On November 21, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported findings from three studies investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in combination with three other immunotherapies – epacadostat, IMLYGICTM (talimogene laherparepvec), and ipilimumab – in patients with advanced melanoma (Press release, Merck & Co, NOV 21, 2015, View Source [SID:1234508309]). The findings, which were featured in separate oral presentations today at the Society for Melanoma Research 2015 International Congress (SMR) in San Francisco, showed robust anti-tumor activity with KEYTRUDA in all three combinations studied.

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"We have demonstrated the benefit of KEYTRUDA as a single agent in advanced/metastatic melanoma and we are now also looking to identify potential combinations for patients with this devastating disease," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "The combination data presented at SMR, including KEYTRUDA combined with epacadostat or IMLYGIC, may further our goal of improving outcomes without substantial increased toxicity."

Additionally, updated data presented at SMR from a Phase 3 study of KEYTRUDA as a single agent showed superior overall response rates (ORR) and progression free survival (PFS) compared to ipilimumab in ipilimumab-naïve patients, with twice as many patients achieving PFS on KEYTRUDA compared to ipilimumab. As previously reported, the study met its endpoint of overall survival. Patient-reported outcomes from the same study were also presented. The KEYTRUDA clinical development program to date includes patients with more than 30 tumor types in more than 160 clinical trials, including more than 80 trials that combine KEYTRUDA with other cancer treatments.

Early Findings from the KEYNOTE-037 Study (KEYTRUDA with Epacadostat)

KEYNOTE-037 is an ongoing Phase 1/2 study of KEYTRUDA (pembrolizumab) in combination with epacadostat (INCB024360) – an investigational selective IDO1 inhibitor – in patients with advanced cancers. The trial is a collaboration between Merck and Incyte Corporation. Data from the melanoma cohort of this study were presented on Nov. 21 at 2:50 p.m. PST by Dr. Omid Hamid, director, Melanoma Center, The Angeles Clinic and Research Institute. These data were previously presented earlier this month at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting as part of a presentation that included several tumor types. The SMR data includes additional safety data.

Early data from this trial showed that in 19 patients with advanced melanoma, the combination of KEYTRUDA (two doses studied – 2 mg/kg or 200 mg every three weeks) with epacadostat (four doses studied – 25, 50, 100 or 300 mg twice daily) demonstrated an ORR of 53 percent (n=10/19), including three complete responses (CRs) and seven partial responses (PRs). The disease control rate (DCR) was 74 percent (n=14/19).

Treatment-related adverse events were consistent with previously reported safety data for KEYTRUDA as a single agent. Fifteen percent (n=9/60) of patients assessed for safety across tumor types experienced Grade 3 investigator-assessed, treatment-related adverse events, including rash (8%), arthralgia (2%), AST increased (2%), mucosal inflammation (2%) and nervous system disorder (2%). Three patients discontinued treatment – one for Grade 3 arthralgia, one for Grade 3 AST increased, and one for Grade 2 nervous system disorder. No Grade 4 treatment-related adverse events or deaths were observed.

As previously announced, based on these findings, a Phase 3 trial of this combination is planned.

Early Findings from the MASTERKEY-265 Study (KEYTRUDA with IMLYGIC)

MASTERKEY-265 is an ongoing Phase 1b study evaluating the safety, efficacy, and tolerability of KEYTRUDA in combination with IMLYGIC – a herpes simplex virus-1 (HSV-1)-based oncolytic immunotherapy – in patients with previously untreated, unresected advanced melanoma. The trial is a collaboration between Merck and Amgen. Data from this study were presented on Nov. 21 at 3:20 p.m. PST by Dr. Georgina Long, associate professor, Melanoma Institute Australia, University of Sydney.

Data presented were of 16 evaluable patients and the first analysis of this study; results showed that the combination of KEYTRUDA (200 mg every two weeks) with IMLYGIC (up to 4 mL of 106 PFU/mL, then 108 PFU/mL every two weeks) resulted in an unconfirmed ORR of 56.3 percent (n=9/16) (95% CI, 19.8, 70.1), including two CRs and seven PRs. The DCR was 68.8 percent (n=11/16) (95% CI, 11, 58.7).

Treatment-related adverse events were consistent with previously reported safety data for KEYTRUDA (pembrolizumab). All 21 patients enrolled had at least one adverse event, and most were Grades 1 and 2. The most common adverse events (occurring in at least 30% of patients) of any grade were fatigue (52%), pyrexia (48%), chills (43%), rash (38%), headache (33%), and nausea (33%). Grade 3 adverse events included headache (5%) and diarrhea (5%). Treatment-related Grade 3 adverse events occurring in 5 patients included anemia, hyperglycemia, hypoglycemia, hypophosphatemia, headache, macular rash and generalized rash. No dose-limiting toxicities were reported.

Based on these findings, a Phase 3 part of this trial is planned.

Early Findings from the KEYNOTE-029 Study (KEYTRUDA with Ipilimumab)

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 to investigate whether lower doses of ipilimumab improve the tolerability of the combination regimen. Early findings from this study were presented on Nov. 21 at 2 p.m. PST by Dr. Georgina Long, associate professor, Melanoma Institute Australia, University of Sydney.

Early findings in 72 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 56 percent (95% CI, 43-67), including three CRs and 37 PRs. The DCR was 79 percent (95% CI, 68-88).

Treatment-related adverse events were observed in 93 percent (n=67/72) of patients. Grade 3-4 treatment-related adverse events were observed in 36 percent of patients (n=26/72), including lipase increased (8%), amylase increased (6%), ALT increased (6%), AST increased (4%), rash (3%), and diarrhea (1%). Grade 3-4 immune-mediated adverse events included thyroiditis, hypophysitis, type 1 diabetes mellitus, pneumonitis, colitis, hepatitis, pancreatitis, severe skin reactions and renal events. There were no treatment-related deaths.

