On June 4, 2018 AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported data which showed clinical improvement in median radiologic progression-free survival (rPFS) with LYNPARZA (olaparib) in combination with abiraterone compared to abiraterone monotherapy, a current standard of care, in metastatic castration-resistant prostate cancer (mCRPC) (Press release, Merck & Co, JUN 4, 2018, View Source [SID1234527144]). LYNPARZA is being jointly developed and commercialized by AstraZeneca and Merck.

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The results of Study 08, a randomized, double-blinded, multi-center Phase 2 trial, comparing LYNPARZA in combination with abiraterone (n=71) to abiraterone monotherapy (n=71) in patients with previously-treated mCRPC, regardless of homologous recombination repair (HRR) mutation status, were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting as a "Best of ASCO (Free ASCO Whitepaper) presentation" and were published online today in The Lancet Oncology. The primary endpoint was rPFS. Secondary endpoints included time to second progression or death (PFS2), overall survival (OS) and health-related quality of life.

LYNPARZA is not FDA-approved for prostate cancer. LYNPARZA is indicated for the treatment of advanced ovarian cancer patients with a gBRCA mutation previously treated with three or more lines of chemotherapy; for the maintenance treatment of recurrent ovarian cancer in response to platinum-based chemotherapy regardless of BRCA mutation status; and for the treatment of gBRCA HER2-negative metastatic breast cancer after chemotherapy and prior endocrine therapy, if appropriate. Physicians should select advanced ovarian cancer and metastatic breast cancer patients for therapy based on a FDA-approved companion diagnostic. Please see Indications for LYNPARZA (olaparib) 100 mg in the U.S. below.

Noel Clarke, professor of urological oncology, Christie NHS Foundation Trust, Manchester, United Kingdom, said, "This is the first time we have seen an improvement with the use of a PARP inhibitor in combination with abiraterone in patients with metastatic castration-resistant prostate cancer, and this effect may be independent of HRR status. The data suggest this therapeutic combination may be a promising new treatment approach for this aggressive disease."

Sean Bohen, executive vice president, global medicines development and chief medical officer at AstraZeneca, said, "A previous trial demonstrated improvements in response rates with LYNPARZA monotherapy in metastatic castration-resistant patients with HRR mutations. The Study 08 combination data suggest that, regardless of their mutation status, men with metastatic castration-resistant prostate cancer may potentially benefit from LYNPARZA in combination with abiraterone."

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, "There is a significant unmet medical need for patients with metastatic castration-resistant prostate cancer as they are a high-risk group with limited treatment options. LYNPARZA is the first PARP inhibitor to demonstrate activity in combination with standard-of-care treatment in prostate cancer. These data from Study 08 represent another important milestone in the clinical development of LYNPARZA."

Median rPFS was 13.8 months with LYNPARZA and abiraterone compared to 8.2 months with abiraterone alone (HR=0.65 [95% CI, 0.44-0.97]; p=0.034). Median PFS2 was 23.3 months versus 18.5 months (HR=0.79 [95% CI, 0.51-1.21]). Median OS was 22.7 months with combination treatment versus 20.9 months with abiraterone alone (HR=0.91; [95% CI, 0.60-1.38]). Pre-specified exploratory subgroup analyses demonstrated an rPFS improvement in patients regardless of HRR status (see Table 1). Study 08 was not powered for subgroup analyses, PFS2 and OS. HRR mutation status was not known for all patients.

