On June 5, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported findings from three separate studies evaluating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in combination with other treatment regimens including talimogene laherparepvec, dabrafenib plus trametinib, or low-dose ipilimumab in patients with advanced melanoma (Press release, Merck & Co, JUN 5, 2016, View Source [SID:1234513009]). These data, from MASTERKEY-265, KEYNOTE-022, and KEYNOTE-029, respectively, are included in the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstracts #9568, #3014, and #9506).

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"We continue to build on our leadership in advanced melanoma by evaluating KEYTRUDA with multiple combination partners utilizing diverse mechanisms of action with the goal of improving outcomes while maintaining tolerability," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "These encouraging early data point to the potential for KEYTRUDA to become an important component of combination therapy in melanoma."

Each of these studies was designed to answer specific questions around the use of KEYTRUDA in various combination treatment settings. In each of the three studies, the safety profile of the combination regimens was shown to be manageable.

"Anti-PD-1 drug therapies, like pembrolizumab, have shown benefit as a monotherapy in the treatment of advanced melanoma, and it is important to understand their potential in combination with other effective therapeutics, including immunotherapies and targeted therapies," said Dr. Georgina Long, professor of melanoma medical oncology and translational melanoma research, Melanoma Institute Australia and University of Sydney. "Physicians are focused on different treatment paths for different types of patients and, with the promising data presented at ASCO (Free ASCO Whitepaper) this year, we aim to better understand the role of monotherapy and develop combination treatment strategies for patients with advanced melanoma who may not benefit as much from monotherapy."

The KEYTRUDA (pembrolizumab) clinical development program includes patients with more than 30 tumor types in more than 270 ongoing or planned studies, including more than 100 trials that combine KEYTRUDA with other cancer treatments – these include other immuno-oncology therapies, standard therapies and targeted therapies.

Findings from MASTERYKEY-265: KEYTRUDA with talimogene laherparepvec (Abstract #9568)

MASTERKEY-265 is an ongoing phase 1b study evaluating the safety, efficacy, and tolerability of KEYTRUDA in combination with talimogene laherparepvec in patients with previously untreated, unresectable advanced melanoma. The trial is a collaboration between Merck and Amgen. Talimogene laherparepvec is a herpes simplex virus-1 (HSV-1)-based oncolytic immunotherapy used for the treatment of melanoma lesions in the skin and lymph nodes.

Updated data from 21 evaluable patients showed that a combination of KEYTRUDA (200 mg every two weeks) with talimogene laherparepvec (up to 4 mL of 106 PFU/mL, then 108 PFU/mL every two weeks) resulted in a confirmed overall response rate (ORR) of 57.1 percent (n=12/21) (95% CI, 34-78.2), per modified immune-related response criteria (irRC) – 23.8 percent were complete responses (n=5/21) and 33.3 percent were partial responses (n=7/21).

The safety profile of KEYTRUDA in combination with talimogene laherparepvec was consistent with that observed in previously reported studies of KEYTRUDA or talimogene laherparepvec monotherapy in patients with advanced melanoma. Seven patients (33%) experienced treatment-related Grade 3-4 adverse events, including: anemia, aseptic meningitis, autoimmune hepatitis, generalized rash, headache, hyperglycemia, hypoglycemia, hypophosphatemia, increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma-glutamyltransferase, muscle spasms, macular rash, rash, and pneumonitis. Two patients (10%) experienced a treatment-related adverse event that led to permanent discontinuation of KEYTRUDA. No patients (0%) experienced a treatment-related adverse event that led to permanent discontinuation of talimogene laherparepvec. No dose-limiting toxicities were reported.

These data were presented by Dr. Long on June 4.

Findings from KEYNOTE-022: KEYTRUDA with dabrafenib plus trametinib (Abstract #3014)

KEYNOTE-022 is an ongoing phase 1/2 study designed to assess the safety and efficacy of KEYTRUDA in combination with dabrafenib plus trametinib in patients with advanced melanoma. Dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) is a combination regimen used in the treatment of certain types of advanced melanoma.

Based on early data from the 15 patients treated in phase 1, treatment with KEYTRUDA (pembrolizumab) (2 mg/kg every three weeks) with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily) resulted in nine partial responses, five of which were confirmed. Additionally, of the patients with lesion data available, 92.3 percent experienced a reduction in tumor size (n=12/13).

