FDA Approves Merck’s KEYTRUDA® (pembrolizumab) Plus Chemotherapy, With or Without Bevacizumab, as Treatment for Patients With Persistent, Recurrent or Metastatic Cervical Cancer Whose Tumors Express PD-L1 (CPS ≥1)

This Is the First Anti-PD-1 Combination Approved as First-Line Treatment for These Patients

KENILWORTH, N.J.–(BUSINESS WIRE)–$MRK #MRK–Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1) as determined by an FDA-approved test. The approval is based on the Phase 3 KEYNOTE-826 trial evaluating KEYTRUDA plus chemotherapy (paclitaxel plus cisplatin or paclitaxel plus carboplatin), with or without bevacizumab, compared to the same chemotherapy regimens, with or without bevacizumab.

In this patient population, KEYTRUDA plus chemotherapy, with or without bevacizumab, demonstrated superior overall survival (OS; HR=0.64 [95% CI, 0.50-0.81]; p=0.0001) and progression-free survival (PFS; HR=0.62 [95% CI, 0.50-0.77]; p<0.0001) compared to chemotherapy, with or without bevacizumab, in patients whose tumors express PD-L1 (CPS ≥1). Additionally, more patients responded to KEYTRUDA plus chemotherapy, with or without bevacizumab, than to chemotherapy, with or without bevacizumab, with an objective response rate (ORR) of 68% (95% CI, 62-74) versus 50% (95% CI, 44-56), respectively. Among patients who responded, the median duration of response (DOR) was 18.0 months (range, 1.3+ to 24.2+) for KEYTRUDA plus chemotherapy, with or without bevacizumab, and 10.4 months (range, 1.5+ to 22.0+) for chemotherapy, with or without bevacizumab.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below.

“Cervical cancer more commonly affects younger women and certain women of color in the U.S., and unfortunately, women diagnosed with persistent, recurrent or metastatic cervical cancer often have a low survival rate,” said Dr. Bradley Monk, oncologist with Arizona Oncology, medical director of U.S. Oncology Research Gynecology Program and professor of obstetrics and gynecology at University of Arizona’s College of Medicine and Creighton University School of Medicine. “There have been no first-line approvals for women with persistent, recurrent or metastatic cervical cancer in the past seven years. I am excited for today’s approval of a new combination with KEYTRUDA, which offers a new treatment option for appropriate patients.”

“Today’s news is a meaningful step forward, as it offers a new therapeutic option for these patients and reinforces the role of KEYTRUDA in treating certain types of cervical cancers, with a second indication for the disease,” said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “The data showing a 36% reduction in the risk of death are compelling, and this approval brings an important new first-line treatment option to women with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1).”

Additionally, the FDA converted the accelerated approval of KEYTRUDA as a single agent 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, to a regular approval based on confirmatory data from KEYNOTE-826. This approval was originally granted in June 2018 based on results from the KEYNOTE-158 trial.

Merck is committed to delivering meaningful advances in women’s cancers. The company is rapidly expanding its extensive clinical development program for KEYTRUDA and several other investigational and approved medicines across gynecologic cancers, including researching KEYTRUDA for the treatment of other types of cervical cancer.

About KEYNOTE-826

The approval was based on data from KEYNOTE-826 (ClinicalTrials.gov, NCT03635567), a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial that enrolled 617 patients with persistent, recurrent or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent. Patients were enrolled regardless of tumor PD-L1 expression status. Patients with autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by metastatic status at initial diagnosis, investigator decision to use bevacizumab and PD-L1 status (CPS <1 vs. CPS 1 to <10 vs. CPS ≥10). Patients were randomized (1:1) to one of the two treatment groups.

Patients in the KEYTRUDA arm received KEYTRUDA 200 mg intravenously every three weeks (Q3W) plus investigator’s choice of paclitaxel plus cisplatin or paclitaxel plus carboplatin Q3W, with or without bevacizumab Q3W. Patients in the placebo arm received placebo plus investigator’s choice of paclitaxel plus cisplatin or paclitaxel plus carboplatin Q3W, with or without bevacizumab Q3W. All study treatments were administered on Day 1 of each 3-week treatment cycle. Cisplatin could be administered on Day 2 of each three-week treatment cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease, unacceptable toxicity or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed every nine weeks for the first year, followed by every twelve weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by investigator review according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ. Additional efficacy outcome measures were ORR and DOR, according to RECIST v1.1, as assessed by investigator review.

