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Merck, known as MSD outside of the United States and Canada, today announced that the phase 3 KEYNOTE-522 trial evaluating Keytruda, Merck’s anti-PD-1 therapy, met its overall survival (OS) endpoint, in combination with chemotherapy as pre-operative (neoadjuvant) treatment and then continuing as a single agent after surgery (adjuvant) for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC). At a pre-specified interim analysis conducted by an independent Data Monitoring Committee, Keytruda demonstrated a statistically significant and clinically meaningful improvement in OS compared to pre-operative chemotherapy. The safety profile of Keytruda was consistent with that observed in previously reported studies; no new safety signals were observed. Results will be presented at an upcoming medical meeting and shared with regulatory authorities.
“This is a significant milestone, as it is the first time an immunotherapy-based regimen has demonstrated a statistically significant overall survival benefit compared to chemotherapy alone in patients with high-risk early-stage triple-negative breast cancer,” said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. “To have achieved overall survival from this landmark study is highly encouraging and builds upon the positive pathological complete response and event-free survival results that led to approvals for this regimen around the world.”
KEYNOTE 522 is the fourth study of a Keytruda-based regimen in an earlier stage of cancer to demonstrate an OS benefit, in addition to KEYNOTE-A18 in cervical cancer, KEYNOTE-671 in non-small cell lung cancer and KEYNOTE-564 in renal cell carcinoma.
In the US, Keytruda has two approved indications in TNBC: for the treatment of patients with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery; and in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumours express PD-L1 (CPS =10) as determined by an FDA-approved test.
Merck has a comprehensive clinical development programme in various subtypes of breast cancer. This includes KEYNOTE-242 evaluating Keytruda monotherapy as adjuvant treatment in patients with TNBC who have residual disease; KEYNOTE-756 evaluating Keytruda plus chemotherapy in patients with high-risk, early-stage estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer; TroFuse-010 evaluating Keytruda plus sacituzumab tirumotecan (sac-TMT), an investigational trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate that Merck is developing in collaboration with Kelun-Biotech, compared to sac-TMT alone and compared to physician’s choice of treatment in patients with unresectable locally advanced or metastatic ER+/HER2- breast cancer; and TroFuse-012 evaluating Keytruda plus sac-TMT versus physician’s choice of treatment in patients with TNBC who received Keytruda-based neoadjuvant therapy and did not achieve a pathological complete response (pCR) at surgery.
KEYNOTE-522 (ClinicalTrials.gov, NCT03036488), is a randomized, double-blind phase 3 trial. The dual primary endpoints were pCR rate, defined as pathological stage ypT0/Tis ypN0 at the time of definitive surgery, and event-free survival, defined as the time from randomization to the time of first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer or death from any cause. A key secondary endpoint was OS. The study enrolled 1,174 patients who were randomized 2:1 to receive either:
The Keytruda regimen: Keytruda plus chemotherapy (paclitaxel and carboplatin), followed by Keytruda plus chemotherapy (cyclophosphamide and either doxorubicin or epirubicin) as neoadjuvant therapy prior to surgery, followed by Keytruda monotherapy as adjuvant therapy post-surgery (n=784) or;
The chemotherapy-placebo regimen: Placebo plus chemotherapy (paclitaxel and carboplatin), followed by placebo plus chemotherapy (cyclophosphamide and either doxorubicin or epirubicin) as neoadjuvant therapy prior to surgery, followed by placebo monotherapy as adjuvant therapy post-surgery (n=390).
Triple-negative breast cancer is the most aggressive type of breast cancer, which has the highest risk of recurrence within the first five years after diagnosis and is associated with worse outcomes compared to other forms of breast cancer. Approximately 10-15% of patients with breast cancer are diagnosed with TNBC. While some breast cancers may test positive for estrogen receptors, progesterone receptors or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three. Triple-negative breast cancer tends to be more common in people who are younger than 40 years of age, who are Black or who have a BRCA1 mutation.
Merck is advancing research aimed at improving outcomes for patients affected by breast and gynaecologic (ovarian, cervical and endometrial) cancers. Merck has a comprehensive clinical development program across these cancers comprised of more than 20 Merck-sponsored phase 3 studies evaluating Keytruda as monotherapy and in combination with other medicines. In the US, Keytruda currently has two approved indications for TNBC, including one for high-risk early-stage disease, and five approved indications across certain types of cervical and endometrial cancers. Among Merck’s research efforts are trials focused on evaluating Keytruda in earlier stages of these cancers, as well as identifying new combinations and coformulations with Keytruda.
Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of Keytruda in later-stage cancers, Merck is evaluating our portfolio of medicines and pipeline candidates in earlier disease states, with more than 30 ongoing registrational studies across multiple types of cancer.
Keytruda is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumour cells. Keytruda is a humanized 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 tumour cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying Keytruda across a wide variety 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.
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