Grade 3-4 adverse events occurring in greater than or equal to 10 percent of patients included ALT increased (n=3), AST increased (n=3), pyrexia (n=3), GGT increased (n=2), and WBC count decreased (n=2). Four patients (26.7%) experienced a treatment-related adverse even that led to discontinuation. There were no treatment-related deaths. The phase 2 part of the study is ongoing and will further evaluate the safety and efficacy of the KEYTRUDA combination regimen compared to dabrafenib plus trametinib.

On June 5, these data will be presented by Dr. Antoni Ribas in a poster session from 8:00 – 11:30 a.m. CDT (Location: Hall A) and in a poster discussion from 4:45 – 6:00 p.m. CDT (Location: Hall B1).

Findings from KEYNOTE-029: KEYTRUDA with low-dose ipilimumab (Abstract #9506)

KEYNOTE-029 is an ongoing phase 1/2 study evaluating the safety, efficacy, and tolerability of KEYTRUDA in combination with low-dose ipilimumab in patients with advanced melanoma. Ipilimumab is a CTLA-4 inhibitor used in the treatment of melanoma.

Findings from 153 evaluable patients with advanced melanoma showed that KEYTRUDA (2 mg/kg every three weeks) in combination with low-dose ipilimumab (1 mg/kg every three weeks for four doses) demonstrated an ORR of 57 percent (95% CI, 49-65) by independent central review – 10 percent were complete responses (n=15/153) and 47 percent were partial responses (n=72/153). The six-month progression-free survival (PFS) rate was 70 percent and the six-month overall survival (OS) rate was 93 percent. At the time of analysis, median PFS (95% CI, 12.4 months-NR) and OS (95% CI, NR-NR) were not reached; 98 percent of responses were ongoing. Median follow-up duration was 10.0 months (range 0.8-14.1).

Sixty-four patients (42%) experienced treatment-related Grade 3-4 adverse events. Thirty-eight patients (25%) experienced immune-mediated Grade 3-4 adverse events, including: colitis, hepatitis, hyperthyroidism, hypophysitis, infusion reaction, pancreatitis, pneumonitis, nephritis, skin reactions, and type 1 diabetes mellitus. Sixteen patients (10%) experienced a treatment-related adverse event that led to ipilimumab discontinuation only, 11 patients (7%) experienced a treatment-related adverse event that led to KEYTRUDA (pembrolizumab) discontinuation after completion or discontinuation of ipilimumab, and 16 patients (10%) experienced a treatment-related adverse event that led to ipilimumab and KEYTRUDA discontinuation, including one patient who discontinued ipilimumab for colitis and later discontinued KEYTRUDA for increased lipase. There were no treatment-related deaths.

These data will be presented in an oral session by Dr. Long on June 6 at 2:51 p.m. CDT (Location: Arie Crown Theater).

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, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 32 (2.0%) of 1567 patients, including Grade 1 (0.8%), 2 (0.8%), and 3 (0.4%) pneumonitis. 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 31 (2%) of 1567 patients, including Grade 2 (0.5%), 3 (1.1%), and 4 (0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA (pembrolizumab) for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-mediated hepatitis occurred in 16 (1%) of 1567 patients, including Grade 2 (0.1%), 3 (0.7%), and 4 (0.1%) hepatitis. 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 13 (0.8%) of 1567 patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (0.1%) hypophysitis. 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 51 (3.3%) of 1567 patients, including Grade 2 (0.6%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 127 (8.1%) of 1567 patients, including Grade 3 (0.1%) 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 7 (0.4%) of 1567 patients, including Grade 2 (0.2%), 3 (0.2%), and 4 (0.1%) nephritis. 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% (unless otherwise indicated) of 1567 patients: arthritis (1.6%), exfoliative dermatitis, bullous pemphigoid, uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

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 (pembrolizumab).

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.

In Trial 6, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In Trial 2, KEYTRUDA was discontinued due to adverse reactions in 12% of 357 patients; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). The most common adverse reactions with KEYTRUDA vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus (28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

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 (pembrolizumab) 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.

On June 5, 2016 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported updated findings from a study evaluating KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in patients with advanced cancers characterized as deficient for DNA mismatch repair (MMR) (Press release, Merck & Co, JUN 5, 2016, View Source [SID:1234513008]). Results showed that among previously treated patients with MMR-deficient tumors, there was an overall response rate (ORR) of 53 percent (n=16/30) (95% CI, 36-70) in patients with a range of advanced non-colorectal solid tumors and an ORR of 57 percent (n=16/28) (95% CI, 39-73) in patients with advanced colorectal cancer; in contrast, no responses were observed in patients with advanced colorectal cancer whose tumors were characterized as MMR-proficient (n=0/25). The findings, from a phase 2 study led by researchers from Johns Hopkins Kimmel Cancer Center in collaboration with Merck, were presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstracts #3003, #103).

