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.

On October 9, 2016 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported positive results from the Company’s Phase 2 study of glembatumumab vedotin in patients with stage III/IV checkpoint inhibitor-refractory, and, if applicable, BRAF/MEK inhibitor-refractory metastatic melanoma (n=62) (Press release, Celldex Therapeutics, OCT 9, 2016, View Source [SID:SID1234515680]). Glembatumumab vedotin is a fully-human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB), a protein overexpressed by multiple tumor types, including metastatic melanoma where greater than 80% of patients overexpress the marker. High tumor expression of gpNMB is associated with shorter metastasis-free survival and reduced overall survival.1 Study results were presented today at the ESMO (Free ESMO Whitepaper) 2016 Congress in Copenhagen in poster titled "A Phase 2 study of glembatumumab vedotin (GV), an antibody-drug conjugate (ADC) targeting gpNMB, in advanced melanoma."

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Study Highlights

The primary endpoint of the study (6 or more objective responses in the first 52 patients enrolled) was exceeded. 7 of 62 (11%) patients experienced a confirmed response, and an additional 3 patients also experienced single timepoint responses.
Median duration of response in this heavily pre-treated patient population was 6.0 months.
53% of patients experienced stable disease (with a minimum duration of six weeks).
A 52% disease control rate (patients without progression for greater than three months) was demonstrated.
52% of patients experienced tumor shrinkage.
Median progression-free survival (PFS) for all patients was 4.4 months.
Patients who experienced rash in Cycle 1 experienced a 20% confirmed response rate and a more prolonged PFS of 5.5 months [p=0.054; HR=0.52 (0.27, 1.02)].
"While immune checkpoint inhibitors and BRAF targeted therapy have dramatically changed outcomes for many patients with metastatic melanoma, patients who either do not respond or progress through these treatments are faced with very limited treatment options," said Patrick Ott, M.D., Ph.D., Clinical Director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber Cancer Institute and an investigator in the study. "The single-agent activity observed in this study and the corresponding duration of response is highly encouraging. I am hopeful that pursuing combination studies of glembatumumab vedotin, including with checkpoint inhibition, could help us bring benefit to an even larger number of melanoma and other cancer patients."

"It’s clear based on these study results that refractory metastatic melanoma is a responsive target indication for glembatumumab vedotin," said Thomas Davis, M.D., Executive Vice President and Chief Medical Officer of Celldex Therapeutics. "gpNMB is very highly expressed in melanoma with all tissue samples on study testing positive, and almost 80% of tumors demonstrating 100% expression in their epithelial cells. We’re encouraged by the results we’ve seen to date in this advanced, checkpoint refractory setting and believe leveraging the immune system through combination therapy is a critical next step for patients in in this indication."

Study Overview
This study was a Phase 2, open-label study of glembatumumab vedotin in patients with unresectable stage III (n=1; 2%) or stage IV (n=61; 98%) melanoma. The median number of prior therapies was three (range of 1 to 6). All patients had progressed after checkpoint therapy, and almost all patients had received both ipilimumab (n=58; 94%) and PD-1/PDL-1 (n=58; 94%) therapy. Twelve patients presented with BRAF mutation, and eleven had prior treatment with BRAF or BRAF/MEK targeted agents. Patients received glembatumumab vedotin every three weeks until disease progression or intolerance. The safety profile was consistent with prior studies of glembatumumab vedotin with rash, neutropenia, and neuropathy experienced as the most significant adverse events. Consistent with previous studies in melanoma and breast cancer, rash was associated with greater clinical benefit.

Clinical Efficacy

Primary Endpoint: Confirmed Response Rate (ORR) Met 7/62 (11%)
Duration of Response Median: 6.0 months
Range: 1.4 + to 8.6+
Any Response, Including Those not Confirmed at Subsequent Assessment 10/62 (16%)
Stable Disease 33/62 (53%)
Disease Control Rate 32/62 (52%)
Patients with Tumor Shrinkage 32/62 (52%)
Progression-free Survival Median: 4.4 months
Range: 0.4 to 15.8+
Tumor tissue (pre-treatment) was available for 58 patients at the time of analysis. All samples were gpNMB positive, and 79% of patients had tumors with 100% of their epithelial cells expressing gpNMB. Given both the high level of expression and the intensity of expression across this patient population, identifying a potential population for gpNMB enrichment is not feasible; therefore, all patients with metastatic melanoma could be evaluated as potential candidates for treatment with glembatumumab vedotin in future studies.

