On April 20, 2015 Curadev Pharma reported that it has entered into a research collaboration and exclusive license agreement with Roche for the development and commercialization of IDO1 and TDO inhibitors (Press release, Curadev, APR 20, 2015, View Source [SID:1234503106]). The agreement covers the development of the lead preclinical immune tolerance inhibitor and a research collaboration with Roche’s research and early development organization to further explore the IDO and TDO pathways.

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IDO1 (indoleamine-2, 3-dioxygenase-1) and TDO (tryptophan-2, 3-dioxygenase) are enzymes that mediate cancer-induced immune suppression. This mechanism is exploited by tumor cells as well as certain type of immune cells, limiting the anti-tumor immune response.

Dual inhibition of the IDO1 and TDO pathways promises to maintain the immune response, prevent local tumor immune escape and potentially avoid resistance to other immunotherapies when used in combination, and could lead to new treatment options for cancer patients. Curadev’s preclinical lead-compound, a small-molecule that shows potent inhibition of the two rate-limiting enzymes in the tryptophan – to kynurenine metabolic pathways, has the potential for mono therapy as well as combination with Roche’s broad oncology pipeline and portfolio.

"We are very excited to be working with the global leader in oncology with their unrivalled expertise in clinical development," said Arjun Surya, PhD, Chief Scientific Officer, Curadev. "The collaboration acknowledges our focused research efforts on patient-critical drug targets that have yielded a drug candidate that could make a significant difference in the development of novel treatments for patients suffering from cancer."

Under the terms of agreement, which includes a research collaboration with Roche’s research and early development organization to further extend Curadev’s findings, Curadev will receive an upfront payment of $25 million and will be eligible to receive up to $530 million in milestone payments based on achievement of certain predetermined events and sales levels as well as escalating royalties potentially reaching double digits for the first product from the collaboration developed and commercialized by Roche. Curadev would also be eligible for milestones and royalties on any additional products resulting from the research collaboration. Roche will fund future research, development, manufacturing and commercialization costs and will also provide additional research funding to Curadev for support of the research collaboration.

On April 20, 2015 Seattle Genetics reported that the U.S. Food and Drug Administration (FDA) has accepted for filing a supplemental Biologics License Application (BLA) for ADCETRIS (brentuximab vedotin) in the AETHERA setting for the post-transplant consolidation treatment of Hodgkin lymphoma (HL) patients at high risk of relapse or progression (Press release, Seattle Genetics, APR 20, 2015, View Source [SID:1234503088]). The FDA granted Priority Review for the application and the Prescription Drug User Fee Act (PDUFA) target action date is August 18, 2015. The submission of the supplemental BLA is based on positive results from a phase 3 clinical trial called AETHERA that was designed to determine if 16 cycles of ADCETRIS as consolidation therapy immediately following an autologous stem cell transplant (ASCT) could extend progression-free survival (PFS) in HL patients at high risk of relapse or progression. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed in classical HL and systemic anaplastic large cell lymphoma (sALCL), as well as other lymphoma subtypes. ADCETRIS is approved in relapsed HL and sALCL but is currently not approved for consolidation therapy in HL patients immediately after ASCT.

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Globally, there are more than 65,000 cases of HL diagnosed each year. Although frontline combination chemotherapy can result in durable responses, up to 30 percent of these patients relapse or are refractory to frontline treatment. The standard for these patients is to proceed to an ASCT but approximately half of all HL patients who undergo an ASCT experience subsequent disease relapse.

"The FDA’s filing of our supplemental BLA and priority review designation for ADCETRIS as consolidation therapy represents a significant milestone towards our goal of making ADCETRIS available to high risk HL patients immediately following an autologous stem cell transplant who currently have no therapeutic options to prevent progression," said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "The phase 3 AETHERA trial demonstrated that using ADCETRIS in this setting significantly improved progression-free survival with a manageable safety profile. We look forward to working with the FDA during their review of our application for approval of this additional indication for ADCETRIS."

The positive results from the phase 3 AETHERA trial were published in The Lancet in March 2015 and were presented at the 56th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2014. Results from the AETHERA trial in 329 HL patients at high risk of relapse following ASCT included:

The trial achieved its primary endpoint and demonstrated a significant increase in PFS per independent review facility, with a hazard ratio of 0.57 and a p-value of 0.001. Median PFS was 43 months for patients who received ADCETRIS versus 24 months for patients who received placebo. The two-year PFS rate was 63 percent in the ADCETRIS arm compared to 51 percent in the placebo arm.

The PFS benefit was consistent across all pre-specified subgroups, including primary refractory patients, patients who relapsed within twelve months of frontline therapy and patients who relapsed after twelve months with extranodal disease.

ADCETRIS-treated patients received a median of 15 treatment cycles and 48 percent received the maximum of 16 cycles, indicating generally acceptable tolerability and a manageable adverse reaction profile.

