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Pembrolizumab Granted 5 Additional Approvals in Japan

Gina Columbus @ginacolumbusonc
Published: Thursday, Jan 03, 2019

Dr. Roy Baynes
Roy Baynes, MD, PhD
The Japan Pharmaceuticals and Medical Devices Agency (PMDA) has approved pembrolizumab (Keytruda) for 5 new indications, including melanoma, advanced microsatellite instability-high (MSI-H) tumors, and 3 expanded uses in advanced non–small cell lung cancer (NSCLC).1

“These 5 simultaneous approvals of Keytruda in Japan represent a significant achievement that involved extensive collaboration with the Japan Pharmaceuticals and Medical Devices Agency,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “We appreciate the agency’s efforts to expedite availability of this important medicine to more patients living with cancer in Japan.”

Pembrolizumab was granted approval for the following areas:

• In combination with pemetrexed and cisplatin/carboplatin for the first-line treatment of patients with unresectable, advanced/recurrent nonsquamous NSCLC, regardless of PD-L1 expression;
• In combination with carboplatin and paclitaxel/nab-paclitaxel (Abraxane) for the first-line treatment of patients with unresectable, advanced/recurrent squamous NSCLC regardless of PD-L1 expression;
• As first-line treatment of patients with PD-L1–positive (tumor proportion score [TPS] ≥1%) patients with unresectable, advanced/recurrent NSCLC;
• As adjuvant treatment for patients with melanoma;
• As treatment for patients with advanced/recurrent MSI-H solid tumors that have progressed following chemotherapy, if refractory or intolerant to standard therapies. The Japan PMDA also approved FALCO, a companion diagnostic for MSI-H.

In addition to the PD-1 inhibitor’s adjuvant approval in melanoma, the dosage and administration for all patients with melanoma was changed from an intravenous (IV) infusion of 2 mg/kg over 30 minutes at a 3-week interval to an IV infusion of the fixed dose of 200 mg over 30 minutes at a 3-week interval.

The first-line approval of pembrolizumab in combination with pemetrexed and either cisplatin or carboplatin for patients with unresectable, advanced/recurrent nonsquamous NSCLC was based on findings from the phase III KEYNOTE-189 trial. Results showed that the combination reduced the risk of death by 51% in patients with NSCLC without EGFR or ALK mutations.2,3 The median overall survival (OS) was not reached with pembrolizumab cohort versus 11.3 months (95% CI, 8.7-15.1) in the chemotherapy-alone arm. At a median follow-up of 10.5 months, the estimated 12-month OS rate was 69.2% (95% CI, 64.1-73.8) in the pembrolizumab arm versus 49.4% (95% CI, 42.1-56.2) in the control group (HR, 0.49; 95% CI, 0.38-0.64; P <.001).

The decision to approve pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel in the first-line squamous NSCLC setting was based on data from the phase III KEYNOTE-407 study, in which the pembrolizumab combination reduced the risk of death by 36% versus chemotherapy alone.4 The median OS was 15.9 months (95% CI, 13.2–not evaluable) with pembrolizumab compared with 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P = .0017).

The single-agent approval for patients with PD-L1–positive unresectable, advanced/recurrent NSCLC approval was based on results from the phase III KEYNOTE-042 study, in which the median OS was 16.7 months with frontline pembrolizumab versus 12.1 months with standard chemotherapy in those with advanced/metastatic NSCLC and TPS ≥1% (HR, 0.81; 95% CI, 0.71-0.93; P = .0018).5 In an exploratory analysis, the median OS was 13.4 months with pembrolizumab compared with 12.1 months for chemotherapy (HR, 0.92; 95% CI, 0.77-1.11) across all patients with PD-L1 TPS of 1% to 49%.

The melanoma approval is based on the phase III EORTC 1325-MG/KEYNOTE-054 trial, findings of which showed that adjuvant pembrolizumab reduced the risk of recurrence or death by 43% in patients with resected, high-risk stage III disease.6,7 At a median follow-up of 15 months, the 1-year recurrence-free survival (RFS) rate was 75.4% (95% CI, 71.3-78.9) with the checkpoint inhibitor versus 61.0% (95% CI, 56.5-65.1) with placebo (HR, 0.57; 98.4% CI, 0.43-0.74; P <.0001). The RFS benefit was observed regardless of PD-L1 or BRAF mutation status.

Finally, the MSI-H indication was based on data of the phase II KEYNOTE-164 and KEYNOTE-158 trials, which demonstrated encouraging response rates in patients with unresectable or metastatic, MSI-H or mismatch repair deficient (dMMR) solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options who received pembrolizumab.

Pembrolizumab was previously approved in Japan for the treatment of patients with curatively unresectable melanoma; PD-L1-positive unresectable, advanced or recurrent NSCLC (TPS ≥1% in second-line setting; TPS ≥50% in first-line setting); relapsed/refractory classical Hodgkin lymphoma; and curatively unresectable urothelial carcinoma following progression on chemotherapy.


  1. Merck’s KEYTRUDA® (pembrolizumab) Receives Five New Approvals in Japan, Including in Advanced Non-Small Cell Lung Cancer (NSCLC), as Adjuvant Therapy for Melanoma, and in Advanced Microsatellite Instability-High (MSI-H) Tumors. Merck. Published January 3, 2019. Accessed January 3, 2019." .
  2. Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. KEYNOTE-189: Randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC. Presented at 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT075.
  3. Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018; 378:2078-2092. doi: 10.1056/NEJMoa1801005.
  4. Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36 (suppl; abstr 105).
  5. Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. In: Proceedings from the 2018 ASCO Annual Meeting; June 1-5; Chicago. Abstract LBA4.
  6. Egermont AMM, Blank CU, Mandala M, et al. Pembrolizumab vs. placebo after complete resection of high-risk stage iii melanoma: efficacy and safety results from the EORTC 1325-MG/KEYNOTE-054 double-blinded phase 3 trial. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT001.
  7. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma [published online April 15, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1802357.

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