Pembrolizumab Approved in Japan for Select Breast Cancer and Colorectal Cancer

Roy Baynes, MD, PhD

The Japan Pharmaceuticals and Medical Devices Agency has approved the use of pembrolizumab (Keytruda) in the treatment of patients with PD-L1–positive, hormone receptor–negative and HER2-negative, inoperable or recurrent breast cancer, and for single-agent use in patients with unresectable, advanced, or recurrent microsatellite instability–high (MSI-H) colorectal cancer (CRC).¹

The regulatory decision for the breast cancer indication was supported by findings from the phase 3 KEYNOTE-355 trial (NCT02819518), which showed that when pembrolizumab was paired with paclitaxel, nab-paclitaxel (Abraxane), or gemcitabine and carboplatin, it significantly improved progression-free survival (PFS) in patients with metastatic triple-negative breast cancer (TNBC) with a PD-L1 combined positive score (CPS) of 10 or higher (hazard ratio [HR], 0.65; 95% CI, 0.49-0.86; P = .0012). The median PFS in the investigative and control arms was 9.7 months (95% CI, 7.6-11.3) and 5.6 months (95% CI, 5.3-7.5), respectively.

The indication for use in CRC was based on data from the phase 3 KEYNOTE-177 trial (NCT02563002), which showed that the PD-1 inhibitor resulted in a significant 40% reduction in the risk of disease progression or death vs standard-of-care chemotherapy in patients with unresectable, advanced or recurrent, MSI-H CRC (HR, 0.60; 95% CI, 0.45-0.80; P = .0002). The median PFS with pembrolizumab was 16.5 months (95% CI, 5.4-32.4) vs 8.2 months (95% CI, 6.1-10.2) with chemotherapy.

“We are pleased to offer 2 potential new treatment options with [pembrolizumab] for patients in Japan based on compelling data from our clinical trial program,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, and chief medical officer at Merck Research Laboratories, stated in a press release. “[Pembrolizumab] has now been approved across 9 tumor types as well as MSI-H tumors in Japan, underscoring our commitment to advancing cancer care.”

KEYNOTE-355: Pembrolizumab/Chemo in TNBC

The double-blind phase 3 KEYNOTE-355 trial enrolled previously untreated patients with locally recurrent inoperable or metastatic TNBC who were 18 years of age or older, had PD-L1 expression, an ECOG performance status of 0 to 1, a life expectancy of 12 weeks or longer from randomization, and acceptable organ function.2 Patients who received systemic steroids, had active central nervous system metastases, or active autoimmune disease were excluded.²

Study participants were randomized 2:1. Those in the investigative arm (n = 566) received pembrolizumab at 200 mg every 3 weeks plus 1 of the following chemotherapy regimens: nab-paclitaxel at 100 mg/m2 on days 1, 8, and 15 every 28 days; paclitaxel at 90 mg/m2 on days 1, 8, and 15 every 28 days; or gemcitabine at 1000 mg/m2 plus carboplatin at area under the curve 2 on days 1 and 8 every 21 days. Those in the control arm (n = 281) received placebo plus chemotherapy.

Treatment was administered until either disease progression or cessation of study therapy. Patients were stratified according to chemotherapy received on the study (taxane vs gemcitabine/carboplatin), PD-L1 expression (CPS ≥1 vs CPS <1), previous treatment with same class of chemotherapy in the neoadjuvant or adjuvant setting (yes vs no).

The primary end points of the trial were PFS in the subset of patients with PD-L1–positive tumors and in the intent-to-treat (ITT) population and overall survival (OS) in both groups. Key secondary end points comprised objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and safety in all treated patients.

The median age of patients in the ITT population across the arms was 53 years and 39.7% had an ECOG performance status of 1. Regarding PD-L1 expression, 75.1% of patients had a CPS of 1 or higher and 37.8% had a CPS of 10 or higher. Slightly more patients (54.9%) received gemcitabine/carboplatin on the study vs 45.2% of those who received taxane treatment.

Additional data presented during the 2020 ASCO Virtual Scientific Program showed that pembrolizumab plus chemotherapy also resulted in an improved median PFS in the subset of patients with a CPS of 1 or higher over chemotherapy alone, at 7.6 months vs 5.6 months, respectively (HR, 0.74; 95% CI, 0.61-0.90; P = .0014). In the ITT population, the PFS favored the pembrolizumab arm with a hazard ratio of 0.82 (95% CI, 0.69-0.97).

The OS results from the trial will be shared at an upcoming medical conference, according to Merck.

