On June 1, 2015 Merck reported the first-time presentation of findings investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in multiple, difficult-to-treat cancers, including advanced small cell lung cancer (SCLC), esophageal cancer and ovarian cancer from the KEYNOTE-028 Phase 1b study (Press release, Merck & Co, JUN 1, 2015, View Source [SID:1234505182]). These data, which were presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, May 29 – June 2, 2015, build upon Merck’s broad and fast-growing immuno-oncology clinical development program for KEYTRUDA.

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"The breadth and depth of the data being shared at ASCO (Free ASCO Whitepaper) reinforces the potential for the broad clinical activity that we have seen with KEYTRUDA in multiple types of cancer," said Dr. Roy Baynes, senior vice president and head of global clinical development, Merck Research Laboratories. "Our goal is to help people with cancer and these data are furthering our understanding of which patients may be more likely to benefit from our anti-PD-1 therapy."

As of ASCO (Free ASCO Whitepaper), data presented has demonstrated anti-tumor activity with KEYTRUDA in 13 different tumor types. Registrational trials are planned or ongoing in eight different tumor types, as monotherapy and in combination with other therapies. KEYTRUDA was the first anti-PD-1 therapy approved in the United States and is currently indicated at a dose of 2 mg/kg administered every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Please see below for complete indication and selected safety information for KEYTRUDA.

About the KEYNOTE-028 Phase 1b Study

KEYNOTE-028 is an ongoing multi-cohort, non-randomized Phase 1b basket trial evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA monotherapy (10 mg/kg dosed every two weeks) in more than 450 patients across 20 different types of cancer. The study evaluated patients with PD-L1 positive advanced solid tumors that have not responded to current therapy or for which current therapy is not appropriate.

Early Findings from Advanced Small Cell Lung Cancer Cohort (Abstract #7502)

These early findings from 20 heavily pre-treated patients with advanced SCLC, presented on Saturday, May 30 by Dr. Patrick Ott, Dana-Farber Cancer Institute, demonstrated an overall response rate (ORR) (confirmed and unconfirmed) of 35 percent (n=7/20) (95% CI, 15-59) (per RECIST v1.1). At the time of the analysis, six of seven responses were ongoing. The median follow-up duration for evaluable patients was 21 weeks (range, 2-48). Adverse events were consistent with previously reported safety data for KEYTRUDA. Treatment-related adverse events (occurring in two or more patients) were observed in 14 patients. Grade 3-4 investigator-assessed, treatment-related adverse events were asthenia (n=1) and blood bilirubin increased (n=1). Some patients experienced adverse events of special interest, including autoimmune thyroiditis (n=1, Grade 2) and colitis (n=1, Grade 5). There was one treatment-related death (colitis).

Early Findings from Advanced Esophageal Cancer Cohort (Abstract #4010)

These early findings from 23 heavily pre-treated patients with advanced esophageal cancer, presented in a clinical science symposium on Sunday, May 31 by Dr. Toshihiko Doi, National Cancer Center Hospital East, Kashiwa, Japan, demonstrated an ORR (confirmed and unconfirmed) of 30.4 percent of patients (n=7/23) (95% CI, 13.2-52.9) (per RECIST v1.1). In patients with squamous cell carcinoma, the ORR was 29.4 percent (n=5/17) and in patients with adenocarcinoma, the ORR was 40 percent (n=2/5). The median duration of response was 40 weeks (0.1+ to 40), with six of seven responses ongoing. Tumor shrinkage was achieved in 52.2 percent of evaluable patients. Adverse events were consistent with previously reported safety data for KEYTRUDA. Treatment-related adverse events (occurring in two or more patients) were observed in nine patients. All investigator-assessed, treatment-related adverse events were Grade 3 and included lymphocyte count decreased (n=2), decreased appetite (n=1), liver disorder (n=1), and pruritic rash (n=1). Some patients experienced adverse events of special interest (Grade 2), including hypothyroidism (n=2) and adrenal insufficiency (n=1). There were no treatment-related deaths.

Early Findings from Advanced Ovarian Cancer Cohort (Abstract #5510)

These early findings from 26 heavily pre-treated patients with advanced ovarian cancer, which will be presented in a clinical science symposium on Monday, June 1 by Dr. Andrea Varga, Gustave Roussy Institute, Villejuif, France, demonstrated an ORR (confirmed and unconfirmed) of 11.5 percent of patients (n=3/26) (95% CI, 2.4-30.2) (per RECIST v1.1). Additionally, there was a disease control rate (DCR) of 34.6 percent (n=9/26) (95% CI, 17.2-55.7). At the time of the analysis, the median duration of response had not been reached (27.9-36.3). Tumor shrinkage was achieved in 23 percent of evaluable patients. Adverse events were consistent with previously reported safety data for KEYTRUDA. Treatment-related adverse events (occurring in two or more patients) were observed in 18 patients. One Grade 3-4 treatment-related adverse event occurred (transaminases increased). Some patients experienced adverse events of special interest, including hyperthyroidism (n=2), hypothyroidism (n=3), myositis (n=1) and pancreatitis (n=1). There were no treatment related deaths.

