Pembrolizumab (Keytruda) was found to reduce the risk of death by 31% in patients with PD-L1–positive (combined positive score [CPS] ≥10) advanced or metastatic esophageal or esophageal junction carcinoma who progressed on standard therapy, according to phase III findings of the KEYNOTE-181 trial that were presented at the 2019 Gastrointestinal Cancers Symposium.
The findings mark the first time that a PD-1 inhibitor has demonstrated an improvement in survival for this patient population. These data will be submitted to the FDA and other regulatory agencies for review.
“The prognosis for patients diagnosed with esophageal cancer is poor, and for those who experience disease progression, there is no established standard of care, underscoring the need for improved therapies in the second-line setting,” said lead study author Takashi Kojima, MD, professor at the Department of Gastroenterology and Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, in a press release ahead of the conference. “The significant improvement in overall survival observed with Keytruda in patients with squamous cell carcinoma or adenocarcinoma whose tumors expressed PD-L1 with a CPS of 10 or greater represents an important scientific advancement and has the potential to benefit patients who currently have limited treatment options.”
In the open-label, randomized KEYNOTE-181 study, investigators evaluated pembrolizumab monotherapy versus chemotherapy in 628 patients with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or Siewert type I adenocarcinoma of the esophagogastric junction that has progressed following standard frontline therapy. Patients were randomized 1:1 to receive pembrolizumab at 200 mg every 3 weeks or investigator’s choice of intravenous chemotherapy, which consisted of docetaxel at 75 mg/m2
on day 1 of each 21-day cycle; paclitaxel at 80 mg to 100 mg/m2
on days 1, 8, and 15 of each 28-day cycle; or irinotecan at 80 mg/m2
on day 1 of each 14-day cycle.
The primary endpoint was OS, which was evaluated in all patients, those with a PD-L1 CPS ≥10, and patients with squamous cell carcinoma. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety/tolerability.
At a median follow-up of 7.1 months for pembrolizumab and 6.9 months for chemotherapy, results showed that in patients with PD-L1–positive tumors (CPS ≥10; n = 222), the median OS was 9.3 months (95% CI, 6.6-12.5) with pembrolizumab compared with 6.7 months (95% CI, 5.1-8.2) for those who received chemotherapy (HR, 0.69; 95% CI, 0.52-0.93; P
= .0074). The 1-year OS rates for pembrolizumab and chemotherapy were 43% and 20%, respectively.
There was a clinically meaningful improvement in OS with pembrolizumab in patients with squamous cell carcinoma (n = 401), with a median OS of 8.2 months (95% CI, 6.7-10.3) and 7.1 months (95% CI, 6.1-8.2) with pembrolizumab and chemotherapy, respectively. However, it did not meet statistical significance per a pre-specified statistical plan (HR, 0.89; 95% CI, 0.75-1.05; P
In the overall ITT population, the difference in OS was not statistically significant (HR, 0.89; 95% CI, 0.75-1.05; P
= .0560), with a median OS of 7.1 months in both treatment arms. Per the pre-specified statistical analysis plan, the secondary endpoints of PFS and ORR were not formally tested, as OS was not reached in the full ITT study population.
The safety profile of pembrolizumab was consistent with what has been reported in prior trials. Treatment-related adverse events (TRAEs) occurred in 64.3% of patients on the pembrolizumab arm compared with 86.1% for chemotherapy. The most common TRAEs with pembrolizumab with an incidence of ≥5% were fatigue (11.8%), hypothyroidism (10.5%), decreased appetite (8.6%), asthenia (7.0%), nausea (7.0%) and diarrhea (5.4%). Grade 3 to 5 TRAEs occurred in 57 patients (18.2%) who received pembrolizumab compared with 121 (40.9%) on chemotherapy. Five 5 treatment-related deaths occurred in each group.
“Esophageal cancer often progresses aggressively, so we are encouraged to see these overall survival results for Keytruda as monotherapy in previously treated patients,” said Roy Baynes, MD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “Merck is committed to understanding the clinical benefit of Keytruda across a range of gastrointestinal cancers, including esophageal cancer. Along with other new data for Keytruda and from our broad oncology portfolio, we are pleased to share our latest clinical research in gastrointestinal cancers at [the 2019 Gastrointestinal Cancers Symposium].”
Pembrolizumab is also being evaluated in combination with chemotherapy in the phase III KEYNOTE-590 trial (NCT03189719) as a first-line treatment for patients with locally advanced or metastatic esophageal carcinoma.
Kojima T, Muro K, Francois E, et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. J Clin Incol. 2019;37 (suppl 4; abstr 2).
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