Table 1: rPFS by HRR status

Median rPFS
(months)

HR

95% CI
LYNPARZA +
abiraterone

abiraterone
Overall (n=142) 13.8 8.2 0.65 0.44-0.97
HRR-mutation (n=21)

17.8 6.5 0.74 0.26-2.12
Wild-type HRR (n=35) 15.0 9.7 0.52 0.24-1.15
Partially-characterized HRR status (n=86)*

13.1 6.4 0.67 0.40-1.13
*Those whose plasma and blood samples both tested negative for HRR mutations, but for whom no valid tumor test result was available

The safety of LYNPARZA in combination with abiraterone was also reported, as was the safety of abiraterone monotherapy. Grade ≥3 adverse events (AEs), serious AEs and treatment discontinuations due to AEs were more frequent with combination treatment than abiraterone alone (54% vs 28%; 34% vs 18%; 30% vs 10%, respectively). The most common grade ≥3 AEs in the combination arm were anemia (21%), pneumonia (6%) and myocardial infarction (6%). Serious cardiovascular events occurred in seven patients in the combination group and one patient in the abiraterone group. LYNPARZA is associated with a number of serious, potentially fatal risks, including MDS-AML, pneumonitis and embryo-fetal toxicity. Please see Important Safety Information for LYNPARZA (olaparib) tablets 100 mg below.

In addition to Study 08, other studies are underway to explore the potential of LYNPARZA as a monotherapy for HRR-mutated mCRPC, including PROfound, which is testing LYNPARZA monotherapy versus enzalutamide or abiraterone in patients with previously-untreated mCRPC. Additional trials are planned to explore LYNPARZA in combination for the treatment of mCRPC regardless of HRR status. LYNPARZA was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration in 2016 for the treatment of BRCA-mutated or ataxia telangiectasia mutated (ATM) gene-mutated mCRPC.

LYNPARZA is a first-in-class PARP inhibitor approved in the U.S. for certain patients with recurrent ovarian and metastatic breast cancer and has treated nearly 5,500 patients since 2014. LYNPARZA has a broad clinical development program, and AstraZeneca and Merck are working together to deliver LYNPARZA as quickly as possible to more patients across multiple cancer types, including prostate and pancreatic cancers.

Indications for LYNPARZA (olaparib) 100 mg in the U.S.

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

In patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Important Safety Information for LYNPARZA (olaparib) tablets 100 mg

Contraindications

There are no contraindications for LYNPARZA.

Warnings and Precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA (olaparib) if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

Adverse Reactions—Maintenance Setting

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%). Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), and decreased appetite (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

Adverse Reactions—Advanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA (olaparib) for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue (including asthenia) (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), increase in mean corpuscular volume (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

Adverse Reactions—gBRCAm, HER2-Negative Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

Drug Interactions

Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA (olaparib). If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.

Use In Specific Populations

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild hepatic impairment (Child-Pugh classification A). There are no data in patients with moderate or severe hepatic impairment.

Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min). In patients with moderate renal impairment (CLcr=31-50 mL/min), reduce the dose to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

About Study 08

Study 08 was a global, randomized, double-blinded, multi-center Phase 2 trial of 142 patients, assessing the efficacy and safety of LYNPARZA tablets (300 mg twice daily) and abiraterone tablets (4 x 250 mg once daily) (n=71) compared to matched placebo and abiraterone tablets (4 x 250 mg once daily) (n=71) in patients regardless of HRR status. Prednisone/prednisolone (5 mg twice daily) was administered to patients in both treatment arms.

Patients in Study 08 had previously received docetaxel for mCRPC. Prior to enrollment, patients had received no more than two lines of chemotherapy.

The primary endpoint was radiologic progression-free survival (rPFS) (time from randomization to radiologic progression or death). rPFS is increasingly used in clinical trials of mCRPC as a clinically-meaningful endpoint focusing on the impact of treatment on disease progression to areas where spread of prostate cancer is common, notably soft tissue and bone.

Secondary endpoints included time to second progression or death (PFS2), overall survival (OS) and health-related quality of life.

About Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Prostate cancer is the second most common cancer in men, with an estimated 1.6 million new cases diagnosed worldwide in 2015, and is associated with a significant mortality rate. Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone. Metastatic castration-resistant prostate cancer (mCRPC) occurs when prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones. Approximately 10-20 percent of men with advanced prostate cancer will develop mCRPC within five years, and at least 84 percent of these will have metastases at the time of mCRPC diagnosis. Of men with no metastases at mCRPC diagnosis, 33 percent are likely to develop metastases within two years. Despite an increase in the number of available therapies for men with mCRPC, five-year survival is only 28 percent.

