On November 14, 2016 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported data on new product candidate CDX-1140, a fully human antibody targeted to CD40 that has demonstrated potent agonist activity (Press release, Celldex Therapeutics, NOV 14, 2016, View Source [SID1234516583]). Found on antigen presenting cells, such as dendritic cells, macrophages and B cells, CD40 is a key activator of the immune response. The data were presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (SITC) (Free SITC Whitepaper) on Saturday, November 12 in a poster titled "Functional characterization of CDX-1140, a novel CD40 antibody agonist for cancer immunotherapy." CDX-1140 is expected to be ready to enter clinical studies in 2017. Schedule your 30 min Free 1stOncology Demo! "The CD40 pathway plays a critical role in the activation of innate and adaptive immune responses," said Tibor Keler, Ph. D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "We believe an ideal CD40 immunotherapy candidate should have the right balance of agonist activity and safety profile to allow systemic dosing at levels that provide good tissue and tumor penetration. The data presented at SITC (Free SITC Whitepaper) show that CDX-1140 has a unique profile to meet this goal relative to other CD40 agonist antibodies and will be an important addition to our growing immunotherapy pipeline."
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
The poster features detailed analyses of the preclinical data and is available on the "Publications" page of the "Science" section of the Celldex website. Key findings include:
CDX-1140 binds CD40 with high affinity and specificity and does not block CD40 ligand binding
CDX-1140 has an unmodified IgG2 backbone and demonstrates potent agonist activity independent of Fc receptor interactions
CDX-1140 demonstrates direct anti-tumor activity in immune-deficient mice challenged with human lymphomas
Pharmacological activity was observed in vivo with minimal evidence of toxicity
Celldex is currently performing manufacturing and IND-enabling studies to support Phase 1 dose-escalation studies. The Company believes that the potential for CDX-1140 will be best defined in combination studies with other immunotherapies or conventional cancer treatments.
Author: [email protected]
Novartis drug PKC412 (midostaurin) granted FDA Priority Review for newly-diagnosed FLT3-mutated AML and advanced systemic mastocytosis
On November 14, 2016 Novartis reported that the US Food and Drug Administration (FDA) granted Priority Review to the PKC412 (midostaurin) new drug application (NDA) for the treatment of acute myeloid leukemia (AML) in newly-diagnosed adults with an FMS-like tyrosine kinase-3 (FLT3) mutation, as well as for the treatment of advanced systemic mastocytosis (SM) (Press release, Novartis, NOV 14, 2016, View Source [SID1234516572]). The premarket approval application (PMA) for the PKC412 (midostaurin) FLT3 companion diagnostic, developed in collaboration with Invivoscribe Technologies, Inc. (IVS)* has also been accepted for review by the FDA. Outside the US, the marketing authorization application for PKC412 (midostaurin) in these indications has already been accepted by the European Medicines Agency (EMA). Schedule your 30 min Free 1stOncology Demo! "FLT3-mutated AML and advanced SM are devastating and rare diseases, with significant unmet needs due to limited existing treatment options," said Bruno Strigini, CEO, Novartis Oncology. "This regulatory designation signifies the importance of midostaurin as a potential therapy for these patients who haven’t had the benefit of targeted medicines."
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
The NDA submission for PKC412 (midostaurin) includes data from the largest clinical trials conducted to date in each indication. In the Phase III RATIFY trial (CALGB 10603), which investigated PKC412 (midostaurin) plus standard chemotherapy versus placebo plus standard chemotherapy in adult patients less than 60 years of age with FLT3-mutated AML, those in the PKC412 (midostaurin) arm experienced a statistically significant improvement in overall survival (OS) with a 23% reduction in risk of death compared to the placebo arm (hazard ratio [HR] = 0.77, P = 0.0074)[1]. Based on these data, PKC412 (midostaurin) was also granted Breakthrough Therapy designation by the FDA earlier this year for newly-diagnosed FLT3-mutated AML.
