Therapy Areas: Respiratory
US Merck's Keytruda in Combination with Chemotherapy Met Primary Endpoint of Progression-Free Survival as First-Line Treatment for Metastatic Triple-Negative Breast Cancer
14 February 2020 - - US-based pharmaceutical company Merck's (NYSE: MRK) pivotal Phase 3 KEYNOTE-355 trial investigating Keytruda, Merck's anti-PD-1 therapy, in combination with chemotherapy met one of its dual primary endpoints of progression-free survival in patients with metastatic triple-negative breast cancer (mTNBC) whose tumors expressed PD-L1 (Combined Positive Score [CPS] ≥10), the company said.

Based on an interim analysis conducted by an independent Data Monitoring Committee, first-line treatment with Keytruda in combination with chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) demonstrated a statistically significant and clinically meaningful improvement in PFS compared to chemotherapy alone in these patients.

Based on the recommendation of the DMC, the trial will continue without changes to evaluate the other dual primary endpoint of overall survival.

The safety profile of Keytruda in this trial was consistent with that observed in previously reported studies; no new safety signals were identified.

The Keytruda breast cancer clinical development program encompasses several internal and external collaborative studies. In addition to KEYNOTE-355, in TNBC these include the ongoing registration-enabling studies KEYNOTE-242 and KEYNOTE-522.

KEYNOTE-355 is a randomized, two-part, Phase 3 trial (ClinicalTrials.gov, NCT02819518) evaluating Keytruda in combination with one of three different chemotherapies (investigator's choice of either nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) compared with placebo plus one of the three chemotherapy regimens for the treatment of locally recurrent inoperable or mTNBC that has not been previously treated with chemotherapy in the metastatic setting.

Part 1 of the study was open-label and evaluated the safety and tolerability of Keytruda in combination with either nab-paclitaxel, paclitaxel or gemcitabine/carboplatin in 30 patients.

Part 2 of KEYNOTE-355 was double-blinded, with dual primary endpoints of OS and PFS in all participants and in participants whose tumors expressed PD-L1 (CPS ≥1 and CPS ≥10).

The secondary endpoints include objective response rate, duration of response, disease control rate and safety.

Part 2 of KEYNOTE-355 enrolled 847 patients who were randomized to receive KEYTRUDA (200 mg intravenously [IV] on day 1 of each 21-day cycle) plus nab-paclitaxel (100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle), paclitaxel (90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle) or gemcitabine/carboplatin (1,000 mg/m2 [gemcitabine] and Area Under the Curve [AUC] 2 [carboplatin] on days 1 and 8 of each 21-day cycle); or placebo (normal saline on day 1 of each 21-day cycle) plus nab-paclitaxel (100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle), paclitaxel (90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle) or gemcitabine/carboplatin (1,000 mg/m2 [gemcitabine] and AUC 2 [carboplatin] on days 1 and 8 of each 21-day cycle).

Triple-Negative Breast Cancer is an aggressive type of breast cancer that characteristically has a high recurrence rate within the first five years after diagnosis.

While some breast cancers may test positive for estrogen receptor, progesterone receptor or human epidermal growth factor receptor 2, TNBC tests negative for all three.

As a result, TNBC does not respond to therapies targeting these markers, making it more difficult to treat. Approximately 15-20% of patients with breast cancer are diagnosed with TNBC.

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 1,000 trials studying Keytruda across a wide variety of cancers and treatment settings.

The Keytruda clinical program 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.
Keytruda is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

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 paclitaxel protein-bound, 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 NSCLC expressing PD-L1 [tumor proportion score ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

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.

Keytruda is indicated for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy.

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 confirmatory trials.

Keytruda, in combination with platinum and fluorouracil, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

Keytruda, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score ≥1] as determined by an FDA-approved test.

Keytruda, as a single agent, 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.

Keytruda is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma, or who have relapsed after 3 or more prior lines of therapy.

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.

Keytruda is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.

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 confirmatory trials.

Keytruda is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Keytruda is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score ≥10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.

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

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