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Agilent Technologies Receives Expanded FDA Approval for the Use of Dako PD-L1 IHC 22C3 pharmDx Companion Diagnostic in Gastric or Gastroesophageal Junction (GEJ) Cancer

On September 22, 2017 Agilent Technologies Inc. (NYSE: A) reported its Dako PD-L1 IHC 22C3 pharmDx assay has an expanded label approved by U.S. Food and Drug Administration (FDA), for use as an aid in identifying gastric or GEJ adenocarcinoma patients for treatment with KEYTRUDA (pembrolizumab), an anti-PD-1 therapy manufactured by Merck & Co., Inc., Kenilworth, N.J., USA (known as MSD outside the United States and Canada) (Press release, Agilent, SEP 22, 2017, http://www.agilent.com/about/newsroom/presrel/2017/22sep-ca17031.html [SID1234520611]).

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The FDA also announced on September 22 that KEYTRUDA is now approved for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. These 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.

The expanded approvals for PD-L1 IHC 22C3 pharmDx and KEYTRUDA means that these patients now have the possibility of receiving a targeted anti-PD-1 immunotherapy.

Gastric cancer is the fifth most common malignancy worldwide and the third most common cause of cancer death. The prognosis for patients diagnosed with advanced stage IV gastric cancer is poor, with only a 4% five-year observed survival rate*. Previously, gastric or GEJ adenocarcinoma patients had few therapeutic options, and those available included highly toxic chemotherapy.

First approved by U.S. FDA in October 2015, for determining PD-L1 expression levels in patients with NSCLC, PD-L1 IHC 22C3, pharmDx is the first FDA-approved assay for the identification of PD-L1 expression in patients with gastric or GEJ adenocarcinoma for treatment with the anti-PD-1 therapy KEYTRUDA.

"We are pleased that the U.S. FDA approved the expansion of use for PD-L1 IHC 22C3 pharmDx assay, as it gives patients with gastric or GEJ cancer the possibility of having their tumor sample tested for PD-L1 expression, and determining eligibility for treatment with KEYTRUDA," said Jacob Thaysen, president of Agilent’s Diagnostics and Genomics Group.

PD-L1 IHC 22C3 pharmDx was used to assess PD-L1 expression in patients treated with KEYTRUDA in the KEYNOTE-059 trial. KEYNOTE-059 is a registrational, phase 2, global, multicenter, non-randomized, open-label multicohort trial investigating the use of KEYTRUDA in patients with advanced gastric or GEJ adenocarcinoma.

PD-L1 IHC 22C3 pharmDx was developed in partnership with Merck & Co., Inc., Kenilworth, N.J., USA, manufacturer of the anti-PD-1 therapy KEYTRUDA.

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

Agilent is a worldwide leader in partnering with pharmaceutical companies to develop immunohistochemical-based diagnostics for cancer therapy.

Eleven Biotherapeutics Announces Completion of Vicinium Manufacturing for Ongoing Clinical Trials in Non-Muscle Invasive Bladder Cancer

On September 22, 2017 Eleven Biotherapeutics, Inc. (NASDAQ:EBIO), a late-stage clinical oncology company advancing novel product candidates based on its Targeted Protein Therapeutics (TPTs) platform, reported that it has completed the manufacturing of all Vicinium necessary for its ongoing Phase 3 registration trial in patients with non-muscle invasive bladder cancer (NMIBC), and for its Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute (Press release, Eleven Biotherapeutics, SEP 22, 2017, View Source [SID1234520610]). In conjunction with this achievement, Eleven is ending its large-scale manufacturing activities and redirecting resources toward completing its Phase 3 trial and preparing for discussions with the U.S. Food and Drug Administration (FDA) regarding, as appropriate, the submission of a Biologics License Application (BLA) for Vicinium in patients with NMIBC. This change will include a reduction of headcount and associated cost savings. For commercialization, the Company plans to engage an external, Current Good Manufacturing Practice (cGMP) compliant, contract manufacturer.

"We are pleased to have completed the manufacture of all Vicinium necessary for our clinical trials, which marks another key achievement on our path to registration," said Stephen Hurly, Chief Executive Officer of Eleven Biotherapeutics. "Ending our large-scale manufacturing operations will result in significant cost savings and enable a refocus of our resources toward completing our clinical trials and preparing to meet with the FDA. We are very thankful to our manufacturing team for their hard work and dedicated service, which played a key role in maturing Eleven into a late-stage company, and brought us closer to our goal of delivering transformational medicines to patients."

