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Novartis granted US FDA Priority Review for Kymriah(TM) (tisagenlecleucel), formerly CTL019, for adults with r/r DLBCL

On January 16, 2018 Novartis reported that its supplemental Biologics License Application (sBLA) for KymriahTM (tisagenlecleucel) suspension for intravenous infusion, formerly CTL019, for the treatment of adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) who are ineligible for or relapse after autologous stem cell transplant (ASCT) has been accepted by the US Food and Drug Administration (FDA) for Priority Review (Press release, Novartis, JAN 16, 2018, View Source [SID1234523192]). In addition, the European Medicines Agency (EMA) has granted accelerated assessment to the Marketing Authorization Application (MAA) for Kymriah for the treatment of children and young adults with r/r B-cell acute lymphoblastic leukemia (ALL) and for adult patients with r/r DLBCL who are ineligible for ASCT. Priority Review and accelerated assessment are granted to therapies which may provide a significant improvement in the safety and effectiveness of the treatment of a serious disease, and the designations are intended to expedite the standard review time. If approved by the FDA and EMA, Kymriah would represent the first chimeric antigen receptor T cell (CAR-T) therapy available for two distinct indications in non-Hodgkin lymphoma and B-cell ALL.

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Kymriah became the first CAR-T cell therapy to receive regulatory approval when it was approved by the FDA in August 2017 for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

"The first approval of a CAR-T therapy truly redefined the future of the cancer treatment landscape, and we are only at the beginning of this new era in cancer care," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "The Priority Review designation and accelerated assessment signal that the FDA and EMA have recognized the potential of Kymriah to provide a much-needed therapeutic option for these patients with relapsed or refractory B-cell ALL and DLBCL. We are now focused on working with these regulatory agencies to bring this potentially transformative therapy to more patients."

Kymriah is a novel immunocellular therapy and a one-time treatment that uses a patient’s own T cells to fight cancer. Kymriah uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence. In 2012, Novartis and the University of Pennsylvania (Penn) entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.

The regulatory applications in the US and EU are based on data from the Novartis-sponsored global clinical trial program of Kymriah in children and young adults with r/r B-cell ALL and adult patients with r/r DLBCL demonstrating the efficacy and safety of Kymriah across studies. Results from the pivotal phase II JULIET clinical trial served as the basis of the sBLA and MAA (applications submitted by pharmaceutical companies to health authorities when seeking approval of a new product) for Kymriah in adult patients with r/r DLCBL. Results from the pivotal phase II ELIANA study were submitted as part of the MAA for Kymriah in children and young adults with r/r B-cell ALL.

JULIET is the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL. JULIET is the largest study examining a CAR-T therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the US, Canada, Australia, Japan and Europe, including: Austria, France, Germany, Italy, Norway and the Netherlands. Data from the six-month primary analysis of JULIET were presented at the annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in December 2017.

ELIANA is the first pediatric global CAR-T cell therapy registration trial, examining patients in 25 centers in the US, Canada, Australia, Japan and the EU, including: Austria, Belgium, France, Germany, Italy Norway, and Spain.

Novartis plans additional regulatory submissions for Kymriah in pediatric and young adult patients with r/r B-cell ALL and adult patients with r/r DLBCL beyond the US and EU in 2018.

About CAR-T
CAR-T is different from typical small molecule or biologic therapies because it is manufactured for each individual patient using their own cells. During the treatment process, T cells are drawn from a patient’s blood and reprogrammed in the laboratory to create T cells that are genetically coded to recognize and fight the patient’s cancer cells and other B cells expressing a particular antigen.

About Kymriah Manufacturing
Kymriah is manufactured for each individual patient using their own cells at the Novartis Morris Plains, New Jersey facility. In the US, the target turnaround time for manufacturing Kymriah in the commercial setting is 22 days. The reliable and integrated manufacturing and supply chain platform for Kymriah allows for an individualized treatment approach on a global scale. The process includes cryopreservation of a patient’s harvested (or leukapheresed) cells, giving treating physicians and centers the flexibility to initiate therapy with Kymriah based on the individual patient’s condition. Building on the company’s experience, having manufactured CAR-T cells for over 300 patients from 11 countries across various indications in clinical trials, it has demonstrated a reproducible product. Novartis continues to advance its CAR-T manufacturing expertise in Morris Plains where we have been supplying CAR-T cells for global clinical trials and where we continue to invest in support of the anticipated demand to meet the needs of patients.