About LYNPARZA (olaparib)

LYNPARZA was the first in class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that LYNPARZA-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

LYNPARZA is being tested in a range of DDR-deficient tumor types.

On June 4, 2018 Tarveda Therapeutics, Inc., a clinical stage biopharmaceutical company discovering and developing Pentarins as a new class of potent and selective medicines to treat a wide range of cancers, reported Phase 1 results that were presented at the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from an ongoing Phase 1/2a study of PEN-221 in patients with somatostatin receptor 2 (SSTR2)-expressing neuroendocrine tumors (NET) or small cell lung cancer (SCLC) (Press release, Tarveda Therapeutics, JUN 4, 2018, View Source [SID1234527160]). The results presented had a data cutoff date of February 23, 2018. As of April 11, 2018, four patients remained on study.

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"PEN-221, our lead Pentarin miniature drug conjugate, is designed to rapidly penetrate deep into solid tumors where it is highly selective for the somatostatin receptor 2 and accumulates its potent DM1 payload," said Richard Wooster, Ph.D., President of Research and Development and Chief Scientific Officer at Tarveda. "Based on the safety results and encouraging signs of antitumor activity seen in our Phase 1 dose escalation and safety study for PEN-221, we have initiated the Phase 2a portion of our Phase 1/2a trial of PEN-221 to explore its potential in treating patients with gastrointestinal midgut and pancreatic neuroendocrine tumors as well as small cell lung cancer."

The Phase 1 portion of the study was designed as a dose escalating study to assess safety, tolerability, pharmacokinetics, and preliminary antitumor activity of PEN-221 in patients with SSTR2-expressing advanced neuroendocrine or small cell lung cancers. The results show that PEN-221 appears to be well-tolerated with evidence of antitumor activity seen in multiple patients. The maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) was established as 18mg and will be further evaluated in the Phase 2a portion of the study.

"There is a very real need for new treatment options for patients living with neuroendocrine tumors and small cell lung cancer," said Melissa Johnson, M.D., Associate Director, Lung Cancer Research Program at Sarah Cannon Research Institute. "PEN-221, an SSTR2 directed drug conjugate linked to a DM1 cytotoxic payload, is an exciting and novel approach to treating patients with SSTR2 expressing tumors identified using biomarker imaging agents OctreoScan or Gallium-68 DOTATATE PET. PEN-221 was well tolerated by patients in this clinical trial. In addition, the encouraging signals of antitumor activity and prolonged stable disease further supports continuation of the study of PEN-221 in the Phase 2a trial."

Phase 1 Trial Design

PEN-221 was administered as a one-hour, intravenous infusion once every three weeks to escalating cohorts of two to six patients with SSTR2 expressing advanced solid tumors including advanced gastroenteropancreatic, lung, thymus or other neuroendocrine tumors or small cell lung cancers or large cell neuroendocrine tumors of the lung. Safety was assessed by vital sign measurements, physical examinations, neurological examinations, ECOG performance status, documentation of adverse events, clinical laboratory tests, and electrocardiography. Disease response was assessed by duration of response and standard RECIST criteria.

Safety Data

A safety analysis of all 23 patients demonstrated that PEN-221 was well-tolerated with no dose limiting toxicities up to 18mg. Two of three patients administered 25mg of PEN-221 experienced dose limiting toxicities that rapidly and fully resolved following treatment discontinuation.

The majority of treatment-related/treatment-emergent adverse events were mild (Grade 1) to moderate (Grade 2) with the most common being fatigue (48%), nausea (48%), diarrhea (44%), and peripheral neuropathy (26%). There were single reports of Grade 3 peripheral neuropathy, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increase and constipation at the 25mg dose. One patient at the 25mg dose experienced a Grade 3 drug induced liver injury.