About Vicinium

Vicinium is manufactured as a single protein anti-epithelial cell adhesion molecule (anti-EpCAM) fusion protein fused with Pseudomonas Exotoxin A (ETA) designed to specifically target and deliver a potent anti-cancer payload directly into tumor cells. It is constructed with a stable, genetically-engineered linker to ensure its potent protein payload remains attached until it is internalized by the cancer cell, which is believed to decrease the risk of toxicity to healthy tissues thereby improving the compound’s safety. Vicinium’s one-step manufacturing process offers significant cost advantages and results in the production of a homogenous product, with less batch-to-batch variability than most antibody drug conjugates. Vicinium is currently in a Phase 3 registration clinical trial for the treatment of high-grade non-muscle invasive bladder cancer (NMIBC) in patients who have previously received two courses of Bacillus Calmette-Guérin (BCG) and whose disease is now BCG-unresponsive. Eleven Biotherapeutics intends to enroll 134 subjects in the trial, including 77 subjects with carcinoma in situ (CIS), at over 70 centers in the United States and Canada. Primary and secondary endpoints include complete response (CR) in CIS subjects, time to disease recurrence and event free survival. The Company expects to complete patient enrollment in the first quarter of 2018 and to report topline three-month data in mid-2018.

FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for Previously Treated Patients with Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer Whose Tumors Express PD-L1 (CPS Greater Than or Equal to 1)

On September 22, 2017 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA (pembrolizumab), the company’s anti-PD-1 (programmed death receptor-1) therapy, 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 (Press release, Merck & Co, SEP 22, 2017, View Source [SID1234520609]). This indication is approved under the FDA’s accelerated approval regulations 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.

"Historically, advanced gastric cancer has been particularly challenging to treat, and new treatment options are needed for these patients," said Charles S. Fuchs, M.D., MPH, lead investigator and director of Yale Cancer Center. "The results observed in the diverse population of heavily pretreated advanced gastric or GEJ patients from the KEYNOTE-059 clinical trial demonstrate that pembrolizumab in the third-line setting has the potential to shift how we care for certain patients facing this difficult-to-treat disease."

Immune-mediated adverse reactions occurred with KEYTRUDA including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions. Based on the severity of the adverse reaction, KEYTRUDA (pembrolizumab) should be withheld or discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions; for Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus. For more information regarding immune-mediated and infusion-related adverse reactions and use in pregnancy, see "Selected Important Safety Information" below.

"KEYTRUDA is now the first PD-1 checkpoint inhibitor approved in the United States for previously treated advanced gastric or GEJ cancer, helping to address a recognized treatment gap," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "This approval marks another milestone – the tenth new indication for KEYTRUDA in just three years – which further demonstrates both our commitment to patients and the progress we have made in the fight against many cancers."

Data Supporting the Approval

The accelerated approval for KEYTRUDA was based on data from a global, multicenter, non-randomized, open-label multi-cohort trial, KEYNOTE-059, that enrolled 259 patients with gastric or GEJ adenocarcinoma who progressed on at least two prior systemic treatments for advanced disease. Previous treatment must have included a fluoropyrimidine and platinum doublet; HER2/neu-positive patients must have previously received treatment with approved HER2/neu-targeted therapy. Patients with active autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible. Patients received KEYTRUDA at a dose of 200 mg every three weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least four weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every six to nine weeks. The major efficacy outcome measures were objective response rate (ORR) according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, as assessed by independent central review, and duration of response.

Among the 259 patients, 55 percent (n=143) had tumors that expressed PD-L1 with a CPS ≥1 and microsatellite stable (MSS) tumor status or undetermined microsatellite instability (MSI) or mismatch repair (MMR) status. The baseline characteristics of these 143 patients were: median age 64 years (47% age 65 or older); 77 percent male; 82 percent White, 11 percent Asian; and ECOG performance status (PS) of 0 (43%) and 1 (57%). Eighty-five percent had M1 disease and seven percent had M0 disease. Fifty-one percent had two and 49 percent had three or more prior lines of therapy in the recurrent or metastatic setting.

For the 143 patients, the ORR was 13.3 percent (95% CI: 8.2, 20.0) – with a complete response rate of 1.4 percent and a partial response rate of 11.9 percent. Among the 19 responding patients, the duration of response ranged from 2.8+ to 19.4+ months, with 11 patients (58%) having responses of six months or longer and five patients (26%) having responses of 12 months or longer.

