On June 4, 2018 Merck KGaA, Darmstadt, Germany, which operates its biopharmaceutical business as EMD Serono in the US and Canada, and Pfizer Inc. (NYSE: PFE) reported that updated efficacy and safety data from the pivotal JAVELIN Merkel 200 trial of BAVENCIO (avelumab) in patients with metastatic Merkel cell carcinoma (mMCC), will be presented as an oral abstract session at the 54th American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on Monday, June 4 from 10:12-10:24 a.m. CDT in Chicago, IL (Press release, Pfizer, JUN 4, 2018, View Source [SID1234527150]). At this two year follow-up update of the pivotal study, BAVENCIO continues to demonstrate clinically meaningful durable responses and stable rates of progression-free survival (PFS) and overall survival (OS) from previous analyses in patients who responded to this treatment. Clinical activity was observed across all patient subgroups, irrespective of PD-L1 expression in tumor tissue or Merkel cell polyomavirus status. The safety profile for BAVENCIO in this trial has not changed with longer follow-up and remains consistent with that observed in the overall JAVELIN clinical development program.

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"These efficacy and safety results build upon the data that supported our FDA approval," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the Biopharma business of Merck KGaA, Darmstadt, Germany. "Alongside our other data at ASCO (Free ASCO Whitepaper), this two-year analysis is a significant advance in our understanding of the utility of BAVENCIO in MCC patients."

In JAVELIN Merkel 200 – an open-label, single-arm Phase II study – patients with histologically confirmed mMCC whose disease had progressed on or after chemotherapy administrated for distant metastatic disease received BAVENCIO 10 mg/kg intravenously every two weeks until disease progression or unacceptable toxicity. Eighty-eight patients were followed for a median of 29.2 months (range 24.8-38.1 months). The confirmed overall response rate (ORR) of 33% (95% confidence interval [CI] 23.3-43.8; complete response in 11.4%) remained unchanged from previous analyses reported at both one year and 18 months. Responses remained ongoing in 19 of 29 patients who responded to treatment, including 12 patients whose duration of response exceeded two years. Durable responses led to stable rates of PFS (29% at 12 months, 29% at 18 months and 26% at 24 months). Median OS was 12.6 months (95% CI 7.5-17.1) and the two-year OS rate was 36% (50% at 12 months and 39% at 18 months). With a minimum follow-up of two years, no new safety signals were identified for BAVENCIO and was consistent with prior reports. Sixty-seven patients (76.1%) had a treatment-related adverse event (TRAE), 10 patients (11.4%) had a Grade 3 or less TRAE and 20 patients (22.7%) had an immune-related adverse event. No treatment-related deaths occurred.

"These results represent a key milestone for patients with mMCC, as chemotherapy has historically been the only treatment option for this devastating disease," said Chris Boshoff, M.D., Ph.D., Senior Vice President and Head of Immuno-Oncology, Early Development and Translational Oncology, Pfizer Global Product Development. "These data, alongside the additional real-world data which are also being presented at ASCO (Free ASCO Whitepaper), strengthen our confidence in BAVENCIO as a treatment option for this rare and aggressive skin cancer."

In addition to these updated JAVELIN Merkel 200 data, results from a global expanded access program for BAVENCIO as a second-line treatment for patients with mMCC will be presented. These data will be presented during a poster session on Monday, June 4 from
1:15-4:45 p.m. CDT.

The alliance’s JAVELIN clinical development program involves at least 30 clinical programs, including seven Phase III trials, and nearly 8,300 patients across more than 15 tumor types.

BAVENCIO (avelumab) was first approved in the US in 2017 by the US Food and Drug Administration (FDA) for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC). In addition to the FDA accelerated approval in mMCC, avelumab is also approved in the US under accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

About JAVELIN Merkel 200

JAVELIN Merkel 200 is an international, multicenter, open-label, single-arm Phase II study of BAVENCIO conducted in 88 patients with metastatic MCC. Patients in this study were generally elderly (median age was 72.5 years, range 33-88 years) and pre-treated, with at least one line of chemotherapy (one [59.1%], two [29.5%] or three or more [11.4%] previous treatments). Patients received BAVENCIO 10 mg/kg intravenously once every two weeks. The protocol-defined analysis set for efficacy and safety consisted of all patients who received at least one dose of study treatment. The cut-off date for the planned primary analysis was six months after start of study treatment of the last patient. The primary endpoint of the study was confirmed best overall response according to RECIST v1.1 and assessed by an independent review committee. Secondary endpoints were duration of response, PFS, OS, response status by RECIST at six and 12 months, safety and tolerability, pharmacokinetics, and immunogenicity of BAVENCIO.