Next Steps
In August 2016, the Company announced that the primary endpoint had been met in this Phase 2 single-agent study of glembatumumab vedotin in metastatic melanoma (post-progression on/after checkpoint therapy) and that the Company was amending the protocol to add a second cohort of patients to a glembatumumab vedotin and varlilumab combination. Varlilumab is Celldex’s fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade. This additional cohort is open to enrollment. Upon completion of enrollment in this cohort, the Company is exploring opening a new arm in the study to assess a glembatumumab vedotin and checkpoint combination. This rationale is strongly supported by preclinical data that suggest that the anti-tumor activity may be enhanced with the combination. In addition, due to their direct cytotoxic properties, microtubule-depolymerizing agents like MMAE also appear to convert tumor-resident tolerogenic dendritic cells into active antigen-presenting cells.2 The Company also intends to conduct exploratory analyses of pre-entry skin biopsies in future patients to investigate potential predictors of response to glembatumumab vedotin, given the association of rash and outcome.

About Glembatumumab Vedotin
Glembatumumab vedotin is a fully-human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB). gpNMB is a protein overexpressed by multiple tumor types, including breast cancer, melanoma, lung cancer, uveal melanoma and osteosarcoma. gpNMB has been shown to be associated with the ability of the cancer cell to invade and metastasize and to correlate with reduced time to progression and survival in breast cancer. The gpNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology. Glembatumumab vedotin is designed to be stable in the bloodstream but to release MMAE upon internalization into gpNMB-expressing tumor cells, resulting in a targeted cell-killing effect. Glembatumumab vedotin is in development for the treatment of locally advanced or metastatic breast cancer with an initial focus in triple negative disease, stage III and IV melanoma, squamous cell lung cancer, uveal melanoma and osteosarcoma.

On October 9, 2016 Novartis reported updated results from a Phase II study (ASCEND-3), which demonstrated that anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) patients taking Zykadia (ceritinib) as their first ALK inhibitor (post-chemotherapy) had a median progression-free survival (PFS) of 18.4 months [95% CI: 10.9-26.3; median follow-up time of 25.9 months, as measured by blinded independent review committee (BIRC)][1] (Press release, Novartis, OCT 9, 2016, View Source [SID:SID1234515677]). Results were presented during an oral session at the Annual European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper) in Copenhagen.

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These results are consistent with findings from the Phase I ASCEND-1 study, which demonstrated a median PFS of 18.4 months (95% CI: 15.2-not reached) as per BIRC assessment with a median follow-up of 11.1 months[2]. The previous analysis by BIRC in ASCEND-3 indicated that the median PFS had not been reached after a median follow-up time of 8.3 months[3].

Further, in a sub-analysis of these data, patients who entered the study with brain metastases at baseline experienced an overall response rate (ORR) of 63.3% (95% CI: 48.3-76.6) and a disease control rate (DCR) of 83.7% (95% CI: 70.3-92.7), both as measured by BIRC. These results were similar to those in patients without brain metastases, who demonstrated an ORR of 64.0% (95% CI: 52.1-74.8) and DCR of 88.0% (95% CI: 78.4-94.4), based on BIRC assessment[1].

"The unfortunate reality of ALK+ NSCLC is that advancement is needed to delay disease progression in these patients," said lead investigator Dr. Enriqueta Felip, Head of the Thoracic Tumors Group, Vall d’Hebron University Hospital. "These data, coupled with a compelling response in the sub-analysis of patients with baseline brain metastases, provide greater evidence of Zykadia’s potential efficacy in the ALKi-naïve population."

At the time of analysis, the estimated 18-month overall survival (OS) rate was 73.4% (95% CI: 64.6-80.4). This population also demonstrated an ORR of 63.7% (95% CI: 54.6-72.2) and median duration of response of 23.9 months (95% CI: 16.6-not estimable), according to BIRC assessment. A decrease in tumor burden from baseline was shown in 94.7% patients (investigator assessment only, no BIRC assessment available)[1].

"Novartis is committed to extending lives of patients with difficult-to-treat forms of cancer, and these data presented at ESMO (Free ESMO Whitepaper) affirm our desire to improve outcomes for those with metastatic NSCLC, specifically," said Alessandro Riva, MD, Global Head, Oncology Development and Medical Affairs, Novartis Oncology. "With our first-line Phase III results forthcoming as well as ongoing brain metastases studies, we look forward to sharing further evidence of Zykadia’s full potential."

