Keytruda Extends OS in Advanced Esophageal Cancer

SAN FRANCISCO — Pembrolizumab (Keytruda) significantly improved overall survival compared with chemotherapy when used as a second-line treatment for patients with advanced esophageal cancer whose tumors express PD-L1, a large randomized trial has shown.

Patients with PD-L1-positive tumors who were treated with pembrolizumab had a median overall survival of 9.3 months compared with 6.7 months in the chemotherapy group (HR 0.69, 95% CI, 0.52-0.93). The 12-month overall survival rate in these PD-L1-positive patients was 43% with pembrolizumab compared with 20% in the chemotherapy group.

The findings suggest, the investigators said, that pembrolizumab should be considered a new standard of care as a second-line treatment in this patient population.

Results of the phase III KEYNOTE-181 trial were presented here by Takashi Kojima, MD, of National Cancer Center Hospital East in Kashiwa, Japan, at the 2019 Gastrointestinal Cancers Symposium.

As explained by Kojima in his presentation, advanced, metastatic esophageal cancer is “highly lethal,” with 572,000 estimated cases worldwide in 2018, and more than 500,000 deaths. In addition, he said, “patients with advanced esophageal cancer after first-line chemotherapy have a poor prognosis, and limited treatment options.”

In the phase II KEYNOTE-180 study, durable responses were seen in patients with squamous cell carcinoma and adenocarcinoma, and in patients with a PD-L1 combined positive score (CPS) ≥10.

KEYNOTE-181 enrolled 628 patients with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or Siewert type I adenocarcinoma of the esophagogastric junction that progressed on or after frontline therapy.

Of those 628 patients, 401 had squamous cell carcinoma, and 222 had a PD-L1 CPS ≥10. Half of the patients were randomly assigned to treatment with pembrolizumab (200 mg every 3 weeks), and the other half to chemotherapy — investigator’s choice of docetaxel (75 mg/m² on day 1 of each 21-day cycle), paclitaxel (80 to 100 mg/m² on days 1, 8, and 15 of each 28-day cycle), or irinotecan (80 mg/m² on day 1 of each 14-day cycle).

The primary endpoints of the study were overall survival in the entire cohort, among those with a PD-LI CPS ≥10, and among those with squamous cell carcinoma. Secondary endpoints included progression-free survival, objective response rate, and safety.

The median follow-up was 7.1 months in the pembrolizumab group and 6.9 months in the chemotherapy group.

Kojima reported that although it did not reach statistical significance, there was a clinically meaningful increase in overall survival with pembrolizumab among patients with squamous cell carcinoma (HR 0.78, 95% CI 0.63-0.96).

Overall survival was comparable in the overall intent-to-treat population (HR 0.89, 95% CI 0.75-1.05), with a median overall survival of 7.1 months in each treatment arm.

Pembrolizumab had a more favorable safety profile than chemotherapy, Kojima said, with a much lower frequency of grade 3-5 treatment-related adverse events (18.2% vs 40.9% with chemotherapy), as well as a lower number of any treatment-related adverse events (64.3% vs 86.1% with chemotherapy).

Five treatment-related deaths occurred in each group.

Kojima said the results of the study suggest that “pembrolizumab should be considered a new standard-of-care” in the second-line for patients with metastatic esophageal cancer and PD-L1 CPS ≥10.

“The efficacy and toxicity results in the [CPS ≥10] group are impressive,” said the discussant for the study, Harry H. Yoon, MD, of the Mayo Clinic in Rochester, Minnesota.

“How should we translate these findings to the clinic?” he asked. “For the patient in front of me, I currently order PD-L1 and HER2 at first metastatic diagnosis in gastroesophageal adenocarcinomas. I think it is reasonable to consider a practice change.”

“That means ordering PD-L1 at first metastatic diagnosis in squamous carcinoma [of the esophagus] patients,” he added. “And pathology labs will also need to record a more detailed PD-L1 CPS score, if they don’t already.”

Yoon noted that 80-90% of patients have primary resistance to PD-1/-L1 monotherapy, and going forward, “our biggest need is to increase response rates in the vast majority of patients who don’t respond to PD-1 monotherapy.”