Additional Findings from the KEYNOTE-006 Study

KEYNOTE-006 is a global, open-label, randomized, pivotal, Phase 3 study of patients with unresectable stage 3 or 4 advanced melanoma who were naïve to ipilimumab and had no more than one prior systemic therapy. Patients received KEYTRUDA 10 mg/kg every two weeks (n=279), KEYTRUDA 10 mg/kg every three weeks (n=277), or four cycles of ipilimumab 3 mg/kg every three weeks (n=278). Today’s findings provide data on additional endpoints of ORR and PFS based on six months of additional follow-up (median follow-up of 13.8 months), as well as the first-time presentation of patient-reported outcomes. Results were featured in two poster sessions by Dr. Jacob Schachter, Ella Lemelbaum Institute for Melanoma, Sheba Medical Center, and Dr. Teresa Petrella, Sunnybrook Health Sciences Centre, University of Toronto.

Findings showed PFS rates for KEYTRUDA at 12 months were twice as high as ipilimumab – 37.7 percent in the KEYTRUDA every two week cohort and 36.3 percent in the every three week group, compared to 17.2 percent with ipilimumab (hazard ratio: 0.60 [95% CI, 0.49-0.74] and hazard ratio: 0.59 [95% CI, 0.48-0.73], respectively). Additionally, the ORR was 36.2 and 36.1 percent in patients receiving KEYTRUDA every two weeks or every three weeks, respectively [(95% CI, 30.6-42.1) and (95% CI, 30.4-42.1), respectively], compared to 12.9 percent for ipilimumab (95% CI, 9.2-17.5).

There continued to be no treatment-related deaths in the KEYTRUDA arm and there were no treatment-related deaths in the ipilimumab arm beyond one that was previously reported. Grade 3-5 treatment-related adverse events were lower for KEYTRUDA than for ipilimumab – 15.1 and 12.6 percent of patients receiving KEYTRUDA every two weeks and every three weeks had Grade 3-4 adverse events, respectively, compared to 19.9 percent of those receiving ipilimumab. Immune-mediated treatment-related adverse events were consistent with previously reported safety data for KEYTRUDA and included hypothyroidism, hyperthyroidism, colitis, hepatitis, hypophysitis, pneumonitis, type 1 diabetes mellitus, uveitis, myositis and nephritis.

Also reported at SMR from this study was a prespecified analysis of new patient-reported health-related quality of life (HRQoL) outcomes, based on measures such as physical, emotional, cognitive, and social functioning (based on European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire). The study showed that HRQoL was maintained to a greater degree with KEYTRUDA than with ipilimumab – the change from baseline at week 12 (difference in least squares) for KEYTRUDA was -2.3 (95% CI, -5.21 to 0.62) for the two-week group and -2.6 (95% CI, -5.44 to 0.23) for the three-week group, respectively, compared to -9.9 (95% CI, -13.01 to -6.72) for the ipilimumab arm.

In addition, KEYTRUDA was associated with a better symptom profile. Patients in the KEYTRUDA arms had smaller increases from baseline in fatigue, pain, dyspnea, appetite loss, and diarrhea, indicating that although these symptoms worsened with KEYTRUDA, they did so to a lesser degree than with ipilimumab. KEYTRUDA also resulted in improvements over baseline in nausea and vomiting and insomnia, whereas these symptoms worsened with ipilimumab.

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 in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks 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. KEYTRUDA is also indicated at the same dosing for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. These indications are 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 these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Pneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. 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 in patients, receiving KEYTRUDA. 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.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients with melanoma, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA.

Colitis occurred in 4 (0.7 %) of 550 patients with NSCLC, including Grade 2 (0.2%) or 3 (0.4%) colitis in patients receiving KEYTRUDA. 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.

Hepatitis occurred in patients receiving KEYTRUDA. Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients with melanoma, including a Grade 4 case in 1 (0.2%) patient, 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 2 (0.5%) of 411 patients with melanoma, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. 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 indicated. Withhold KEYTRUDA (pembrolizumab) for Grade 2 and withhold or discontinue for Grade 3 or Grade 4 hypophysitis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients with melanoma, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients with melanoma, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Hyperthyroidism occurred in 10 (1.8%) of 550 patients with NSCLC, including Grade 2 (0.7%) or 3 (0.3%). Hypothyroidism occurred in 38 (6.9%) of 550 patients with NSCLC, including Grade 2 (5.5%) or 3 (0.2%). 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 Grade 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. 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.

Nephritis occurred in patients receiving KEYTRUDA. Nephritis occurred in 3 (0.7%) patients with melanoma, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. 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 of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following steroid taper. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Across clinical studies with KEYTRUDA, the following clinically significant, immune-mediated adverse reactions have occurred: bullous pemphigoid and Guillain-Barré syndrome. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients with melanoma treated with KEYTRUDA (pembrolizumab): exfoliative dermatitis, uveitis, arthritis, myositis, 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 treated with KEYTRUDA: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening 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.

Among the 411 patients with metastatic melanoma, KEYTRUDA was discontinued for adverse reactions in 9% of 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients. The most frequent serious adverse reactions, reported in 2% or more of patients, were renal failure, dyspnea, pneumonia, and cellulitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

Among the 550 patients with metastatic NSCLC, KEYTRUDA was discontinued due to adverse reactions in 14% of patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in 2% or more 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%), decreased appetite (25%), dyspnea (23%), and cough (29%).

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.