In the RATIFY trial, no statistically significant differences were observed in the overall rate of grade 3 or higher hematologic and non-hematologic adverse events (AEs) in the PKC412 (midostaurin) treatment group versus the placebo group[5]. The most frequent all grade AEs were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae (small red skin spots) and pyrexia[5]. A total of 36 deaths occurring within 30 days of the last dose of study drug were reported, with no difference in treatment-related deaths observed between groups[5].
Data from the Phase II single-arm study (CPKC412D2201) evaluating the efficacy of PKC412 (midostaurin) in patients with advanced SM were also published in the New England Journal of Medicine in June 2016. The study showed that treatment with PKC412 (midostaurin) resulted in an overall response rate of 60% (defined as complete or partial resolution of organ damage) with a median duration of response of 24.1 months (95% CI, 10.8-not estimated [NE]) and a median OS of 28.7 months (95% CI, 18.1-NE)[2]. The most frequent AEs were low-grade nausea, vomiting and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred mostly in patients with pre-existing cytopenias[2].
A Priority Review designation is granted by the FDA to therapies that may provide significant improvements in the treatment, diagnosis or prevention of serious conditions[3]. According to the FDA, the goal is to take action on a Priority Review application within six months, compared to 10 months under the standard review process[3]. Novartis has been granted a growing number of Priority Review designations by the FDA, underscoring the company’s ongoing commitment to developing innovative therapies for rare diseases or underserved cancer patients.
Since PKC412 (midostaurin) remains investigational at this time, both within the US and globally, Novartis opened a Global Individual Patient Program (compassionate use program) and in the US, an Expanded Treatment Protocol, to enable access to eligible patients with newly-diagnosed AML and advanced SM. Physicians who wish to request PKC412 (midostaurin) for eligible patients should contact a Novartis medical representative in their respective countries. In the US, physicians can call 1-888-NOW-NOVA (1-888-669-6682) for more information.
About AML and the FLT3 mutation
AML is a rare and aggressive cancer of the blood and bone marrow[6]. It is the most common acute leukemia in adults[7]. Of the approximately 350,000 people with leukemias worldwide[8], about 25% have AML[7]. AML has a low survival rate, with around 25% of patients surviving at 5 years[9].
AML is associated with the accumulation of blood cells that are unable to mature properly, causing a buildup of immature "blast" cells that do not allow room for normal blood cell development[6]. Mutations in specific genes are found in many cases of AML, and molecular testing is recommended for newly-diagnosed patients to help determine prognosis and best possible treatment[4].
FLT3 is a receptor tyrosine kinase, a type of cell-surface receptor, which plays a role in the proliferation, or increase, in the number of certain blood cells. The FLT3 gene mutation is one of the most common in AML, occurring in about one-third of patients, and commonly results in faster disease progression, a higher relapse rate and shorter survival[10]-[12].
About the FLT3 companion diagnostic
In order to help identify patients who may have a FLT3 mutation and potentially benefit from treatment with PKC412 (midostaurin), Novartis is collaborating with IVS for the development and FDA approval of the FLT3 companion diagnostic. The same test is being CE marked in Europe. Regulatory submissions for the companion diagnostic are being led by IVS.
About advanced SM
Systemic mastocytosis (SM) comprises a group of rare diseases, affecting between 1 in 20,000 to 40,000 people worldwide[13]. The disease is characterized by uncontrolled growth and accumulation of mast cells – or mediators of allergic responses – in one or more organs[14]. In advanced SM, mast cells accumulate in such high quantities that they begin to cause organ damage[15]. Patients also suffer from debilitating systemic symptoms such as pruritus (severe itching of the skin), among other symptoms, caused by mast cells releasing inflammatory mediators such as histamine into the blood[15]. Median OS is currently between 3.5 years to less than six months depending on subtype[14].
The uncontrolled proliferation of mast cells is caused in many people by a KIT gene mutation – the most common mutation, encoding the D816V substitution, occurs in approximately 90% of patients[16]. The KIT gene mutation results in activation of the KIT enzyme, which triggers the abnormal proliferation and survival of mast cells[15].
