Therapy Areas: Oncology
US Merck Increases Focus on Advanced Prostate Cancer, Expanding Immuno-Oncology Programme with Three New Phase 3 Trials
15 February 2019 - - US-based biopharmaceutical company Merck (NYSE: MRK) has presented interim data from the Phase 1b/2 KEYNOTE-365 umbrella trial investigating Keytruda, Merck's anti-PD-1 therapy, in combination with various agents for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), the company said.

These early findings show anti-tumor activity across three cohorts of the study, which investigated Keytruda in combination with Lynparza (Cohort A, Abstract #145); docetaxel and prednisone (Cohort B, Abstract #170); and enzalutamide (Cohort C, Abstract #171) with a safety profile consistent with each therapy alone.

These results are being presented TODAY at the 2019 Genitourinary Cancers Symposium (ASCO GU) in San Francisco.

Based on the findings, Merck is initiating three new pivotal Phase 3 trials with Keytruda in combination with Lynparza (KEYLYNK-010, NCT03834519), docetaxel and prednisone (KEYNOTE-921, NCT03834506) and enzalutamide (KEYNOTE-641, NCT03834493).

Merck's existing clinical development program in metastatic prostate cancer includes studies evaluating Keytruda and Lynparza as monotherapy and in combination with other anti-cancer therapies with various mechanisms of action.

Ongoing trials include the Phase 2 KEYNOTE-199 trial for Keytruda monotherapy and, in collaboration with AstraZeneca, the Phase 3 trials PROfound evaluating Lynparza monotherapy and PROPEL evaluating Lynparza in combination with abiraterone as a first-line therapy in patients with mCRPC.

With the initiation of KEYLYNK-010, KEYNOTE-921 and KEYNOTE-641, Merck now has the largest clinical programme with an anti-PD-1 therapy in prostate cancer and the only program to evaluate overall survival as a co-primary endpoint across three Phase 3 trials.

KEYNOTE-365 (NCT02861573) is an ongoing global, open-label, non-randomized, multi-cohort, multi-center, Phase 1b/2 study evaluating the safety and efficacy of Keytruda (200 mg fixed dose every three weeks) in combination with Lynparza (Cohort A), docetaxel and prednisone (Cohort B) and enzalutamide (Cohort C) for the treatment of patients with mCRPC.

The primary endpoints are safety, prostatic specific antigen response rate (measured by confirmed decrease in PSA of 50% or greater) and overall response rate as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; secondary endpoints include disease control rate, radiographic progression-free survival and OS.

The study is designed to enroll 400 patients across four cohorts, with outcome measures assessed individually for each cohort. Data at ASCO GU include interim efficacy and safety findings from three of the study cohorts (A, B and C).

Cohort A is reported on 41 enrolled patients previously treated with docetaxel, and up to one other chemotherapy and up to two second-generation anti-hormone therapies. Patients in Cohort A received Keytruda in combination with Lynparza (400 mg capsules orally twice daily).

The efficacy analysis from Cohort A presented at ASCO GU showed a PSA response rate of 12 % in the total cohort population (n=5/41), 14 % among patients with measurable disease (n=4/28) and 8 % (n=1/13) among patients with non-measurable disease.

The median time to PSA progression was 15.3 (95% CI, 9.3-27.1) and 18.1 (95% CI, 9.3-21.0) weeks for patients with measurable and non-measurable disease, respectively.

Among patients with measurable disease, the ORR was 7% (95% CI, 1-23), with a partial response rate of 7% (n=2/28).

The disease control rate (of 6 months or more) was 29% (95% CI, 16-45) in the total cohort population, 32% (95% CI, 16-52) among patients with measurable disease and 23% (95% CI, 5-54) among patients with non-measurable disease.

In an analysis of rPFS and OS endpoints, the median rPFS was 4.7 months (95% CI, 4.0-7.7) and the six-month rPFS rate was 48%; the median OS was 13.5 months at the time of analysis (95% CI, 7.7-NR) and the six-month OS rate was 73%.

Analysis of the safety data showed that 49% of patients had a grade 3 or 4 treatment-related adverse event, the most common (occurring in ≥10% of patients) of which was anemia. Immune-mediated adverse events observed in this cohort were grade 1 or 2 and occurred in 49% of patients; the most commonly reported immune-mediated adverse event was hypothyroidism. One patient died of a TRAE of unknown cause.

Cohort B is reported on 72 enrolled patients previously treated with either abiraterone acetate or enzalutamide and who had not received chemotherapy. Patients in Cohort B received Keytruda in combination with docetaxel (75 mg) plus prednisone orally twice daily.