Novartis has also successfully established the CTL019 manufacturing process at the Fraunhofer-Institut for cell therapy and immunology (Fraunhofer-Institut für Zelltherapie and Immunologie) facility in Leipzig, Germany, which currently supports the manufacturing of CTL019 for global clinical trials.

Novartis Leadership in Immuno-Oncology
Novartis is at the forefront of investigational immunocellular therapy as the first pharmaceutical company to initiate global CAR-T trials, and has significantly invested in CAR-T research and worked with pioneers in the field. KymriahTM, the first approved CAR-T cell therapy, is the cornerstone of this strategy. Active research programs are underway targeting other hematologic malignancies and solid tumors, and include efforts focused on next generation CAR-Ts that involve simplified manufacturing schemes and gene edited cells.

KymriahTM (tisagenlecleucel) US Important Safety information (for patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse)
The full prescribing information, including Boxed WARNING, for Kymriah can be found at: View Source

Kymriah may cause side effects that are severe or life-threatening, such as Cytokine Release Syndrome (CRS) or Neurological Toxicities. Patients with CRS may experience symptoms including high fever, difficulty breathing, chills/shaking chills, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, or dizziness/lightheadedness. Patients may be admitted to the hospital for CRS and treated with other medications.

Patients with neurological toxicities may experience symptoms such as altered or decreased consciousness, headaches, delirium, confusion, agitation, anxiety, seizures, difficulty speaking and understanding, or loss of balance. Patients should be advised to call their health care provider or get emergency help right away if they experience any of these signs and symptoms of CRS or neurological toxicities.

Because of the risk of CRS and neurological toxicities, Kymriah is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) in the US called Kymriah REMS.

Serious allergic reactions, including anaphylaxis, may occur after Kymriah infusion.
Kymriah can increase the risk of life-threatening infections that may lead to death. Patients should be advised to tell their health care provider right away if they develop fever, chills, or any signs or symptoms of an infection.

Patients may experience prolonged low blood cell counts (cytopenia), where one or more types of blood cells (red blood cells, white blood cells, or platelets) are decreased. The patient’s health care provider will do blood tests to check all of their blood cell counts after treatment with Kymriah. Patients should be advised to tell their health care provider right away if they get a fever, are feeling tired, or have bruising or bleeding.

Patients may experience hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with Kymriah, and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with Kymriah. Patients should tell their health care provider about their treatment with Kymriah before receiving a live virus vaccine.

After treatment with Kymriah, patients will be monitored life-long by their health care provider, as they may develop secondary cancers or recurrence of their leukemia.

Patients should not drive, operate heavy machinery, or do other dangerous activities for 8 weeks after receiving Kymriah because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness, and seizures.

Some of the most common side effects of Kymriah are difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, confusion, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, and dizziness/lightheadedness. However, these are not all of the possible side effects of Kymriah. Patients should talk to their health care provider for medical advice about side effects.

Prior to a female patient starting treatment with Kymriah, their health care provider may do a pregnancy test. There is no information available for Kymriah use in pregnant or breast-feeding women. Therefore, Kymriah is not recommended for women who are pregnant or breast feeding. If either sex partner has received Kymriah, patients should talk to their health care provider about birth control and pregnancy.

Patients should tell their health care provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

After receiving Kymriah, patients should be advised that some commercial HIV tests may cause a false positive test result. Patients should also be advised not to donate blood, organs, or tissues and cells for transplantation after receiving Kymriah.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, regarding our ability to implement, scale and sustain commercial manufacturing for the investigational or approved products described in this press release, regarding our ability to build and sustain a network of treatment centers to offer the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Neither can there be any guarantee that Novartis will successfully implement, scale and sustain commercial manufacturing for the investigational or approved products described in this press release, or successfully build and sustain a network of treatment centers to offer the investigational or approved products described in this press release. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, our ability to successfully implement, scale and sustain commercial manufacturing and build and sustain a network of treatment centers; the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; general economic and industry conditions, including the effects of the persistently weak economic and financial environment in many countries; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

Gamida Cell Announces Initiation of a Phase I Study of NAM-NK Cells Immunotherapy Program for Non-Hodgkin Lymphoma and Multiple Myeloma

On January 16, 2018 Gamida Cell, a leading cellular and immune therapeutics company, reported the initiation of a phase I study evaluating its proprietary NAM-expanded natural killer cells (NAM-NK Cells) in patients with relapsed or refractory CD20+ non-Hodgkin lymphoma (NHL) and multiple myeloma (Press release, Gamida Cell, JAN 16, 2018, View Source [SID1234523184]).