Regarding safety, adverse effects (AEs) were experienced by 96.8% of 219 patients with a PD-L1 CPS of 10 or higher who were included in the safety analysis set and received pembrolizumab, according to the Japanese package insert; this included 19 out of 19 Japanese patients.

The most common toxicities with the immunotherapy that were experienced by 20% or more patients included anemia (48.9%), nausea (41.1%), neutropenia (39.7%), alopecia (34.7%), fatigue (29.2%), decreased neutrophil count (23.7%), diarrhea (21.9%), and vomiting (20.1%).

KEYNOTE-177: Pembrolizumab Monotherapy in CRC

The phase 3 KEYNOTE-177 trial enrolled treatment-naïve patients with MSI-H/mismatch repair deficient (dMMR) stage IV CRC who had measurable disease and an ECOG performance status of 0 or 1.³

A total of 307 participants were randomized 1:1 to receive either pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles (n = 153) or investigator’s choice of chemotherapy (n = 154) which could include any of the following regimens: mFOLFOX6 every 2 weeks, mFOLFOX6 plus bevacizumab (Avastin) every 2 weeks, mFOLFOX6 plus cetuximab (Erbitux) every 2 weeks, FOLFIRI every 2 weeks, FOLFIRI plus bevacizumab every 2 weeks, or FOLFIRI plus cetuximab every 2 weeks.

Participants received treatment until intolerable toxicity, disease progression, or withdrawal decision made by either the physician or the patient. Notably, those on the control arm were permitted to crossover to receive pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles if they had verified progressive disease per RECIST v1.1 criteria and central review.

The co-primary end points were PFS per RECIST v1.1 criteria and blinded independent central review (BICR) and OS. Key secondary end points comprised ORR per RECIST v1.1 criteria and BICR, PFS2, health-related quality of life, and safety.

Those on the study had a median age of 62.8 years, 49.8% were male, 51.8% had an ECOG performance status of 0, 50.2% had recurrent disease, and 40.7% had liver metastasis. Most of the patients (72.3%) were from the Western Europe/North America region, had right-sided tumors (68.1%), and did not receive prior therapy (73.0%).

Additional findings presented during the 2021 ASCO Annual Meeting showed that the median PFS2 in the investigative and control arms was 54.0 months (95% CI, 44.4–not reached [NR]) and 24.9 months (95% CI, 16.6-32.6), respectively (HR, 0.61; 95% CI, 0.44-0.83).

Pembrolizumab elicited an ORR of 45.1% vs 33.1% with chemotherapy. The ORR in the investigative arm was comprised of a 13.1% complete response rate, a 32.0% partial response rate, and a stable disease rate of 19.6%; in the control arm, these rates were 3.9%, 29.2%, and 42.2%, respectively.

The DCR with pembrolizumab was 64.7% vs 75.3% with chemotherapy. Moreover, the median DOR had not been reached (range, 2.3+ to 53.5+) in the investigative arm vs 10.6 months (range, 2.8 to 48.3+) in the control arm, with 83.5% and 33.6% of patients, respectively, experiencing a response duration of 24 months or longer.

Thirty-six percent of 154 patients on the chemotherapy arm crossed over to receive the PD-1 inhibitor after confirmed progressive disease. Thirty-seven additional patients received PD-1/PD-L1 therapy outside of the study for an effective crossover rate of 60% in the ITT population.

The median OS had not yet been reached (95% CI, 49.2–NR) in the pembrolizumab arm vs 36.7 months (95% CI, 27.6–NR) in the chemotherapy arm (HR, 0.74; 95% CI, 0.53-1.03; P = .0359).

Regarding safety, 97.4% of those on the pembrolizumab arm vs 99.3% of those on the chemotherapy arm experienced AEs; 79.7% and 98.6%, respectively, were related to treatment and 21.6% and 66.4%, respectively, were grade 3 or higher in severity. Fifteen patients on the investigative arm discontinued treatment vs 10 patients on the control arm.

Additionally, 30.7% of those who received pembrolizumab experienced immune-mediated AEs and infusion reactions vs 14.7% of those who were given chemotherapy; 9.2% and 2.1% of patients, respectively, reported grade 3 or higher AEs.

References

1. Merck’s KEYTRUDA (pembrolizumab) receives two new approvals in Japan. News release. Merck. August 26, 2021. Accessed August 26, 2021. https://bit.ly/3sQ0f3B
2. Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol. 2020;38(suppl 15):1000. doi:10.1200/JCO.2020.38.15_suppl.1000
3. Andre T, Shiu K-K, Kim TW, et al. Final overall survival for the phase III KN177 study: pembrolizumab versus chemotherapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). J Clin Oncol. 2021;39(suppl 15):3500. doi:10.1200/JCO.2021.39.15_suppl.3500