About KEYTRUDA (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

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 unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 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.

Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 100 clinical trials – across more than 30 tumor types and enrolling more than 16,000 patients – both as a monotherapy and in combination with other therapies.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively. 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 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients respectively, 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 (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, 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, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, 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.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, 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, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. 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 corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

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. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Based on its mechanism of action, KEYTRUDA may 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.

For the treatment of advanced melanoma, KEYTRUDA was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in ≥20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. 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. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. The two main types of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In 2012, there were an estimated 1.8 million new cases of lung cancer diagnosed worldwide. SCLC accounts for about 10-15 percent of all lung cancer cases.

About Esophageal Cancer

Esophageal cancer is a type of cancer that begins in the inner layer (mucosa) of the esophagus and grows outward. There are two main types of esophageal cancer: squamous cell carcinoma and adenocarcinoma. In 2012, there were an estimated 456,000 new cases of esophageal cancer and 400,000 esophageal cancer deaths worldwide, making it the eighth most common cancer.

About Ovarian Cancer

Ovarian cancer is a type of cancer that begins in the ovaries. There are three main types of ovarian tumors: epithelial ovarian tumors, ovarian germ cell tumors, and ovarian stromal tumors. In 2012, there were an estimated 239,000 new cases of ovarian cancer and 152,000 ovarian cancer deaths worldwide.

About PD-L1 and PD-L1 Expression

PD-L1, also called programmed death-ligand 1, is a protein expressed on many types of cells, including some cancer cells. Under normal conditions, the interaction of PD-L1 with another protein, called programmed death receptor-1 (PD-1), serves as an important immune system checkpoint, keeping the immune system in balance and preventing the body from attacking its own cells when inflammation or an infection is present. When cancerous tumors express PD-L1, however, they are able to escape detection and destruction by cytotoxic T-cells – a type of cancer-killing immune cell – allowing the tumor to survive and grow. Tumor PD-L1 expression has been observed at varying levels across many tumor types, including breast, lung and bladder cancer. High levels of PD-L1 expression are under investigation for potential use as a way to help identify patients with an enhanced likelihood to respond to certain immune-based treatment approaches.

On May 31, 2015 Gilead Sciences, Inc. (Nasdaq:GILD) reported results from the Phase 3 clinical Study 119 of an investigational use of Zydelig (idelalisib) in combination with ofatumumab in previously-treated patients with chronic lymphocytic leukemia (CLL) (Press release, Gilead Sciences, MAY 31, 2015, View Source;p=irol-newsArticle&ID=2054590 [SID:1234506559]). In Study 119, there was a 73 percent reduction in the risk of disease progression or death in patients receiving Zydelig in combination with ofatumumab compared to ofatumumab alone (hazard ratio (HR) = 0.27; 95 percent CI: 0.19, 0.39; p<0.0001). Detailed results will be presented today during a poster session at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstract #7023).

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"The data reported today reinforce prior results showing that idelalisib, here in combination with the anti-CD20 monoclonal antibody ofatumumab, not only significantly improved overall and lymph node response rates, but more importantly progression-free survival in patients with previously treated CLL," said Jeffrey A. Jones, MD, MPH, Associate Professor of Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). "Importantly, these improvements were also observed in patients with genetic features typically associated with poor prognosis."

Study 119 was a randomized, controlled, open-label Phase 3 study evaluating the efficacy and safety of Zydelig in combination with ofatumumab. The study enrolled 261 adult patients with previously treated CLL whose disease had progressed less than 24 months following completion of prior therapy, and had not previously been refractory to ofatumumab. Eligible patients were randomized 2:1 to receive an ofatumumab 1,000 mg dosing regimen (12 infusions, first infusion 300mg) over 24 weeks plus Zydelig (150 mg) twice daily (n=174) continuously until disease progression or unacceptable toxicity or an ofatumumab 2,000 mg dosing regimen (12 infusions, first infusion 300mg) over 24 weeks (n=87).

The primary endpoint was progression-free survival (PFS), defined as the time from randomization to definitive disease progression or death assessed by an independent review committee. Median PFS in the Zydelig/ofatumumab arm was 16.3 months, compared to 8.0 months in the ofatumumab monotherapy arm. Statistically significant improvements were also observed for overall response rate (75 percent vs. 18 percent; odds ratio (OR) = 15.9, p<0.0001) and lymph node response rate (93.3 percent vs. 4.9 percent; OR=486.96, p<0.0001). Median PFS in the approximately 40 percent of patients with 17p deletion or TP53 mutation was 13.7 months vs. 5.8 months (HR=0.32, p<0.0001). A statistically significant difference was not achieved in median overall survival (20.9 months vs. 19.4 months; HR=0.74, p=0.27).

The safety profile of Zydelig was similar to prior studies in previously-treated patients with CLL. Grade ≥3 adverse events occurring in the Zydelig plus ofatumumab arm included diarrhea/colitis (20.2 percent), pneumonia (12.7 percent) and febrile neutropenia (11.6 percent).

