KEYTRUDA® (pembrolizumab) Plus Chemotherapy Before Surgery and Continued as a Single Agent After Surgery Showed Statistically Significant Event-Free Survival (EFS) Result Versus Neoadjuvant Chemotherapy Alone in High-Risk Early-Stage TNBC

KEYNOTE-522 Is the First Phase 3 Study With an Immunotherapy to Show Positive EFS Results in High-Risk Early-Stage Triple-Negative Breast Cancer

Merck Has Submitted These Data From KEYNOTE-522 to the US FDA for Review

KENILWORTH, N.J.–(BUSINESS WIRE)–$MRK #MRK–Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced positive event-free survival (EFS) data from the pivotal neoadjuvant/adjuvant Phase 3 study KEYNOTE-522. The trial investigated neoadjuvant KEYTRUDA, Merck’s anti-PD-1 therapy, plus chemotherapy followed by adjuvant KEYTRUDA as monotherapy (the KEYTRUDA regimen) compared with neoadjuvant chemotherapy followed by adjuvant placebo (the chemotherapy-placebo regimen) in patients with high-risk early-stage triple-negative breast cancer (TNBC). This is the first time an anti-PD-1/L1 therapy has demonstrated a statistically significant EFS result as combined neoadjuvant and adjuvant therapy for these patients. These results are being presented today during a European Society for Medical Oncology (ESMO) Virtual Plenary.

After a median follow-up of 39 months, the KEYTRUDA regimen reduced the risk of EFS events by 37% (HR=0.63 [95% CI, 0.48-0.82]; p=0.00031) versus the chemotherapy-placebo regimen – a statistically significant and clinically meaningful EFS result. EFS was defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause. As previously announced, KEYNOTE-522 met the dual primary endpoint of pathological complete response (pCR) at the first interim analysis. The trial is continuing to allow for additional follow-up of overall survival (OS), a key secondary endpoint. At this fourth interim analysis, although these data have not crossed the boundary for statistical significance, there was a 28% reduction in the risk of death with the KEYTRUDA regimen versus the chemotherapy-placebo regimen (HR=0.72 [95% CI, 0.51-1.02]; p=0.03214). The safety profile of the KEYTRUDA regimen was consistent with the known profiles of each regimen, and no new safety concerns were identified.

“Given the high rates of recurrence within the first five years of diagnosis, patients with high-risk early-stage TNBC need new treatment options,” said Dr. Peter Schmid, lead, Centre for Experimental Cancer Medicine, Barts Cancer Institute in London, England. “KEYNOTE-522 was designed to study whether the combined neoadjuvant and adjuvant regimen with KEYTRUDA could help treat the cancer earlier. Now, with more than three years of follow-up, we see the potential of this approach. These event-free survival data are very encouraging for patients and show that this combination of KEYTRUDA plus chemotherapy as neoadjuvant therapy, followed by single-agent KEYTRUDA as adjuvant therapy, may offer women with high-risk early-stage TNBC a new treatment option for this aggressive disease.”

“These highly anticipated event-free survival results in this TNBC population build upon earlier findings from the KEYNOTE-522 trial and further support the potential use of KEYTRUDA in these patients,” said Dr. Vicki Goodman, vice president, clinical research, Merck Research Laboratories. “KEYNOTE-522 is the first large randomized Phase 3 study to report a statistically significant and clinically meaningful EFS result among patients with stage II and stage III TNBC. We have submitted these data to the FDA and are working closely with the agency on its review of our application.”

KEYTRUDA is currently approved under accelerated approval in the U.S. in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10) as determined by an FDA-approved test.

Merck is rapidly advancing a broad portfolio in women’s cancers with an extensive clinical development program for KEYTRUDA and several other investigational and approved medicines across multiple gynecologic and breast cancers. The KEYTRUDA clinical development program for TNBC encompasses several internal studies and external collaborative trials, including the ongoing studies KEYNOTE-242 and KEYNOTE-355.