"There is significant need for novel therapeutic approaches for refractory non-Hodgkin lymphoma and multiple myeloma, which are aggressive malignancies with limited treatment options," said Veronika Bachanova, M.D., Ph.D., hematologist/oncologist at University of Minnesota Health and lead investigator of the clinical study at the Masonic Cancer Center, University of Minnesota. "We initiated this phase I study based on encouraging preclinical data to bring a potential immunotherapeutic treatment approach to patients with these life-threatening cancers."

The phase I study is designed to determine the maximum tolerated dose of NAM-NK Cells; secondary endpoints include overall antitumor response and toxicity. The study is currently recruiting and will enroll approximately 24 patients aged 18 to 70 years old. Participants will undergo a lymphodepleting preparative regimen of cyclophosphamide and fludarabine, and then receive two doses of NAM-NK Cells followed by a short course of interleukin-2 (IL-2). Monoclonal antibodies, rituximab for NHL or elotuzumab for multiple myeloma, are administered prior to and after the NAM-NK Cells infusion to facilitate tumor targeting and antibody dependent cellular cytotoxicity.

"NAM-expanded NK cells have demonstrated increased killing potential and increased in vivo persistence and proliferation in preclinical studies," said Tony Peled, Ph.D., chief scientific officer at Gamida Cell. "We are pleased to see the NAM-NK Cell program enter clinical testing and are committed to collaborating with Dr. Bachanova and her team at the Masonic Cancer Center."

About NAM-NK Cells
Gamida Cell applied the capabilities of its NAM technology to the expansion of highly functional NK cells. In addition to a higher killing potential, NAM-NK Cells secretes higher levels of inflammatory cytokines that facilitate recruitment and activation of other endogenous immune cells to attack tumors. NAM-NK Cells is in phase I development (NCT03019666) in patients with relapsed or refractory CD20+ non-Hodgkin lymphoma and multiple myeloma.

About the Masonic Cancer Center
Masonic Cancer Center, University of Minnesota is a comprehensive cancer center designated by the National Cancer Institute. For more than 25 years, researchers, educators, and care providers have worked to discover the causes, prevention, detection and treatment of cancer and cancer-related disease. Learn more about the Masonic Cancer Center and the phase I clinical trial at cancer.umn.edu.

Exelixis and Ipsen Announce Phase 3 Trial Results of Cabozantinib Demonstrating Significant Overall Survival Benefit in Patients with Previously Treated Advanced Hepatocellular Carcinoma

On January 16, 2018 Exelixis, Inc. (NASDAQ:EXEL) and Ipsen (Euronext:IPN; ADR:IPSEY) reported detailed results of the pivotal phase 3 CELESTIAL trial in patients with previously treated advanced hepatocellular carcinoma (HCC), which will be presented in a late-breaking oral session at the 2018 ASCO (Free ASCO Whitepaper)-GI Symposium being held in San Francisco, January 18-20, 2018 (Press release, Exelixis, JAN 16, 2018, View Source;p=RssLanding&cat=news&id=2326897 [SID1234523150]). In CELESTIAL, cabozantinib provided a statistically significant and clinically meaningful improvement versus placebo in overall survival (OS), the trial’s primary endpoint, at the planned second interim analysis (pre-specified critical p-value ≤ 0.021) for the population of second- and third-line patients enrolled in this study. Median OS was 10.2 months with cabozantinib versus 8.0 months with placebo (HR 0.76, 95 percent CI 0.63-0.92; p=0.0049). Median progression-free survival (PFS) was more than doubled, at 5.2 months with cabozantinib and 1.9 months with placebo (HR 0.44, 95 percent CI 0.36-0.52; p<0.0001). Objective response rates per RECIST 1.1 were 4 percent with cabozantinib and 0.4 percent with placebo (p=0.0086). Disease control (partial response or stable disease) was achieved by 64 percent of the cabozantinib group compared with 33 percent of the placebo group.