About PKC412 (midostaurin)
PKC412 (midostaurin) is an investigational, oral, multi-targeted kinase inhibitor in development for the treatment of patients with AML with a FLT3 mutation and for patients with advanced SM. The safety and efficacy profile has not been fully established, and it is not approved for any indication in any market at this time. There is no guarantee that PKC412 (midostaurin) will become commercially available.
Spectrum Pharmaceuticals Provides Third Quarter Financial Update
On November 14, 2016 Spectrum Pharmaceuticals, Inc. (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations with a primary focus in Hematology and Oncology reported financial results for the three-month period ended September 30, 2016 (Press release, Spectrum Pharmaceuticals, NOV 14, 2016, View Source [SID1234516595]). Schedule your 30 min Free 1stOncology Demo! As previously disclosed, the Company was re-examining the accounting treatment of the 2013 acquisition of the rights to CE Melphalan from Ligand Pharmaceuticals. This re-examination has now concluded and the Company has determined that no change was required.
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
Three-Month Period Ended September 30, 2016 (All numbers are approximate)
GAAP Results
Total product sales were $30.3 million in the third quarter of 2016. Product sales in the third quarter included: FUSILEV (levoleucovorin) net sales of $4.9 million, FOLOTYN (pralatrexate injection) net sales of $11.3 million, ZEVALIN (ibritumomab tiuxetan) net sales of $2.6 million, MARQIBO (vinCRIStine sulfate LIPOSOME injection) net sales of $1.9 million, BELEODAQ (belinostat for injection) net sales of $3.6 million, and EVOMELA (melphalan) for injection net sales of $5.9 million.
Spectrum recorded net loss of $17.5 million, or $(0.22) per basic and diluted share in the three-month period ended September 30, 2016, compared to net loss of $18.7 million, or $(0.28) per basic and diluted share in the comparable period in 2015. Total research and development expenses were $13.3 million in the quarter, as compared to $9.9 million in the same period in 2015. Selling, general and administrative expenses were $19.5 million in the quarter, compared to $19.4 million in the same period in 2015.
The Company ended the quarter with Cash and Cash Equivalents of $171.9 million.
Non-GAAP Results
Spectrum recorded non-GAAP net loss of $5.3 million, or $(0.07) per basic and diluted share in the three-month period ended September 30, 2016, compared to non-GAAP net loss of $7.9 million, or $(0.12) per basic and diluted share in the comparable period in 2015. Non-GAAP research and development expenses were $12.8 million, as compared to $9.4 million in the same period of 2015. Non-GAAP selling, general and administrative expenses were $15.6 million, as compared to $17.2 million in the same period in 2015.
Merck’s KEYTRUDA® (pembrolizumab) Significantly Improves Overall Survival Compared to Chemotherapy in Previously Treated Patients with Advanced Bladder (Urothelial) Cancer
On November 12, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported results from the pivotal KEYNOTE-045 study investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in patients with advanced bladder (urothelial) cancer previously treated with platinum-containing chemotherapy (Press release, Merck & Co, NOV 12, 2016, View Source [SID1234516529]). As previously announced, KEYTRUDA was superior to investigator-choice chemotherapy for the primary endpoint of overall survival (OS) in this phase 3 study, and was stopped early. Specifically, there was a 27 percent reduction in the risk of death in patients treated with KEYTRUDA compared to chemotherapy (OS, HR = 0.73, p-value: 0.0022). Data presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 31st Annual Meeting are the first publicly presented findings from this study.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
"The improved overall survival for patients receiving KEYTRUDA in this trial are clinically significant and could impact how physicians consider treating patients with previously treated advanced urothelial cancer," said Dr. Roger Dansey, senior vice president, oncology late-stage development, Merck Research Laboratories. "These data add to the growing body of evidence from our clinical development program for KEYTRUDA in a range of cancers, including advanced urothelial cancer."
Study findings are being presented by Dr. Joaquim Bellmunt from Dana-Farber Cancer Institute on Saturday, Nov. 12th from 11:45 a.m. – 12:00 p.m. ET (Abstract #470).