About Avelumab

Avelumab is a human anti-programmed death ligand-1 (PD-L1) antibody. Avelumab has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, avelumab has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.[2]-[4] Avelumab has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.[4]-[6] In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Approved Indications in the US

The FDA granted accelerated approval for avelumab (BAVENCIO) for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information from the US FDA Approval Label

BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis, and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% (21/1738) of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.

BAVENCIO can cause immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis was reported in 0.9% (16/1738) of patients, including two (0.1%) patients with Grade 5, and 11 (0.6%) with Grade 3.

BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis, and permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including seven (0.4%) with Grade 3.

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% (8/1738) of patients, including one (0.1%) with Grade 3.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% (98/1738) of patients, including three (0.2%) with Grade 3.

Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade ≥ 3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients, including two cases of Grade 3 hyperglycemia.

BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% (1/1738) of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1,738 patients treated with BAVENCIO: myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.

BAVENCIO can cause severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Patients should be premedicated with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% (439/1738) of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, ≥ 20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥ 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

The most common adverse reactions (all grades, ≥ 20%) in patients with locally advanced or metastatic urothelial carcinoma (UC) were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%), and urinary tract infection (21%).

Selected laboratory abnormalities (Grades 3-4, ≥ 3%) in patients with locally advanced or metastatic UC were hyponatremia (16%), increased gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).

On June 4, 2018 OncoSec Medical Incorporated (OncoSec) (NASDAQ:ONCS), a company developing intratumoral cancer immunotherapies, reported the presentation of a Trials in Progress poster at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting taking place in Chicago, IL (Press release, OncoSec Medical, JUN 4, 2018, View Source [SID1234527149]).

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Titled, Trial in Progress, A Phase 2 Study of Intratumoral pIL-12 Plus Electroporation In Combination With Intravenous Pembrolizumab In Patients With Stage III/IV Melanoma Progressing on Either Pembrolizumab or Nivolumab Treatments (PISCES/KEYNOTE-695), the poster provides an update on OncoSec’s global, multi-center, registration-directed open-label Phase 2b clinical trial, assessing the Company’s investigational therapy, (intratumoral pIL-12 [tavokinogene telseplasmid] delivered with electroporation) ("tavo" or "ImmunoPulse IL-12"), and the approved anti-PD-1 therapy pembrolizumab, in patients with unresectable metastatic melanoma who have progressed or are progressing on an anti-PD-1 therapy.

PISCES/KEYNOTE-695, a phase 2b, Simon 2-stage multicenter study of tavo in combination with intravenous KEYTRUDA, will enroll approximately 48 patients with histological diagnosis of melanoma with progressive locally advanced or metastatic disease defined as Stage III or Stage IV. Stage 1 of the study will enroll 23 patients. The primary endpoint will be the Best Overall Response Rate (BORR).

Numerous sites in the U.S., Australia, and Canada are open and enrolling patients. The Company anticipates that enrollment in stage 1 will be completed by the third quarter 2018.

"Despite the addition of immunotherapy and targeted therapies, disease progression continues to occur in a significant percentage of advanced melanoma patients," said OncoSec Chief Clinical and Regulatory Officer, Sharron Gargosky, Ph.D. "We are pleased with our progress as we continue to enroll patients in the KEYNOTE-695 trial, which is evaluating the tolerability and efficacy of pembrolizumab plus tavo in Stage III/IV melanoma patients who have progressed or are progressing on approved checkpoint inhibitors."

The Company’s prior Phase 2 combination study of tavo and pembrolizumab (OMS-102) in 22 patients unlikely to respond to anti-PD-1 therapy demonstrated a 50% best overall response rate and a 41% complete response rate. In addition, the trial showed a 57% progression free survival (PFS) rate at 15 months (median PFS not yet reached) and 100% (11/11) duration of response. In clinical studies to date, tavo has demonstrated a favorable safety profile and has been well tolerated.

PISCES/KEYNOTE-695 is the second combination study conducted with tavo and pembrolizumab and, if successful, could form the basis for a BLA under the accelerated approval pathway.

Tavo has received both Orphan Drug and Fast-Track Designation by the U.S. Food & Drug Administration.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

ImmunoPulse is a registered trademark of OncoSec Medical Incorporated.

To learn more about the trial, visit www.oncosec.com. Additional details can also be found at www.clinicaltrials.gov via NCT03132675.

