On October 9, 2016 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported safety and preliminary efficacy data from a phase 1 study of DS-8201a, a novel investigational HER2-targeting antibody drug conjugate, which suggest that it was well-tolerated with no dose-limiting toxicities (Press release, Daiichi Sankyo, OCT 9, 2016, View Source [SID:SID1234515728]). These results, from the dose escalation part of a two-part phase 1 study of DS-8201a, will be presented today during a late-breaking poster discussion session at the ESMO (Free ESMO Whitepaper) 2016 Congress, the annual meeting of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper).

DS-8201a is an investigational antibody drug conjugate comprised of a humanized anti-HER2 antibody attached by a peptide linker to a novel topoisomerase I inhibitor (DXd) payload, utilizing Daiichi Sankyo’s proprietary payload and linker-payload technology.

Preliminary overall efficacy results in 20 evaluable patients demonstrated an objective response rate of 35 percent (seven partial responses) and disease control rate of 90 percent, including 12 patients previously treated with ado-trastuzumab emtansine (T-DM1) and five patients with HER2 low expression (IHC2+/FISH- or IHC1+). In 15 patients with HER2+ disease defined as IHC3+ or IHC2+/FISH+, the disease control rate was 100 percent. Seventeen patients are still on treatment, and five of the first 10 patients have been under active treatment (0.8 to 6.4 mg/kg) for more than 24 weeks. Median progression free survival has not been reached.

"Despite recent advances in treating HER2+ breast and gastric cancer, there still remains a large unmet need for patients with HER2+ disease whose tumors are no longer controlled by currently approved targeted HER2 treatments or for tumors that express low HER2," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "These preliminary results are compelling and warrant further clinical evaluation of DS-8201a in several different patient populations expressing HER2."

"The components that make up DS-8201a are unique from any other antibody drug conjugate currently in clinical development and may explain the clinical activity observed at such an early phase of development," said José Baselga, MD, PhD, Physician-in-Chief and Chief Medical Officer at Memorial Sloan Kettering Cancer Center, New York, NY. "While the results of this study provide important preliminary proof-of-concept for the novel mechanism of action of DS-8201a, additional research will be needed to further confirm these findings."

A total of 22 patients (16 breast cancer, 5 gastric cancer, 1 gastroesphageal junction adenocarcinoma) were treated in the dose escalation part of the study. The maximum tolerated dose was not reached (0.8-8.0 mg/kg given every three weeks) and there have been no dose-limiting toxicities at pharmacologically-active exposure and a favorable pharmacokinetic profile. Seven grade 3 adverse events were seen in three patients (1 hypokalemia, 1 anemia, 1 neutrophil count decreased, 2 lymphocyte count decrease, 1 ALP increase and 1 cholangitis). Most common adverse events were mild or moderate gastrointestinal and hematological events.

HER2+ Breast Cancer Subgroup Analyses
A total of 18 patients enrolled in the study received one or more prior anti-HER2 therapies (18 received trastuzumab, 13 ado-trastuzumab emtansine, 5 pertuzumab, 4 lapatinib). In 12 evaluable HER2+ breast cancer patients previously treated with ado-tratuzumab emtansine (T-DM1), the objective response rate was 42 percent with a disease control rate of 92 percent.
"It is impressive that DS-8201a showed activity in these patients since many were heavily pre-treated with more than one HER2-targeting agent including T-DM1, and some with very substantial tumor load or large tumors," said Kenji Tamura, MD, PhD, Chairman, Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan and lead investigator of the study. "This finding will be further evaluated in the second part of this study where one cohort will include only advanced breast cancer patients previously treated with T-DM1."

About DS-8201a
Pre-clinical models have demonstrated that DS-8201a has a unique mechanism of action (MOA) where it selectively binds to the HER2 receptor on a tumor cell surface, triggering an antibody-dependent cell cytotoxic (ADCC) response.1 DS-8201a is then internalized via endocytosis (transportation into cells by an energy-using process) and the intracellular lysosomal enzymes break down the peptide to release the DXd payload, which then inhibits topoisomerase I activity, causing DNA damage and cell death.1
The linker-payload combination of DS-8201a allows for a higher drug-to-antibody ratio (DAR) of about 8 compared to a DAR of about 3.5 seen with ado-trastuzumab emtansine (T-DM1).1 The higher DAR of DS-8201a may help target low expressing HER2 tumors by supplying more payload per antibody to a tumor.1