The Maximum Tolerated Dose and Recommended Phase 2 Dose of PEN-221 is 18mg administered once every 3 weeks.

Efficacy data

There was preliminary evidence of antitumor activity:

Among 15 NET patients who were evaluable for response, 11 had stable disease (SD) at 9 weeks, of whom 8 were sustained for 18-45 weeks, including 2 ongoing patients with SD for 44 and 45 weeks at the time of this data review.
Target lesion shrinkage leading to minor responses at the time of this data review were observed in 3/7 patients who had either a GI or pancreatic NET (dose range 8-18 mg).
The only SCLC patient had SD for 12 weeks.
As of April 11, 2018, four patients remained in the Phase 1 portion of the study with stable disease of 5, 7, 12, 14 months respectively.

About PEN-221

PEN-221 is a miniature drug conjugate consisting of a peptide ligand, that is highly selective in targeting SSTR2, joined through a cleavable linker to the potent cytotoxic payload DM1. SSTR2 is overexpressed on the cell surface of a range of solid tumors including neuroendocrine tumors and small cell lung cancers. In non-clinical experiments, PEN-221 binds with high affinity and selectivity to SSTR2. On binding, PEN-221 triggers SSTR2 internalization resulting in the accumulation of the DM1 payload in tumor cells followed by cell cycle arrest and apoptosis.

PEN-221 is being evaluated in Phase 2a expansion cohorts enrolling patients with midgut neuroendocrine tumors, pancreatic neuroendocrine tumors, and small cell lung cancer (ClinicalTrials.gov Identifier: NCT02936323).

About Pentarins
Tarveda is developing Pentarins, potent and selective miniature drug conjugates with high affinity for specific cell surface and intracellular targets. Pentarins are engineered to bind to their tumor cell targets and provide sustained release of their potent therapeutic payloads deep into solid tumor tissue. Comprised of a targeting ligand conjugated to a potent cancer cell killing agent through a tuned chemical linker, Pentarins are designed to overcome the deficits of both larger antibody drug conjugates and small molecules that limit their therapeutic effectiveness against solid tumors. Together, the components of Tarveda’s Pentarins have distinct, yet synergistic, anticancer attributes: the small size of Pentarins allows for rapid and deep penetration into the tumor tissue, the ligand’s targeting ability allows for specific binding and retention in tumor cells, and the chemical linker is tuned to optimize the release of the potent, cell killing payload inside the cancer cells for efficacy.

On June 4, 2018 Checkpoint Therapeutics, Inc. ("Checkpoint") (NASDAQ: CKPT), a clinicalstage, immuno-oncology biopharmaceutical company focused on the acquisition, development andbcommercialization of novel treatments for patients with solid tumor cancers, reported that James F. Oliviero, President and Chief Executive Officer, will participate in two investor conferences in June (Press release, Checkpoint Therapeutics, JUN 4, 2018, View Source [SID1234527113]).

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• Jefferies 2018 Global Healthcare Conference on Friday, June 8, 2018, at 10:30 a.m. EDT at the Grand Hyatt in New York City

• JMP Securities Life Sciences Conference on Thursday, June 21, 2018, at 12:30 p.m. EDT at the St. Regis New York in New York City

Live webcasts of the presentations will be available on the Events page of the Investors & Media section
of Checkpoint’s website: www.checkpointtx.com. An archived replay of the webcast will be available for
approximately 30 days following the presentation.

On June 4, 2018 MEI Pharma, Inc. (Nasdaq: MEIP), a pharmaceutical company focused on leveraging its extensive development and oncology expertise to identify and advance new therapies for cancer, reported that data presented at ASCO (Free ASCO Whitepaper) 2018 from an investigator-initiated study of ME-344 in patients with HER2 negative breast cancer demonstrate evidence of inhibition of tumor proliferation as measured by Ki-67 reductions (Press release, MEI Pharma, JUN 4, 2018, View Source [SID1234527129]). These interim data are consistent with preclinical results indicating ME-344’s potential to reverse resistance to anti-angiogenic therapy, thereby warranting the continuation of the ongoing study.