"There have been few advancements in the treatment of bladder cancer in the past several decades, with chemotherapy being the only option," said Dr. Dean F. Bajorin, study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center. "These data demonstrate the potential for pembrolizumab to provide a meaningful improvement in overall survival for patients with advanced urothelial cancer who previously have received platinum-containing chemotherapy."
The KEYTRUDA (pembrolizumab) clinical development program includes more than 30 tumor types in more than 360 clinical trials, including nearly 200 trials that combine KEYTRUDA with other cancer treatments. Currently, Merck has the largest immuno-oncology clinical development program in bladder cancer, with 27 trials underway involving KEYTRUDA as monotherapy and in combination, including four registration-enabling studies.
Findings from KEYNOTE-045
KEYNOTE-045 is a randomized, pivotal, phase 3 study evaluating KEYTRUDA monotherapy compared to investigator-choice chemotherapy (paclitaxel, docetaxel, vinflunine) in the treatment of patients with metastatic or locally advanced, unresectable (inoperable) urothelial cancer (urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra) that has recurred or progressed following platinum-based chemotherapy. The co-primary endpoints are OS and progression-free survival (PFS); secondary endpoints are overall response rate (ORR), duration of response, and safety. The study randomized 542 patients to receive KEYTRUDA (200 mg every three weeks) (n=270) or investigator-choice chemotherapy (n=272) – either paclitaxel (175 mg/m2 every three weeks), docetaxel (75 mg/m2 every three weeks), or vinflunine (320 mg/m2 every three weeks). The study was designed to assess key endpoints in patients with or without PD-L1 expression (the total study population, n=542), as well as in patients with PD-L1 expressing tumors (expression of 10% or more) (n=74/270 in the KEYTRUDA arm; n=90/272 in the chemotherapy arm).
Findings presented at SITC (Free SITC Whitepaper) from the total study population showed a significant improvement in OS with KEYTRUDA compared to chemotherapy, with a 27 percent reduction in the risk of death (HR: 0.73 [95% CI, 0.59 – 0.91], p-value: 0.0022). Median OS was 10.3 months (95% CI, 8.0 – 11.8) with KEYTRUDA, compared to 7.4 months (95% CI, 6.1 – 8.3) in the chemotherapy arm. The estimated one-year OS rate was 43.9 percent with KEYTRUDA, compared to 30.7 percent in the chemotherapy arm.
In the OS analysis of patients with PD-L1 expression, there was a 43 percent reduction in the risk of death with KEYTRUDA, compared to chemotherapy (HR: 0.57 [95% CI, 0.37 – 0.88], p-value: 0.0048). Median OS was 8.0 months (95% CI, 5.0 – 12.3) with KEYTRUDA, compared to 5.2 months (95% CI, 4.0 – 7.4) in the chemotherapy arm. The estimated one-year OS rate was 39.8 percent with KEYTRUDA, compared to 26.9 percent in the chemotherapy arm.
An analysis of the study’s second primary endpoint, PFS, in the total study population showed a median PFS of 2.1 months (95% CI, 2.0 – 2.2) with KEYTRUDA, compared to 3.3 months (95% CI, 2.3 – 3.5) in the chemotherapy arm (HR: 0.98 [95% CI, 0.81 – 1.19], p-value: 0.42). The six-month PFS rate was 28.8 percent with KEYTRUDA, compared to 26.8 in the chemotherapy arm; the one-year PFS rate was 16.8 percent with KEYTRUDA, compared to 6.2 percent in the chemotherapy arm.
The difference in response rates between the two arms was 9.6 percentage points (p-value: .0011), which was statistically significant and in favor of KEYTRUDA. The ORR was 21.1 percent with KEYTRUDA (7.0% were complete responses), compared to 11.4 percent in the chemotherapy arm (3.3% were complete responses). In patients with PD-L1 expression, ORR was 21.6 percent with KEYTRUDA (6.8% were complete responses), compared to 6.7 percent in the chemotherapy arm (2.2% were complete responses).