The efficacy analysis from Cohort B presented at ASCO GU showed a PSA response rate of 31% in the total cohort population (n=22/72), 22% among patients with measurable disease (n=8/36) and 39% among patients with non-measurable disease (n=14/36). The median time to PSA progression was 24.1 (95% CI, 15.1-30) and 30.4 (95% CI, 15.0-36.3) weeks for patients with measurable and non-measurable disease, respectively.

Among patients with measurable disease, the ORR was 14 % (95% CI, 5-29), with a partial response rate of 14% (n=5/36). The disease control rate (of six months or more) was 57 % (95% CI, 45-69) in the total cohort population, 50% (95% CI, 33-67) among patients with measurable disease and 64% (95% CI, 46-79) among patients with non-measurable disease.

The median duration of response was 4.9 months (95% CI, 4.0-8.3+). In an analysis of rPFS and OS endpoints, the median rPFS was 8.3 months (95% CI, 7.5-10.2) and the six-month rPFS rate was 79%; the median OS had not been reached at the time of analysis (95% CI, 12.9-NR); the six-month OS rate was 96%.

Analysis of the safety data showed that 36% of patients had a grade 3-5 TRAE, the most common (occurring in ≥10% of patients) of which was febrile neutropenia. Immune-mediated adverse events occurred in 33% of patients, the most common (occurring in ≥ 10% of patients) of which were infusion-related reactions and colitis; two patients died due to TRAEs (pneumonitis).

Cohort C is reported on 69 enrolled patients previously treated with abiraterone acetate and who had not received chemotherapy.

Patients in Cohort C received Keytruda in combination with enzalutamide (160 mg per day orally).

The efficacy analysis from Cohort C presented at ASCO GU showed a PSA response rate of 26 % in the total population (n=18/69), 40% among patients with measurable disease (n=10/25), and 18% among patients with non-measurable disease (n=8/44).

The median time to PSA progression was 18.4 (95% CI, 15.4-48.3) and 12.4 (95% CI, 12.0-15.1) weeks for patients with measurable and non-measurable disease, respectively.

Among patients with measurable disease, the ORR was 20% (95% CI, 7-41), with a complete response of 8% (n=2/25) and partial response of 12% (n=3/25).

The disease control rate (of 6 months or more) was 33% (95% CI, 22-46) in the total population, 32% (95% CI 15-53) among patients with measurable disease and 34% (95% CI, 20-50) among patients with non-measurable disease.

The median duration of response was 8.3 months (range, 0.0+-13.0+) and at the time of analysis, 75% of patients had responses lasting for six months or longer.

In an analysis of rPFS and OS endpoints, the median rPFS was 6.1 months (95% CI, 4.0-8.1); the six-month rPFS rate was 59%; the median OS had not been reached at the time of analysis (95% CI, 12.2-NR); the six-month OS rate was 91%.

Analysis of the safety data showed that 41 % of patients had a grade 3 or 4 TRAE, the most common (occurring in ≥ 10% of patients) of which was rash.

Immune-mediated adverse events occurred in 41 % of patients, the most common (occurring in ≥ 10% of patients) of which were severe skin reactions and hypothyroidism. No patients died of TRAEs.

Prostate cancer is typically driven by male sex hormones called androgens, including testosterone. Castration-resistant prostate cancer is characterized when the cancer continues to grow despite surgery or treatment to lower the amount of male sex hormones.

When CRPC spreads to other parts of the body, it is referred to as metastatic castration-resistant prostate cancer or mCRPC.

Prostate cancer is the second most common cancer in men, with an estimated 1.3 m new cases diagnosed worldwide in 2018.

In the United States, an estimated 174,650 men will be diagnosed with prostate cancer in 2019 and one in nine men will be diagnosed in his lifetime.

Approximately 10-20% of men with prostate cancer will develop CRPC within five years; within two years of a CRPC diagnosis, 33% of men will develop mCRPC.

Keytruda is an anti-PD-1 therapy that works by increasing the ability of the body's immune system to help detect and fight tumor cells.

Keytruda is a humanised monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry's largest immuno-oncology clinical research program. There are currently more than 900 trials studying Keytruda across a range of cancers and treatment settings.

The Keytruda clinical programme seeks to understand the role of Keytruda across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with Keytruda, including exploring several different biomarkers.

Keytruda is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Keytruda, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

Keytruda, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

Keytruda, as a single agent, is indicated for the first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression [Tumor Proportion Score ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

Keytruda, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy.

Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Keytruda.

In metastatic NSCLC, Keytruda is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering Keytruda in combination with chemotherapy, Keytruda should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for the chemotherapy agents administered in combination with Keytruda, as appropriate.

Keytruda is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In HNSCC, Keytruda is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
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