The most common adverse events in the ADCETRIS arm were peripheral sensory neuropathy (56 percent), neutropenia (35 percent), upper respiratory tract infection (26 percent), fatigue (24 percent) and peripheral motor neuropathy (23 percent). The most common adverse events in the placebo arm were upper respiratory tract infection (23 percent), fatigue (18 percent) peripheral sensory neuropathy (16 percent), cough (16 percent) and neutropenia (12 percent). Eighty-five percent of patients with peripheral neuropathy on the ADCETRIS arm had resolution or improvement in symptoms with a median time to improvement of 23.4 weeks.

Submission of safety data from the AETHERA trial to the FDA is a post-marketing requirement.

About ADCETRIS

ADCETRIS is being evaluated broadly in more than 30 ongoing clinical trials, including four phase 3 studies, in earlier lines of its approved HL and sALCL indications as well as in many additional types of CD30-positive malignancies, including cutaneous T-cell lymphoma, B-cell lymphomas and mature T-cell lymphomas.

ADCETRIS (brentuximab vedotin) is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS for intravenous injection received accelerated approval from the FDA and approval with conditions from Health Canada for two indications: (1) the treatment of patients with HL after failure of ASCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and (2) the treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. The indications for ADCETRIS are approved under accelerated approval based on overall response rate. An improvement in patient-reported outcomes or survival has not been established. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive HL following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in more than 50 countries. See important safety information below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda will be solely responsible for development costs.

About Hodgkin Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system and is the most common type of blood cancer. There are two major categories of lymphoma: HL and non-Hodgkin lymphoma. HL is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell generally expresses CD30.

According to the American Cancer Society, approximately 9,050 cases of HL will be diagnosed in the United States during 2015 and more than 1,150 will die from the disease.

On April 20, 2015 Merck KGaA and Pfizer reported the initiation and first patient treated in the international Phase III study (EMR 100070-004) designed to assess the efficacy and safety of the investigational cancer immunotherapy avelumab (MSB0010718C), compared with docetaxel, in patients with stage IIIb/IV non-small cell lung cancer (NSCLC) who have experienced disease progression after receiving a prior platinum-containing doublet therapy(Press release, Pfizer, APR 20, 2015, View Source [SID:1234503077]).

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The Phase III study is an open-label, multicenter, 1:1 randomized clinical trial where patients with stage IIIb/IV NSCLC will receive either avelumab or docetaxel, regardless of PD-L1 status. Approximately 650 patients will participate across 290 sites in more than 30 countries in North America, South America, Asia, Africa and Europe. In North America, clinical trials on behalf of Merck KGaA, Darmstadt, Germany, will be conducted by EMD Serono, the company’s US and Canadian biopharmaceutical businesses. The study is part of the JAVELIN clinical trial program for avelumab.

The primary endpoint of the study is overall survival (OS) in patients with programmed death-ligand 1 positive (PD-L1+) stage IIIb/IV NSCLC who have experienced disease progression after receiving a prior platinum-containing doublet therapy. Secondary endpoints will be assessed across the entire study population regardless of PD-L1 status and include OS; overall response rate (ORR); progression-free survival (PFS); and patient-reported outcomes.

"New and innovative treatment strategies are urgently needed to improve overall survival for patients with NSCLC, and we are investigating avelumab as a potential treatment option for patients with this very difficult-to-treat disease," said Dr. Luciano Rossetti, Global Head of R&D of the biopharmaceutical business of Merck KGaA, Darmstadt, Germany. "The treatment of the first patient in the Phase III trial is an important milestone for our immuno-oncology alliance."

"This trial marks the first of several registration studies we are planning to initiate this year together, and underscores our commitment to accelerating the development of medications for patients with cancer," said Dr. Mace Rothenberg, Senior Vice President of Clinical Development and Medical Affairs and Chief Medical Officer for Pfizer Oncology. "Through this alliance, we will have the opportunity to combine the promising anti-PD-L1 antibody, avelumab, with our combined portfolios of approved and investigational oncology therapies, which may provide an exciting opportunity to potentially broaden the use of immunotherapy for patients with cancer."

The JAVELIN clinical trial program also includes an international Phase II trial to investigate avelumab in patients with metastatic Merkel cell carcinoma; an international Phase I trial to investigate avelumab in patients with metastatic or locally advanced solid tumors, and a Phase I trial to investigate avelumab in Japanese patients with metastatic or locally advanced solid tumors with an expansion part in Asian patients with gastric cancer. The Phase I program for avelumab includes more than 840 patients treated across multiple tumor types, including NSCLC, breast cancer, gastric cancer, ovarian cancer, bladder cancer, melanoma and mesothelioma.

*Avelumab is the proposed International Nonproprietary Name (INN) for the anti-PD-L1 monoclonal antibody (MSB0010718C)

About Non-Small Cell Lung Cancer

Globally, lung cancer is the most common cause of cancer-related deaths in men and the second most common in women, responsible for almost twice as many deaths as both breast and prostate cancer combined1. NSCLC is the most common type of lung cancer, accounting for 85 to 90 percent of all lung cancers2. Locally advanced and metastatic disease account for approximately 35 to 40 percent3 and 70 percent4 of patients, respectively with NSCLC.