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"The goal of this study is to gain a better understanding of the escape pathways that may be utilized by tumors against antiangiogenic therapeutics. The interim results from this study suggest that there may be an important therapeutic role for mitochondrial inhibitors like ME-344, providing a potential novel mechanism to improve patient outcomes in combination with antiangiogenic therapeutics," stated the study principal investigator, Miguel Quintela-Fandino, M.D., Ph.D., Director of the Clinical Research Program, Centro Nacional De Investigaciones Oncologicas, Madrid, Spain.

"We are looking forward to continuing our work with Dr. Quintela-Fandino as we further elucidate the opportunity to advance ME-344 as part of a novel approach for the treatment of cancer," said Daniel P. Gold, Ph.D., president and chief executive officer of MEI Pharma.

The ME-401 ASCO (Free ASCO Whitepaper) 2018 poster can be accessed on the MEI Pharma website.

ME-344 Clinical Data
The ongoing study is a multicenter, investigator-initiated, randomized, open-label, clinical trial evaluating ME-344 in a total of up to 40 patients with HER2-negative breast cancer in combination with the vascular endothelial growth factor inhibitor bevacizumab (marketed as Avastin). Patients are randomized one-to-one to either ME-344 plus Avastin or saline plus Avastin. The interim data review was predefined to take place after 20 patients were randomized.

The primary efficacy endpoint is inhibition of cell proliferation as measured by Ki-67 reductions. Mean absolute (relative) Ki67 decreases were 5.13 (29%) and 1.2 (9%) in the active versus control arms (P=0.06). Patients with standardized uptake values via PET scan ≥ 10% experienced an absolute average Ki67 decrease of 16.6 vs. 2.3 in the active versus control arms (P=0.19). Treatment was generally well tolerated; two Grade 3 adverse events (high blood pressure) were reported, 1 in each arm, and deemed related to bevacizumab.

About ME-344
ME-344 is a novel, tumor selective, isoflavone-derived mitochondrial inhibitor drug candidate. It directly targets the OXPHOS complex 1, a pathway involved in the production of adenosine triphosphate, or ATP, in the mitochondria. Treatment of tumor cells with ME-344 results in a rapid loss of ATP and cancer cell death. ME-344 demonstrated evidence of single-agent activity against refractory solid tumors in a Phase I study, and in preclinical studies, tumor cells treated with ME-344 resulted in a rapid loss of ATP and cancer cell death.

In addition to single-agent activity, ME-344 may also have potential in combination with antiangiogenic therapeutics. While antiangiogenics reduce the rate of glycolysis in tumors as a mechanism to block growth, tumor metabolism often shifts to mitochondrial metabolism to continue energy production to support continued tumor proliferation. In such cases of tumor plasticity in the presence of treatment with antiangiogenics, targeting the alternative metabolic source with ME-344 may open an important therapeutic opportunity.