Of the 617 enrolled patients, 548 patients (89%) had tumors expressing PD-L1 with a CPS ≥1. Among these 548 enrolled patients with tumors expressing PD-L1, 273 patients were randomized to KEYTRUDA in combination with chemotherapy, with or without bevacizumab, and 275 patients were randomized to placebo in combination with chemotherapy, with or without bevacizumab. Sixty-three percent of the 548 patients received bevacizumab as part of study treatment. At study entry, 21% of patients had metastatic disease only, and 79% had persistent or recurrent disease, with or without distant metastases, of whom 39% had received prior chemoradiation only, and 17% had received prior chemoradiation plus surgery.

The key efficacy results for patients with tumors expressing PD-L1 (CPS ≥1) are summarized below:

Endpoint	KEYTRUDA + Chemotherapy* With or Without Bevacizumab n=273	Placebo + Chemotherapy* With or Without Bevacizumab n=275
OS
Number of patients with event (%)	118 (43.2)	154 (56.0)
Median in months (95% CI)	NR (19.8, NR)	16.3 (14.5, 19.4)
Hazard ratio† (95% CI)	0.64 (0.50, 0.81)
p-Value‡	0.0001
PFS
Number of patients with event (%)	157 (57.5)	198 (72.0)
Median in months (95% CI)	10.4 (9.7, 12.3)	8.2 (6.3, 8.5)
Hazard ratio† (95% CI)	0.62 (0.50, 0.77)
p-Value§	<0.0001
ORR
ORR¶ (95% CI)	68% (62, 74)	50% (44, 56)
Complete response rate	23%	13%
Partial response rate	45%	37%
DOR
Median in months (range)	18.0 (1.3+, 24.2+)	10.4 (1.5+, 22.0+)
* Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) † Based on the stratified Cox proportional hazard model ‡ p-Value (one-sided) is compared with the allocated alpha of 0.0055 for this interim analysis (with 72% of the planned number of events for final analysis) § p-Value (one-sided) is compared with the allocated alpha of 0.0014 for this interim analysis (with 82% of the planned number of events for final analysis) ¶ Response: Best objective response as confirmed complete response or partial response + Denotes ongoing response NR = not reached

Select Safety Profile From KEYNOTE-826

Fatal adverse reactions occurred in 4.6% of patients receiving KEYTRUDA plus chemotherapy, with or without bevacizumab, including three cases of hemorrhage, two cases of sepsis, two cases due to unknown causes and one case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA plus chemotherapy, with or without bevacizumab. Serious adverse reactions in ≥3% of patients included febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each).

KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was colitis (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 66% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were thrombocytopenia (15%), neutropenia (14%), anemia (11%), increased alanine aminotransferase (ALT) (6%), leukopenia (5%), fatigue/asthenia (4.2%), urinary tract infection (3.6%), increased aspartate aminotransferase (AST) and pyrexia (3.3% each), diarrhea, acute kidney injury and increased blood creatinine (2.6% each), colitis (2.3%), and decreased appetite and cough (2% each).

For patients treated with KEYTRUDA plus chemotherapy with bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%) and decreased appetite (21%). The most common adverse reactions (all grades ≥20%) for KEYTRUDA plus chemotherapy, with or without bevacizumab (n=307), were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%).

About Cervical Cancer

Cervical cancer forms in the cells lining the cervix, which is the lower part of the uterus. While screenings and prevention have resulted in declining cervical cancer rates, the disease continues to affect many people in the U.S. and around the world. Cervical cancer is the fourth most commonly diagnosed cancer in women and the fourth leading cause of cancer-related death in women worldwide. It is estimated there were more than 604,000 new cases of cervical cancer diagnosed and nearly 342,000 deaths resulting from the disease in 2020 globally. In the U.S., it is estimated there will be nearly 14,500 new cases of invasive cervical cancer diagnosed and almost 4,300 deaths resulting from the disease in 2021. For patients in the U.S. who are diagnosed with cervical cancer, the five-year relative survival rate is 66.3%. For patients diagnosed with cervical cancer that has spread to distant parts of the body, this drops to 17.6%.

About KEYTRUDA^® (pembrolizumab) Injection, 100 mg

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 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 1,600 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 in the U.S.

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.

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 HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

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. 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 any platinum-containing chemotherapy, or
• who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Non-muscle Invasive Bladder Cancer

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient 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.

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.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. 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 locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

• in combination with platinum- and fluoropyrimidine-based chemotherapy, or
• as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test.

Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (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 cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

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 adult patients with advanced renal cell carcinoma.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. 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 TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction.

Contacts

Media Contacts:

Melissa Moody

(215) 407-3536

Andrea Park

(929) 481-2599

Investor Contacts:

Peter Dannenbaum

(908) 740-1037

Raychel Kruper

(908) 740-2107

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