Pembrolizumab Receives 2 New Approvals Across Oncology in Japan

The Japan Pharmaceuticals and Medical Devices Agency has approved pembrolizumab (Keytruda) for the treatment of patients with radically unresectable, advanced, or recurrent esophageal squamous cell carcinoma (ESCC) whose tumors are PD-L1–positive, and at an additional recommended dosage of 400 mg every 6 weeks as an intravenous infusion across all adult indications, according to an announcement from Merck.¹

“We remain committed to improving outcomes for as many patient with cancer as possible, including those with ESCC, which is a leading cause of cancer-related death in Japan,” said Jonathan Cheng, MD, vice president of Oncology Clinical Research at Merck Research Laboratories, stated in a press release. “With today’s approvals, specific patients with ESCC can receive a much-needed new treatment option, and adult patients receiving [pembrolizumab] will now have the option of a dosing schedule that reduces how often they are at the clinic for treatment.”

The regulatory decision for the ESCC indication was based on results from the phase 3 KEYNOTE-181 trial (NCT02564263). The approval of the agent for the 6-week dosing schedule was based on pharmacokinetic, efficacy, and safety data from cohort B of the KEYNOTE-555 trial (NCT03665597).

Data from KEYNOTE-181 showed that the median overall survival (OS) with the PD-1 inhibitor was 10.3 months (95% CI, 7.0-13.5) versus just 6.7 months (95% CI, 4.8-8.6) with chemotherapy in patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after 1 prior line of systemic therapy for advanced disease whose tumors were PD-L1 positive (HR, 0. 64; 95% CI, 0.46-0.90).²

Moreover, in the PD-L1 subgroup whose combined positive score (CPS) was 10 or more, the median progression-free survival (PFS) was 3.2 months with pembrolizumab versus 2.3 months with chemotherapy (HR, 0.66; 95% CI, 0.48-0.92). The overall response rate (ORR) with the immunotherapy was 22% (95% CI, 14.0-33.0); this included a complete response (CR) rate of 5% and a partial response (PR) rate of 18%. In those who received chemotherapy, the ORR was 7% with a 1% CR rate and a 6% PR rate.

In the multicenter, randomized, open-label, active-controlled trial, a total of 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after 1 previous line of systemic therapy for advanced disease were enrolled. Patients with HER2-neu-positive esophageal cancer had to have received previous treatment with an approved HER2-neu-targeted agent.

In the trial, participants were randomized 1:1 to receive pembrolizumab at a dose of 200 mg every 3 weeks or investigator’s choice of intravenous chemotherapy comprised of docetaxel at 75 mg/m2 on day 1 of each 21-day treatment cycle, paclitaxel at 80 mg/m2 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.

Patients were stratified via tumor histology and geographic region. Study treatment on either arm was continued until intolerable toxicity or progressive disease. Patients who received pembrolizumab were allowed to continue beyond the first RECIST v1.1-defined disease progression if they were found to be clinically stable; specifically, treatment could continue until the first radiographic evidence of progression was confirmed 5 or more weeks later with repeat imaging. Participants were able to receive treatment with the PD-1 inhibitor without disease progression for up to 24 months.

To be eligible for participation on the trial, patients had to have tumor specimens available for PD-L1 testing at a central laboratory. Participants’ PD-L1 status was identified through the use of the PD-L1 IHC 22C3 pharmDx assay. Those with a history of noninfectious pneumonitis that required steroids or current pneumonitis, active autoimmune disease, or a condition that required immunosuppression, were excluded from enrollment.

Investigators evaluated tumors every 9 weeks. The primary end point of the trial was OS in patients with ESCC, those with tumors expressing a PD-L1 CPS of 10 or more, as well as all patients who underwent randomization. Key secondary end points included PFS, ORR, duration of response (DOR), all in accordance with RECIST v1.1 criteria, as assessed by blinded independent central review.

Additional results from the trial showed that the median DOR was longer with pembrolizumab compared with chemotherapy, at 9.3 months versus 7.7 months, respectively.

The median duration of exposure was 2.1 months in the immunotherapy arm. With regard to safety, adverse effects reported with pembrolizumab were comparable to previous data observed with the agent in melanoma and non–small cell lung cancer.

Interim pharmacokinetic, efficacy, and safety data from cohort B of the phase 1b KEYNOTE-555 trial validated findings from a model-based assessment, of which a consistent benefit-risk profile was shown for the pembrolizumab dosing regimen of 400 mg every 6 weeks versus 200 mg every 3 weeks.³

In the trial, investigators enrolled a total of 101 patients with metastatic melanoma. The demographics of the cohort proved to be comparable to other prior trials that were done with the PD-1 inhibitor in metastatic melanoma, with a mean age of 62 years, a mean body weight of 85 kg, and 34% of patients being female.

Results showed that the observed concentrations for the dosing schedule were within the 90% prediction intervals of stimulated concentrations using the model. The geometric mean of observed trough concentrations at 6 weeks at 400 mg every 6 weeks was 14.5 ug/mL; this is 18% lower than what is seen at the 200-mg-every-3-weeks dose, or 18.1 ug/mL, and 11% higher than at a dose of 2 mg/kg given every three weeks, or 13.4 ug/mL. Moreover, the geometric mean of observed peak concentration at the end of infusion was 400 mg every 6 weeks at 136 ug/mL; this is 38% lower than the highest clinically evaluated dose of 10 mg/kg given every 2 weeks, or 220 ug/mL.

Additionally, the ORR in cohort B was found to be similar to the ORR reported in previous studies with the immunotherapy in this patient population, indicating comparable efficacy between the every-6-week and every-3-week regimens. Safety was also found to be similar with the every-6-week versus every-3-week regimen.

“This offers convenience and flexibility to both patients and providers, the need for which is particularly exemplified by the current COVID-19 pandemic,” Mallika Lala, PhD, associate principle scientist for the quantitative pharmacology and pharmacometrics group at Merck, started in a presentation of the data at the 2020 AACR Virtual Annual Meeting I.

In July 2019, pembrolizumab was approved by the FDA for the treatment of patients with recurrent or locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 with a CPS of 10 or more as determined by an FDA-approved test, with progressive disease on 1 or more previous systemic therapies.

References

1. Merck’s Keytruda (pembrolizumab) receives two new approvals in Japan. News release. Merck. Accessed August 24, 2020. Accessed August 24, 2020. https://bit.ly/3hrBcNR.
2. FDA approves pembrolizumab for advanced esophageal squamous cell cancer. News release. FDA. July 30, 2019. Accessed August 24, 2020. https://bit.ly/32kdBs5.
3. Lala M, Akala O, Chartash E, et al. Pembrolizumab 400 mg Q6W dosing: first clinical outcomes data from Keynote-555 cohort B in metastatic melanoma patients. Presented at: AACR Virtual Annual Meeting I; April 27-28, 2020; Virtual. Abstract CT042. https://bit.ly/32jDVTe.