On September 20, 2019 EMD Serono, the biopharmaceutical business of Merck KGaA, Darmstadt, Germany in the US and Canada, and Pfizer Inc. (NYSE: PFE) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending approval of BAVENCIO (avelumab) in combination with axitinib for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC) (Press release, Pfizer, SEP 20, 2019, View Source [SID1234539664]). The opinion was based on positive findings from the Phase III JAVELIN Renal 101 study, which demonstrated a significant extension in median progression-free survival (PFS) and a clinically meaningful improvement in objective response rate (ORR) for the combination across all prognostic risk groups compared with sunitinib.1 The CHMP positive opinion will be reviewed by the European Commission (EC), with a decision anticipated in the fourth quarter of this year. EMD Serono and Pfizer have a global strategic alliance to jointly develop and commercialize BAVENCIO.
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"Today’s positive CHMP opinion is a significant step toward potentially transforming the treatment landscape and bringing much needed options to people living with advanced renal cell carcinoma in Europe. We believe that the combination of BAVENCIO plus axitinib has the potential to help address a significant need for patients with advanced renal cell carcinoma for first-line treatments with a benefit across all prognostic risk groups, and we look forward to a decision from the European Commission," said Luciano Rossetti, Head of Global R&D for EMD Serono.
In 2018, an estimated 136,500 new cases of kidney cancer were diagnosed in Europe, and approximately 54,700 people died from the disease.2 RCC is the most common form of kidney cancer, accounting for about 3% of all cancers in adults.2 Approximately 20% to 30% of patients are first diagnosed with RCC at the advanced stage, and 30% of patients treated for an earlier stage go on to develop metastases.3,4 About half of patients living with advanced RCC do not go on to receive additional treatment after first-line therapy,5,6 for reasons that may include poor performance status or adverse events from their initial treatment.5,7,8 The five-year survival rate for patients with metastatic RCC is approximately 12%.9
"Kidney cancer represents a significant burden in Europe, where incidence rates are among the highest in the world," said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development. "Pfizer has been a leader in the development of kidney cancer treatments for more than a decade, and it is a privilege to continue our efforts to bring a new treatment option to this community."
The U.S. Food and Drug Administration (FDA) approved BAVENCIO in combination with axitinib for the first-line treatment of patients with advanced RCC in May 2019.10 A supplemental application for BAVENCIO in combination with axitinib in unresectable or metastatic RCC was submitted in Japan in January 2019.
About the JAVELIN Renal 101 Study
The Phase III JAVELIN Renal 101 study is a randomized, multicenter, open-label study of BAVENCIO in combination with axitinib in 886 patients with untreated advanced or metastatic RCC. The major efficacy outcome measures were PFS as assessed by a Blinded Independent Central Review (BICR) using RECIST v1.1 and overall survival (OS) in the first-line treatment of patients with advanced RCC who have PD-L1-positive tumors (PD‑L1 expression level ³1%). If PFS was statistically significant in patients with PD-L1-positive tumors, it was then tested in all patients irrespective of PD-L1 expression. PFS based on BICR assessment per RECIST v1.1 and OS irrespective of PD‑L1 expression, objective response, time to response (TTR), duration of response (DOR) and safety are included as secondary endpoints. The study is continuing for OS.
About the JAVELIN Clinical Development Program
The clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs and more than 10,000 patients evaluated across more than 15 different tumor types. In addition to RCC, these tumor types include gastric/gastro-esophageal junction cancer, head and neck cancer, Merkel cell carcinoma, non-small cell lung cancer and urothelial carcinoma.
About BAVENCIO (avelumab)
BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.11-13 BAVENCIO has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.13-15 In November 2014, EMD Serono and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.
BAVENCIO Approved Indication in the US
BAVENCIO (avelumab) in combination with axitinib is indicated in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
BAVENCIO Important Safety Information from the US FDA-Approved Label
BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis, and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.
BAVENCIO can cause hepatotoxicity and immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis occurred with BAVENCIO as a single agent in 0.9% of patients, including two (0.1%) patients with Grade 5, and 11 (0.6%) with Grade 3.
BAVENCIO in combination with axitinib can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. Withhold BAVENCIO and axitinib for moderate (Grade 2) hepatotoxicity and permanently discontinue the combination for severe or life-threatening (Grade 3 or 4) hepatotoxicity. Administer corticosteroids as needed. In patients treated with BAVENCIO in combination with axitinib, Grades 3 and 4 increased ALT and AST occurred in 9% and 7% of patients, respectively, and immune-mediated hepatitis occurred in 7% of patients, including 4.9% with Grade 3 or 4.
BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis until resolution. Permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% of patients, including seven (0.4%) with Grade 3.
BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.
Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% of patients, including one (0.1%) with Grade 3.
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% of patients, including three (0.2%) with Grade 3.
Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade ≥3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% of patients, including two cases of Grade 3 hyperglycemia.
BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% of patients.
BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO as a single agent or in 489 patients who received BAVENCIO in combination with axitinib: myocarditis including fatal cases, pancreatitis including fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.
BAVENCIO can cause severe or life-threatening infusion-related reactions. Premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent infusions based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.
BAVENCIO in combination with axitinib can cause major adverse cardiovascular events (MACE) including severe and fatal events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue BAVENCIO and axitinib for Grade 3-4 cardiovascular events. MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with axitinib compared to 3.4% treated with sunitinib. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%).
BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.
Please see full US Prescribing Information and Medication Guide available at View Source
Axitinib Important Safety Information from the US FDA-Approved Label
Hypertension including hypertensive crisis has been observed with axitinib. Blood pressure should be well controlled prior to initiating axitinib. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue axitinib if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of axitinib, and discontinuation should be considered if there is evidence of hypertensive crisis.
Arterial and venous thrombotic events have been observed with axitinib and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events.
Hemorrhagic events, including fatal events, have been reported with axitinib. Axitinib has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the axitinib dose.
Cardiac failure has been observed with axitinib and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with axitinib. Management of cardiac failure may require permanent discontinuation of axitinib.
Gastrointestinal perforation and fistula, including death, have occurred with axitinib. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment.
Hypothyroidism requiring thyroid hormone replacement has been reported with axitinib. Monitor thyroid function before initiation of, and periodically throughout, treatment.
No formal studies of the effect of axitinib on wound healing have been conducted. Stop axitinib at least 24 hours prior to scheduled surgery.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed with axitinib. If signs or symptoms occur, permanently discontinue treatment.
Proteinuria has been observed with axitinib. Monitor for proteinuria before initiation of, and periodically throughout, treatment with axitinib. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.
Liver enzyme elevation has been observed during treatment with axitinib. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment.
For patients with moderate hepatic impairment, the starting dose should be decreased. Axitinib has not been studied in patients with severe hepatic impairment.
Axitinib can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception during treatment.
Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided.
Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.
Please see full Prescribing Information for axitinib.
ADVERSE REACTIONS (BAVENCIO + AXITINIB)
Fatal adverse reactions occurred in 1.8% of patients with advanced renal cell carcinoma (RCC) receiving BAVENCIO in combination with axitinib. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%).
The most common adverse reactions (all grades, ≥20%) in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were diarrhea (62% vs 48%), fatigue (53% vs 54%), hypertension (50% vs 36%), musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%), palmar-plantar erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%), decreased appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs 16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23% vs 16%), abdominal pain (22% vs 19%), and headache (21% vs 16%).
Selected laboratory abnormalities (all grades, ≥20%) worsening from baseline in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were blood triglycerides increased (71% vs 48%), blood creatinine increased (62% vs 68%), blood cholesterol increased (57% vs 22%), alanine aminotransferase increased (ALT) (50% vs 46%), aspartate aminotransferase increased (AST) (47% vs 57%), blood sodium decreased (38% vs 37%), lipase increased (37% vs 25%), blood potassium increased (35% vs 28%), platelet count decreased (27% vs 80%), blood bilirubin increased (21% vs 23%), and hemoglobin decreased (21% vs 65%).
The most common adverse reactions (all grades, ≥20%) in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were diarrhea (62% vs 48%), fatigue (53% vs 54%), hypertension (50% vs 36%), musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%), palmar-plantar erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%), decreased appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs 16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23% vs 16%), abdominal pain (22% vs 19%), and headache (21% vs 16%).
Selected laboratory abnormalities (all grades, ≥20%) worsening from baseline in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were blood triglycerides increased (71% vs 48%), blood creatinine increased (62% vs 68%), blood cholesterol increased (57% vs 22%), alanine aminotransferase increased (ALT) (50% vs 46%), aspartate aminotransferase increased (AST) (47% vs 57%), blood sodium decreased (38% vs 37%), lipase increased (37% vs 25%), blood potassium increased (35% vs 28%), platelet count decreased (27% vs 80%), blood bilirubin increased (21% vs 23%), and hemoglobin decreased (21% vs 65%).