Among the 259 patients, 7 (3%) had tumors that were determined to be MSI-High. An objective response was observed in 4 patients, including 1 complete response. The duration of response ranged from 5.3+ to 14.1+ months.

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or non-small cell lung cancer (NSCLC). The most common adverse reactions for KEYTRUDA (pembrolizumab) (reported in ≥20% of patients) were fatigue, musculoskeletal pain, decreased appetite, pruritis, diarrhea, nausea, rash, pyrexia, cough, dyspnea, and constipation.

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 550 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 (pembrolizumab), 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 (pembrolizumab) 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 (pembrolizumab) is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

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

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

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

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.

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.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

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

About the Merck Access Program for KEYTRUDA

At Merck, we are committed to supporting accessibility to our cancer medicines. Merck provides multiple programs to help ensure that appropriate patients who are prescribed KEYTRUDA have access to our anti-PD-1 therapy. The Merck Access Program provides reimbursement support for patients receiving KEYTRUDA, including information to help with out-of-pocket costs and co-pay assistance for eligible patients. Merck also offers free product through our patient assistance program to eligible patients, primarily the uninsured, who, without our assistance, could not afford their medicine. More information is available by calling 855-257-3932 or visiting www.merckaccessprogram-keytruda.com.

Roche receives EU approval of TECENTRIQ® (atezolizumab) in a specific type of metastatic lung cancer and two types of metastatic bladder cancer

On September 22, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the European Commission (EC) has granted a marketing authorisation for TECENTRIQ (atezolizumab) as a monotherapy for the treatment of people with locally advanced or metastatic non-small cell lung cancer (NSCLC) after they have been previously treated with chemotherapy regardless of PD-L1 status (Press release, Hoffmann-La Roche, SEP 22, 2017, View Source [SID1234520608]). People with EGFR-activating mutations or ALK-positive tumour mutations should also have received targeted therapy before receiving TECENTRIQ. This approval is based on results from the large randomised Phase III OAK study and the randomised Phase II POPLAR study.1,2 The Phase III OAKstudy showed that TECENTRIQ helped people in the overall study population live a median of 13.8 months–4.2 months longer than those treated with docetaxel chemotherapy (median OS: 13.8 vs 9.6 months; hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.62, 0.87).1

The EC has also granted marketing authorisation for TECENTRIQ as a monotherapy for the treatment of people with locally advanced or metastatic urothelial carcinoma (mUC) who have been previously treated with a platinum-containing chemotherapy or who are considered ineligible for cisplatin chemotherapy, regardless of PD-L1 status. This approval is based on results from the randomised Phase III IMvigor211 study and cohorts 1 and 2 from the single-arm Phase II IMvigor210 study. The Phase III IMvigor211 study did not meet its primary endpoint of OS, compared with chemotherapy. However, the study showed that the median duration of response (mDOR), a secondary endpoint, for those receiving TECENTRIQ was 21.7 months (95% CI: 13.0, 21.7) in the overall study population, compared with 7.4 months (95% CI: 6.1, 10.3) for those receiving chemotherapy.3

At the time of data cutoff, the majority (63%) of people who responded to treatment with TECENTRIQ continued to respond, compared with 21% of people treated with chemotherapy.3 Results from cohort 1 of the Phase II IMvigor210 study showed that TECENTRIQ achieved a median OS of 15.9 months (10.4, NE) in the overall study population.4

"We are delighted that the European Commission has approved TECENTRIQ, the first anti-PD-L1 cancer immunotherapy approved in the EU, as a monotherapy in both advanced bladder and advanced lung cancer", said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "The totality of the data for TECENTRIQ across all indications including long-term responses in advanced bladder cancer and the overall survival advantage observed in our phase III advanced lung cancer study means that we are able to extend the benefits of TECENTRIQ to people living with these types of cancer regardless of their levels of PD-L1 expression."
TECENTRIQ is already approved in the USA and in several other countries for people with metastatic NSCLC – and for people with locally advanced or mUC who are not eligible for cisplatin chemotherapy, or who have had disease progression during or following platinum-containing therapy.

About the OAK study
OAK is a global, multicentre, open-label, randomised, controlled Phase III study that evaluated the efficacy and safety of TECENTRIQ compared with docetaxel. It enrolled 1,225 patients with both squamous and non-squamous disease, regardless of the programmed death-ligand 1 (PD-L1) status of their tumours, and randomised them (1:1) to receive either TECENTRIQ administered intravenously at 1,200 mg every 3 weeks until loss of clinical benefit, or docetaxel administered intravenously at 75 mg/m2 every 3 weeks.