About the DS-8201a Phase 1 Study
DS-8201a, given as an intravenous infusion every three weeks, is currently being evaluated in an open-label two-part phase 1 study in patients with advanced/unresectable or metastatic breast cancer, gastric or gastroesophageal junction adenocarcinoma, or other solid tumors that is/are refractory to or intolerable with standard treatment or for which no standard treatment is available.
The primary objective of part 1 of the study (dose escalation) is to assess the safety and tolerability of DS-8201a and determine the maximum tolerated dose (MTD). Secondary objectives include evaluating the pharmacokinetics, efficacy and human anti-human antibody (HAHA) against DS-8201a.
The second part (dose expansion) of the ongoing phase 1 clinical trial is enrolling patients in Japan and the United States into one of four cohorts: patients with HER2+ breast cancer previously treated with T-DM1; patients with HER2+ gastric or gastroesophageal junction adenocarcinoma previously treated with trastuzumab; patients with HER2 low expressing breast cancer; and patients with other solid cancers that express HER2. For more information about the study visit ClinicalTrials.gov.

Unmet Need in HER2+ Metastatic Breast Cancer
HER2 (known as human epidermal growth factor receptor 2) is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells.2 About one in five breast cancers overexpress the HER2/neu gene, which causes these cancers to grow more aggressively.2 To be considered HER2+, cancer cells are tested by one of two methods: immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH).2 IHC test results are reported as: 0, IHC1+, IHC2+ or IHC3+. A finding of IHC3+ is considered HER2+.2 A finding of IHC2+ is borderline and typically is confirmed by a positive FISH test.2
Several unmet needs remain today in HER2+ metastatic breast cancer. Many tumors advance to the point where no currently approved HER2-targeted treatment continues to control the disease.3 Additionally, there are no existing options indicated for HER2 low expressing tumors (IHC2+/FISH- or IHC1+) as well as HER2 heterogeneously expressing tumors (tumors with some tumor cells having high HER2 expression and some having low HER2 expression), which generally have poor prognosis.1,4

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On October 9, 2016 TRACON Pharmaceuticals (NASDAQ:TCON), a clinical stage biopharmaceutical company focused on the development and commercialization of novel targeted therapeutics for cancer, wet age-related macular degeneration and fibrotic diseases, reported final updated results from a Phase 1b clinical trial combining TRC105 with Inlyta (axitinib) in patients with advanced or metastatic renal cell carcinoma (RCC) (Press release, Tracon Pharmaceuticals, OCT 9, 2016, View Source;p=irol-newsArticle&ID=2210295 [SID:SID1234515718]). Data were presented today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress in Copenhagen, Denmark. Preliminary data from this trial were previously presented at the Kidney Cancer Association meeting in November 2015 and the ASCO (Free ASCO Whitepaper) Genitourinary Cancers Symposium in February 2015.

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The open-label dose escalation and expansion Phase 1b study enrolled a total of 18 patients (17 of whom were evaluable for response) who had received at least one prior line of therapy with a VEGF receptor tyrosine kinase inhibitor (VEGFR TKI). The median number of prior therapies in the group was three with a range of one to six. All patients in the trial received a combination of TRC105 and Inlyta. Data are summarized in the table below.

Summary of Phase 1b Results for TRC105-Inlyta Combination
Patients ORR Stable
Disease Overall Disease
Control Median PFS Median PFS in Clear Cell
RCC Subset (n=12)
N = 17 29%
(5/17) 59%
(10/17) 88%
(15/17) 11.3 months 11.3 months
For comparison, the objective response rate (ORR) seen in the large subgroup of VEGFR TKI-refractory patients treated with Inlyta (n=194) in the Inlyta AXIS Phase 3 study in second line clear cell RCC patients (a separate trial) was 11.3%, and median progression-free survival (PFS) was 4.8 months.

All patients in TRACON’s Phase 1b study have now completed treatment and the randomized Phase 2b TRAXAR clinical trial of TRC105 in combination with Inlyta is currently enrolling patients with advanced or metastatic RCC. TRACON expects top-line data from the TRAXAR study to be available in the first half of 2017. A Trials-in-Progress poster for the TRAXAR study was also presented at the meeting. The poster presentations are available on the Publications page under the News section of the TRACON website at www.traconpharma.com.