Avelumab

Avelumab (also known as MSB0010718C) is an investigational fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November, 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

JAVELIN Clinical Trial Program for Avelumab

JAVELIN is an expansive international clinical trial program exploring the use of PD-L1 inhibition with avelumab to treat multiple types of cancer. The JAVELIN clinical trial program includes a Phase III study designed to assess the efficacy and safety of avelumab compared with docetaxel in patients with stage IIIb/IV NSCLC who have experienced disease progression after receiving a prior platinum-containing doublet therapy; an international Phase II open-label multicenter trial to investigate the clinical activity and safety of avelumab in patients with metastatic Merkel cell carcinoma; an international Phase I open-label, multiple ascending dose trial to investigate the safety, tolerability, pharmacokinetics, biological and clinical activity in patients with metastatic or locally advanced solid tumors; and a Phase I trial to investigate the tolerability, safety, pharmacokinetics, biological, and clinical activity of avelumab in Japanese patients with metastatic or locally advanced solid tumors with an expansion part in Asian patients with gastric cancer.

Alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc, New York, US

Immuno-oncology is a top priority for Merck KGaA, Darmstadt, Germany, and Pfizer Inc. The global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc, New York, US, enables the companies to benefit from each other’s strengths and capabilities and further explore the therapeutic potential of avelumab, an investigational anti-PD-L1 antibody initially discovered and developed by Merck KGaA, Darmstadt, Germany. The immuno-oncology alliance will jointly develop and commercialize avelumab and advance Pfizer’s PD-1 antibody. The companies will collaborate on up to 20 high priority immuno-oncology clinical development programs, including combination trials, many of which are expected to commence in 2015.

On April 20, 2015 TetraLogic Pharmaceuticals and Merck reported they have entered into an oncology clinical study collaboration (Press release, Merck & Co, APR 20, 2015, http://www.mercknewsroom.com/news-release/oncology-newsroom/tetralogic-and-merck-collaborate-evaluation-birinapant-combination-ke [SID:1234503073]). The companies will collaborate on a Phase 1 study to evaluate the safety and efficacy of birinapant, TetraLogic’s SMAC-mimetic, in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in patients with relapsed or refractory solid tumors. The study is expected to begin in late 2015.

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KEYTRUDA and birinapant target different elements of cancer’s block against the immune system. TetraLogic’s birinapant (TL32711) is a potent, bivalent SMAC-mimetic that binds with differential affinity to multiple members of the IAP family in order to re-establish the immune system’s ability to kill abnormal cells via an extracellular TNF signal. Merck’s KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 (programmed death receptor-1) and its ligands, PD-L1 and PD-L2. The proposed collaboration is based on preclinical data that suggest SMAC-mimetics have the potential to enhance existing immuno-oncology agents, such as KEYTRUDA.

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"We are very excited to work with Merck to evaluate birinapant in combination with KEYTRUDA," said J. Kevin Buchi, President and Chief Executive Officer of TetraLogic. "Both molecules are designed to help the body’s immune system better attack cancer cells, and we think the combination could be very promising."

"We are establishing a broad base of clinical evidence with our anti-PD-1 therapy, KEYTRUDA, as monotherapy across different types of cancer," said Dr. Eric Rubin, vice president and therapeutic area head, oncology early-stage development, Merck Research Laboratories. "We believe there is great potential to advance our clinical program and the field of immuno-oncology research through strategic collaborations and synergistic combinations, such as with KEYTRUDA and birinapant."

Under the terms of the agreement, TetraLogic and Merck, through subsidiaries, will collaborate on an initial Phase 1 dose-escalation study of birinapant in combination with KEYTRUDA in patients with relapsed or refractory solid tumors. TetraLogic will sponsor and fund the study and Merck will provide KEYTRUDA. The companies have formed a Joint Development Committee to collaboratively oversee the conduct of the study. Results from the study will be used to determine the path for further clinical development of the combination.

About Birinapant

Cancer and chronically infected cells are able to evade a critical mechanism by which the immune system normally kills abnormal or genetically modified cells. They do this by upregulating the Inhibitors of Apoptosis (IAP) Proteins. Birinapant (TL32711) is a potent, bivalent SMAC-mimetic that binds with differential affinity to multiple members of the IAP family in order to re-establish the immune system’s ability to kill abnormal cells via an extracellular TNF signal. Birinapant has been studied in over 350 patients, and is currently in Phase 1 and Phase 2 trials for Myelodysplastic Syndrome (MDS), Ovarian Cancer and Hepatitis B.

About KEYTRUDA (pembrolizumab)

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

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 85 clinical trials – across more than 30 tumor types and over 14,000 patients – both as a monotherapy and in combination with other therapies.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis.

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

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

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

Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

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

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

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

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

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

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.