In a subgroup analysis of patients whose only prior therapy for advanced HCC was sorafenib (70 percent of patients in the study), median OS was 11.3 months with cabozantinib versus 7.2 months with placebo (HR 0.70, 95 percent CI 0.55-0.88). Median PFS in the subgroup was 5.5 months with cabozantinib versus 1.9 months with placebo (HR 0.40, 95 percent CI 0.32-0.50). Adverse events were consistent with the known safety profile of cabozantinib.

Ghassan K. Abou-Alfa, M.D., Memorial Sloan Kettering Cancer Center, New York and lead investigator on CELESTIAL, will present detailed findings, including analyses of OS and PFS in various patient subgroups, during Oral Abstract Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract, which begins at 2:15 p.m. PT on Friday, January 19, 2018.

"Patients with advanced hepatocellular carcinoma often have a poor prognosis and limited treatment options following prior systemic therapy," said Dr. Abou-Alfa. "The clinically significant benefits in both overall survival and progression-free survival shown in the CELESTIAL trial suggest that, if approved, cabozantinib could become an important addition to the treatment landscape for these patients."

"We are excited by the potential benefit cabozantinib may offer to patients with previously treated advanced hepatocellular carcinoma," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "Given the worldwide prevalence of advanced hepatocellular carcinoma, there is a continued urgency to bring new treatment options to this patient population. We look forward to submitting our supplemental New Drug Application to the FDA for cabozantinib in the first quarter of 2018, and to further advancing our mission to help cancer patients recover stronger and live longer."

"Patients diagnosed with advanced hepatocellular carcinoma urgently need new treatment options," said Alexandre Lebeaut, M.D., Executive Vice-President, R&D, Chief Scientific Officer, Ipsen. "The positive results of the pivotal phase 3 CELESTIAL trial are encouraging for both physicians and patients, and we have committed to file in the first half of 2018 a variation of the initial application to the EMA and other relevant regulatory agencies."

The most common (≥10 percent) grade 3 or 4 adverse events in the cabozantinib group compared to the placebo group were palmar-plantar erythrodysesthesia (17 percent vs. 0 percent), hypertension (16 percent vs. 2 percent), increased aspartate aminotransferase (12 percent vs. 7 percent), fatigue (10 percent vs. 4 percent), and diarrhea (10 percent vs. 2 percent). Treatment-related grade 5 adverse events occurred in six patients in the cabozantinib group (hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism and hepatorenal syndrome) and in one patient in the placebo group (hepatic failure). Sixteen percent of patients in the cabozantinib arm and three percent of patients in the placebo arm discontinued treatment due to treatment-related adverse events.

Webcast for the Financial Community

Exelixis and its partner Ipsen will jointly host a live webcast on Friday, January 19. The webcast will begin at 6:30 p.m. PT / 9:30 p.m. ET. During the webcast, Exelixis and Ipsen management and an invited guest speaker will review results from the CELESTIAL trial.

To access the webcast link, log onto www.exelixis.com and proceed to the News & Events / Event Calendar page under the Investors & Media heading. Please connect to the company’s website at least 15 minutes prior to the webcast to ensure adequate time for any software download that may be required to view the program. To listen to an audio-only version of the program by phone, please dial 855-793-2457 (domestic) or 631-485-4921 (international/toll dial) and use passcode 2478857. A telephone replay will be available until 11:59 p.m. ET on January 26, 2018. Access numbers for the telephone replay are: 855-859-2056 (domestic) and 404-537-3406 (international); the passcode is 2478857. A webcast replay will also be available archived on www.exelixis.com for one year.

About the CELESTIAL Study

CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial was designed to enroll 760 patients with advanced HCC who received prior sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Enrollment of the trial was completed in September 2017. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms during the blinded treatment phase of the trial.

The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and PFS. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.

Based on available clinical trial data from various published trials conducted in the second-line setting of advanced HCC, the CELESTIAL trial design assumed a median OS of 8.2 months for the placebo arm. A total of 621 events provide the study with 90 percent power to detect a 32 percent increase in median OS (HR = 0.76) at the final analysis. Two interim analyses were planned and conducted at approximately 50 percent and 75 percent of the planned 621 events. At the first interim analysis conducted by the independent data monitoring committee the observed hazard ratio was 0.71 and the p-value was 0.0041, which did not cross the stopping boundary for the first interim analysis (p ≤ 0.0037).

On October 16, 2017, Exelixis announced that the independent data monitoring committee recommended that the trial be stopped for efficacy following review of the second planned interim analysis, as the trial had met its primary endpoint of OS (pre-specified critical p-value ≤ 0.021).