On June 4, 2018 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported long-term efficacy data from the Phase 3 KEYNOTE-006 study and the melanoma cohort of the Phase 1b KEYNOTE-001 study investigating KEYTRUDA, Merck’s anti-PD-1 therapy, in patients with advanced melanoma. A new analysis from KEYNOTE-006 demonstrated durable efficacy benefits among patients who completed two years of KEYTRUDA treatment, combined with updated overall survival (OS) results across both studies, confirming anti-tumor activity in advanced melanoma patients (Press release, Merck & Co, JUN 4, 2018, View Source [SID1234527145]). At a median follow-up of 20.3 months after completion of KEYTRUDA in KEYNOTE-006, 86 percent of patients remained progression-free, the co-primary endpoint for the study. For the primary endpoint of OS in KEYNOTE-006, the four-year OS rate was 41.7 percent in the pooled KEYTRUDA arms vs. 34.1 percent in the ipilimumab arm; in treatment-naïve patients, OS rates were 44.3 percent in the pooled KEYTRUDA arms and 36.4 percent in the ipilimumab arm. In KEYNOTE-001, the five-year OS rate, a secondary endpoint for the study, was 34 percent in all patients and 41 percent in treatment-naïve patients. The safety profile of KEYTRUDA in both studies was consistent with what has been seen in previous trials among patients with advanced melanoma. Results for KEYNOTE-006 (Abstract #9503) and KEYNOTE-001 (Abstract #9516) are being presented today at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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"Looking across the findings for both KEYNOTE-006 and KEYNOTE-001 we are seeing further validation that KEYTRUDA is significantly extending the survival of first-line metastatic melanoma patients, regardless of tumor BRAF-mutation status," said Scot Ebbinghaus, M.D., vice president, clinical research, Merck Research Laboratories. "In KEYNOTE-006, we are also seeing durable efficacy benefits for patients who complete two years of KEYTRUDA treatment. We are pleased to share data that further reinforce KEYTRUDA monotherapy as a standard of care in advanced melanoma patients and deliver on our goal of improving and extending the lives of melanoma patients."

"Pembrolizumab had already established superior survival outcomes versus ipilimumab in advanced melanoma patients, and this is further reinforced with four years of data in KEYNOTE-006," said Professor Georgina V. Long, conjoint medical director of Melanoma Institute Australia (MIA), and chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, The University of Sydney. "Importantly, we’re now seeing ongoing efficacy for patients who complete the protocol-specified two years of pembrolizumab treatment, as well as additional anti-tumor activity for the patients who progress after a first course of treatment and complete a second course of treatment."

"Updated data for KEYNOTE-001 demonstrate significant survival benefits in advanced melanoma patients," said Omid Hamid, M.D., chief of Translational Research and Immuno-Oncology and director of Melanoma Therapeutics, The Angeles Clinic and Research Institute, Los Angeles, California. "Five-year survival is a true milestone for oncology patients, particularly among those living with metastatic melanoma, so it is incredibly exciting to share these updated data."

Merck’s long-term commitment to melanoma includes a broad clinical development program studying KEYTRUDA as monotherapy and in combination with other novel mechanisms. The program, which is comprised of more than 4,500 patients across 10 Merck-sponsored clinical studies, is evaluating KEYTRUDA across all settings and stages of the disease.

Additional Data and Safety Information from KEYNOTE-006 (Abstract #9503)

KEYNOTE-006 is a global, open-label, randomized, pivotal, Phase 3 study (ClinicalTrials.gov, NCT01866319) evaluating KEYTRUDA compared to ipilimumab in patients with unresectable stage III or IV melanoma who had either not been treated previously (first-line treatment setting) or who had received a prior targeted therapy for BRAF-mutation positive melanoma (in the KEYTRUDA arm, 34% received prior therapy with a BRAF/MEK inhibitor; in the ipilimumab arm, 35% received prior therapy). The study randomized 834 patients to receive KEYTRUDA 10 mg/kg every three weeks, KEYTRUDA 10 mg/kg every two weeks, or four cycles of ipilimumab 3 mg/kg every three weeks. Treatment continued until unacceptable toxicity or disease progression; patients without disease progression could be treated for up to 24 months. Upon disease progression, eligible patients could receive an additional one year of KEYTRUDA. The co-primary endpoints were progression-free survival (PFS) and OS; secondary endpoints were overall response rate (ORR), duration of response (DOR) and safety, with an exploratory analysis for health-related quality of life (QoL).

With a median follow-up of 45.9 months (range, 0.3-50.0), the four-year OS rate was 41.7 percent in the pooled KEYTRUDA arms (n=556) and 34.1 percent in the ipilimumab arm (n=278); investigator-reported ORR was 42 percent and 17 percent, respectively. Median DOR was not reached for KEYTRUDA (range, 1.0+ to 46.1+ months) or ipilimumab (range, 1.1+ to 45.6+ months); 62 percent of patients in the KEYTRUDA arms and 59 percent of patients in the ipilimumab arm had a response lasting ≥ 42 months.

