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New Data Evaluating KEYTRUDA® (pembrolizumab) in Combination with Chemotherapy for First-Line Treatment of Non-Small Cell Lung Cancer Demonstrate Response Rates Ranging from 48 to 71 Percent

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced findings from an initial proof-of-concept study of KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, combined with standard treatments, one with bevacizumab and others without, in non-small cell lung cancer (NSCLC) including chemotherapy in previously untreated patients with NSCLC; the study showed overall response rates (ORR) ranging from 48 to 71 percent, depending on the therapy used. These data, from the phase 1/2 KEYNOTE-021 trial, will be presented today at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) by Dr. Shirish Gadgeel of the Barbara Ann Karmanos Cancer Institute (Abstract #9016) from 8:00 – 11:30 a.m. CDT (Location: Hall A) and in a poster discussion from 3:00 – 4:15 p.m. CDT (Location: E354b).

“Combining KEYTRUDA and chemotherapy in the first-line lung cancer treatment setting is an important part of our effort to develop more treatment options for patients with non-small cell lung cancer,” said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. “This study has helped us to identify chemotherapy options for combination with KEYTRUDA regardless of PD-L1 expression to take forward in phase 3 trials.”

The findings presented at ASCO 2016 were based on 74 patients who were treated with KEYTRUDA and one of three different chemotherapy regimens in the phase 1b portion of the study. The data, across all three cohorts including patients with and without PD-L1 tumor expression, showed an ORR of 57 percent (n=42/74, 95% CI, 45-68), including one complete response and 41 partial responses. Median duration of follow-up was 12 months (range <1-21).

“These results are encouraging because they provide initial evidence that adding chemotherapy to KEYTRUDA may increase response rates and open new treatment paths for a broader range of patients with advanced non-small cell lung cancer,” said Dr. Gadgeel, professor, leader of the multidisciplinary thoracic oncology team, Karmanos Cancer Institute/Wayne State University in Detroit.

The highest response rates were observed in a group of 24 patients who received KEYTRUDA (pembrolizumab) in combination with carboplatin plus pemetrexed (Cohort C), with an ORR of 71 percent (n=17/24, 95% CI, 49-87), including one complete response and 16 partial responses. In this same group, median progression-free survival (PFS) was 10.2 months (95% CI, 6.3-15.2), and median overall survival (OS) was not reached (95% CI, 13.9-NR). Median duration of follow-up was 16 months (range 4-21).

In the group that received KEYTRUDA plus carboplatin and paclitaxel (Cohort A), ORR was 52 percent (n=13/25, 95% CI, 31-72) and all responses were partial responses. Median PFS in this cohort was 10.3 months (95% CI, 3.7-NR), and median OS was not reached (95% CI, 11.0-NR). Median duration of follow-up was 13 months (range 2-21).

In the cohort that received KEYTRUDA in addition to carboplatin, paclitaxel, and bevacizumab (Cohort B), ORR was 48 percent (n=12/25, 95% CI, 28-69) and all responses were partial responses. Median PFS was not reached (95% CI, 4.1-NR), and median OS was not reached (95% CI, NR-NR). Median duration of follow-up was 9 months (range <1-17).

Overall Response Rates by Cohort

ORR (confirmed), % (n) [95% CI]

 

Cohort A (KEYTRUDA + carboplatin and paclitaxel) N=25

 

 

Cohort B (KEYTRUDA + carboplatin, paclitaxel, and bevacizumab) N=25

 

Cohort C (KEYTRUDA + carboplatin and pemetrexed) N=24

 

 

All Patients N=74

 

Total Population   52% (13)

[31-72]

  48% (12)

[28-69]

  71% (17)

[49-87]

  57% (42)

[45-68]

Complete Response

  0   0   4% (1)   1% (1)
Partial Response   52% (13)   48% (12)   67% (16)   55% (41)

Median duration of follow-up

  13 months

(range 2-21)

  9 months

(range <1-17)

  16 months

(range 4-21)

  12 months

(range <1-21)

Responses were seen across all levels of PD-L1 expression, including in patients with PD-L1 negative tumors. PD-L1 levels assessed included high expression (tumor proportion score [TPS] of greater than or equal to 50 percent), any expression (TPS of greater than or equal to 1 percent), and negative expression (PD-L1 of less than 1 percent).