The following key additional data from the Phase 1b study were also presented at the meeting:

The recommended Phase 2 dose of TRC105 of 10 mg/kg dosed weekly was well-tolerated in combination with Inlyta and no dose limiting toxicities were observed.
The most common adverse events were low grade epistaxis, headache, fatigue, diarrhea, and gingival bleeding.
The Inlyta dose was escalated from 5 mg BID to 7 mg BID in 22% of patients and to 10 mg BID in 11% of patients.
Serum concentrations of TRC105 above target concentrations were maintained continuously at the 8 mg/kg and 10 mg/kg TRC105 dose levels.
Plasma levels of TGF-b receptor 3 (betaglycan) at baseline were significantly higher in patients with a partial response, while levels of osteopontin were significantly lower at baseline for patients that achieved a partial response. Both markers correlated with time on study and their potential prognostic/predictive value are being investigated in the Phase 2b TRAXAR study.
About the TRAXAR Phase 2b Clinical Trial in RCC

The Phase 2b TRAXAR clinical trial is a multicenter, open-label, randomized clinical trial of TRC105 in combination with Inlyta versus Inlyta in patients with advanced or metastatic RCC. The primary endpoint of the Phase 2b study is progression-free survival. The company expects to enroll approximately 150 patients who have failed one prior VEGF inhibitor in the study. Patients may have also failed one prior mTOR inhibitor and one prior immunotherapy. For additional information on this clinical trial, please visit www.clinicaltrials.gov, identifier NCT01806064.

About TRC105 (carotuximab)

TRC105 (carotuximab) is a novel, clinical stage antibody to endoglin, a protein overexpressed on proliferating endothelial cells that is essential for angiogenesis, the process of new blood vessel formation, and also expressed on fibroblasts, a cell that causes fibrosis. TRC105 is currently being studied in multiple Phase 2 clinical trials sponsored by TRACON or the National Cancer Institute for the treatment of solid tumor types in combination with VEGF inhibitors. The ophthalmic formulation of TRC105, DE-122, is currently in a Phase 1/2 trial for patients with wet AMD. TRC205, a second generation antibody to endoglin, is undergoing preclinical testing in models of fibrosis. For more information about the clinical trials, please visit TRACON’s website at View Source

On October 9, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported results from two major studies of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) at the ESMO (Free ESMO Whitepaper) 2016 Congress, the annual meeting of the European Society for Medical Oncology:

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In KEYNOTE-024, which evaluated squamous and non-squamous NSCLC patients whose tumors expressed high levels of PD-L1 (tumor proportion score, or TPS, of 50 percent or more), KEYTRUDA provided a 50 percent reduction in the risk of disease progression or death and a 40 percent reduction in the risk of death compared to platinum doublet, the current standard of care (Press release, Merck & Co, OCT 9, 2016, View Source [SID:SID1234515683]). These data were also published today in The New England Journal of Medicine. Based upon the results observed from KEYNOTE-024, to date KEYTRUDA is the only anti-PD-1 to demonstrate superior progression-free survival (PFS) and overall survival (OS) compared to chemotherapy for the first-line treatment of both squamous and non-squamous NSCLC in patients whose tumors express high levels of PD-L1 and do not express EGFR or ALK genetic aberrations.

In KEYNOTE-021, Cohort G, which included patients with metastatic non-squamous NSCLC regardless of PD-L1 expression level, KEYTRUDA (pembrolizumab) plus chemotherapy (carboplatin plus pemetrexed) achieved a 55 percent objective response rate (ORR) compared to 29 percent for chemotherapy alone, the standard of care, and reduced the risk of disease progression or death by 47 percent. To date, KEYTRUDA is the only anti-PD-1 therapy to demonstrate superior efficacy in combination with chemotherapy compared to chemotherapy alone in patients receiving first-line treatment. These data were published today in The Lancet Oncology.

"Chemotherapy has been the standard treatment for most patients with advanced non-small cell lung cancer for decades, but survival rates remain low," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "Our new data suggest that KEYTRUDA treatment can offer meaningful improvement over chemotherapy in a broad array of patients. In this sense, these studies may represent a turning point in worldwide efforts to control lung cancer. We sincerely thank the patients and the clinical investigators for their participation in our studies. Together we are working to improve the health of more and more patients with cancer."