About PISCES/KEYNOTE-695 (Anti-PD-1 IL-12 Stage III/IV Combination Electroporation Study)
PISCES/KEYNOTE-695 is a global, multicenter phase 2b, open-label trial of intratumoral plasma encoded IL-12 (tavokinogene telseplasmid or "tavo") delivered by electroporation in combination with intravenous pembrolizumab in patients with stage III/IV melanoma who have progressed or are progressing on either pembrolizumab or nivolumab treatment. The Simon 2-stage study of intratumoral tavo plus electroporation in combination with pembrolizumab will enroll approximately 48 patients with histological diagnosis of melanoma with progressive locally advanced or metastatic disease defined as Stage III or Stage IV. The primary endpoint will be the Best Overall Response Rate (BORR).

About Metastatic Melanoma1
Melanoma is a type of skin cancer that begins in skin cells called melanocytes. As the cancer progresses, melanoma becomes more difficult to treat once it spreads beyond the skin, such as the lymphatic system (metastatic disease). Given its occurrence young individuals, the potential years of life lost to melanoma can be higher when compared with other cancers. Although melanoma is a rare form of skin cancer, it accounts for over 75% of skin cancer deaths. The American Cancer Society estimates that approximately 87,000 new melanoma cases and 10,000 deaths from the disease will occur in the United States in 2017. Additionally, the World Health Organization estimates that approximately 132,000 new cases of melanoma are diagnosed around the world every year.

On June 4, 2018 NewLink Genetics Corporation (NASDAQ:NLNK) reported that data from two Phase 2 studies of indoximod, used in combination with other agents, were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, NewLink Genetics, JUN 4, 2018, View Source [SID1234527148]).

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"Our data in advanced melanoma suggest that indoximod in combination with checkpoint blockade shows encouraging response rates potentially in both PD-L1 positive and negative patients," said Charles J. Link, Jr, MD, Chairman and Chief Executive Officer. "We wish to thank the patients and their caregivers who participated in both of these studies."

Indoximod in combination with checkpoint inhibition in advanced melanoma
Results from a single-arm Phase 2 study of indoximod in combination with checkpoint inhibitors for patients with advanced melanoma were presented today by Yousef Zakharia, MD, Assistant Professor of Medicine, Division of Hematology, Oncology and Blood & Marrow Transplantation at the University of Iowa and Holden Comprehensive Cancer Center.

In this study, of 102 total patients enrolled, 101 patients with advanced melanoma were treated with indoximod plus standard-of-care checkpoint inhibition as approved for melanoma. 70 patients with cutaneous or mucosal melanoma were treated with pembrolizumab plus indoximod and had an on-treatment imaging, meeting the per-protocol, pre-specified definition of evaluable for efficacy. Of the remaining 32 patients, 15 had uveal melanoma, 4 received ipilimumab, 4 received nivolumab, and one patient was never treated. In addition, 8 patients came off study prior to the first on-treatment imaging study. The full data set, including the expanded biopsy cohort, is provided on the company’s website in the "Posters & Presentations" section under the "Investors & Media" tab.
Key findings from the 70 evaluable for efficacy patients presented from the study include:
–
ORR for combination therapy of 56%
–
CR of 19%
–
Median PFS of 12.4 months
–
PD-L1 ≥ 1% staining of 54% (22/41 patients with archival tissue)
–
ORR by PD-L1 status
◦
PD-L1 (+) patients: ORR of 77%
◦
PD-L1 (-) patients: ORR of 42%
–
Combination was well tolerated

Indoximod in combination with chemotherapy in metastatic pancreatic cancer
Results from a Phase 2 study of indoximod plus chemotherapy for patients with metastatic pancreatic cancer were presented at ASCO (Free ASCO Whitepaper) by Nathan Bahary, MD, PhD, Associate Professor in the Division of Oncology and Medical Director of the Pancreatic Cancer Program at the University of Pittsburgh Medical Center. Key findings from this study show that the combination was well tolerated with a median Overall Survival (mOS) of 10.9 months and an Overall Response Rate (ORR) of 46.1%. Although the study did not meet the prespecified primary goal of a 30% decrease in the risk of death compared with historical controls, the combination demonstrated potentially promising activity with an immunologic correlation for response to therapy. These data may be found on the company’s website in the "Posters & Presentations" section under the "Investors & Media" tab.

Exhibit 99.1

About Indoximod
Indoximod is an investigational, orally available small molecule targeting the IDO pathway. The IDO pathway is a key immuno-oncology target involved in regulating the tumor microenvironment and immune escape. Indoximod is being evaluated in combination with treatment regimens including chemotherapy, radiation, checkpoint blockade and cancer vaccines across multiple indications such as AML, DIPG and melanoma.