In March 2017, the FDA granted orphan drug designation to cabozantinib for the treatment of advanced HCC. Orphan drug designation is granted to treatments for diseases that affect fewer than 200,000 people in the U.S. and provides certain incentives for medications intended for the treatment, diagnosis or prevention of rare diseases.

About HCC

Liver cancer is the second-leading cause of cancer death worldwide, accounting for more than 700,000 deaths and nearly 800,000 new cases each year.1 In the U.S., the incidence of liver cancer has more than tripled since 1980.2 HCC is the most common form of liver cancer, making up about three-fourths of the estimated nearly 42,000 new cases in the U.S. in 2018.2 HCC is the fastest-rising cause of cancer-related death in U.S.3 Without treatment, patients with advanced HCC usually survive less than 6 months.4

About CABOMETYX (cabozantinib)

CABOMETYX tablets are approved in the United States for the treatment of patients with advanced RCC. CABOMETYX tablets are also approved in the European Union, Norway, Iceland and Switzerland for the treatment of advanced RCC in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy. Ipsen also submitted to European Medicines Agency (EMA) the regulatory dossier for cabozantinib as a treatment for first-line advanced RCC in the European Union on August 28, 2017; on September 8, 2017, Ipsen announced that the EMA validated the application. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan, including RCC.

CABOMETYX is not indicated for the treatment of advanced HCC.

Please see Important Safety Information below and full U.S. prescribing information at View Source

U.S. Important Safety Information

Hemorrhage: Severe and fatal hemorrhages have occurred with CABOMETYX. In two RCC studies, the incidence of Grade ≥ 3 hemorrhagic events was 3% in CABOMETYX-treated patients. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.

Gastrointestinal (GI) Perforations and Fistulas: In RCC studies, fistulas were reported in 1% of CABOMETYX-treated patients. Fatal perforations occurred in patients treated with CABOMETYX. In RCC studies, gastrointestinal (GI) perforations were reported in 1% of CABOMETYX-treated patients. Monitor patients for symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula which cannot be appropriately managed or a GI perforation.

Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. In RCC studies, venous thromboembolism occurred in 9% (including 5% pulmonary embolism) and arterial thromboembolism occurred in 1% of CABOMETYX-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.

Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension, including hypertensive crisis. In RCC studies, hypertension was reported in 44% (18% Grade ≥ 3) of CABOMETYX-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.

Diarrhea: In RCC studies, diarrhea occurred in 74% of patients treated with CABOMETYX. Grade 3 diarrhea occurred in 11% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): In RCC studies, palmar-plantar erythrodysesthesia (PPE) occurred in 42% of patients treated with CABOMETYX. Grade 3 PPE occurred in 8% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade 3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced dose.

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

Embryo-fetal Toxicity may be associated with CABOMETYX. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during CABOMETYX treatment and for 4 months after the last dose.

Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, hypertension, PPE, weight decreased, vomiting, dysgeusia, and stomatitis.
Strong CYP3A4 Inhibitors: If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage.

Strong CYP3A4 Inducers: If concomitant use with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.

Lactation: Advise women not to breastfeed while taking CABOMETYX and for 4 months after the final dose.
Hepatic Impairment: In patients with mild to moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information View Source

Merck’s KEYTRUDA(R) (pembrolizumab) Significantly Improved Overall Survival and Progression-Free Survival as First-Line Treatment in Combination with Pemetrexed and Platinum Chemotherapy for Patients with Metastatic Nonsquamous Non-Small Cell Lung Cancer (KEYNOTE-189)

On January 16, 2018 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the pivotal Phase 3 KEYNOTE-189 trial investigating KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in combination with pemetrexed (Alimta) and cisplatin or carboplatin, for the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), met its dual primary endpoints of overall survival (OS) and progression-free survival (PFS) (Press release, Merck & Co, JAN 16, 2018, View Source [SID1234523144]). Based on an interim analysis conducted by the independent Data Monitoring Committee, treatment with KEYTRUDA in combination with pemetrexed plus platinum chemotherapy resulted in significantly longer OS and PFS than pemetrexed plus platinum chemotherapy alone. The safety profile of KEYTRUDA in this combination was consistent with that previously observed.

Results from KEYNOTE-189 will be presented at an upcoming medical meeting and submitted to regulatory authorities.