The median duration of response for patients treated with KEYTRUDA had not yet been reached at the time of analysis (range: 1.6+ to 15.6+ months) – with 68 percent of responses estimated to last for 12 months or more. In the chemotherapy arm, the median duration of response was 4.3 months (range: 1.4+ to 15.4+ months) – with 35 percent of responses estimated to last for 12 months or more.
The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies involving patients with advanced urothelial cancer. The treatment-related adverse events observed in this trial (any grade occurring in 10 percent or more) were pruritus (19.5% with KEYTRUDA; 2.7% with chemotherapy), fatigue (13.9% with KEYTRUDA; 27.8% with chemotherapy), nausea (10.9% with KEYTRUDA; 24.3% with chemotherapy), diarrhea (9.0% with KEYTRUDA; 12.9% with chemotherapy), decreased appetite (8.6% with KEYTRUDA; 16.1% with chemotherapy), asthenia (5.6% with KEYTRUDA; 14.1% with chemotherapy), anemia (3.4% with KEYTRUDA; 24.7% with chemotherapy), constipation (2.3% with KEYTRUDA; 20.4% with chemotherapy), peripheral sensory neuropathy (0.8% with KEYTRUDA; 11.0% with chemotherapy), peripheral neuropathy (0.4% with KEYTRUDA; 10.6% with chemotherapy), neutrophil count decreased (0.4% with KEYTRUDA (pembrolizumab); 14.1% with chemotherapy), alopecia (37.6% with chemotherapy) and neutropenia (15.3% with chemotherapy). Immune-mediated adverse events were thyroid abnormalities (9.4% with KEYTRUDA (pembrolizumab); 1.6% with chemotherapy), pneumonitis (4.1% with KEYTRUDA; 0.4% with chemotherapy), colitis (2.3% with KEYTRUDA; 0.4% with chemotherapy), infusion reactions (0.8% with KEYTRUDA; 3.9% with chemotherapy), severe skin toxicity (0.8% with KEYTRUDA; 1.2% with chemotherapy), nephritis (0.8% with KEYTRUDA), adrenal insufficiency (0.4% with KEYTRUDA) and myositis (0.4% with chemotherapy). Fifteen patients in the KEYTRUDA arm and 28 patients in the chemotherapy arm discontinued treatment due to a treatment-related adverse event; there were four treatment-related deaths in each arm.
About Bladder Cancer
Bladder cancer begins when cells in the urinary bladder start to grow uncontrollably. As more cancer cells develop, they can form a tumor and spread to other areas of the body. Urothelial carcinoma, the most common type of bladder cancer, starts in the urothelial cells that line the inside of the bladder. In 2012, approximately 430,000 people worldwide were diagnosed with bladder cancer and 165,000 died from the disease. The incidence of bladder cancer is elevated in North America, Europe, North Africa, the Middle East, Australia and New Zealand.
About KEYTRUDA (pembrolizumab)
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.
KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single use vial.
KEYTRUDA Indications and Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks until disease progression or unacceptable toxicity.
Lung Cancer
KEYTRUDA 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) 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.
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.
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.
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 (pembrolizumab) 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.
KEYTRUDA can cause other clinically important immune-mediated adverse reactions. 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%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.
KEYTRUDA can cause severe or life-threatening infusion-related reactions, 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.
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 (pembrolizumab).
In KEYNOTE-002, KEYTRUDA was discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA (pembrolizumab) occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculopapular rash (1%). The most common adverse reactions with KEYTRUDA vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus (28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.
KEYTRUDA 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%).
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.
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.
Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.