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"We continue to be encouraged by the findings of this ongoing study evaluating KEYTRUDA in patients with mismatch repair deficient tumors," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "Characterization of biomarkers with the potential to predict clinical outcomes for patients receiving immune therapy for cancer is an important element of our clinical program for KEYTRUDA."

Merck is conducting a phase 2 registration study (KEYNOTE-164) to evaluate the efficacy and safety of KEYTRUDA monotherapy in patients with previously treated, locally advanced unresectable or metastatic (Stage IV) MMR-deficient or microsatellite instability-high (MSI-H) colorectal cancer and a phase 3 study (KEYNOTE-177) in a treatment-naïve patient population. An additional phase 2 clinical trial (KEYNOTE-158) is evaluating patients with advanced tumors classified as MSI-H, excluding colorectal carcinoma.

The KEYTRUDA (pembrolizumab) 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.

Updated Findings from Non-Colorectal Cancer Cohort (Abstract #3003) and Colorectal Cancer Cohort (Abstract #103)

The phase 2 study evaluated the clinical activity of KEYTRUDA monotherapy (10 mg/kg every two weeks) in patients with previously treated, progressive metastatic disease with or without MMR-deficiency. Three groups were evaluated: MMR-deficient non-colorectal cancers (n=30), MMR-deficient colorectal cancer (n=28), and MMR-proficient colorectal cancer (n=25). MMR status was assessed locally using a standard immunohistochemistry (IHC) or polymerase chain reaction (PCR)-based method for detection of microsatellite instability. The key endpoints of the study were ORR, duration of response (DOR), progression-free survival (PFS) measured by RECIST v1.1, and overall survival (OS).

Abstract #3003 described findings from a cohort of patients with MMR-deficient non-colorectal cancers (including ampullary/biliary, endometrial, gastric, pancreatic, prostate, sarcoma, and small bowel) who received KEYTRUDA. Results demonstrated an ORR of 53 percent (n=16/30) (95% CI, 36-70) – 30 percent were complete responses (n=9/30) and 23 percent were partial responses (n=7/30). Additionally, 17 percent of patients had stable disease (n=5/30), and the disease control rate was 70 percent (n=21/30) (95% CI, 52-83). Median PFS and OS were not reached at the time of analysis; median duration of follow-up was 10 months.

Abstract #103 described findings from two cohorts of patients with colorectal cancer (MMR-deficient and MMR-proficient) who received KEYTRUDA. Among those patients with MMR-deficient tumors, an ORR of 57 percent was observed (n=16/28) (95% CI, 39-73) – 11 percent were complete responses (n=3/28) and 46 percent were partial responses (n=13/28). Additionally, 32 percent of patients had stable disease (n=9/28) and the disease control rate was 89 percent (n=25/28) (95% CI, 73-96). The median PFS and OS were not reached; median duration of follow-up was 9.3 months. Among patients with MMR-proficient tumors, no responses were observed (n=0/25) and the disease control rate was 16 percent (n=4/25) (95% CI, 6-35); 16 percent had stable disease (n=4/25). Additionally, in patients with MMR-proficient tumors, the median PFS was 2.3 months and the median OS was 5.98 months; median duration of follow-up was 6 months.

The safety profile of KEYTRUDA (pembrolizumab) was consistent with that observed in previously reported studies. For patients in the MMR-deficient non-colorectal cancers cohort, Grade 3-4 treatment-related adverse events included diarrhea/colitis (n=3) and pancreatitis (n=1). For patients in the colorectal cancer cohorts (MMR-deficient and MMR-proficient), Grade 3-4 treatment-related adverse events included diarrhea/colitis (n=1), pancreatitis (n=2), rash/pruritus (n=1), anemia (n=1), leukopenia (n=1), and thrombocytopenia (n=1).

Initial findings from this study evaluating KEYTRUDA (41 patients) were presented at the 2015 ASCO (Free ASCO Whitepaper) Annual Meeting and simultaneously published online in the New England Journal of Medicine (Le et al. New Eng. J. Med. 372, 26, 2509). On November 2, 2015, Merck announced that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to KEYTRUDA for the treatment of patients with MSI-H metastatic colorectal cancer.

