Merck, Eisai welcome final study results for Keytruda/Lenvima combo treatment in advanced endometrial cancer presented at ESMO 2019 congress

“The results of this Keytruda plus Lenvima study are a welcome development in the treatment of women with advanced endometrial cancer, a patient group with an unmet medical need,” said Dr. Vicky Makker, principal investigator and medical oncologist, Memorial Sloan Kettering Cancer Center.

KENILWORTH, N.J., & WOODCLIFF LAKE, N.J.–(BUSINESS WIRE)–$MRK #MRK–Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai today announced final results from the full endometrial cancer cohort of KEYNOTE-146/Study 111 evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, plus LENVIMA, an orally available kinase inhibitor discovered by Eisai. The primary endpoint was objective response rate (ORR) at week 24 as assessed by investigators per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). The findings are being presented today in a proffered paper presentation at the European Society for Medical Oncology (ESMO) 2019 Congress (Abstract #994O).

“The results of this KEYTRUDA plus LENVIMA study are a welcome development in the treatment of women with advanced endometrial cancer, a patient group with an unmet medical need,” said Dr. Vicky Makker, principal investigator and medical oncologist, Memorial Sloan Kettering Cancer Center.

KEYNOTE-146/Study 111 supported the U.S. Food and Drug Administration (FDA) approval for the combination of KEYTRUDA plus LENVIMA for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This indication is approved under accelerated approval based on tumor response rate and durability of response. In Sept. 2019, the Australian Therapeutic Goods Administration (TGA) and Health Canada also approved the combination of KEYTRUDA plus LENVIMA for the treatment of advanced endometrial carcinoma. Continued approval for this indication may be contingent in each jurisdiction upon verification and description of clinical benefit in the confirmatory trial.

“The data observed in KEYNOTE-146/Study 111 reinforce the importance of our collaboration with Eisai to evaluate this combination in different types of cancer,” said Dr. Jonathan Cheng, Vice President, Oncology Clinical Research, Merck Research Laboratories. “We look forward to sharing these important data with the scientific community and highlighting the progress being made with the joint efforts of our two companies.”

“These data from the full endometrial cohort of KEYNOTE-146/Study 111 represent a step forward for patients impacted by advanced endometrial cancer,” said Dr. Takashi Owa, Vice President, Chief Medicine Creation and Chief Discovery Officer, Oncology Business Group at Eisai. “At Eisai, our commitment to human health care is at the forefront of everything we do, and we are hopeful for the potential of this combination across multiple cancer types.”

Trial Design and New Data from KEYNOTE-146/Study 111 (Abstract #994O)

KEYNOTE-146/Study 111 (ClinicalTrials.gov, NCT02501096) is a Phase 1b/2, open-label, single-arm trial of 108 patients with metastatic endometrial carcinoma that had progressed following at least one prior systemic therapy in any setting, with a median follow-up of 18.7 months. Ninety-four patients had tumors that were not MSI-H or dMMR, 11 patients had tumors that were MSI-H or dMMR, and three patients had tumors of unknown status. Patients were treated with LENVIMA 20 mg orally once daily in combination with KEYTRUDA 200 mg intravenously every three weeks.

The primary endpoint was ORR at week 24. Key secondary endpoints include overall ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), clinical benefit rate (CBR), safety and tolerability at the time of data cutoff (January 10, 2019). Tumor responses for primary and secondary endpoints were assessed by investigators per irRECIST. Pre-specified exploratory endpoints include independent imaging review (IIR) per irRECIST and RECIST version 1.1 and antitumor activity by PD-L1 status.

As assessed by investigators per irRECIST, in the total study population of 108 patients, irrespective of microsatellite instability (MSI) or mismatch repair (MMR) status, the KEYTRUDA plus LENVIMA combination demonstrated an ORR at week 24 of 38.0% (N=41) (95% CI: 28.8%-47.8%). At data cutoff, overall ORR was 38.9% (N=42) (95% CI: 29.7%-48.7%), with a complete response rate of 7.4% (N=8) and a partial response rate of 31.5% (N=34). Median DOR was 21.2 months (range: 1.2+ to 35.6+ months). In the 94 patients with tumors that were not MSI-H or dMMR, at data cutoff, the KEYTRUDA plus LENVIMA combination demonstrated an ORR at week 24 of 36.2% (N=34) (95% CI: 26.5%-46.7%). At data cutoff, overall ORR was 37.2% (N=35) (95% CI: 27.5%-47.8%), with a complete response rate of 7.4% (N=7) and a partial response rate of 29.8% (N=28). Median DOR was not estimable (range: 1.2+ to 33.8+ months). In the 11 patients with tumors that were MSI-H or dMMR, the KEYTRUDA plus LENVIMA combination demonstrated an ORR at week 24 of 63.6% (N=7) (95% CI: 30.8%-89.1%). At data cutoff, overall ORR was 63.6% (N=7) (95% CI: 30.8%-89.1%), with a complete response rate of 9.1% (N=1) and a partial response rate of 54.5% (N=6). Median DOR was 21.2 months (range: 6.1+ to 35.6+ months).

