Phase 3 KEYNOTE-590 Trial Finds Pembrolizumab, Chemo Combo Effective for Advanced Esophageal Cancer

According to topline results from the phase 3 KEYNOTE-590 trial (NCT03189719), frontline pembrolizumab (Keytruda) plus chemotherapy significantly improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) compared with chemotherapy alone in patients with locally advanced unresectable or metastatic esophageal cancer.¹

The results, which were presented during the 2020 ESMO Virtual Congress, showed that the median OS was 12.4 months (95% CI, 10.5-14.0) in patients who received the chemoimmunotherapy regimen versus 9.8 months (95% CI, 8.8-10.8) in those given chemotherapy alone (HR, 0.73; 95% CI, 0.62-0.86; P <.0001). Moreover, the 12-month OS rate with pembrolizumab plus chemotherapy was 51% versus 39% with chemotherapy alone; at 24 months, these rates were 28% versus 16%, respectively.

The median investigator-assessed PFS per RECIST v1.1 criteria was 6.3 months (95% CI, 6.2-6.9) with pembrolizumab plus chemotherapy versus 5.8 months (95% CI, 5.0-6.0) with chemotherapy alone (HR, 0.65; 95% CI, 0.55-0.76; P <.0001). At 12 months, the PFS rates in the investigational and control arms were 25% versus 12%, respectively; the 18-month rates were 16% versus 6%, respectively.

“First-line pembrolizumab plus chemotherapy versus chemotherapy plus placebo provided a statistically significant and clinically meaningful improvement in OS, PFS, and ORR in patients with locally advanced unresectable or metastatic esophageal cancer, including gastroesophageal junction carcinoma,” Peter Enzinger, MD, lead investigator and director of the Center for Esophageal and Gastric Cancer at Dana-Farber Cancer Institute, said in a press conference ahead of the meeting.

For patients with advanced esophageal cancer, the standard first-line treatment has been fluoropyrimidine in combination with platinum-based chemotherapy, according to Enzinger. For the second-line setting, docetaxel, paclitaxel, irinotecan, and ramucirumab (Cyramza) plus or minus paclitaxel for adenocarcinoma, is largely used. “Unfortunately, the standard of care has remained relatively unchanged for a long period of time,” Enzinger said.

Previously, pembrolizumab has demonstrated antitumor activity with a tolerable toxicity profile when used as monotherapy in patients with advanced or metastatic esophageal cancer in 2 pivotal studies: KEYNOTE-180 (NCT02559687) and KEYNOTE-181 (NCT02564263).

In the KEYNOTE-180 trial, the agent elicited an ORR of 14%, with a median duration of response (DOR) that had not been reached in third-line patients with esophageal squamous cell carcinoma (ESCC) and tumors with a PD-L1 combined positive score (CPS) of 10 or higher.² In KEYNOTE-181, single-agent pembrolizumab led to a median OS of 10.3 months versus 6.7 months with chemotherapy (HR, 0.64), an ORR of 22% versus 7%, respectively, and a median DOR of 9.3 months versus 7.7 months, respectively, in second-line patients with ESCC and a CPS of 10 or higher.^3,4

Data from KEYNOTE-181 supported the July 2019 FDA approval of pembrolizumab in patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1, as determined by an FDA-approved test, with disease progression after 1 or more prior lines of systemic therapy.

In the randomized, double-blind, placebo-controlled phase 3 trial, investigators set out to examine pembrolizumab in combination with chemotherapy versus placebo plus chemotherapy in the frontline treatment of patients with advanced esophageal cancer.

To participate, patients had to be treatment naïve and have locally advanced resectable or metastatic esophageal cancer, ESCC, or advanced/metastatic esophagogastric junction Siewert type 1 adenocarcinoma. An ECOG performance status of 0 or 1 and measurable disease per RECIST v1.1 criteria was also required.

Patients were stratified based on region (Asia vs non-Asia region), disease (ESCC vs esophageal), and ECOG performance status (0 vs 1). Participants were randomized in a 1:1 fashion. In the experimental arm (n = 370), patients received pembrolizumab intravenously (IV) at a dose of 200 mg every 3 weeks for up to 35 cycles plus chemotherapy comprised of 800 mg/m2 of IV 5-fluorouracil for days 1 through 5 every 3 weeks for up to 35 cycles and 80 mg/m2 of IV cisplatin every 3 weeks for up to 6 cycles. In the control arm (n = 370), patients received the same schedule of chemotherapy plus placebo.

The primary end points were OS and PFS per RECIST v1.1 criteria and investigator assessment. Specifically, investigators examined OS in the following patient subgroups: those with ESCC with a PD-L1 CPS of 10 or higher, ESCC, a PD-L1 CPS of 10 or higher, and the entire study population. They examined PFS in the following subgroups: those with ESCC, those with a PD-L1 CPS of 10 or higher, and all patients. The secondary end point was ORR per RECIST v1.1 criteria and investigator evaluation. Tumor response was evaluated at week 9 and then every 9 weeks thereafter.

With regard to safety, treatment-related AEs were reported in 98.4% and 97.3% of those on the investigational and control arms, respectively. Grade 3 or higher events were experienced by more patients on the chemoimmunotherapy arm versus the chemotherapy alone arm, at 71.9% versus 67.6%, respectively.

Treatment-related AEs (TRAEs) that resulted in discontinuation occurred in 19.5% of those on pembrolizumab/chemotherapy versus 11.6% in the chemotherapy arm. Moreover, 2.4% of those in the experimental arm had TRAEs that resulted in death versus 1.4% of those in the control arm.

Immune-mediated AEs and infusion reactions were reported in 25.7% versus 11.6% of patients in the pembrolizumab/chemotherapy and chemotherapy arms, respectively. Grade 3 or higher immune-mediated toxicities were observed in 7.0% versus 2.2%, respectively.

“Pembrolizumab plus chemotherapy should be a new standard of care as first-line therapy in patients with locally advanced unresectable or metastatic esophageal cancer, including gastroesophageal junction carcinoma, regardless of histology and biomarker status,” concluded Enzinger.

References:

1. Enzinger P. Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA8_PR.

2. Shah MA, Kojima T, Hochhauser D, et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. JAMA Oncol. 2019;5(4):546-550. doi:10.1001/jamaoncol.2018.5441

3. Shah MA, Adenis A, Enzinger PC, et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: phase 3 KEYNOTE-181. J Clin Oncol. 2019;27(suppl 15):4010. doi:10.1200/JCO.2019.37.15_suppl.4010

4. Pembrolizumab prescribing information. 2020. Merck Sharp & Dohme Corp. Kenilworth, NJ. Accessed September 20, 2020.