In treatment-naïve patients, the four-year OS rates were 44.3 percent in the pooled KEYTRUDA arms (n=368) and 36.4 percent in the ipilimumab arm (n=181); ORR was 47 percent and 17 percent, respectively. Median DOR was not reached for KEYTRUDA (range, 1.6+ to 46.0+ months) or ipilimumab (range, 1.1+ to 42.2+ months); 65 percent of patients in the KEYTRUDA arms and 68 percent of patients in the ipilimumab arm had a response lasting ≥ 42 months.

Per study protocol, 18.5 percent of patients (n=103) completed two years of KEYTRUDA. With a median follow-up of 20.3 months (range, 0.03-24.8), 86 percent of patients (n=89) remained progression-free. Eight patients received second-course KEYTRUDA; three discontinued treatment. Among the eight patients, there was one complete response and three partial responses; three patients had stable disease, while the remaining patient had progressive disease.

The safety profile of KEYTRUDA was consistent with what has been seen in previously reported studies among patients with advanced melanoma. Five patients had an immune-mediated adverse event during second-course KEYTRUDA; there were no grade 3-4 immune-mediated adverse events or deaths.

Additional Data and Safety Information from KEYNOTE-001 (Abstract #9516)

KEYNOTE-001 is a Phase 1b multicenter, open-label, multi-cohort trial (ClinicalTrials.gov, NCT01295827) evaluating KEYTRUDA in various advanced cancers, including 655 patients with advanced melanoma. Patients in the melanoma cohorts received 2 mg/kg or 10 mg/kg of KEYTRUDA every three weeks or 10 mg/kg of KEYTRUDA every two weeks until unacceptable toxicity or disease progression. The primary endpoint was confirmed ORR. The secondary endpoints included PFS, OS and DOR.

After median follow-up of 55 months (range, 48-69), 35 patients remained on KEYTRUDA therapy. The investigator-reported ORR, the primary endpoint for KEYNOTE-001, was 41 percent in all patients (including 16% who achieved a complete response) and 52 percent in treatment-naïve patients (including 25% who achieved a complete response). The estimated five-year OS rate was 34 percent in all patients (n=655) and 41 percent in treatment naïve patients (n=151). Median OS was 23.8 months (95% CI, 20.2-30.4) in all patients and 38.6 months (95% CI, 27.2-NR) in treatment-naïve patients.

Median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5) in all patients and treatment-naïve patients, respectively.

Median DOR was not reached (range, 1.3+ to 66.3+ months) in all responders and in treatment-naïve patients (range, 1.3+ to 60.8+ months); 73 percent of all responses and 82 percent of treatment-naïve responses were ongoing at data cut-off. The longest response observed in all patients was ongoing at 66 months.

The safety profile of KEYTRUDA was consistent with what has been seen in previously reported studies among patients with advanced melanoma. Treatment-related adverse events (TRAEs) occurred in 86 percent (n=562) of patients including 17 percent with grade 3-4 and eight percent who discontinued. Twelve percent of patients experienced a serious TRAE including five percent who discontinued treatment. Immune-mediated adverse events and infusion reactions were reported in 23 percent of patients. Most cases of immune-related adverse events, including hypothyroidism and pneumonitis, were grade 1 or 2. Hypothyroidism was the most commonly reported immune-mediated adverse event, followed by pneumonitis, colitis and skin disorders.

About Melanoma

Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The incidence of melanoma has been increasing over the past four decades – approximately 232,000 new cases were diagnosed worldwide in 2012. In the U.S., melanoma is one of the most common types of cancer diagnosed and is responsible for the vast majority of skin cancer deaths. In 2018, an estimated 91,270 people are expected to be diagnosed and an estimated 9,320 people are expected to die of the disease in the U.S. alone.

Merck Investor Webcast

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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 750 trials studying KEYTRUDA 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 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 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

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 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. 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 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 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-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%).