The co-primary endpoints were overall survival (OS) in the first 850 randomised patients (intention-to-treat population) and in a PD-L1-selected subgroup of this primary analysis population.

About the POPLAR study
The Phase II, multicentre, international, randomised, open-label, controlled study, POPLAR, was conducted in patients with locally advanced or metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression. The primary efficacy outcome was OS. A total of 287 patients were randomised 1:1 to receive either TECENTRIQ (1,200 mg by intravenous infusion every 3 weeks until loss of clinical benefit) or docetaxel (75 mg/m2 by intravenous infusion on Day 1 of each 3-week cycle until disease progression). Randomisation was stratified by PD-L1 expression status on tumour-infiltrating immune cells (IC), by the number of prior chemotherapy regimens and by histology.

An updated analysis with a total of 200 deaths observed and a median survival follow-up of 22 months showed a median OS of 12.6 months in patients treated with TECENTRIQ vs 9.7 months in patients treated with docetaxel (HR 0.69, 95% CI: 0.52, 0.92). Objective response rate (ORR) was 15.3% vs 14.7% and median duration of response (DOR) was 18.6 months vs 7.2 months for TECENTRIQ vs docetaxel, respectively.

About non-small cell lung cancer
Lung cancer is the leading cause of cancer death globally.5 Each year 1.59 million people die as a result of the disease; this translates into more than 4,350 deaths worldwide every day.5 Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. NSCLC is the most prevalent type, accounting for around 85% of all cases.6

About the IMvigor211 study
IMvigor211 is a Phase III study of TECENTRIQ in comparison with chemotherapy in people with advanced bladder cancer who were previously treated with a platinum-based chemotherapy. The study evaluated the efficacy and safety of TECENTRIQ compared with physician’s choice of chemotherapy (vinflunine, paclitaxel or docetaxel) administered every 3 weeks in 931 people with previously treated mUC,who had progressed during or following a platinum-based regimen. The primary efficacy endpoint was OS and key secondary endpoints include ORR, progression-free survival, DOR and safety. The IMvigor211 study did not meet its primary endpoint of OS, compared with chemotherapy. These data were presented in full at EACR-AACR-SIC.

The primary efficacy endpoint, OS, was to be tested in a successive fashion (hierarchical testing) in study populations defined by PD-L1 expression. Statistical significance needed to be achieved for the study populations in the following order: IC2/3 (≥5%), IC1/2/3 (≥1%), and ITT group. However, because such significance was not achieved for OS in the IC2/3 population, results could not be evaluated for statistical significance in the IC1/2/3 and ITT populations, and these analyses are considered descriptive in nature.

The first population tested comprised people with the highest levels of PD-L1 expression (IC2/3), followed by those with any observable level of PD-L1 expression (IC1/2/3), and followed by the overall study population (intention-to-treat: ITT). Per the pre-specified hierarchical testing order, the IC2/3 (≥5%) population was tested first, with an OS HR of 0.87 (95% CI: 0.63, 1.21; median OS (mOS) of 11.1 vs 10.6 months for TECENTRIQ and chemotherapy respectively). In the overall study population (ITT), people treated with TECENTRIQ achieved a mOS of 8.6 months (CI: 95%; 7.8, 9.6), compared with 8.0 months (CI: 95%; 7.2, 8.6) with chemotherapy (HR 0.85, 95% CI 0.73–0.99).

Overall response rates were similar to those previously reported in the Phase II IMvigor210 study and similar between the two study arms. The median duration of response (mDOR), a secondary endpoint, for those receiving TECENTRIQ was 21.7 months (95% CI: 13.0, 21.7) in the overall study population, compared with 7.4 months (95% CI: 6.1, 10.3) for those receiving chemotherapy. At the time of data cutoff, the majority (63%) of people who responded to treatment with TECENTRIQ continued to respond, compared with 21% of people treated with chemotherapy.