Based on the Study 119 trial results, Gilead has filed a supplemental New Drug Application (sNDA) with the U.S. Food and Drug Administration to include data from this study in the U.S. label. Gilead plans to submit a supplemental filing to the European Medicines Agency later this year.

"Zydelig has now demonstrated strong efficacy in two randomized Phase 3 studies among previously treated CLL patients," said Norbert Bischofberger, PhD, Gilead’s Executive Vice President, Research and Development and Chief Scientific Officer. "We continue to explore the clinical profile of Zydelig in combination with both standard and novel treatment regimens, including seven ongoing or completed Phase 3 clinical trials for B-cell malignancies."

The Zydelig U.S. Prescribing Information includes a BOXED WARNING regarding fatal and serious toxicities of hepatotoxicity, severe diarrhea/colitis, pneumonitis, and intestinal perforation; see below for Important Safety Information.

The use of Zydelig in combination with ofatumumab is investigational and the safety and efficacy of this combination has not yet been established.

Dr. Jones is an uncompensated advisory board member to Gilead and receives research grant support to support this Phase 3 trial at The OSUCCC – James.

About Zydelig (idelalisib)

Zydelig is an oral inhibitor of phosphoinositide 3-kinase (PI3K) delta, a protein that plays a role in the activation, proliferation and viability of B cells, a critical component of the immune system. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and by inhibiting the protein, Zydelig blocks several cellular signaling pathways that drive B-cell viability.

On July 23, 2014, Zydelig received accelerated approval from the U.S. Food and Drug Administration as monotherapy for patients with relapsed follicular lymphoma (FL) or small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies, and full approval in combination with rituximab for patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy due to comorbidities. On September 19, 2014, the European Commission granted marketing authorization for Zydelig as monotherapy in FL patients who are refractory to two prior lines of treatment, and in combination with rituximab for CLL patients who have received at least one prior therapy, or in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemoimmunotherapy.

Additional information about clinical studies of Zydelig and Gilead’s investigational cancer agents can be found at www.clinicaltrials.gov.

Important U.S. Safety Information

BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS AND INTESTINAL PERFORATION

Fatal and/or serious hepatotoxicity occurred in 14 percent of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended.

Fatal and/or serious and severe diarrhea or colitis occurred in 14 percent of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended.

Fatal and serious pneumonitis can occur. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended.

Fatal and serious intestinal perforation can occur in Zydelig-treated patients. Discontinue Zydelig for intestinal perforation.

Contraindications

History of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis (TEN).
Warnings and Precautions

Hepatotoxicity: Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26% of patients. In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3x upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5x ULN, withhold Zydelig and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue Zydelig for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs.
Severe diarrhea or colitis: Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea.

Pneumonitis: Evaluate for pneumonitis in patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5 percent

Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting.

Severe cutaneous reactions: One case of TEN occurred in a study of Zydelig in combination with rituximab and bendamustine. Other severe or life-threatening (grade ≥3) cutaneous reactions have been reported. Monitor patients for the development of severe cutaneous reactions and discontinue Zydelig if a reaction occurs.

Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported. Discontinue Zydelig permanently and institute appropriate supportive measures if a reaction occurs.

Neutropenia: Treatment-emergent grade 3-4 neutropenia occurred in 31 percent of Zydelig-treated patients in clinical trials. In all patients, monitor blood counts ≥every 2 weeks for the first 3 months. In patients with neutrophil counts <1.0 Gi/L, monitor weekly.

Embryo-fetal toxicity: Zydelig may cause fetal harm. Women who are or become pregnant while taking Zydelig should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Zydelig and to use effective contraception during and at least 1 month after treatment with Zydelig.

Adverse Reactions

Most common adverse reactions (incidence ≥10 percent and ≥2 percent than rituximab alone, all grades) were pyrexia, nausea, pneumonia, diarrhea, chills, rash, vomiting and headache.

Most frequent serious adverse reactions (SAR) were pneumonia (17 percent), pyrexia (9 percent), sepsis (8 percent), febrile neutropenia (5 percent) and diarrhea (5 percent); SAR were reported in 49 percent of patients and 10 percent of patients discontinued due to adverse reactions.

Most common lab abnormalities (incidence ≥30 percent and ≥5 percent than rituximab alone; all grades) were neutrophils decreased, hypertriglyceridemia, hyperglycemia and ALT elevation.

Drug Interactions

CYP3A inducers: Avoid coadministration with strong CYP3A inducers.
CYP3A inhibitors: When coadministered with strong CYP3A inhibitors, monitor closely for Zydelig toxicity.
CYP3A substrates: Avoid coadministration with CYP3A substrates.

Dosage and Administration

Adult starting dose: One 150 mg tablet twice daily, swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown.

Dose modification: Consult the Zydelig full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: pneumonitis, ALT/AST elevations, bilirubin elevations, diarrhea, neutropenia, and thrombocytopenia. For other severe or life-threatening toxicities, withhold Zydelig until toxicity is resolved and reduce the dose to 100 mg, twice daily, upon resuming treatment. If severe or life-threatening toxicities recur upon rechallenge, Zydelig should be permanently discontinued.

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