On June 4, 2018 Molecular Templates, Inc. (Nasdaq:MTEM), a clinical stage biopharmaceutical company focused on the discovery and development of Engineered Toxin Bodies, a new class of targeted biologic therapies that possess unique mechanisms of action in oncology, reported that data on two of its pipeline programs were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2018, held June 1-5 in Chicago, Illinois (Press release, Molecular Templates, JUN 4, 2018, View Source [SID1234527147]).

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MT-3724

Poster Title: Safety and Efficacy of Anti-CD20 Immunotoxin MT-3724 in Relapsed/Refractory B-cell non-Hodgkin Lymphoma (NHL) in a Phase 1 Study
First Author: Paul A. Hamlin, MD, Memorial Sloan Kettering Cancer Center
The poster summarized interim results from a Phase I and Phase Ib extension study of B-cell non-Hodgkin’s lymphoma (NHL) patients treated with MT-3724 who had previously relapsed after anti-CD20 Mab and chemotherapy. Consistent with the mechanism of action, enzymatic ribosome inactivation, the best activity is observed in heavily pretreated patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) (N=18; median of five prior therapies).

Patients with high circulating levels of rituximab (RTX) at study entry showed poor response to MT-3724 due to competitive inhibition and blocking of CD20 receptor by RTX. As a result, the ongoing Phase Ib extension and future studies of MT-3724 will enroll only patients with low levels of RTX.

The preliminary objective response rate in DLBCL patients with low serum Rituxan levels at study entry (N=10) was 30%, with a disease control rate of 70%, including two stable disease patients that had tumor reductions of 47% and 49%. The ongoing Phase Ib study will further characterize the response rate and duration of response.

MT-3724 was generally well tolerated and a redefined maximum tolerated dose (MTD) of 50 mcg/kg with a maximum of 6 mg per dose was implemented based on experience with patients with high body weight who received a high total dose at 75mcg/kg. Enrollment in the study has recently resumed after approval of the new MTD.

In addition to this ongoing Phase Ib extension, Molecular Templates expects to start Phase II combinations studies in 2H18 and a Phase II monotherapy study at the end of the year that may be pivotal.

Evofosfamide

Poster Title: Unexpected Pharmacokinetics of Evofosfamide Observed in Phase III MAESTRO Study
First Author: Jack P. Higgins, Ph.D., Molecular Templates, Inc.
This poster compares the pharmacokinetic (PK) profile of evofosfamide from the Phase II ("404" study) and Phase III ("MAESTRO") trials completed in patients with advanced pancreatic cancer. The Phase II ("404") study of evofosfamide in pancreatic cancer (N=214) showed promising response rates, progression-free survival, and overall survival. MAESTRO, a Phase III study in the same patient population (N=693) failed to replicate the clinical benefit seen in the Phase II ("404") study. A new ethanol-based formation was introduced before the initiation of MAESTRO and the drug exposure was substantially lower than the exposure in the Phase II ("404") study at the same dose. In the Japanese MAESTRO patients who received evofosfamide (N=59), substantially higher drug exposure was observed with correspondingly better clinical outcomes versus patients in the study from the rest of the world. We surmise that the formulation change may have adversely affected drug exposure and may have caused the reduced clinical benefit observed in MAESTRO.

Evofosfamide (in the current ethanol-based formulation) at higher doses is currently being evaluated in a Phase I study, in combination with ipilimumab, in an attempt to replicate the exposure seen with the previous formulation in Phase II ("404") study. Molecular Templates plans to explore potential partnership opportunities for further development of evofosfamide.

On June 4, 2018 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported interim data from a cohort of the Phase 2 KEYNOTE-158 study evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy in patients with previously treated advanced small cell lung cancer (SCLC) (Press release, Merck & Co, JUN 4, 2018, View Source [SID1234527146]). Findings showed an overall response rate (ORR) of 18.7 percent in patients in the SCLC cohort (95% CI, 11.8–27.4), the primary endpoint of the study. Additionally, in a pre-specified exploratory analysis, ORR was 35.7 percent in patients whose tumors expressed PD-L1 with a combined positive score (CPS) of ≥1 (95% CI, 21.6–52.0). These results, as well as other findings from the KEYNOTE-158 (Abstract #8506) cohort in SCLC, are being presented for the first time today at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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"In this study, KEYTRUDA demonstrated promising overall response rates in the overall population of small cell lung cancer patients, and in patients whose tumors express PD-L1," said Dr. Hyun Cheol Chung, professor, Cancer Metastasis Research Center, and professor, Yonsei Cancer Center, South Korea. "As an oncologist, I am encouraged by these results evaluating KEYTRUDA as a monotherapy in a type of lung cancer that has seen little progress in meaningful treatment advances."