About the IMvigor210 study (Cohort 2)
In Cohort 2, the co-primary efficacy endpoints were confirmed ORR, as assessed by an IRF using RECIST (Response Evaluation Criteria in Solid Tumours) v1.1 and investigator-assessed ORR according to Modified RECIST (mRECIST) criteria. There were 310 patients treated with TECENTRIQ 1,200 mg by intravenous infusion every 3 weeks until loss of clinical benefit. The study met its co-primary endpoints in Cohort 2, ORRs per IRF-assessed RECIST v1.1 and investigator-assessed mRECIST, compared with a prespecified historical control response rate of 10%.
The confirmed ORR for all comers per IRF-RECIST v1.1 were 15.8% (95% CI: 11.9, 20.4). The confirmed ORR for all comers per investigator-assessed imRECIST were 19.7% (95% CI: 15.4, 24.6). The rate of complete response per IRF-RECIST v1.1 in the all-comer population was 6.1% (95% CI: 3.7, 9.4). For Cohort 2, median DOR per IRF-RECIST v1.1 was not reached in any PD-L1-expression subgroup or in all comers, but was reached in patients with PD-L1 expression <1% (13.3 months; 95% CI 4.2, NE). An analysis was also performed with a median duration of survival follow-up of 21.1 months for Cohort 2, the OS rate at 12 months was 37% in all comers.

About the IMvigor210 study (Cohort 1)
The approval for patients who are ineligible for cisplatin-based chemotherapy is based on results from Cohort 1, which consisted of 119 people with locally advanced or mUC who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant (before surgery) or adjuvant (after surgery) chemotherapy. Clinically relevant IRF-assessed ORRs per RECIST v1.1 were shown; however, when compared to a pre-specified historical control response rate of 10%, statistical significance was not reached for the primary endpoint. The median OS results for all comers were 15.9 (10.4, NE).

Pooled safety profile
The safety of TECENTRIQ is based on pooled data in 2,160 patients with mUC and NSCLC. The most common adverse all-grade reactions were fatigue (35.4%), decreased appetite (25.5%), nausea (22.9%), dyspnoea (21.8%), diarrhoea (18.6%), pyrexia (18.3%), rash (18.6%), vomiting (15.0%), arthralgia (14.2%), asthenia (13.8%) and pruritus (11.3%).

About urothelial carcinoma
Metastatic urothelial carcinoma (mUC) is associated with a poor prognosis and limited treatment options. Until recently this disease had not seen any major advances for more than 30 years.7 UC is the ninth most common cancer worldwide, with 430,000 new cases diagnosed in 2012, and it results in approximately –165,000 deaths globally each year.5 Men are three times more likely to suffer from UC than women8, and the disease is three times more common in developed countries than in less developed countries.9

About TECENTRIQ (atezolizumab)
TECENTRIQ is a monoclonal antibody designed to bind with a protein called PD-L1. TECENTRIQ is designed to bind to PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, TECENTRIQ may enable the activation of T cells. TECENTRIQ has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers

Bristol-Myers Squibb’s Opdivo® (nivolumab) Receives FDA Approval for the Treatment of Hepatocellular Carcinoma Patients Previously Treated with Sorafenib

On September 22, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported the U.S. Food and Drug Administration (FDA) has approved Opdivo (nivolumab) injection for intravenous use for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (Press release, Bristol-Myers Squibb, SEP 22, 2017, View Source [SID1234520606]). Approval for this indication has been granted 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.1 In the CheckMate -040 trial, 14.3%* (95% CI: 9.2-20.8; 22/154) of patients responded to treatment with Opdivo. The percentage of patients with a complete response was 1.9% (3/154) and the percentage of patients with a partial response was 12.3% (19/154).1 Among responders (n=22), responses ranged from 3.2 to 38.2+ months; 91% of those patients had responses of six months or longer and 55% had responses of 12 months or longer.1

Opdivo is associated with the following Warnings and Precautions including: immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; and embryo-fetal toxicity.1 Please see the Important Safety Information section below.

"We are proud to bring the potential for clinically meaningful responses with Immuno-Oncology therapy to these advanced-stage HCC patients, who have had limited treatment options for years," said Chris Boerner, president, U.S. Commercial, Bristol-Myers Squibb. "Today’s approval marks an important step toward our mission of delivering transformational medicines to treat conditions with a high unmet need."

The burden of liver cancer in the U.S. is significant and is expected to increase in the decades to come.5,6 A recently-released American Cancer Society (ACS) report published in CA: A Cancer Journal for Clinicians notes that death rates for liver cancer are increasing at a faster pace than any other cancer, doubling since the mid-1980s.5

"Unfortunately, the majority of HCC patients are diagnosed with advanced-stage disease and are not candidates for potentially curative surgical interventions," said Adrian M. Di Bisceglie, M.D., co-director, Saint Louis University Liver Center, Chief of Hepatology. "More options are needed for advanced-stage HCC patients who have failed prior systemic therapy."