Merck has submitted KEYNOTE-024 data to regulatory agencies in the United States, Europe, and Japan. The U.S. Food and Drug Administration has granted Breakthrough Therapy Designation and Priority Review, with a PDUFA, or target action, date of Dec. 24, 2016.

Merck is currently advancing multiple registration-enabling studies in NSCLC with KEYTRUDA as monotherapy and in combination, including the combination of KEYTRUDA plus a platinum/pemetrexed-based chemotherapy regimen in patients with previously untreated, non-squamous NSCLC in the ongoing phase 3 KEYNOTE-189 trial. The KEYTRUDA clinical development program includes more than 350 clinical trials across more than 30 tumor types, including more than 100 trials that combine KEYTRUDA with other cancer treatments.

KEYNOTE-024: Data Showed KEYTRUDA was Superior to Chemotherapy for PFS and OS in First-Line Treatment of Metastatic NSCLC

KEYNOTE-024 included 305 patients who were previously untreated and whose tumors expressed high levels of PD-L1 (TPS of 50 percent or more). Patients were randomized to receive a 200 mg fixed dose of KEYTRUDA every three weeks (n=154) or four to six cycles of investigator’s choice of one of five platinum-based chemotherapy regimens (n=151): carboplatin or cisplatin plus pemetrexed, carboplatin or cisplatin plus gemcitabine, or carboplatin plus paclitaxel. Pemetrexed maintenance therapy was permitted for patients with non-squamous histologies. Patients randomized to the control arm had the option of crossing over to KEYTRUDA (pembrolizumab) upon disease progression. The median follow-up was 11.2 months (range, 6.3-19.7). The primary endpoint was PFS; secondary endpoints were OS, ORR, and safety.

The findings published in The New England Journal of Medicine demonstrated that KEYTRUDA reduced the risk of progression or death by 50 percent compared to chemotherapy (HR, 0.50 [95% CI, 0.37-0.68]; p<0.001). The median PFS for KEYTRUDA was 10.3 months (95% CI, 6.7-not reached) compared to 6.0 months for chemotherapy (95% CI, 4.2-6.2). At six months, 62.1 percent of patients treated with KEYTRUDA were alive and had no disease progression (95% CI, 53.8-69.4) compared to 50.3 percent of those receiving chemotherapy (95% CI, 41.9-58.2). This benefit was observed in all study subgroups.

Additionally, KEYTRUDA resulted in a 40 percent reduction in the risk of death compared with chemotherapy (HR, 0.60 [95% CI, 0.41-0.89]; p=0.005); this finding includes the 66 patients (43.7%) on the chemotherapy arm who crossed over in-study to receive KEYTRUDA once their cancer had progressed; median OS was not reached in either group. Further, ORR was 44.8 percent for patients receiving KEYTRUDA (95% CI, 36.8-53.0), including six complete responses, compared to 27.8 percent with chemotherapy (95% CI, 20.8-35.7), including one complete response.

"These data from KEYNOTE-024 demonstrate the potential of KEYTRUDA to change the way non-small cell lung cancer is currently treated," said Dr. Martin Reck, head of the thoracic oncology dept., LungenClinic Grosshansdorf, Germany, and lead author of The New England Journal of Medicine paper. "This provides additional evidence that testing for PD-L1 levels should become standard in lung cancer at first diagnosis to guide treatment decisions."

Additional Findings and Safety Information from KEYNOTE-024

The safety of KEYTRUDA was consistent with what has been seen in previous trials among patients with metastatic NSCLC. The most common treatment-related adverse events for KEYTRUDA were diarrhea (n=22), fatigue (n=16), and pyrexia (n=16). Grade 3-5 treatment-related adverse events for KEYTRUDA included diarrhea (n=6) and pneumonitis (n=4). There was one treatment-related death in a patient receiving KEYTRUDA (cause unknown).

Additionally, based on an analysis of duration of response, a pre-specified exploratory endpoint, the median duration of response was not reached with KEYTRUDA (range, 1.9+ to 14.5+ months). The median duration of response with the chemotherapy group was 6.3 months (range, 2.1+ to 12.6+). Median time to response was 2.2 months for both groups.