About DNA Mismatch Repair and Microsatellite Instability

Analysis of tumor DNA for microsatellite instability can be used to identify tumors with defective DNA mismatch repair (MMR) systems. DNA MMR is a process that in normal cells permits the recognition and repair of genetic mismatches generated during DNA replication. A defective MMR system results in the persistence of DNA mismatches that may then be incorporated into the genetic code as mutations. The average tumor has dozens of mutations; however, tumors with DNA MMR-deficiency may harbor thousands, especially in regions of repetitive DNA known as microsatellites. Tumors that are found to have mutations in select microsatellite sequences, called microsatellite instability (MSI), are considered DNA MMR-deficient. These tumors are referred to as being "MSI-high." Overall, DNA MMR-deficiency is present in approximately 15-20 percent of tumors in Stage II disease, 10 percent in Stage III disease and approximately 5 percent or less in Stage IV disease. In colorectal cancers, MMR-deficiency is seen in approximately 15-20 percent of non-hereditary colorectal cancers and in most hereditary colorectal cancers associated with Lynch Syndrome.

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 (pembrolizumab) 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, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 32 (2.0%) of 1567 patients with melanoma, including Grade 1 (0.8%), 2 (0.8%), and 3 (0.4%) pneumonitis. Pneumonitis occurred in 19 (3.5%) of 550 patients with NSCLC, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis and 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 31 (2%) of 1567 patients with melanoma, including Grade 2 (0.5%), 3 (1.1%), and 4 (0.1%) colitis. Immune-mediated colitis occurred in 4 (0.7%) of 550 patients with NSCLC, 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. Hepatitis occurred in 16 (1%) of 1567 patients with melanoma, including Grade 2 (0.1%), 3 (0.7%), and 4 (0.1%) hepatitis. 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 13 (0.8%) of 1567 patients with melanoma, including Grade 2 (0.3%), 3 (0.3%), and 4 (0.1%) hypophysitis. Hypophysitis occurred in 1 (0.2 %) of 550 patients with NSCLC, 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 (pembrolizumab) for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

Hyperthyroidism occurred in 51 (3.3%) of 1567 patients with melanoma, including Grade 2 (0.6%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 127 (8.1%) of 1567 patients with melanoma, including Grade 3 (0.1%) hypothyroidism. Hyperthyroidism occurred in 10 (1.8%) of 550 patients with NSCLC, including Grade 2 (0.7%) or 3 (0.3%) hyperthyroidism. Hypothyroidism occurred in 38 (6.9%) of 550 patients with NSCLC, 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. Nephritis occurred in 7 (0.4%) of 1567 patients with melanoma including, Grade 2 (0.2%), 3 (0.2%), and 4 (0.1%) nephritis. 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 (pembrolizumab) 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% (unless otherwise indicated) of 1567 patients with melanoma: arthritis (1.6%), exfoliative dermatitis, bullous pemphigoid, uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients with NSCLC: 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 (pembrolizumab).

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.

In Trial 6, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In Trial 2, KEYTRUDA was discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). The most common adverse reactions with KEYTRUDA vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus (28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA (pembrolizumab).

KEYTRUDA was discontinued due to adverse reactions in 14% of 550 patients with NSCLC. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported 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 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.

On June 5, 2016 Foundation Medicine, Inc. (NASDAQ:FMI) and it collaborators reported data showing that higher tumor mutational burden, as estimated by comprehensive genomic profiling with FoundationOne, successfully predicted a greater likelihood of response and longer response duration to cancer immunotherapies in patients with advanced bladder cancer and metastatic melanoma as well as several other tumor types (Press release, Foundation Medicine, JUN 5, 2016, View Source [SID:1234513005]). The results were presented in two oral sessions, and several poster discussions at the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) taking place in Chicago.

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"Successful application of cancer immunotherapy in the clinic is one of the most important advances in cancer treatment in decades," said Vincent Miller, M.D., chief medical officer at Foundation Medicine. "These data suggest that tumor mutational burden could serve as an independent predictive biomarker to aid clinicians in identifying patients who are most likely to benefit from cancer immunotherapies that target either the PD-1 or PD-L1 proteins."

