT consisting of 45 Gy delivered in 25 fractions, along with weekly carboplatin and paclitaxel. Following completion of neoadjuvant therapy, patients underwent surgical resection. Those who tolerated neoadjuvant treatment without significant toxicity were eligible to receive up to three additional cycles of adjuvant pembrolizumab.
The primary objective was to evaluate pathologic response, particularly pCR, in comparison with historical controls treated with CRT alone. Secondary assessments included major pathologic response rates, acute treatment-related toxicities, and exploratory survival outcomes such as progression-free survival (PFS) and overall survival (OS).
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Results of PROCEED Trial
A total of 35 patients were enrolled, of whom 30 completed the full neoadjuvant regimen followed by surgical resection. Pathologic evaluation demonstrated a pCR in 11 of 30 patients, corresponding to a pCR rate of 36.7%. In addition, 50% of patients achieved a major pathologic response, indicating substantial tumor regression beyond complete responders.
From a safety perspective, the addition of pembrolizumab to neoadjuvant CRT was generally well tolerated. Rates of grade 3–4 adverse events were comparable to those historically reported with CRT alone, and importantly, no grade 5 (treatment-related fatal) toxicities were observed. Immune-related toxicities did not appear to meaningfully compromise treatment delivery or surgical feasibility.
Exploratory survival analyses suggested that patients achieving a major pathologic response experienced numerically longer progression-free and overall survival compared with those without deep responses, reinforcing the prognostic relevance of pathologic response in this disease setting.
Conclusion
The PROCEED phase II trial provides encouraging evidence that integrating pembrolizumab into neoadjuvant chemoradiotherapy for esophagogastric cancers is feasible, safe, and associated with numerically higher pCR rates compared with historical benchmarks. The depth of pathologic response observed supports the biological rationale for combining immune checkpoint inhibition with CRT in the curative-intent setting.
While these findings are limited by the single-arm design and modest sample size, they highlight the potential of immunotherapy-based neoadjuvant strategies to improve outcomes in locally advanced esophagogastric malignancies. Future randomized studies with refined patient selection and biomarker integration will be essential to define which patients derive the greatest benefit and to establish this approach as a new standard of care.
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