Interim Phase 1/2 Data Show Encouraging Clinical Benefit for Lirilumab in Combination With Opdivo (nivolumab) in Patients With Advanced Platinum Refractory Squamous Cell Carcinoma of the Head and Neck
On November 12, 2016 Bristol-Myers Squibb Company (NYSE:BMY) and Innate Pharma SA (Euronext Paris: FR0010331421 – IPH) reported an interim efficacy analysis from a Phase 1/2 study of the combination of lirilumab and Opdivo (nivolumab) in the cohort of advanced platinum refractory squamous cell carcinoma of the head and neck (SCCHN), including exploratory biomarker analyses of patient response by level of PD-L1 expression (Press release, Bristol-Myers Squibb, NOV 12, 2016, View Source [SID1234516510]). Among 29 evaluable patients with SCCHN, the objective response rate (ORR), a secondary endpoint measured by Response Evaluation Criteria In Solid Tumors (RECIST), was 24% (n=7). Seventeen percent (n=5) of these evaluable patients had deep responses, with reductions in tumor burden greater than 80%. Early signals of enhanced clinical benefit were observed in PD-L1 positive tumors, with an ORR of 41% (7/17) in patients with ≥1% PD-L1 expression.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
Lirilumab is directed against the inhibitory killer-cell immunoglobulin-like receptors (KIRs) expressed predominantly on natural killer (NK) cells, which belong to the innate immune system, while Opdivo blocks the inhibitory function of the PD-1 receptor on T cells. These data mark the first report of potential efficacy with an anti-KIR antibody in combination with an anti-PD-1 therapy, and were presented at a late-breaking oral presentation (abstract 456) at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 31 Annual Meeting on November 12 at 11:15 a.m. EST in National Harbor, Maryland. Preliminary efficacy and exploratory biomarker analyses of patient response by biomarker subgroups were presented.
The safety profile associated with lirilumab in combination with Opdivo was generally consistent with that observed with Opdivo monotherapy. The overall rate of treatment-related adverse events (TRAEs) was reported as 72% (114/159) and the rate of Grade 3-4 TRAEs was 15% (24/159). Discontinuations due to TRAEs occurred in 8% of patients (12/159). These safety data were also reported at the 2016 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress.
"The interim efficacy results indicate that targeting both the KIR and PD-1 pathways with lirilumab and Opdivo, respectively, may provide enhanced clinical activity, particularly in PD-L1 positive tumors, with deep and durable responses in some patients," said Rom Leidner, Medical Oncologist, Earle A. Chiles Research Institute, Providence Cancer Center, and lead author of the study. "We look forward to continuing the study of this novel combination in patients with advanced platinum refractory squamous cell carcinoma of the head and neck, which is the seventh-leading cause of cancer globally."
"The preliminary signals of anti-tumor activity we are seeing with the combination of lirilumab and Opdivo in head and neck cancer patients compare favorably to data previously presented on Opdivo monotherapy in a similar patient population. We are encouraged by the suggestion of enhanced benefit, particularly in inflamed tumors as defined by increasing PD-L1 expression," said Tim Reilly, head of Oncology Early Assets Development at Bristol-Myers Squibb. "We aim to apply what we have been learning about these complementary mechanisms and biomarker subgroups to maximize the potential clinical benefit of lirilumab and Opdivo across a range of tumor types and are excited about continuing to expand our study of Opdivo with complementary pathways."
"We are very encouraged by these interim efficacy data and are eagerly awaiting the next steps of the clinical development of the combination of lirilumab and Opdivo" said Pierre Dodion, Chief Medical Officer of Innate Pharma. "These clinical data constitute crucial progress that validates our pioneering work on the role of innate immunity and NK cells in cancer. They support our ambition to be at the forefront of developing novel combination immunotherapies."
About CA223-001: A Phase 1/2 Dose Escalation and Cohort Expansion Study of the Safety, Tolerability and Efficacy of Anti-KIR (Lirilumab) Administered in Combination With Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors
CA223-001 is a Phase 1/2 dose escalation and cohort expansion study of lirilumab in combination with nivolumab in 159 patients with advanced solid tumors. In this trial, patients received lirilumab (0.1, 0.3, 1.0, or 3.0 mg/kg) once every 4 weeks and nivolumab (3 mg/kg) once every 2 weeks.