Hepatocellular carcinoma is often diagnosed in the advanced-stage where treatment options are limited and there is a high unmet need for patients who are intolerant to or who have progressed on sorafenib therapy.5,7,8

"In recent years, there has been growing interest in leveraging immuno-oncology knowledge and discoveries to add to the treatment options available for patients with advanced-stage liver cancer," said Anthony B. El-Khoueiry, M.D., lead investigator and associate professor of clinical medicine and phase I program director at the Keck School of Medicine of University of Southern California (USC) and the USC Norris Comprehensive Cancer Center. "The approval of Opdivo provides us with an encouraging approach and a new treatment option for appropriate patients with HCC following prior systemic therapy."

Approval Based on Notable Overall Response Rate and Duration of Response

CheckMate -040 included a Phase 1/2, open-label, multicenter study evaluating Opdivo in patients with HCC who progressed on or were intolerant to sorafenib.1,9 In this study, 154 patients received Opdivo 3 mg/kg administered intravenously every two weeks. The recommended dose is 240 milligrams administered as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity.1 Efficacy outcome measures included confirmed overall response rate (as assessed by blinded independent central review using RECIST v1.1 and modified RECIST for HCC) and duration of response.1 The median age of patients participating in the study was 63 (range: 19-81), all patients had received prior sorafenib therapy and 19% of patients had received two or more prior systemic therapies.1 Patients were enrolled regardless of PD-L1 expression level and whether or not they were infected with active Hepatitis B virus (HBV) or active Hepatitis C virus (HCV).1,2 Data from CheckMate -040 were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2017 Annual Meeting in June.

In the CheckMate -040 trial, 14.3%* (95% CI: 9.2-20.8; 22/154) of patients responded to treatment with Opdivo. The percentage of patients with a complete response was 1.9% (3/154) and the percentage of patients with a partial response was 12.3% (19/154). Among responders (n=22), responses ranged from 3.2 to 38.2+ months; 91% of those patients had responses of six months or longer and 55% had responses of 12 months or longer.1 The median time to response was 2.8 months (range: 1.2-7.0).2 The overall response rate based on modified RECIST was 18.2% (95% CI: 12.4-25.2; 28/154). Complete response rate was 3.2% (5/154); partial response rate was 14.9% (23/154).1 Responses were observed across PD-L1 expression levels.2

"I advocate for others because I know firsthand the terrible toll cancers of the liver take on a patient and their loved ones. In my opinion, HCC is an example of a cancer where awareness is out of sync with the impact of the disease," said Suzanne Lindley, Co-Founder, Yes! Beat Liver Tumors. "Today’s approval shines a light of awareness and hope on a disease with a high unmet medical need."

Select Safety Profile

The safety of Opdivo was evaluated in a 154-patient subgroup of patients with HCC and Child-Pugh A cirrhosis who progressed on or were intolerant to sorafenib in the CheckMate -040 study. Patients were required to have an aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of no more than five times the upper limit of normal and total bilirubin of less than 3 mg/dL. The median duration of exposure to Opdivo was six months. Treatment with Opdivo resulted in treatment-emergent Grade 3 or 4 AST in 18% (27/154) of patients, Grade 3 or 4 ALT in 11% (16/154) of patients, and Grade 3 or 4 bilirubin in 7% (11/154) of patients. Immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients.1 Serious adverse reactions occurred in 49% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia. The most common adverse reactions (≥20%) in patients receiving Opdivo (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). Opdivo was discontinued due to adverse reactions in 11% of patients and 32% of patients had a dose delay for an adverse reaction.2

About Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the fastest-growing cause of cancer death in the U.S.3,5,10 The incidence of liver cancer in the U.S. has more than tripled since 1980.3 It is estimated that there will be approximately 41,000 new cases of liver and intrahepatic bile duct cancer and 29,000 deaths from these diseases in the U.S. this year.4 The majority of these cases are caused by Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infections, making chronic infection with HBV or HCV the most common risk factor for liver cancer.10,11 However, the increasing prevalence of metabolic syndrome and nonalcoholic steatohepatitis (NASH) is expected to contribute to increased rates of HCC in the U.S. in the foreseeable future.12,13

INDICATION

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 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.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients.

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients.

In Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients.

Immune-Mediated Skin Adverse Reactions

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients.

Embryo-Fetal Toxicity

Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in at least 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia.

Common Adverse Reactions

In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%).

Please see U.S. Full Prescribing Information for OPDIVO.

About the Opdivo Clinical Development Program