In a pre-specified exploratory analysis, tumor responses also were assessed by IIR per RECIST version 1.1. In the total study population of 108 patients, at data cutoff, the KEYTRUDA plus LENVIMA combination demonstrated an ORR of 40.7% (N=44) (95% CI: 31.4%-50.6%), with a complete response rate of 10.2% (N=11) and a partial response rate of 30.6% (N=33). Median DOR was 14.8 months (range: 1.2+ to 35.6+ months). The median PFS was 7.5 months (95% CI: 5.0-8.3), and the median OS was 16.7 months (95% CI: 15.0-NE). In the 94 patients with tumors that were not MSI-H or dMMR, at data cutoff, the KEYTRUDA plus LENVIMA combination demonstrated an ORR of 38.3% (N=36) (95% CI: 28.5%-48.9%), with a complete response rate of 10.6% (N=10) and a partial response rate of 27.7% (N=26). Median DOR was not estimable (range: 1.2+ to 33.1+ months). The median PFS was 5.4 months (95% CI: 4.4-7.6), and the median OS was 16.4 months (95% CI: 13.5-25.9). In the 11 patients with tumors that were MSI-H or dMMR, at data cutoff, the KEYTRUDA plus LENVIMA combination demonstrated an ORR of 63.6% (N=7) (95% CI: 30.8%-89.1%), with a complete response rate of 9.1% (N=1) and a partial response rate of 54.5% (N=6). Median DOR was not estimable (range: 2.1+ to 35.6+ months). The median PFS was 18.9 months (95% CI: 3.9-NE), and the median OS was not estimable (95% CI: 7.4-NE).

Treatment-related treatment-emergent adverse events (TEAEs) leading to discontinuation of KEYTRUDA and/or LENVIMA occurred in 18.5% of patients (N=20). Both KEYTRUDA and LENVIMA were discontinued in 9.3% of patients (N=10); LENVIMA was discontinued in 15.7% of patients (N=17), regardless of action taken with KEYTRUDA; and KEYTRUDA was discontinued in 13% of patients (N=14), regardless of action taken with LENVIMA. Treatment-related TEAEs leading to dose reduction of LENVIMA occurred in 64.8% of patients (N=70 patients). Treatment-related TEAEs leading to interruption of KEYTRUDA and/or LENVIMA occurred in 72.2% of patients (N=78); interruption of both KEYTRUDA and LENVIMA occurred in 27.8% of patients (N=30); interruption of LENVIMA occurred in 67.6% of patients (N=73), regardless of action taken with KEYTRUDA; and interruption of KEYTRUDA occurred in 39.8% of patients (N=43), regardless of action taken with LENVIMA.

In the total study population (N=108), treatment-related TEAEs occurred in 97.2% of patients (N=105) who received the KEYTRUDA plus LENVIMA combination. The most common treatment-related TEAEs (any grade) (≥20%) were hypertension (60.2%), diarrhea (52.8%), decreased appetite (47.2%), fatigue (51.9%), hypothyroidism (43.5%), nausea (39.8%), stomatitis (33.3%), arthralgia (31.5%), dysphonia (27.8%), vomiting (26.9%), palmar-plantar erythrodysesthesia syndrome (25.9%), decreased weight (25.9), proteinuria (22.2%), and headache (20.4%). Treatment-related TEAEs (Grade 3-4) occurred in 69.4% of patients (N=75) receiving the KEYTRUDA plus LENVIMA combination. The most common treatment-related TEAEs (≥3%) with the KEYTRUDA and LENVIMA combination were hypertension (32.4%), fatigue (8.3%) diarrhea (6.5%), and proteinuria (3.7%).

In the total study population (N=108), immune-related TEAEs occurred in 57.4% of patients (N=62) who received the KEYTRUDA plus LENVIMA combination. The most common immune-related TEAE (any grade) (≥20%) was hypothyroidism (47.2%). Immune-related TEAEs (Grade 3-4) occurred in 13% of patients (N=14) who received the KEYTRUDA plus LENVIMA combination. The most common immune-related TEAE (Grade ≥3) (≥3%) was severe skin reactions (4.6%).