Overall Response Rates by PD-L1 Tumor Proportion Score

PD-L1 TPS Status [95% CI]

  Cohort A

N=25

  Cohort B

N=25

  Cohort C

N=24

  All Patients

N=74

TPS ≥50%   56% (5/9)

[21-86]

  50% (4/8)

[16-84]

  75% (6/8)

[35-97]

  60% (15/25)

[39-79]

TPS ≥1%   53% (8/15)

[27-79]

  50% (10/20)

[27-73]

  69% (11/16)

[41-89]

  57% (29/51)

[42-71]

TPS <1%   44% (4/9)

[14-79]

  40% (2/5)

[5-85]

  75% (6/8)

[35-97]

  54% (12/22)

[32-76]

The safety profile of KEYTRUDA (pembrolizumab) in combination with chemotherapy in this study was consistent with that observed previously. One dose-limiting toxicity event occurred in Cohort C, which subsequently led to discontinuation (Grade 3 toxic epidermal necrolysis). Three patients in Cohort B discontinued due to treatment-related adverse events (Grade 3 pneumonitis, drug hypersensitivity, and autoimmune colitis). No patients in Cohort A discontinued because of treatment-related adverse events. Grade 3-5 adverse events occurred in 56, 71, and 67 percent of patients in Cohorts A, B, and C, respectively. In Cohort B, the most common Grade 3-4 adverse events were drug hypersensitivity (8%), febrile neutropenia (8%), neutropenia (8%), white blood cell count decreased (8%), pneumonia (8%), and pulmonary embolism (8%). Immune-mediated adverse events, primarily Grades 1-2, were observed across cohorts. The most common Grade 3 immune-mediated adverse events were colitis (4% Cohort C), rash papular (4% Cohort A), pancreatitis (4% Cohort B), pneumonitis (4% Cohort B), and toxic epidermal necrolysis (4% Cohort C). There were no treatment-related deaths across cohorts; there was one death in Cohort B (Grade 5 pericardial effusion) which was not treatment-related.

Based on these findings, Merck has initiated two phase 3 trials in patients with previously untreated NSCLC. KEYNOTE-189 is evaluating the combination of KEYTRUDA plus a platinum/pemetrexed-based chemotherapy regimen in patients with non-squamous NSCLC. KEYNOTE-407 will study KEYTRUDA combined with carboplatin and paclitaxel or nab-paclitaxel in patients with squamous NSCLC. Merck has a robust clinical development program for KEYTRUDA in lung cancer, with five registration-enabling studies currently underway. The KEYTRUDA clinical development program includes more than 30 tumor types in more than 270 clinical trials, including more than 100 trials that combine KEYTRUDA with other cancer treatments.

About the KEYNOTE-021 Study (Cohorts A-C)

KEYNOTE-021 is a phase 1/2 multicenter, open-label, randomized, multi-cohort trial with Cohorts A, B, and C evaluating KEYTRUDA (pembrolizumab) in combination with chemotherapy in patients with chemotherapy-naïve, EGFR- and ALK-negative unresectable or metastatic NSCLC. Patients were randomized to receive 2 mg/kg or 10 mg/kg of KEYTRUDA every three weeks plus one of several chemotherapy regimens for four cycles – Cohort A (any histology): carboplatin AUC 6 plus paclitaxel 200 mg/m2 followed by maintenance KEYTRUDA; Cohort B (non-squamous histology): carboplatin AUC 6 plus paclitaxel 200 mg/m2 plus bevacizumab 15 mg/kg followed by maintenance KEYTRUDA plus bevacizumab; or Cohort C (non-squamous histology): carboplatin AUC 5 plus pemetrexed 500 mg/m2 followed by maintenance KEYTRUDA plus pemetrexed. The primary efficacy outcome measures were ORR as assessed every six weeks for the first 18 weeks, followed by every nine weeks for the remainder of the first year, using RECIST v1.1 by a central imaging vendor. Secondary outcome measures included OS, PFS, and duration of response.

About KEYTRUDA ® (pembrolizumab) Injection 100 mg

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA 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.

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is also indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 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. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every three weeks for the approved indications.

Selected Important Safety Information for KEYTRUDA ®  (pembrolizumab)

Immune-mediated pneumonitis occurred in 19 (3.5%) of 550 patients, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis and occurred more frequently in patients with a history of asthma/chronic obstructive pulmonary disease (5.4%) or prior thoracic radiation (6.0%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA (pembrolizumab) for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-mediated colitis occurred in 4 (0.7%) of 550 patients, including Grade 2 (0.2%) or 3 (0.4%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-mediated hepatitis occurred in patients receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 1 (0.2%) of 550 patients, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

Hyperthyroidism occurred in 10 (1.8%) of 550 patients, including Grade 2 (0.7%) or 3 (0.3%) hyperthyroidism. Hypothyroidism occurred in 38 (6.9%) of 550 patients, including Grade 2 (5.5%) or 3 (0.2%) hypothyroidism. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3 (0.1%) of 2117 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Immune-mediated nephritis occurred in patients receiving KEYTRUDA. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Other clinically important immune-mediated adverse reactions can occur. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA (pembrolizumab) when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2117 patients. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

KEYTRUDA was discontinued due to adverse reactions in 14% of 550 patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), cough (29%), decreased appetite (25%), and dyspnea (23%).

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck Oncology, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 270 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic 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 125 years, Merck has been a global health care leader working to help the world be well. Merck is known as MSD outside the United States and Canada. 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. For more information, visit www.merck.com and connect with us on Twitter, Facebook, YouTube and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA

This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s 2015 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Please see Prescribing Information for KEYTRUDA (pembrolizumab) at  http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf  and

Patient Information/Medication Guide for KEYTRUDA at  http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf .

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