Cancer immunotherapy works by helping the immune system mount an effective anti-cancer response, a process that depends in part on the recognition of cancer-specific proteins called neoantigens. Tumor mutational burden has been shown to correlate well with the number of neoantigens, and therefore it may help identify patients most likely to respond to cancer immunotherapies. By combining comprehensive genomic profiling of 315 genes utilizing the FoundationOne assay, with Foundation Medicine’s advanced and proprietary algorithm that filters out normal individual genomic variants, FoundationOne can reliably and accurately measure tumor mutational burden without the need for whole exome sequencing. Foundation Medicine expects to provide a CLIA-certified version of tumor mutational burden on all FoundationOne and FoundationOne Heme reports to physicians in the third quarter 2016.

Overview of Data Presentations

The IMvigor 210 study of TecentriqTM (atezolizumab; anti-PD-L1; Genentech/Roche) in locally advanced or metastatic urothelial carcinoma evaluated three separate biomarkers: PD-L1 protein expression as measured by immunohistochemistry, molecular subtype as measured by gene expression and The Cancer Genome Atlas, and mutational load (often referred to as tumor mutational burden) as measured by FoundationOne. All three biomarkers were shown to be independent predictors of response to Tecentriq.

"PD-L1 Expression, Cancer Genome Atlas (TCGA) Subtype and Mutational Load are Independent Predictors of Response to Atezolizumab (atezo) in Metastatic Urothelial Carcinoma (mUC; Imvigor210)", by Jonathan E. Rosenberg, M.D., Memorial Sloan Kettering Cancer Center [Abstract #104, Clinical Science Symposium, Sunday June 5, 9:57-10:09 AM].
"These results are particularly exciting given the amount of variability inherent to using immunohistochemistry (IHC) to measure biomarkers. There are many different PD-L1 IHC tests, for example, and pathologists often do not see agreement between them," stated Vamsidhar Velcheti, M.D., assistant professor, Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic. "We need a truly quantitative and reproducible approach to predicting response to immunotherapies, and measuring tumor mutational burden using FoundationOne may provide us with that solution."

In a separate melanoma study, higher mutational burden as measured by FoundationOne was associated with a greater likelihood of response and a more durable response to pembrolizumab; anti-PD-1; Merck, nivolumab; anti-PD-1; Bristol Myers Squibb, and Tecentriq, thereby providing oncologists with greater confidence in the potential for clinical benefit from a host of newly approved immunotherapies.

"Hybrid Capture-Based Next Generation Sequencing (HC NGS) in Melanoma Identifies Markers of Response to Anti-PD1/PD-L1", by Douglas Buckner Johnson, M.D., M.S.C.I., Vanderbilt-Ingram Cancer Center [Abstract #105, Clinical Science Symposium, Sunday June 5, 10:21-10:33 AM]
Dr. Miller continued, "The clinical reality is that some patients respond very well to cancer immunotherapies and others do not. As a result, the ability to leverage our molecular information platform to identify the right candidates for these immunotherapies is an important advance for the field of precision medicine. Matching the right therapy with the right patient has the potential to both improve outcomes and increase efficiency in the current care model."

These conclusions were further supported by two additional presentations at ASCO (Free ASCO Whitepaper) 2016 that demonstrated that total mutational burden could also predict response to cancer immunotherapy in lung and colorectal cancers:

"Total Mutational Burden (TMB) in Lung Cancer and Relationship with Response to PD-1/PD-L1 Targeted Therapies", by David R. Spigel, M.D., Sarah Cannon Research Institute [Abstract #9017, Poster Session, Saturday June 4, 8:00-11:30 AM].
"Tumor Mutational Burden as a Potential Biomarker for PD1/PD-L1 Therapy in Colorectal Cancer", by Thomas J. George, M.D., F.A.C.P., University of Florida [Abstract #3587, Poster Session, Saturday June 4, 8:00-11:30 AM].

On June 5, 2016 Exelixis, Inc. (NASDAQ:EXEL) and Ipsen (Euronext:IPN; ADR:IPSEY) reported overall survival (OS) results from the phase 3 METEOR trial of CABOMETYX (cabozantinib) tablets in patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy (Press release, Exelixis, JUN 5, 2016, View Source;p=RssLanding&cat=news&id=2175112 [SID:1234513004]). The findings will be presented during an oral abstract session today at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, and were published today in The Lancet Oncology.1 The OS results demonstrate that CABOMETYX reduces the risk of death by one third versus everolimus.

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Exelixis previously announced that METEOR met its primary endpoint, progression-free survival (PFS), and secondary endpoints, OS and objective response rate.

"The overall survival benefit conferred by treatment with CABOMETYX — which was consistently favorable across a variety of prespecified and post-hoc patient subgroups — is a strong complement to the progression-free survival and objective response rate findings previously reported," said Toni Choueiri, M.D., Clinical Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. "With the recent FDA approval of CABOMETYX, patients in need of additional options now have access to a differentiated treatment demonstrated to help them live longer while also delaying the progression of their cancer."