During dose escalation, patients with advanced solid tumors who progressed after ≥ 1 prior therapy received lirilumab 0.1–3.0 mg/kg once every 4 weeks (Q4W) plus nivolumab 3.0 mg/kg Q2W. Cohort expansion was initiated at the maximum dose of lirilumab 3.0 mg/kg Q4W plus nivolumab 3.0 mg/kg Q2W in patients with advanced solid tumors. The data reported at SITC (Free SITC Whitepaper) pertain to an expansion cohort in SCCHN. Key study endpoints include safety (primary), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and biomarker assessments.
The purpose of this Phase 1/2 open label study is to determine the safety of the combination of lirilumab and nivolumab and to explore the preliminary anti-tumor activity of the combination in patients with a range of advanced solid tumors.
About Lirilumab (IPH2102/BMS-986015):
Lirilumab is a fully human monoclonal antibody that is designed to act as a checkpoint inhibitor by blocking the interaction between KIR2DL-1,-2,-3 inhibitory receptors and their ligands. Blocking these receptors facilitates activation of NK cells and potentially some subsets of T cells, ultimately leading to destruction of tumor cells.
Lirilumab is licensed to Bristol-Myers Squibb Company. As part of the agreement with Innate Pharma, Bristol-Myers Squibb holds exclusive worldwide rights to develop, manufacture and commercialize lirilumab and related compounds blocking KIR receptors, for all indications. Under the agreement, Innate Pharma conducts the development of lirilumab through Phase 2 in acute myeloid leukemia ("AML").
Innate Pharma is currently testing lirilumab in a randomized, double-blind, placebo-controlled Phase 2 trial as maintenance treatment in elderly patients with AML in first complete remission ("EffiKIR" trial). In addition, lirilumab is also being evaluated by Bristol-Myers Squibb in clinical trials in combination with other agents in a variety of tumor types.
About Head & Neck Cancer
Cancers that are known as head and neck cancers usually begin in the squamous cells that line the moist mucosal surfaces inside the head and neck, such as inside the mouth, the nose and the throat. Head and neck cancer is the seventh most common cancer globally, with an estimated 400,000 to 600,000 new cases per year and 223,000 to 300,000 deaths per year. The five-year survival rate is reported as less than 4% for metastatic Stage IV disease. Squamous cell carcinoma of the head and neck (SCCHN) accounts for approximately 90% of all head and neck cancers with global incidence expected to increase by 17% between 2012 and 2022. Risk factors for SCCHN include tobacco and alcohol consumption. The Human Papilloma Virus (HPV) infection is also a risk factor leading to rapid increase in oropharyngeal SCCHN in Europe and North America. Quality of life is often impacted for SCCHN patients, as physiological function (breathing, swallowing, eating, drinking), personal characteristics (appearance, speaking, voice), sensory function (taste, smell, hearing), and psychological/social function can be affected.
About Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.
Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.
In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 57 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 47 countries, including the United States and the European Union.
U.S. FDA APPROVED INDICATIONS FOR OPDIVO
OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials
OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.
OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.
OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.
OPDIVO (nivolumab) is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.
IMPORTANT SAFETY INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.
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. In patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients.
In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).
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. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.
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. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.
Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.
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 with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) 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 with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.
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. In patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients.
Immune-Mediated Skin Adverse Reactions and Dermatitis
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. In patients receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6% (92/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.
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. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.
Other Immune-Mediated Adverse Reactions
Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: 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), myositis, myocarditis, rhabdomyolysis, 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. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients.
Complications of Allogeneic HSCT after OPDIVO
Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. 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.
Embryo-Fetal Toxicity
Based on their mechanisms of action, OPDIVO and YERVOY 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- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.
Lactation
It is not known whether OPDIVO or YERVOY 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. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.
Serious Adverse Reactions
In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]). In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infections, and sepsis.
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (≥20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice.
In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).
Checkmate Trials and Patient Populations
Checkmate 067 – advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate 017 – squamous non-small cell lung cancer (NSCLC); Checkmate 057 – non-squamous NSCLC; Checkmate 025 – renal cell carcinoma; Checkmate 205/039 – classical Hodgkin lymphoma; Checkmate 141 – squamous cell carcinoma of the head and neck.
Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.