About KEYNOTE-024

KEYNOTE-024 is a randomized, phase 3 study (ClinicalTrials.gov, NCT02142738) evaluating KEYTRUDA (pembrolizumab) as monotherapy compared to standard of care platinum-based chemotherapy in the treatment of patients with metastatic NSCLC. Patients enrolled were those who had received no prior systemic chemotherapy treatment for their advanced disease, whose tumors did not harbor an EGFR sensitizing mutation or ALK translocation, and whose tumors expressed high levels of PD-L1 (TPS of 50 percent or more) as determined by a central laboratory using an FDA approved companion diagnostic, the Dako PD-L1 IHC 22C3 PharmDx test, from Agilent Technologies.

KEYNOTE-021, Cohort G: KEYTRUDA Combined with Chemotherapy Showed Higher Response Rates Compared to Chemotherapy Alone as First-Line Treatment of Metastatic NSCLC

KEYNOTE-021, Cohort G, included 123 previously untreated patients with metastatic non-squamous NSCLC regardless of PD-L1 expression and whose tumors did not have EGFR mutations or ALK translocations. Patients were randomized to receive KEYTRUDA plus platinum doublet chemotherapy with pemetrexed and carboplatin (n=60) or platinum doublet chemotherapy alone (n=63). Patients randomized to the chemotherapy-only arm had the option of crossing over to KEYTRUDA monotherapy upon disease progression. The median follow-up was 10.6 months (range, 0.8-19.3).

The findings published in The Lancet Oncology demonstrated that ORR nearly doubled by adding KEYTRUDA to chemotherapy, with an ORR of 55 percent (n=33/60) compared to 29 percent (n=18/63) for chemotherapy alone (treatment difference 26%, 95% CI, 9-42%, p=0.0016); all responses were partial. Median duration of response was not reached in either group (range, 1.4+-13.0+ for KEYTRUDA plus chemotherapy; 1.4+-15.2+ for chemotherapy alone). Responses in both groups were durable, with 88 percent (n=29/33) of responders in the KEYTRUDA plus chemotherapy group and 78 percent (n=14/18) of responders in the chemotherapy alone group experiencing ongoing response at the time of data cut-off.

Additionally, the KEYTRUDA combination significantly reduced the risk of disease progression or death compared to chemotherapy alone (hazard ratio 0.53, 95% CI, 0.31-0.91, p=0.0102). Median PFS was 13.0 months with KEYTRUDA plus chemotherapy compared to 8.9 months with chemotherapy alone. OS was similar between the two arms, with 92 percent survival at six months in both, and 75 percent and 72 percent survival at 12 months in the KEYTRUDA combination and chemotherapy alone, respectively.

Of treated patients on the KEYTRUDA (pembrolizumab) plus chemotherapy arm, 47 percent remained on treatment as of the cut-off date, compared to 31 percent on chemotherapy alone. Of the treated patients who discontinued treatment on the chemotherapy-only arm, 52 percent (n=32/62) subsequently received anti-PD-L1 therapy, with 32 percent crossing over to KEYTRUDA monotherapy as allowed by the study protocol and 19 percent receiving it outside of study crossover.

"The results from KEYNOTE-021 show that pembrolizumab plus chemotherapy nearly doubled the number of patients responding to treatment than chemotherapy alone," said Dr. Corey Langer, director of thoracic oncology and professor of medicine at the Hospital of the University of Pennsylvania and lead author of The Lancet Oncology paper. "We are now gaining a better understanding that pembrolizumab combined with chemotherapy may play an important role in the first-line treatment of patients with non-small cell lung cancer."

Additional Safety Information from KEYNOTE-021, Cohort G

The most common treatment-related adverse events (occurring in at least 15% of patients) for KEYTRUDA plus chemotherapy were fatigue, nausea, anemia, rash, vomiting, diarrhea, increased AST, constipation, decreased appetite, increased ALT, dysgeusia, and decreased neutrophils. Grade 3-4 treatment-related adverse events in this arm included fatigue, nausea, anemia, rash, vomiting, increased AST, increased ALT, and decreased neutrophils. The most common immune-mediated adverse events in patients receiving KEYTRUDA plus chemotherapy were hypothyroidism and hyperthyroidism. Additionally, pneumonitis, infusion reactions, and severe skin toxicity were noted. These immune-mediated adverse events occurred at similar rates to patients receiving KEYTRUDA as a single agent. There was one treatment-related death from sepsis in a patient receiving KEYTRUDA plus chemotherapy, and two (one from sepsis and one from pancytopenia) in patients receiving chemotherapy alone.

