Merck’s KEYTRUDA® (pembrolizumab) Plus Chemotherapy Showed Statistically Significant Increase in Pathological Complete Response Versus Chemotherapy as Neoadjuvant Therapy in Early-Stage Triple-Negative Breast Cancer (TNBC)

Interim Results from Pivotal Neoadjuvant/Adjuvant Phase 3 KEYNOTE-522 Trial Presented for the First Time at ESMO 2019 Congress During Presidential Symposium

As Previously Announced, KEYTRUDA Plus Chemotherapy Has Been Granted Breakthrough Therapy Designation by US FDA for Neoadjuvant Treatment of High-Risk, Early-Stage TNBC

KENILWORTH, NJ, USA I September 30, 2019 I Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced results from the pivotal neoadjuvant/adjuvant Phase 3 KEYNOTE-522 trial in patients with early-stage triple-negative breast cancer (TNBC). The trial investigated a regimen of neoadjuvant KEYTRUDA, Merck’s anti-PD-1 therapy, plus chemotherapy, followed by adjuvant KEYTRUDA as monotherapy (the KEYTRUDA regimen) compared with a regimen of neoadjuvant chemotherapy followed by adjuvant placebo (the chemotherapy-placebo regimen). Interim findings – which are from the first randomized trial of an anti-PD-1 therapy in the neoadjuvant/adjuvant setting for TNBC – are being presented today during the Presidential Symposium at the European Society for Medical Oncology (ESMO) 2019 Congress (Abstract #LBA8).

In the neoadjuvant phase, KEYTRUDA plus chemotherapy (n=401) resulted in a statistically significant increase in pathological complete response (pCR) versus chemotherapy (n=201), from 51.2% with neoadjuvant chemotherapy to 64.8% for neoadjuvant KEYTRUDA plus chemotherapy, in patients with early-stage TNBC (p=0.00055). Pathological complete response, one of the dual primary endpoints was defined as ypT0/Tis ypN0 (i.e., no invasive residual cancer in breast and lymph nodes). The improvement seen when adding KEYTRUDA to neoadjuvant chemotherapy was observed regardless of PD-L1 expression. In the other dual primary endpoint of event-free-survival (EFS), with a median follow-up of 15.5 months, the KEYTRUDA regimen reduced the risk of progression in the neoadjuvant phase and recurrence in the adjuvant phase by 37% – a favorable trend for EFS – compared with the chemotherapy-placebo regimen (HR=0.63 [95% CI, 0.43-0.93]). The safety profiles of KEYTRUDA and chemotherapy in KEYNOTE-522 were consistent with previous studies.

“This innovative trial is the first to employ combined neoadjuvant and adjuvant treatment with KEYTRUDA in patients with early-stage TNBC,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “The results of the KEYNOTE-522 study, reported today, are very encouraging and have the potential to change the treatment of patients diagnosed with TNBC.”

“As an oncologist specializing in the treatment of TNBC, I am highly encouraged by the significant improvement in pCR rates with KEYTRUDA plus chemotherapy in the neoadjuvant setting and the positive trend for event free-survival demonstrated in this trial,” said Dr. Peter Schmid, lead, Centre for Experimental Cancer Medicine, Barts Cancer Institute. “There is significant need for new treatment regimens that can increase pCR rates in this patient population.”

As previously announced, KEYTRUDA plus chemotherapy was granted Breakthrough Therapy designation (BTD) by the U.S. Food and Drug Administration (FDA) for the neoadjuvant treatment of patients with high-risk, early-stage TNBC. The BTD was granted based on data from Phase 1b KEYNOTE-173 and Phase 2 I-SPY2 trial, which demonstrated encouraging anti-tumor activity with neoadjuvant KEYTRUDA plus chemotherapy in these patients.

“These findings from the KEYNOTE-522 trial are exciting for the TNBC community – a community in particular need of scientific advances,” said Hayley Dinerman, executive director, Triple Negative Breast Cancer Foundation. “We are committed to supporting patients with TNBC, and we are pleased to see new data focused on earlier lines of treatment.”

As previously announced, Merck plans to share early interim analysis data from KEYNOTE-522 with regulatory authorities. The company continues to progress a robust clinical development program for KEYTRUDA in breast cancer, which encompasses several internal studies and external collaborative trials, including KEYNOTE-355 and KEYNOTE-242.