Results from the randomized Phase III ASCEND-5 study were also presented for the first time, and were included as part of a late-breaking oral session as well as in the ESMO (Free ESMO Whitepaper) press program. The ASCEND-5 study assessed median PFS in patients previously treated with crizotinib and one or two prior regimens of cytotoxic chemotherapy (including platinum doublet), who then received either Zykadia or standard chemotherapy. Results demonstrated a statistically significant and clinically meaningful improvement in median PFS by BIRC for patients taking Zykadia versus chemotherapy (HR 0.49, 95% CI 0.36-0.67; p<0.001 one sided). Median PFS by BIRC for Zykadia and chemotherapy were 5.4 months (95% CI: 4.1-6.9) vs. 1.6 months (95% CI: 1.4-2.8), respectively[4].

The ALK gene arrangement, one of the three most common biomarkers – or genetic drivers -of NSCLC, affects approximately 2-7% of cases each year[5],[6]. More than half of these patients are either former smokers or have never smoked[7],[8],[9]. These patients are candidates for treatment with a targeted ALK inhibitor[6].

About ASCEND-3
ASCEND-3 is a Phase II single-arm, open-label, multicenter study which included 124 patients with ALK+ NSCLC who had received up to three lines of chemotherapy and had no prior experience with an ALK inhibitor. Brain metastases at baseline were seen in 39.5% of patients. The most frequent adverse events were diarrhea [85.5% (3.2% grade 3/4)], nausea [77.4% (6.5% grade 3/4)] and vomiting [71.8% (6.5% grade 3/4)][1].

About ASCEND-5
ASCEND-5 is an open-label, randomized, active-controlled, multicenter Phase III study to compare the efficacy and safety of Zykadia to standard second-line chemotherapy (pemetrexed or docetaxel) in patients with advanced ALK+ NSCLC who progressed on prior crizotinib and one or two prior regimens of chemotherapy. Of 231 patients, 115 were randomized to ceritinib and 116 to chemotherapy. Of patients discontinuing chemotherapy due to disease progression, 75 crossed over to Zykadia. The most frequent adverse events were diarrhea [72.2% (4.3% grade 3/4)], nausea [66.1% (7.8% grade 3/4)] and vomiting [52.2% (7.8% grade 3/4)] with ceritinib; fatigue [28.3% (4.4% grade 3/4)], nausea [23.0% (1.8% grade 3/4)], alopecia [21.2% (0% grade 3/4)] and neutropenia [20.4% (15.0% grade 3/4)] with chemotherapy[4].

About Zykadia
Zykadia is an oral, selective inhibitor of anaplastic lymphoma kinase (ALK), a gene that can fuse with others to form an abnormal "fusion protein" that promotes the development and growth of certain tumors in cancers including non-small cell lung cancer (NSCLC). Zykadia was granted conditional approval in the EU for the treatment of adult patients with ALK-positive advanced NSCLC previously treated with crizotinib. In the US, Zykadia was granted accelerated approval for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.

Zykadia is currently approved in over 55 countries worldwide. Please visit www.NovartisOncology.com/news/product-portfolio/zykadia (link is external) for additional information.

Zykadia Important Safety Information
Zykadia may cause serious side effects.

Zykadia may cause stomach upset and intestinal problems in most patients, including diarrhea, nausea, vomiting and stomach-area pain. These problems can be severe. Patients should follow their doctor’s instructions about taking medicines to help these symptoms, and should call their doctor for advice if symptoms are severe or do not go away.

Zykadia may cause severe liver injury. Patients should have blood tests prior to the start of treatment with Zykadia, every two weeks for the first month of treatment and monthly thereafter, and should talk to their doctor right away if they experience any of the following symptoms: tiredness (fatigue), itchy skin, yellowing of the skin or the whites of the eyes, nausea or vomiting, decreased appetite, pain on the right side of the abdomen, urine turns dark or brown, or bleeding or bruising more easily than normal.

Zykadia may cause severe or life-threatening swelling (inflammation) of the lungs during treatment that can lead to death. Symptoms may be similar to those symptoms from lung cancer. Patients should tell their doctor right away about any new or worsening symptoms, including trouble breathing or shortness of breath, fever, cough, with or without mucous, or chest pain.

Zykadia may cause very slow, very fast, or abnormal heartbeats. Doctors should check their patient’s heart during treatment with Zykadia. Patients should tell their doctor right away if they feel new chest pain or discomfort, dizziness or lightheadedness, faint, or have abnormal heartbeats, blue discoloration of lips, shortness of breath, swelling of lower limbs or skin, or if they start to take or have any changes in heart or blood pressure medicines.