About KEYNOTE-021, Cohort G

Cohort G of the multicenter, open-label, phase 1/2 multi-cohort KEYNOTE-021 study evaluated the efficacy and safety of KEYTRUDA in combination with pemetrexed and carboplatin compared with pemetrexed and carboplatin in patients with metastatic, non-squamous, EGFR- and ALK-negative NSCLC in the first-line treatment setting. Patients were randomized 1:1 to four cycles of KEYTRUDA (200 mg plus carboplatin AUC 5 (5 mg/mL/min) plus pemetrexed 500 mg/m2 every three weeks), or carboplatin plus pemetrexed alone, followed by maintenance pemetrexed with or without KEYTRUDA. Randomization was stratified by PD-L1 expression (positive expression defined as TPS of one percent or more; negative expression defined as TPS of less than one percent). Patients randomized to the chemotherapy arm were allowed to cross over to KEYTRUDA (pembrolizumab) monotherapy if they experienced disease progression. Response was assessed by blinded, independent central review using RECIST 1.1 every six weeks for the first 18 weeks, every nine weeks through the first year, and every 12 weeks in the second year. The primary endpoint was ORR; secondary endpoints included PFS, duration of response, and OS.

About KEYTRUDA (pembrolizumab)

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 administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single use vial.

KEYTRUDA Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks.

Lung Cancer

KEYTRUDA is 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, at a dose of 2 mg/kg every three weeks. 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.

Head and Neck Cancer

KEYTRUDA 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 at a fixed dose of 200 mg every three weeks. 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.

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 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 (pembrolizumab) 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 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%).

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 350 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.

On October 9, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, demonstrated superiority in overall survival (OS) at 18 months compared to standard of care chemotherapy (docetaxel) in patients with metastatic non-small cell lung cancer (NSCLC) previously treated with platinum-containing chemotherapy whose tumors expressed PD-L1 (tumor proportion score [TPS] of one percent or more), as well as patients with high levels of PD-L1 expression (TPS of 50 percent or more) (Press release, Merck & Co, OCT 9, 2016, http://www.mercknewsroom.com/news-release/oncology-newsroom/keytruda-pembrolizumab-showed-continued-overall-survival-benefit-comp [SID:SID1234515682]). These data, from the phase 2/3 KEYNOTE-010 trial, will be presented at the ESMO (Free ESMO Whitepaper) 2016 Congress, the annual meeting of the European Society for Medical Oncology, in Copenhagen (Abstract #LBA48).

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"These findings – which show superior survival with longer follow-up across patients with PD-L1 expression (tumor proportion score of one percent or more), as well as improved quality of life – point to KEYTRUDA as a durable treatment option for many previously treated patients with advanced non-small cell lung cancer," said Roy S. Herbst, M.D., Ph.D., professor of medicine and chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale New Haven. "These data also reinforce the value of using PD-L1 as a biomarker to identify patients who are likely to benefit from KEYTRUDA."

In additional data at the ESMO (Free ESMO Whitepaper) 2016 Congress from KEYNOTE-010, an analysis of patient-reported health-related quality of life outcomes showed more patients treated with KEYTRUDA (pembrolizumab) reported positive outcomes compared to patients treated with chemotherapy (Abstract #1219P).

Separately at the ESMO (Free ESMO Whitepaper) 2016 Congress, researchers presented an analysis of PD-L1 prevalence across three separate studies, including KEYNOTE-010. Overall, 66 percent of patients with metastatic NSCLC expressed any level of PD-L1, and 28 percent expressed high levels of PD-L1 (Abstract #1060P).

"Our research in immuno-oncology continues to show tremendous promise, with our goal being to extend the lives of significant numbers of patients with non-small cell lung cancer," said Roger Dansey, M.D., senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "In this longer-term analysis of KEYNOTE-010, among patients who responded to treatment, four times as many patients receiving KEYTRUDA were still alive without disease progression compared to docetaxel. It is gratifying to see these results continue with additional follow-up."

