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Pembrolizumab reduces mortality risk in advanced PD-L1-positive esophageal cancer
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Pembrolizumab significantly improved OS compared with chemotherapy as second-line treatment for patients with advanced or metastatic esophageal or esophagogastric junction carcinoma whose tumors expressed PD-L1, according to results of the randomized phase 3 KEYNOTE-181 trial scheduled for presentation at this year’s Gastrointestinal Cancers Symposium.
Pembrolizumab (Keytruda, Merck) is the first anti-PD-1 therapy to demonstrate a survival benefit for this patient population.
“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,” Takashi Kojima, MD, professor in the department of gastroenterology and gastrointestinal oncology at National Cancer Center Hospital East in Kashiwa, Japan, said in a Merck-issued press release. “The significant improvement in overall survival observed with Keytruda [among] patients with squamous cell carcinoma or adenocarcinoma whose tumors expressed PD-L1 with a [combined positive score (CPS)] of 10 or greater represents an important scientific advancement and has the potential to benefit patients who currently have limited treatment options.”
The open-label KEYNOTE-181 trial included 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 after first-line standard therapy.
The majority (n = 401; 63.8%) had squamous cell carcinoma, and 222 had PD-L1 CPS of 10 or higher.
Researchers randomly assigned patients 1:1 to pembrolizumab 200 mg every 3 weeks, or investigator’s choice off IV chemotherapy with docetaxel (75 mg/m2 on day 1 of each 21-day cycle), paclitaxel (80 mg/m2 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).
OS in the entire cohort, among those with PD-L1 CPS of 10 or higher, and among those with squamous cell carcinoma served as the primary endpoint. PFS, objective response rate and safety/tolerability served as secondary endpoints.
Median follow-up was 7.1 months in the pembrolizumab group and 6.9 months in the chemotherapy group.
Results showed no significant OS benefit with pembrolizumab in the intention-to-treat population (HR = 0.89; 95% CI, 0.75-1.05), with median OS of 7.1 months in both treatment groups. Due to the prespecified statistical analysis plan, investigators did not formally test the secondary endpoints.
However, in the subgroup of patients whose tumors had PD-L1 CPS of 10 or higher, pembrolizumab appeared associated with a statistically significant improvement in median OS (9.3 months vs. 6.7 months; HR = 0.69; 95% CI, 0.52-0.93), as well as a higher rate of 12-month OS (43% vs. 20%).
In the subgroup of patients with squamous cell carcinoma, pembrolizumab-treated patients achieved longer median OS, but the difference did not reach statistical significance (8.2 months vs. 7.1 months; HR = 0.78; 95% CI, 0.63-0.96).
The safety profile of pembrolizumab in KEYNOTE-181 appeared consistent with that observed in prior trials.
Fewer patients assigned pembrolizumab than chemotherapy experienced treatment-related adverse events (64.3% vs. 86.1%) or grade 3 to grade 5 treatment-related adverse events (18.2% vs. 40.9%).
The most common treatment-related adverse events in the pembrolizumab group included fatigue (11.8%), hypothyroidism (10.5%), decreased appetite (8.6%), asthenia (7%), nausea (7%) and diarrhea (5.4%).
Five treatment-related deaths occurred in each group.
Merck officials intend to submit data from KEYNOTE-181 to the FDA and other regulatory authorities.
The FDA previously approved pembrolizumab for treatment of certain patients with melanoma, lung cancer, head and neck cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma and microsatellite instability-high cancers.
Perspective
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David H. Ilson, MD, PhD
Immune checkpoint inhibitors have a modest signal of activity in advanced esophagogastric cancer refractory to chemotherapy. Substantial and durable benefit of immune checkpoint inhibitors is seen in the rare patient with microsatellite instability-high cancer, and PD-L1 expression may also be a surrogate biomarker indicating a greater benefit of these agents.
In the KEYNOTE-61 trial in gastric and gastroesophageal junction cancer, however, pembrolizumab was not shown to be superior to conventional paclitaxel in second-line therapy in patients with PD-L1 CPS of 1 or higher, although enhanced efficacy was seen in patients with CPS score of 10 or higher.
Kojima and colleagues now report results of KEYNOTE-181, a randomized trial comparing second-line chemotherapy (docetaxel, paclitaxel or irinotecan) with pembrolizumab treatment in patients with squamous cell or adenocarcinoma of the esophagus or gastroesophageal junction.
The trial was complicated by use of three primary endpoints — OS in patients with CPS score of 10 or higher, in patients with squamous cancer and in all patients — leading to diminution of statistical relevance of any individual endpoint. In addition, in esophageal and gastroesophageal junction adenocarcinoma, arguably paclitaxel alone is an inferior control arm, with the care standard the superior combination of paclitaxel and ramucirumab (Cyramza, Eli Lilly).
Of the 628 patients enrolled, the majority had squamous cancer (64%) and a minority of patients had CPS of at least 10 (34%-37%).
Of the three primary endpoints, only OS improvement over chemotherapy was achieved among patients with CPS of 10 or higher, with nonsignificant differences in OS for the intent-to-treat patients, and a trend toward improved OS in squamous cancers. Because of the imbalance in patient numbers for histology subsets, conclusions about the efficacy in adenocarcinoma vs. squamous cell cancer cannot be made in this trial.
The higher response rate overall for pembrolizumab, the lesser degree of side effects compared with chemotherapy, and the potential benefit in CPS-selected patients all indicate a potential path forward for regulatory approval in second-line therapy in esophageal cancer. Results of trials of immune checkpoint inhibitors in first line therapy are anxiously awaited.
Reference:
Shitara K, et al. Lancet. 2018;doi:10.1016/S0140-6736(18)31257-1.
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