In METEOR, at a median follow-up of nearly 19 months, CABOMETYX demonstrated an increase in median OS of nearly 5 months versus everolimus: 21.4 months versus 16.5 months for everolimus (HR 0.66, 95% CI [0.53-0.83], P=0.0003), corresponding to a 34 percent reduction in the risk of death.

CABOMETYX treatment resulted in consistent benefits in OS and PFS across various pre-specified and post-hoc analysis subgroups. Benefits were independent of Memorial Sloan Kettering Cancer Center risk group (favorable, intermediate, or poor), number and type of prior vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) therapies (one, or more than one), duration of first VEGFR TKI treatment (6 months or less, or more than 6 months), presence of bone and/or visceral metastases, and levels of the MET biomarker in tumors (high, low, or unknown). Additional details on benefits seen in subgroups of patients based on the presence of bone metastases and prior VEGFR TKI therapy will be presented in a poster session at 1 p.m. CDT on June 6.

"We are excited to share the detailed overall survival results from the METEOR trial with the oncology community at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "The five-year survival rate for patients diagnosed with advanced kidney cancer is only 12 percent, underscoring the need for new treatment options that help patients live longer while delaying the progression of their disease. Critically, CABOMETYX — the first FDA-approved therapy to demonstrate a benefit in all three key efficacy parameters — now shows consistent survival benefit across all subgroups of patients evaluated in METEOR."

"Recent data from the METEOR trial confirms the benefit in median overall survival of almost 5 months that CABOMETYX can provide to patients with advanced renal cell carcinoma," said Marc de Garidel, Chairman and CEO, Ipsen. "We are dedicated to diligently working with Exelixis and regulatory authorities to bring cabozantinib to patients who seek new therapeutic options with established survival benefits."

At the time of the analysis, the median duration of treatment in the trial was 8.3 months with CABOMETYX versus 4.4 months with everolimus. Dose reductions occurred for 62 percent and 25 percent of patients, respectively. Discontinuation rate due to an adverse event not related to disease progression was 12 percent with CABOMETYX and 11 percent with everolimus.

The most common grade 3 or 4 adverse events were hypertension (15 percent), diarrhea (13 percent) and fatigue (11 percent) in the CABOMETYX arm and anemia (17 percent), fatigue (7 percent) and hyperglycemia (5 percent) in the everolimus arm. Serious adverse events ≥ grade 3 occurred in 130 (39 percent) of cabozantinib-treated patients and in 129 (40 percent) of everolimus-treated patients.

On April 25, 2016 CABOMETYX was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy.

Please see Important Safety Information below and full U.S. prescribing information for CABOMETYX (cabozantinib) tablets at View Source

About the METEOR Phase 3 Pivotal Trial

METEOR was an open-label, event-driven trial of 658 patients with advanced renal cell carcinoma who had failed at least one prior VEGFR TKI therapy. The primary endpoint was PFS in the first 375 patients treated. Secondary endpoints included OS and objective response rate in all enrolled subjects. The trial was conducted at approximately 200 sites in 26 countries, and enrollment was weighted toward Western Europe, North America, and Australia.

Patients were randomized 1:1 to receive 60 mg of CABOMETYX daily or 10 mg of everolimus daily and were stratified based on the number of prior VEGFR TKI therapies received and on MSKCC risk criteria. No cross-over was allowed between the study arms.

METEOR met its primary endpoint of significantly improving PFS. Compared with everolimus, CABOMETYX was associated with a 42 percent reduction in the rate of disease progression or death. Median PFS for CABOMETYX was 7.4 months versus 3.8 months for everolimus (HR=0.58, 95% CI 0.45-0.74, P<0.0001). CABOMETYX also significantly improved the objective response rate compared with everolimus (P<0.0001). These data were presented at the European Cancer Congress in September 2015 and published in The New England Journal of Medicine.2