Zykadia may cause high levels of glucose in the blood. People who have diabetes or glucose intolerance, or who take a corticosteroid medicine have an increased risk of high blood sugar with Zykadia. Patients should have glucose blood tests prior to the start of treatment with Zykadia and during treatment. Patients should follow their doctor’s instructions about blood sugar monitoring and call their doctor right away with any symptoms of high blood sugar, including increased thirst and/or urinating often.

Zykadia may cause high levels of pancreatic enzymes in the blood and may cause pancreatitis. Patients should have blood tests prior to the start of treatment with Zykadia and as needed during their treatment with Zykadia. Patients should talk to their doctor if they experience signs and symptoms of pancreatitis which including upper abdominal pain that may spread to the back and get worse with eating.

Before patients take Zykadia, they should tell their doctor about all medical conditions, including liver problems; diabetes or high blood sugar; heart problems, including a condition called long QT syndrome; if they are pregnant, if they think they may be pregnant, or if they plan to become pregnant; are breastfeeding or plan to breastfeed.

Zykadia may harm unborn babies. Women who are able to become pregnant must use a highly effective method of birth control (contraception) during treatment with Zykadia and up to 3 months after stopping Zykadia. It is not known if Zykadia passes into breast milk. Patients and their doctor should decide whether to take Zykadia or breastfeed, but should not do both.

Patients should tell their doctor about medicines they take, including prescription medicines, over-the-counter medicines, vitamins and herbal supplements. If they take Zykadia while using oral contraceptives, the oral contraceptives may become ineffective.

The most common adverse reactions with an incidence of >=10% were diarrhea, nausea, vomiting, tiredness (fatigue), liver laboratory test abnormalities (requires blood test monitoring), abdominal pain, decreased appetite, constipation, rash, kidney laboratory test abnormalities (requires blood test monitoring), heartburn and anemia. Grade 3-4 adverse reactions with an incidence of >=5% were liver laboratory test abnormalities, tiredness (fatigue), diarrhea, nausea and hyperglycemia (requires blood test monitoring).

Patients should stop taking Zykadia and seek medical help immediately if they experience any of the following, which may be signs of an allergic reaction:

Difficulty in breathing or swallowing
Swelling of the face, lips, tongue or throat
Severe itching of the skin, with a red rash or raised bumps
Patients should tell their doctor of any side effect that bothers them or does not go away. These are not all of the possible side effects of Zykadia. For more information, patients should ask their doctor or pharmacist.

Patients should take Zykadia exactly as their health care provider tells them. Patients should not change their dose or stop taking Zykadia unless their health care provider advises them to. Zykadia should be taken once a day on an empty stomach. Patients should not eat for at least 2 hours before and 2 hours after taking Zykadia. If a dose of Zykadia is missed, they should take it as soon as they remember. If their next dose is due within the next 12 hours, they should skip the missed dose and take the next dose at their regular time. They should not take a double dose to make up for a forgotten dose. Patients should not drink grapefruit juice or eat grapefruit during treatment with Zykadia, as it may make the amount of Zykadia in their blood increase to a harmful level. If patients have to vomit after swallowing Zykadia capsules, they should not take more capsules until their next scheduled dose.

Please see full Prescribing Information for Zykadia.

On October 9, 2016 Important clinical study results from one of Eli Lilly and Company’s (NYSE: LLY) ongoing immuno-oncology collaborations with Merck (known as MSD outside the U.S. and Canada) were reported today at the ESMO (Free ESMO Whitepaper) 2016 Congress, the annual meeting of the European Society for Medical Oncology (Press release, Eli Lilly, OCT 9, 2016, View Source [SID:SID1234515675]). Specifically, data released from KEYNOTE-021, Cohort G, which evaluated ALIMTA (pemetrexed) plus carboplatin in combination with Merck’s KEYTRUDA (pembrolizumab) in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC), showed that the combination of ALIMTA, KEYTRUDA and carboplatin demonstrated superior efficacy compared to ALIMTA and carboplatin – standard of care – alone.