"These new data for KEYTRUDA in small cell lung cancer underscore why Merck is pursuing a broad clinical development program across all types of lung cancer," said Dr. Jonathan Cheng, vice president, oncology clinical research, Merck Research Laboratories. "We are encouraged by the response rates observed in this study, and continue to evaluate the potential of KEYTRUDA in combination with chemotherapy as first-line treatment in patients with extensive stage small cell lung cancer in the ongoing pivotal Phase 3 KEYNOTE-604 study."

Merck has an extensive clinical development program in lung cancer and is advancing multiple registration-enabling studies with KEYTRUDA in combination with other treatments and as monotherapy. The program, which is comprised of nearly 9,000 patients across 15 clinical studies, is evaluating KEYTRUDA across multiple settings and stages of the disease. In SCLC specifically, KEYTRUDA is being studied in combination with chemotherapy in the ongoing Phase 3 KEYNOTE-604 study in patients with newly diagnosed extensive stage disease.

Additional Data from KEYNOTE-158 (Abstract #8506)

KEYNOTE-158 (ClinicalTrials.gov, NCT02628067) is an ongoing global, open-label, non-randomized, multi-cohort, multi-center, Phase 2 study evaluating KEYTRUDA in patients with multiple types of advanced solid tumors – including SCLC – that have progressed on standard of care therapy. The SCLC cohort of the study enrolled 107 patients, regardless of biomarker status, who received KEYTRUDA as monotherapy (200 mg fixed dose every three weeks). The primary endpoint was ORR as evaluated by independent central review using RECIST v1.1. Secondary endpoints are progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety.

In the overall SCLC patient cohort (n=107), data at ASCO (Free ASCO Whitepaper) showed an ORR of 18.7 percent (95% CI, 11.8-27.4), with a complete response rate of three percent and a partial response rate of 16 percent. Median DOR was not reached (range, 2.1+ to 18.7+ months) and 73 percent of patients had a DOR of 12 months or longer. Median PFS was 2.0 months (95% CI, 1.9-2.1) with six- and 12-month PFS rates of 23.7 percent and 16.8 percent, respectively. Median OS was 8.7 months (95% CI, 5.6-12.0) with six- and 12-month OS rates of 57.5 percent and 40.2 percent, respectively.

In the pre-specified, exploratory analyses based on PD-L1 status, patients whose tumors expressed PD-L1 (n=42) showed an ORR of 35.7 percent (95% CI, 21.6–52.0), with a complete response rate of five percent and a partial response rate of 31 percent. Additionally, median PFS was 2.1 months (95% CI, 2.0-8.1) with six- and 12-month PFS rates of 38.9 percent and 28.5 percent, respectively. Median OS was 14.9 months (95% CI, 5.6-NR) with six- and 12-month OS rates of 66.0 percent and 53.1 percent, respectively.

In patients whose tumors did not express PD-L1 (n=50), ORR was six percent (95% CI, 1.3-16.5), with a complete response rate of two percent and a partial response rate of four percent. Median PFS was 1.9 months (95% CI, 1.6-2.0) with six- and 12-month PFS rates of 14.3 percent and 8.2 percent, respectively. Median OS was 5.9 months (95% CI, 3.3-10.1) with six- and 12-month OS rates of 48.3 percent and 30.7 percent, respectively. In other pre-specified subgroup analyses, the ORR was generally consistent across clinically relevant subgroups, including patients (n=61) who had received two or more prior lines of therapy where the ORR was 23 percent (95% CI, 13.2-35.5).

The safety profile was consistent with what has been seen in previously reported studies of KEYTRUDA monotherapy in lung cancer. Treatment-related adverse events (TRAEs) occurring in 10 percent or more of patients were fatigue (14%), pruritus (12%), hypothyroidism (12%), decreased appetite (10%) and nausea (10%). Thirteen patients had grade 3-4 TRAEs; two deaths occurred due to TRAEs (pneumonia and encephalopathy). Immune-mediated adverse events and infusion reactions were reported in some patients. Hypothyroidism was the most commonly reported immune-mediated adverse event, followed by hyperthyroidism and severe skin reactions.

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 die of colon, breast and prostate cancers combined. The two main types of lung cancer are non-small cell and small cell. SCLC accounts for about 10 to 15 percent of all lung cancers. The five-year survival rate for patients diagnosed in the United States with any stage of small cell lung cancer is estimated to be six percent.

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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%).