Study Design and Additional Data From KEYNOTE-522

KEYNOTE-522 is a Phase 3, randomized, double-blind trial (ClinicalTrials.gov, NCT03036488). The dual primary endpoints are pCR, defined as pathological stage ypT0/Tis ypN0 at the time of definitive surgery, and EFS, defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause in all patients randomized. Secondary endpoints include pCR rate using alternative definitions, OS in all patients randomized, pCR rate according to all definitions, EFS and OS in patients whose tumors express PD-L1 (CPS ≥1), safety and health-related quality of life assessments. The study enrolled 1,174 patients who were randomized 2:1 to receive either:

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

As previously announced, KEYNOTE-522 met the success criterion for the dual primary endpoint of pCR at the first interim analysis; pCR was observed in 64.8% of patients treated with KEYTRUDA plus chemotherapy (n=401), an increase of 13.6% (p=0.00055) from 51.2% in patients treated with placebo plus chemotherapy (n=201). At the fourth interim analysis, KEYNOTE-522 met the success criterion for the dual primary endpoint of EFS. The study is continuing to allow for additional follow-up of OS.

At three years, 84.5% of patients treated with the KEYTRUDA regimen were alive and did not experience an EFS event compared to 76.8% of patients treated with the chemotherapy-placebo regimen.

In pre-specified exploratory subgroup analyses of EFS, the EFS benefit seen with the KEYTRUDA regimen was independent of PD-L1 expression. In the PD-L1-positive subgroup (n=973), defined as CPS ≥1, treatment with the KEYTRUDA regimen reduced the risk of EFS events by 33% (HR=0.67 [95% CI, 0.49-0.92]) versus the chemotherapy-placebo regimen. In the PD-L1-negative subgroup (n=197), defined as CPS <1, treatment with the KEYTRUDA regimen reduced the risk of EFS events by 52% (HR=0.48 [95% CI, 0.28-0.85]) versus the chemotherapy-placebo regimen.

In a pre-specified but non-randomized exploratory analysis of EFS by pCR outcome, the reduction in EFS events with the KEYTRUDA regimen was observed independent of pCR outcome at definitive surgery.

Treatment-related adverse events (TRAEs) were examined in the neoadjuvant phase, the adjuvant phase and the combined phases. TRAEs in the neoadjuvant phase have been previously reported. At the time of this data cutoff, no patients were still receiving protocol treatment. For the combined neoadjuvant and adjuvant phases, TRAEs occurred in 98.9% of patients receiving the KEYTRUDA regimen (n=783) and 99.7% of patients receiving the chemotherapy-placebo regimen (n=389); Grade 3-5 TRAEs occurred in 77.1% versus 73.3%, respectively. TRAEs led to death in 0.5% of patients receiving the KEYTRUDA regimen (n=4) and 0.3% of patients receiving the chemotherapy-placebo regimen (n=1). No new safety concerns were identified. In the adjuvant phase, TRAEs occurred in 53.7% of patients receiving adjuvant KEYTRUDA (n=588) and 48.6% of patients receiving adjuvant placebo (n=331), including 6.3% and 2.7%, respectively, who had at least one Grade ≥3 event.

Immune-mediated adverse events (AEs) and infusion reactions of any grade in the combined neoadjuvant and adjuvant phases occurred in 43.6% of patients receiving the KEYTRUDA regimen and 21.9% of patients receiving the chemotherapy-placebo regimen. The most common of these events (occurring in ≥10% of patients) were infusion reactions (18.0%) and hypothyroidism (15.1%) in patients receiving the KEYTRUDA regimen and infusion reactions (11.6%) in patients receiving the chemotherapy-placebo regimen. Immune-mediated AEs led to death in 0.3% of patients receiving the KEYTRUDA regimen (n=2) and no patients receiving the chemotherapy-placebo regimen. In the adjuvant phase, immune-mediated AEs and infusion reactions occurred in 10.2% of patients receiving adjuvant KEYTRUDA and 6.0% of patients receiving adjuvant placebo, including 2.9% and 0.3%, respectively, who had at least one Grade ≥3 event.

About Triple-Negative Breast Cancer (TNBC)

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 receptors, progesterone receptors or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three. Approximately 10-15% of patients with breast cancer are diagnosed with TNBC. TNBC tends to be more common in people who are younger than 40 years of age, who are African American or who have a BRCA1 mutation.

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 1,500 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 (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 cisplatin-containing chemotherapy and whose tumors express PD-L1 (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 mUC who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

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 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.

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, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

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 programmed death receptor-1 (PD-1) or the programmed death ligand 1 (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. 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. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.

Contacts

Media:

Melissa Moody

(215) 407-3536

Ayn Wisler

(908) 740-5590

Investors:

Peter Dannenbaum

(908) 740-1037

Courtney Ronaldo

(908) 740-6132

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