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In KEYNOTE-021, Cohort G, which included patients with advanced nonsquamous NSCLC regardless of PD-L1 expression level, the combination of pemetrexed, pembrolizumab and carboplatin achieved a 55 percent objective response rate (ORR) compared to 29 percent for pemetrexed-plus-carboplatin alone, and reduced the risk of disease progression or death by 47 percent. Median progression-free survival (PFS) was 13.0 months with the pemetrexed-pembrolizumab-carboplatin combination. To date, this combination of pemetrexed-pembrolizumab-carboplatin is the only anti-PD-1-containing regimen to demonstrate superior efficacy compared to chemotherapy alone in NSCLC patients receiving first-line treatment.

"These randomized study data of ALIMTA and KEYTRUDA in first-line nonsquamous non-small cell lung cancer build on the early results we’ve seen in this combination and are very encouraging," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "To see a near-doubling in the number of patients responding to this combination gives us hope for what may be able to be achieved above and beyond what is seen with the ALIMTA-containing standard-of-care regimen. These types of clinical advancements are truly exciting as we continue our pursuit to bring meaningful benefits to patients facing cancer."

Dr. Gaynor added, "These data also reflect the progress that Lilly is making in its oncology R&D strategy to develop cancer treatments across three key areas of disease modification: tumor cell signaling, tumor microenvironment and immuno-oncology. This approach allows for testing of combinations of internally derived agents to address tumor heterogeneity and drug resistance, through our own efforts and research collaborations."

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

The findings demonstrated that ORR nearly doubled with the pemetrexed-pembrolizumab-carboplatin combination, with an ORR of 55 percent (n=33/60), compared to 29 percent (n=18/63) for the control arm 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 the pemetrexed-pembrolizumab-carboplatin combination; 1.4+-15.2+ for the control arm). Responses in both groups were durable, with 88 percent (n=29/33) of responders in the pemetrexed-pembrolizumab-carboplatin combination group and 78 percent (n=14/18) of responders in the control arm group experiencing ongoing response at the time of data cut-off.

Additionally, the pemetrexed-pembrolizumab-carboplatin combination significantly reduced the risk of disease progression or death compared to the control arm (hazard ratio 0.53, 95% CI, 0.31-0.91, p=0.0102). Median PFS was 13.0 months with the pemetrexed-pembrolizumab-carboplatin combination compared to 8.9 months in the control arm. Overall survival (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 pemetrexed-pembrolizumab-carboplatin combination and control arm, respectively.

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

Additional Safety Information from KEYNOTE-021, Cohort G
The most common treatment-related adverse events (occurring in at least 15% of patients) for the pemetrexed-pembrolizumab-carboplatin combination 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 the pemetrexed-pembrolizumab-carboplatin combination 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 pembrolizumab as a single agent. There was one treatment-related death from sepsis in a patient receiving the pemetrexed-pembrolizumab-carboplatin combination, and two (one from sepsis and one from pancytopenia) in patients on the control arm.

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 pembrolizumab in combination with pemetrexed and carboplatin compared with pemetrexed and carboplatin in patients with advanced, nonsquamous, EGFR- and ALK-negative NSCLC in the first-line treatment setting. Patients were randomized 1:1 to four cycles of pembrolizumab (200 mg) plus pemetrexed (500 mg/m2 every three weeks) plus carboplatin AUC 5 (5 mg/mL/min), or pemetrexed plus carboplatin alone, followed by maintenance pemetrexed with or without pembrolizumab. 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 control arm were allowed to cross over to 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 KEYNOTE-189, a Phase 3 Trial of Pemetrexed-Pembrolizumab-Platinum Combination
KEYNOTE-189, a randomized Phase 3 study evaluating pemetrexed-plus-platinum chemotherapy (carboplatin or cisplatin) with and without pembrolizumab as initial therapy in NSCLC patients, is currently enrolling. The first results from this study could be available before the end of 2017.

Pemetrexed (marketed under the brand name ALIMTA) is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides.

Pembrolizumab (marketed under the brand name 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. Pembrolizumab 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.

NOTES TO EDITORS

About ALIMTA (pemetrexed)
In 2004, ALIMTA received consecutive approvals: it was the first agent to be approved in combination with cisplatin as a treatment for patients with malignant pleural mesothelioma, whose disease is unresectable or who are otherwise not candidates for curative surgery, and then as a single agent for the treatment of patients with locally advanced or metastatic NSCLC after prior treatment.

In 2008, ALIMTA, in combination with cisplatin, was approved as an initial chemotherapy treatment for locally advanced or metastatic NSCLC for patients with nonsquamous histology. At the time of this initial treatment approval, the FDA also approved a change to the indication for subsequent treatment. ALIMTA is now indicated as a single agent for the treatment of patients with locally advanced or metastatic, nonsquamous NSCLC after prior therapy.