Exelixis to Host Investor/Analyst Briefing Later Today

Exelixis will host a live investor/analyst briefing today, Sunday, June 5, 2016, from 7:30-9:30 p.m. EDT / 6:30-8:30 p.m. CDT / 4:30-6:30 p.m. PDT. During the briefing, Exelixis management and invited guest speakers will review and provide context for the cabozantinib data presented at the ASCO (Free ASCO Whitepaper) Annual Meeting. The briefing will be webcast live and can be accessed by logging on to www.exelixis.com and proceeding to the Event Calendar page under Investors & Media. Please connect to the company’s website at least 15 minutes prior to the webcast to ensure adequate time for any software download that may be required to listen to the webcast. An archived replay of the webcast will also be available on the Event Calendar page under Investors & Media at www.exelixis.com for one year. A telephone replay of the webcast will be available until 11:59 p.m. EDT on June 7, 2016. Access numbers for the phone replay are: 855-859-2056 (domestic) and 404-537-3406 (international); the passcode is 15007787.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2016 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.3 Clear cell RCC is the most common type of kidney cancer in adults.4 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.3 Approximately 17,000 patients in the U.S. and 37,000 globally require second-line or later treatment.5

The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.6,7 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.8-11 MET and AXL may provide escape pathways that drive resistance to VEGFR inhibitors.7,8

About CABOMETYX

CABOMETYX targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.

CABOMETYX, the tablet formulation of cabozantinib, is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy.

On January 28, 2016, the European Medicines Agency (EMA) validated Exelixis’ Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma who have received one prior therapy. The MAA has been granted accelerated assessment, making it eligible for a 150-day review, versus the standard 210 days. On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan.

Important Safety Information

Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.

Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.

Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.

Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.

Diarrhea: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to diarrhea occurred in 26% of patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-fetal Toxicity: CABOMETYX can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.

Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation.

Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided.

Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.

Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility ―CABOMETYX may impair fertility in females and males of reproductive potential.

Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

Please see full Prescribing Information at View Source

On June 5, 2016 Exelixis, Inc. (NASDAQ:EXEL) reported that its collaborator Genentech, a member of the Roche Group, will present preliminary results from a phase 1b clinical trial evaluating the safety and clinical activity of cobimetinib, an Exelixis-discovered MEK inhibitor, in combination with atezolizumab, an anti-PD-L1 antibody discovered and developed by Genentech, in patients with metastatic colorectal cancer (CRC) (Press release, Exelixis, JUN 5, 2016, View Source;p=RssLanding&cat=news&id=2175111 [SID:1234513003]). The results will be the subject of an oral presentation (Abstract #3502) today at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which is being held June 3-7 in Chicago, Illinois. Johanna Bendell, M.D., director of the Gastrointestinal Cancer Research Program at the Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee, will present the results.

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"These early data on the combination of cobimetinib, an Exelixis-discovered MEK inhibitor, and atezolizumab, an anti-PD-L1 antibody discovered and developed by Genentech, are encouraging and warrant further study in people with previously-treated metastatic colorectal cancer, including those with microsatellite stable disease," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "Based on these results, Genentech has initiated the COTEZO phase 3 trial in patients with unresectable locally advanced or metastatic colorectal cancer."

This ongoing phase 1b trial includes both a dose escalation stage and dose expansion stage. The trial’s primary objective is the evaluation of the safety and tolerability of the combination. Secondary endpoints include objective response rate (ORR) per RECIST, duration of response, progression-free survival (PFS), overall survival (OS), as well as evaluation of biomarkers.

As of the February 12, 2016 data cut-off, 23 patients with advanced CRC (22 with mutant KRAS and one with wild-type KRAS) were enrolled during the trial’s escalation and expansion phases. No dose-limiting toxicities were observed. The median follow-up for safety in CRC patients was 3.8 months, with a range of 1.1 to 15.1 months. There were no all-cause grade 5 or treatment-related grade 4 AEs reported, and incidence of treatment-related grade 3 AEs was 35% (n=8). The most common treatment-related AEs, regardless of severity, included: diarrhea (70% of patients); fatigue (52%); dermatitis acneiform (44%); rash (35%); and nausea, maculopapular rash and pruritus (each 26%).

The ORR for the combination was 17%, including four confirmed partial responses; additionally five patients achieved stable disease. The median duration of response was not yet reached, with a range of 5.4 to more than 11.1 months.

Median PFS for all CRC patients enrolled in the trial was 2.3 months, with a range of 1.8 to 9.5 months. The six-month PFS was 35%. Median OS for all CRC patients was not evaluable, while six-month OS was 72%.

Recently Initiated COTEZO Phase 3 Pivotal Trial

In June 2016 Genentech initiated COTEZO, a phase 3 pivotal trial of the combination of cobimetinib and atezolizumab in unresectable locally advanced or metastatic colorectal cancer. The trial is expected to enroll 360 patients who have received at least two prior chemotherapies in the metastatic disease setting. The primary endpoint of the COTEZO trial is overall survival. More information about the COTEZO phase 3 pivotal trial is available at www.clinicaltrials.gov.