Merck has a robust clinical development program for KEYTRUDA in lung cancer, with multiple registration-enabling studies currently underway. The KEYTRUDA clinical development program includes more than 30 tumor types in more than 350 clinical trials, including more than 100 trials that combine KEYTRUDA with other cancer treatments.

Efficacy and Safety Findings from KEYNOTE-010 (Abstract #LBA48)

KEYNOTE-010 is a global, open-label, randomized, pivotal phase 2/3 study evaluating KEYTRUDA (2 mg/kg or 10 mg/kg every three weeks) compared to standard of care chemotherapy (docetaxel, 75 mg/m2 every three weeks) in patients with previously treated metastatic NSCLC. The primary endpoints were OS and progression-free survival (PFS) and were assessed based on patients whose tumors expressed PD-L1 (TPS of one percent or more) and high levels of PD-L1 (TPS of 50 percent or more). Secondary endpoints included overall response rate (ORR) and duration of response. KEYNOTE-010 is the first study of its kind to evaluate the potential of an immunotherapy compared to chemotherapy based on prospective measurement of PD-L1 expression in patients with metastatic NSCLC. As previously announced, the study met its primary objective, showing that KEYTRUDA significantly improved OS compared to chemotherapy in patients with PD-L1 expression (TPS of one percent or more). Findings were similar in patients who received the FDA-approved dose of KEYTRUDA (2 mg/kg every three weeks) and an investigational dose of KEYTRUDA (10 mg/kg every three weeks). These data also served as the basis for the KEYTRUDA (pembrolizumab) application approval by the European Medicines Agency (EMA) in July of this year and are currently under review by the U.S. Food and Drug Administration (FDA) for the second-line or greater NSCLC treatment setting.

At the ESMO (Free ESMO Whitepaper) 2016 Congress, data from this study of 1,034 patients included six months of additional follow-up, with a median follow-up of 19.2 months (range, 11.7-29.7), and showed superior outcomes of OS, PFS, and ORR with KEYTRUDA compared to docetaxel in patients with PD-L1 expression (TPS of one percent or more) as well as high levels of PD-L1 expression (TPS of 50 percent or more) – with consistency of outcomes across KEYTRUDA doses.

In patients with PD-L1 expression (TPS of one percent or more), OS at 18 months was 37 percent (HR, 0.72 [95% CI, 0.60-0.87]; p=0.0003) with KEYTRUDA 2 mg/kg, 43 percent (HR, 0.60 [95% CI, 0.50-0.73]; p<0.00001) with KEYTRUDA 10 mg/kg, and 24 percent with docetaxel. Among all patients, median OS was 10.5 months with KEYTRUDA 2 mg/kg, 13.6 months with KEYTRUDA 10 mg/kg, and 8.6 months with docetaxel. ORR was 19 percent (95% CI, 15-23, p=0.00025) with KEYTRUDA 2 mg/kg, 20 percent (95% CI, 16-25, p=0.00004) with KEYTRUDA 10 mg/kg and 10 percent (95% CI, 7-13) with docetaxel. Responses to KEYTRUDA continued to be durable; among patients with any level of PD-L1 expression who responded to treatment, 60 percent on each of the KEYTRUDA treatment arms were alive, progression-free, and had not received additional therapy for their disease, compared to 15 percent in the docetaxel treatment arm.

In patients with high levels of PD-L1 expression (TPS of 50 percent or more), OS at 18 months was 46 percent (HR, 0.54 [95% CI, 0.39-0.73]; p=0.00004) with KEYTRUDA 2 mg/kg, 52 percent with KEYTRUDA 10 mg/kg (HR, 0.48 [95% CI, 0.35-0.66]; p<0.00001), and 24 percent with docetaxel. In this group, median OS was 15.8 months with KEYTRUDA 2 mg/kg, 18.8 months with KEYTRUDA 10 mg/kg, and 8.2 months with docetaxel. ORR was 29 percent (95% CI, 22-38, p<0.00001) with KEYTRUDA 2 mg/kg, 32 percent (95% CI, 24-40, p<0.00001) with KEYTRUDA 10 mg/kg, and nine percent (95% CI, 5-14) with docetaxel. Responses to KEYTRUDA continued to be durable; among patients with high levels of PD-L1 expression who responded to treatment, 68 and 63 percent on the KEYTRUDA 2 mg/kg and 10 mg/kg treatment arms, respectively, were alive, progression-free, and had not received additional therapy for their disease, compared to 15 percent in the docetaxel treatment arm.