Study Design and Additional Data from KEYNOTE-522 Trial (Abstract #LBA8)

KEYNOTE-522 is a Phase 3, randomized, double-blind trial (ClinicalTrials.gov, NCT03036488). The dual primary endpoints of pCR and EFS were evaluated based on a pre-specified group sequential approach. Secondary endpoints include: pCR rate using alternative definitions (ypT0 ypN0, i.e., no invasive or noninvasive residual cancer in breast and lymph nodes, and ypT0/Tis, i.e., no invasive residual tumor in breast at the time of definitive surgery); overall survival (OS); pCR, EFS and OS in patients whose tumors express PD-L1 combined positive score (CPS) ≥1; and safety. The study enrolled 1,174 patients who were randomized 2:1 to receive either:

  • The KEYTRUDA regimen: KEYTRUDA (Q3W) plus paclitaxel (weekly) and carboplatin (weekly or Q3W) for four cycles, followed by KEYTRUDA plus cyclophosphamide and either doxorubicin or epirubicin (Q3W) for four cycles as neoadjuvant therapy prior to surgery, followed by nine cycles of KEYTRUDA (Q3W) as adjuvant monotherapy post-surgery (n=784) or;
  • The chemotherapy-placebo regimen: Placebo (Q3W) plus paclitaxel (weekly) and carboplatin (weekly or Q3W) for four cycles, followed by placebo plus cyclophosphamide and either doxorubicin or epirubicin (Q3W) for four cycles, followed by nine cycles of placebo (Q3W) as adjuvant therapy post-surgery (n=390).

For secondary endpoints of pCR using alternative definitions, the rates of pCR defined as ypT0 ypN0 were 59.9% versus 45.3%, and the rates of pCR defined as ypT0/Tis were 68.6% versus 53.7% for neoadjuvant KEYTRUDA plus chemotherapy (n=401) versus neoadjuvant chemotherapy (n=201).

In an exploratory sub-group analysis of pCR based on PD-L1 expression, the improvement seen when adding KEYTRUDA to neoadjuvant chemotherapy was observed regardless of PD-L1 expression. In the PD-L1 CPS ≥1 subgroup, the rates of pCR were 68.9% for neoadjuvant KEYTRUDA plus chemotherapy (n=334) versus 54.9% for neoadjuvant chemotherapy (n=164). In the PD-L1 CPS<1 subgroup, the rates of pCR were 45.3% for neoadjuvant KEYTRUDA plus chemotherapy (n=64) versus 30.3% versus neoadjuvant chemotherapy (n=33).

During the neoadjuvant phase, treatment-related adverse events (TRAEs) of any grade occurred in 99.0% of patients receiving KEYTRUDA plus chemotherapy (n=781) and 99.7% of patients receiving chemotherapy (n=389). Grade 3-5 TRAEs occurred in 76.8% of patients receiving KEYTRUDA plus chemotherapy and 72.2% of patients receiving chemotherapy. The most common Grade 3-5 TRAEs (occurring in ≥10% of patients) were neutropenia (34.6%), decreased neutrophil count (18.7%), anemia (18.2%), and febrile neutropenia (17.7%) for KEYTRUDA plus chemotherapy and neutropenia (33.2%), decreased neutrophil count (23.1%), and anemia (14.9%) for chemotherapy. TRAEs resulting in discontinuation of any treatment occurred in 23.3% of patients receiving KEYTRUDA plus chemotherapy and 12.3% of patients receiving chemotherapy. TRAEs led to death in two patients receiving KEYTRUDA plus chemotherapy and one patient receiving chemotherapy.

During the adjuvant phase, TRAEs of any grade occurred in 48.1% of patients receiving KEYTRUDA (n=547) and 43.0% of patients receiving placebo (n=314). Grade 3-5 TRAEs occurred in 5.7% of patients receiving KEYTRUDA monotherapy and 1.9% of patients receiving placebo. There were no TRAEs occurring in ≥10% of patients. TRAEs resulting in discontinuation of treatment occurred in 3.3% of patients receiving KEYTRUDA monotherapy and 1.3% of patients receiving placebo. TRAEs led to death in one patient receiving KEYTRUDA monotherapy.

Immune-mediated adverse events and infusion reactions of any grade in the combined neoadjuvant and adjuvant phases occurred in 42.3% of patients receiving the KEYTRUDA regimen and 21.3% of patients receiving the chemotherapy-placebo regimen. The most common of these events (occurring in ≥10% of patients) were infusion reactions (17.7%) and hypothyroidism (14.9%) in the KEYTRUDA regimen and infusion reactions (11.6%) in the chemotherapy-placebo regimen. Immune-mediated adverse events led to death in one patient in the KEYTRUDA regimen.

About Triple-Negative Breast Cancer (TNBC)

TNBC 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 (HER2), 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.

About KEYTRUDA® (pembrolizumab) Injection, 100 mg

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 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 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.

Selected KEYTRUDA® (pembrolizumab) Indications

Melanoma

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.

Non-Small Cell Lung Cancer

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 (TPS) ≥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.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one 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.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), 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 (CPS) ≥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.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), 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.

Primary Mediastinal Large B-Cell Lymphoma

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.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) ≥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.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

  • solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
  • colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

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. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted 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.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. 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.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 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.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). 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.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

About Merck

For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world - including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

SOURCE: Merck

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