Additional Cobimetinib Data Presented at ASCO (Free ASCO Whitepaper) 2016

The oral presentation in colorectal cancer is one of eight cobimetinib abstracts being presented at the ASCO (Free ASCO Whitepaper) 2016 Annual Meeting this week. Additional data presentations include studies of cobimetinib in combination with other therapies to treat triple-negative breast cancer and BRAF-mutant melanoma. For full logistical information on these other presentations, please see Exelixis’ ASCO (Free ASCO Whitepaper) announcement press release issued on April 20, 2016, available online here.

About the Cobimetinib Development Collaboration

Exelixis discovered cobimetinib internally and advanced the compound to investigational new drug (IND) status. In late 2006, Exelixis entered into a worldwide collaboration agreement with Genentech, under which Exelixis received initial upfront and milestone payments for signing the agreement and submitting the IND. Following the determination of the maximum tolerated dose in phase 1 by Exelixis, Genentech exercised its option to further develop cobimetinib.

Under the terms of the collaboration, Exelixis is entitled to an initial equal share of U.S. profits and losses resulting from sales of cobimetinib to treat any form of cancer, which will decrease as sales increase, and will share in U.S. marketing and commercialization costs. In November 2013, Exelixis exercised its option to co-promote cobimetinib in the United States and, under the terms of the agreement, the company is fielding 25 percent of the U.S. sales force for the product’s first commercial indication in specific forms of BRAF mutation-positive advanced melanoma, closely coordinating its efforts with Genentech. Outside of the United States, Exelixis is eligible to receive royalties on any sales.

Cobimetinib in combination with vemurafenib is now approved in multiple countries, including the United States, European Union, Switzerland, Canada, Australia and Brazil, to treat specific forms of BRAF mutation-positive advanced melanoma. Further country approvals are anticipated in 2016 and beyond. Cobimetinib is also the subject of a clinical development program aimed at evaluating its potential in combination with a variety of investigational and approved therapies in disease settings including metastatic melanoma, triple-negative breast cancer and advanced solid tumors.

COTELLIC Indication

COTELLIC (cobimetinib) is a prescription medicine that is used with ZELBORAF (vemurafenib), to treat a type of skin cancer called melanoma that has spread to other parts of the body or cannot be removed by surgery, and that has a certain type of abnormal "BRAF" gene.

A patient’s healthcare provider will perform a test for the BRAF gene to make sure that COTELLIC is right for them. It is not known if COTELLIC is safe and effective in children under 18 years of age.

COTELLIC Important Safety Information

Patients should avoid sunlight during treatment with COTELLIC. COTELLIC can make their skin sensitive to sunlight. They may burn more easily and get severe sunburns. To help protect against sunburn, they should wear clothes that protect their skin, including their head, face, hands, arms, and legs. They should use lip balm and a broad-spectrum sunscreen with SPF 30 or higher.

COTELLIC may cause serious side effects, including risk of new skin cancers, bleeding problems, heart problems, severe rash, eye problems, liver problems, muscle problems (rhabdomyolysis), and photosensitivity. Patients should tell their doctor if they are pregnant or plan to become pregnant, as COTELLIC and ZELBORAF can harm an unborn baby. Patients who take COTELLIC should use effective methods of birth control during treatment, for 2 weeks after stopping COTELLIC, and for at least 2 months after stopping ZELBORAF. Do not breastfeed during treatment with COTELLIC and for 2 weeks after the final dose. Patients along with their healthcare provider should decide if they will take ZELBORAF or breastfeed. Patients should not do both.

Patients should tell their healthcare provider about all the medicines they take. Some types of medicines will affect the blood levels of COTELLIC.

Common side effects of COTELLIC include diarrhea, sunburn or sun sensitivity, nausea, fever, and vomiting. COTELLIC can also cause changes in blood test results.

Patients should tell their healthcare provider if they have any side effect that bothers them or that does not go away. These are not all the possible side effects of COTELLIC. For more information about side effects, patients should ask their healthcare provider or pharmacist.

Patients should call their doctor for medical advice about side effects. They may report side effects to FDA at (800) FDA-1088 or www.fda.gov/medwatch. They may also report side effects to Genentech at (888) 835-2555.

Please see full COTELLIC Prescribing Information and Patient Information for additional Important Safety Information.