"KEYNOTE-189 showed significant improvement in overall survival and progression-free survival for patients receiving KEYTRUDA in the first-line setting in combination with traditional chemotherapy, compared with those receiving chemotherapy alone," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "We are deeply grateful to the KEYNOTE-189 patients and investigators for their important contributions to this landmark study, and we look forward to presenting the data in the near future."

About KEYNOTE-189

KEYNOTE-189 is a randomized, double blind, placebo controlled, Phase 3 study (ClinicalTrials.gov, NCT02578680) investigating KEYTRUDA (pembrolizumab) in combination with pemetrexed and cisplatin or carboplatin compared with pemetrexed and cisplatin or carboplatin alone in patients with advanced or metastatic nonsquamous non-small cell lung cancer, regardless of PD-L1 expression. Patients had no EGFR or ALK genomic tumor aberrations, and had not previously received systemic therapy for advanced disease. The KEYNOTE-189 study was done in collaboration with Eli Lilly and Company, the makers of pemetrexed. The dual primary endpoints are OS and PFS; secondary endpoints include overall response rate (ORR) and duration of response (DOR). The study enrolled 614 patients randomized 2:1 to receive either KEYTRUDA (200 mg fixed dose every three weeks) plus pemetrexed (500 mg/m2 ) (with vitamin supplementation) plus cisplatin (75 mg/m2) or carboplatin AUC 5 on day 1 every 3 weeks (Q3W) for 4 cycles followed by KEYTRUDA 200 mg plus pemetrexed (500 mg/m2 ) Q3W or KEYTRUDA placebo 200 mg plus pemetrexed (500 mg/m2) (with vitamin supplementation) plus cisplatin (75 mg/m2) or carboplatin AUC 5 on day 1 every 3 weeks (Q3W) for 4 cycles followed by KEYTRUDA placebo 200 mg plus pemetrexed (500 mg/m2) Q3W until disease progression, unacceptable toxicity, physician decision or consent withdrawal. Patients on the control arm who experienced disease progression, verified by central independent review, were permitted to undergo treatment assignment unblinding and crossover to receive open-label KEYTRUDA.

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. Each year, more people die of lung cancer than colon, breast and prostate cancers combined. The two main types of lung cancer are non-small cell and small cell. NSCLC is the most common type of lung cancer, accounting for about 85 percent of all cases. The five-year survival rate for patients suffering from highly advanced, metastatic (Stage IV) lung cancers is estimated to be two percent.

About KEYTRUDA (pembrolizumab) Injection 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that 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.

Merck has the industry’s largest immuno-oncology clinical research program, which currently involves more than 650 trials studying KEYTRUDA (pembrolizumab) across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.

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. 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. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. 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. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL,

KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA (pembrolizumab) is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
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. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. 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. The recommended dose of KEYTRUDA is 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). 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.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC, occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3 (0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. 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.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. These immune-mediated reactions may occur in any organ system. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA (pembrolizumab). Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 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.

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA on any trial, 6 patients (26%) developed graft-versus-host disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

In clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled clinical trials.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

In KEYNOTE-006, KEYTRUDA (pembrolizumab) was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

In KEYNOTE-021(G1), when KEYTRUDA was administered in combination with carboplatin and pemetrexed (carbo/pem) in advanced nonsquamous NSCLC, KEYTRUDA was discontinued in 10% of 59 patients. The most common adverse reaction resulting in discontinuation of KEYTRUDA (≥2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 39% of patients; the most common (≥2%) were fatigue (8%), neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%).The most common adverse reactions (≥20%) with KEYTRUDA compared to carbo/pem alone were fatigue (71% vs 50%), nausea (68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), vomiting (39% vs 27%), dyspnea (39% vs 21%), diarrhea (37% vs 23%), decreased appetite (31% vs 23%), headache (31% vs 16%), cough (24% vs 18%), dizziness (24% vs 16%), insomnia (24% vs 15%), pruritus (24% vs 4.8%), peripheral edema (22% vs 18%), dysgeusia (20% vs 11%), alopecia (20% vs 3.2%), upper respiratory tract infection (20% vs 3.2%), and arthralgia (15% vs 24%). This study was not designed to demonstrate a statistically significant difference in adverse reaction rates for KEYTRUDA as compared to carbo/pem alone for any specified adverse reaction.