In 2009, ALIMTA was approved as a maintenance therapy for locally advanced or metastatic NSCLC, specifically for patients with a nonsquamous histology whose disease has not progressed after four cycles of platinum-based initial chemotherapy.

In 2012, ALIMTA was approved by the FDA as maintenance therapy for locally-advanced or metastatic NSCLC, following initial ALIMTA-plus-cisplatin treatment for locally advanced or metastatic nonsquamous NSCLC.

ALIMTA is not indicated for treatment of patients with squamous cell NSCLC. Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Indications and Important Safety Information for ALIMTA (pemetrexed for injection)

Indications
ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

Important Safety Information

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Contraindication
ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and Precautions
Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Additionally, intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued throughout treatment as they may reduce the severity of treatment-related hematologic and GI toxicities.

Dexamethasone or its equivalent should be administered the day before, the day of, and the day after ALIMTA treatment.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance < 45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function.

Do not initiate a cycle of treatment in patients unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

Drug Interactions
See Warnings and Precautions for specific information regarding NSAID administration in patients with renal insufficiency.

Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA.

Use in Specific Patient Populations
It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

Dosage and Administration Guidelines
Complete blood cell counts, including platelet counts and periodic chemistry tests, which include renal and hepatic function tests, should be performed on all patients receiving ALIMTA.

Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence) – 1st-line advanced nonsquamous non-small cell lung cancer (NS NSCLC)
The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following non-ALIMTA containing, platinum-based induction therapy
The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs 0%); and neuropathy-sensory (1% vs 0%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, after non-ALIMTA containing platinum-based induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and rash/desquamation (10% vs 3%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following ALIMTA plus cisplatin induction therapy
The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, following ALIMTA plus cisplatin induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).

Abbreviated Adverse Reactions (% incidence) – 2nd-line advanced NS NSCLC
The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus docetaxel, respectively, for the 2nd-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (5% vs 40%); leukopenia (4% vs 27%); thrombocytopenia (2% vs 0%); anemia (4% vs 4%); fatigue (5% vs 5%); nausea (3% vs 2%); anorexia (2% vs 3%); vomiting (2% vs 1%); increased ALT (2% vs 0%); increased AST (1% vs 0%); and stomatitis/pharyngitis (1% vs 1%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus docetaxel, respectively, were fatigue (34% vs 36%); nausea (31% vs 17%); anorexia (22% vs 24%); anemia (19% vs 22%); vomiting (16% vs 12%); stomatitis/pharyngitis (15% vs 17%); rash (14% vs 6%); diarrhea (13% vs 24%); leukopenia (12% vs 34%); thrombocytopenia (8% vs 1%); increased ALT (8% vs 1%); increased AST (7% vs 1%); constipation (6% vs 4%); fever (8% vs 8%); pruritus (7% vs 2%); alopecia (6% vs 38%); and neutropenia (11% vs 45%).

Abbreviated Adverse Reactions (% incidence) – MPM
The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus cisplatin alone, respectively, for the treatment of patients with malignant pleural mesothelioma (MPM) were neutropenia (23% vs 3%); leukopenia (15% vs 1%); thrombocytopenia (5% vs 0%); anemia (4% vs 0%); nausea (12% vs 6%); vomiting (11% vs 4%); fatigue (10% vs 9%); creatinine elevation (1% vs 1%); stomatitis/pharyngitis (3% vs 0%); anorexia (1% vs 1%); diarrhea (4% vs 0%); constipation (1% vs 1%); dyspepsia (1% vs 0%); dehydration (4% vs 1%); neuropathy-sensory (0% vs 1%); rash (1% vs 0%); and creatinine clearance decrease (1% vs 2%).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus cisplatin alone, respectively, were neutropenia (56% vs 13%); leukopenia (53% vs 17%); anemia (26% vs 10%); thrombocytopenia (23% vs 9%); nausea (82% vs 77%); vomiting (57% vs 50%); fatigue (48% vs 42%); creatinine elevation (11% vs 10%); creatinine clearance decreased (16% vs 18%); conjunctivitis (5% vs 1%); anorexia (20% vs 14%); diarrhea (17% vs 8%); constipation (12% vs 7%); dyspepsia (5% vs 1%); dehydration (7% vs 1%); neuropathy-sensory (10% vs 10%); taste disturbance (8% vs 6%); rash (16% vs 5%); alopecia (11% vs 6%); and stomatitis/pharyngitis (23% vs 6%).