Adding Pembrolizumab to Standard Therapy May Benefit Some GI Cancer Patients

NEW YORK (Reuters Health) – Gastroesophageal cancer patients with locally advanced disease and high baseline tissue expression of PD-L1 may benefit from the addition of pembrolizumab to standard neoadjuvant chemoradiation and surgery, researchers suggest.

“Adding immunotherapy concurrently to neoadjuvant chemoradiation shows promise for improving outcomes of some patients with this disease and potentially increasing cure rates,” Dr. Harry Yoon of Mayo Clinic in Rochester, Minnesota told Reuters Health by email. “But these findings need to be tested and confirmed in independent cohorts.”

“Most data indicate that PD-L1, while not perfect, is an important predictor of efficacy,” he noted. “So our findings fit with that emerging picture in metastatic disease and, along with other recent studies, suggest that PD-L1 could be relevant in non-metastatic disease.”

As reported in Clinical Cancer Research, Dr. Yoon and colleagues enrolled 31 patients (median age, 62; 97%, men; 100% white) with gastroesophageal junction adenocarcinoma (cT1-3NanyM0) in a phase 1b/2 trial.

Participants received neoadjuvant pembrolizumab-containing chemoradiation (CROSS regimen) followed by surgical resection and adjuvant pembrolizumab.

The primary endpoints were tolerability in the first 16 patients and pathologic complete response (pCR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS).

Twenty-nine patients received all expected doses of neoadjuvant pembrolizumab and 28 underwent R0 resection. Safety endpoints were met.

However, the primary efficacy endpoint was not met; only 22.6% of patients achieved pCR. Further analysis showed that patients with high (i.e., combined positive score of 10 or more) baseline PD-L1 expression in the tumor microenvironment (TME) had a significantly higher pCR rate than those with low expression (50% vs. 13.6%).

Those with high PD-L1 expression also experienced longer PFS and OS than propensity-score-matched patients.

Among trial patients with a PD-L1 combined positive score <10, an unprespecified analysis explored whether extracellular vesicles (EVs) could identify further responders, and determined that an elevated plasma level of PD-L1-expressing EVs was significantly associated with higher pCR.

Summing up, the authors write, “Adding pembrolizumab to trimodality therapy showed acceptable tolerability but did not meet the pre-specified pCR endpoint. Exploratory analyses suggested that high PD-L1 expression in the TME and/or on EVs may identify patients most likely to achieve tumor response.”

Dr. Yoon urges clinicians to enroll patients in a large US multicenter trial underway that is testing the combination of immunotherapy, chemoradiation and surgery in patients with nonmetastatic gastroesophageal cancer (

However, he adds, “I would not recommend adding immunotherapy routinely to neoadjuvant therapy in non-metastatic disease off-trial. It remains unproven.”

Dr. Joseph Chao, an esophageal and gastric cancer specialist at City of Hope in Duarte, California, commented on the study in an email to Reuters Health. Although promising, he said, “the results still remain hypothesis-generating as this was a phase 2 non-randomized trial, and the association of clinical outcomes in relation to patients’ tumor PD-L1 status was exploratory. The primary endpoint of improving pCR in PD-L1 unselected patients was not met.”

Like Dr. Yoon, he noted, “This approach should not yet be applied in routine clinical practice, but does support both future and ongoing randomized studies incorporating addition of pembrolizumab concurrent with chemoradiation therapy. Assessment of PD-L1 status in circulating extracellular vesicles is also a promising biomarker that should be studied in future larger trials.”

The study was supported by funds from Merck and Mayo Clinic. Dr. Yoon reports receiving honoraria from Merck (paid to Mayo Clinic) and several other coauthors have received funds from Merck.

SOURCE: Clinical Cancer Research, online May 12, 2022.

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