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (reported in at least 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA (pembrolizumab) was discontinued due to adverse reactions in 5% of 210 patients with cHL, and treatment was interrupted due to adverse reactions in 26% of patients. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse reactions (≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. The most common adverse reactions (occurring in ≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reactions (in ≥20% of patients) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and 3 patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients, the most frequent (≥2%) of which were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). The most common adverse reactions (≥20%) in patients who received KEYTRUDA vs those who received chemotherapy were fatigue (38% vs 56%), musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%), decreased appetite (21% vs 21%), nausea (21% vs 29%), and rash (20% vs 13%). Serious adverse reactions occurred in 39% of KEYTRUDA (pembrolizumab)-treated patients, the most frequent (≥2%) of which were urinary tract infection, pneumonia, anemia, and pneumonitis.

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.

There is limited experience in pediatric patients. In a study, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 1–17 doses), with 34 patients (85%) receiving KEYTRUDA for 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, 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 evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

Leap Therapeutics Announces First Patient Dosed with TRX518 Combination Therapy in Advanced Solid Tumors Trial

On January 16, 2018 Leap Therapeutics, Inc. (Nasdaq:LPTX), a biotechnology company developing targeted and immuno-oncology therapeutics, reported that the first patient has been dosed in a Phase 1 clinical trial evaluating Leap’s GITR agonist, TRX518, in combination with gemcitabine chemotherapy or in combination with KEYTRUDA (pembrolizumab) or Opdivo (nivolumab), anti-PD-1 therapies marketed by Merck (known as MSD outside the United States and Canada) or Bristol-Myers Squibb, respectively (Press release, Leap Therapeutics, JAN 16, 2018, View Source;p=RssLanding&cat=news&id=2326652 [SID1234523143]).

"TRX518 has demonstrated the ability to reduce immunosuppressive regulatory T cells and to activate tumor-killing T effector cells in clinical and preclinical studies. The combination of TRX518 with anti-PD-1 immunotherapy has strong scientific rationale and could act synergistically, enabling improved responses without significant additional toxicity. We look forward to evaluating the safety and efficacy of TRX518 in combination with pembrolizumab or nivolumab," commented Diwakar Davar, M.D., Assistant Professor of Medicine of the University of Pittsburgh and an investigator on the study.

"There is strong preclinical evidence for synergistic efficacy when combining immune activators targeting GITR with chemotherapy," commented Cynthia Sirard, M.D., Vice President, Clinical Development of Leap Therapeutics. "This trial represents an important step in our strategy to evaluate the combination activity of TRX518 as a backbone immunotherapy."

The TRX518-003 study is a multipart study evaluating TRX518 as a monotherapy and in combination with gemcitabine, KEYTRUDA (pembrolizumab), or Opdivo (nivolumab) in patients with advanced solid tumor malignancies.

The combination arms evaluating TRX518 with gemcitabine includes both dose escalation and dose confirmation cohorts and are designed to evaluate the safety, pharmacokinetics/pharmacodynamics, and efficacy of the combination. The study will enroll patients who have metastatic or locally advanced, incurable solid malignancies for which gemcitabine is clinically appropriate (e.g., non-small cell lung, breast, ovarian, pancreatic, and renal cancer). The TRX518 + gemcitabine study will enroll approximately 32 patients.

The combination arms evaluating TRX518 with pembrolizumab or nivolumab includes both dose escalation and dose confirmation cohorts and are designed to evaluate the safety, pharmacokinetics/pharmacodynamics, and efficacy of the combinations. The study will enroll patients who have received treatment with pembrolizumab or nivolumab for ≥4 months with a best response of stable disease and plans to continue treatment in accordance with package insert; or are not currently taking, but eligible for treatment with, pembrolizumab or nivolumab in accordance with the approved indications for each as referenced in the package insert. The TRX518 + PD-1 antagonist study will enroll approximately 64 patients.

About TRX518
TRX518 is a humanized monoclonal antibody with agonist activity targeting glucocorticord-inducible TNF-superfamily receptor (GITR). TRX518 is engineered to enhance immune responses to cancer. TRX518 is being studied in two ongoing repeat-dose clinical trials in patients with advanced solid tumor malignancies. Data from the trials have shown that patients receiving TRX518 monotherapy achieved durable stable disease with signs of pharmacodynamic activity including CD8+ T cell activation and modulation of immunosuppressive regulatory T cells.