The safety profile of KEYTRUDA was consistent with that observed in previously reported studies of KEYTRUDA. Treatment-related adverse events remained lower with KEYTRUDA compared to docetaxel. Among the total study population, 13, 17, and 36 percent of patients experienced Grades 3-5 treatment-related adverse events with KEYTRUDA (pembrolizumab) 2 mg/kg, KEYTRUDA 10 mg/kg, and docetaxel, respectively. Compared with the previous analysis, two additional patients in the KEYTRUDA 2 mg/kg arm and five patients in the KEYTRUDA 10 mg/kg arm experienced immune-mediated adverse events, none of which led to death. Grade 3-5 immune-mediated adverse events that occurred in two or more patients included pneumonitis (n=14), severe skin toxicities (n=8), and colitis (n=4). Additional immune-mediated adverse events observed in at least two patients in the KEYTRUDA arms of the study included hypothyroidism, hyperthyroidism, pancreatitis, adrenal insufficiency, myositis, thyroiditis, hepatitis, hypophysitis, and type 1 diabetes mellitus. In this study to date, there have been 10 treatment-related adverse events that led to death, two with KEYTRUDA 2 mg/kg, three with KEYTRUDA 10 mg/kg, and five with docetaxel.

These data will be presented in a poster discussion session on Oct. 9 from 2:45 – 4:15 p.m. CEST (Abstract #LBA48) (Location: Oslo).

Patient-Reported Outcomes Findings from KEYNOTE-010 (Abstract #1219P)

Also reported at the ESMO (Free ESMO Whitepaper) 2016 Congress were health-related quality of life (HRQoL) outcomes from the KEYNOTE-010 trial. Findings were based on patient-reported assessments using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), EORTC QLQ Lung Cancer 13, and EuroQol-5D-3L instruments to measure for outcomes such as physical, role, emotional, cognitive, and social functioning, as well as lung cancer and treatment-related symptoms, among other measures.

Overall, from baseline to the 12-week assessment, patients treated with KEYTRUDA (2 mg/kg or 10 mg/kg every three weeks) reported numeric improvements, some of which were significant, in HRQoL and prolonged time to deterioration of lung cancer symptoms (defined using a composite endpoint of cough, dyspnea, and chest pain) compared with docetaxel (75 mg/m2 every three weeks).

These findings, along with results from additional patient-reported outcomes analyses, suggest that HRQoL and symptoms were maintained or improved more with KEYTRUDA than with docetaxel.

These data were presented in a poster session on Oct. 8 from 1 – 2 p.m. CEST (Location: Hall E).

PD-L1 Prevalence Findings from KEYNOTE-001, -010, and -024 (Abstract #1060P)

Results from a third NSCLC abstract at the ESMO (Free ESMO Whitepaper) 2016 Congress explored, for the first time, the prevalence of PD-L1 in patients screened across multiple studies. The analysis assessed 4,784 patients with NSCLC who had tumors evaluable for PD-L1 expression and were screened for eligibility in three registrational studies of KEYTRUDA (pembrolizumab) – KEYNOTE-001, KEYNOTE-010, and KEYNOTE-024. Based on this pooled analysis, 66 percent of patients across all three trials were determined to express PD-L1 (TPS of one percent or more) and 28 percent were determined to have high levels of PD-L1 expression (TPS of 50 percent or more). These findings were similar across demographic and disease characteristics examined, including prior lines of therapy, age, tumor source (primary and metastases), and histology (squamous and non-squamous).

These data will be presented in a poster session on Oct. 9 from 1 – 2 p.m. CEST (Location: Hall E).

About KEYTRUDA (pembrolizumab)

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 administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single use vial.

KEYTRUDA Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks.

Lung Cancer

KEYTRUDA is 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, at a dose of 2 mg/kg every three weeks. 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.

Head and Neck Cancer

KEYTRUDA (pembrolizumab) 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 at a fixed dose of 200 mg every three weeks. 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.

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 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 (pembrolizumab) 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 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 (pembrolizumab).

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%).

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.