On May 9, 2017 Merck and Pfizer Inc. (NYSE: PFE) reported that the US Food and Drug Administration (FDA) has approved BAVENCIO (avelumab) Injection for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy therapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy FDA Grants Bavencio (avelumab) Approval for a Common Type of Advanced Bladder Cancer (Press release, Merck KGaA, MAY 9, 2017, View Source;newsType=1 [SID1234518979]). BAVENCIO was previously granted accelerated approval from the FDA for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). These indications are approved under accelerated approval based on tumor response and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.1 BAVENCIO will be co-commercialized by EMD Serono, the biopharmaceutical business of Merck in the US and Canada, and Pfizer.
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"This approval for BAVENCIO in patients with locally advanced or metastatic urothelial carcinoma exemplifies our unwavering commitment to finding new treatments for the most challenging cancers," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the biopharma business of Merck. "Coming just a few weeks after the approval for metastatic Merkel cell carcinoma, we continue to demonstrate our ability to accelerate access to innovative medicines for patients in need."
"This approval builds on the ongoing clinical development program for BAVENCIO in urothelial carcinoma and reinforces our commitment to providing new medicines to patients with difficult-to-treat cancers," said Liz Barrett, Global President, Pfizer Oncology. "By drawing on the strength of the alliance, as well as Pfizer’s deep experience in genitourinary cancers, we believe BAVENCIO will be an important treatment option, and we hope it will help to improve outcomes for these patients."
Bladder cancer makes up approximately 90% of urothelial carcinomas and is the sixth most common cancer in the US.2,3 When the disease has metastasized, the five-year survival rate is approximately 5%.4 Despite advances in the treatment of locally advanced or metastatic urothelial carcinoma, the prognosis for patients remains poor and more treatment options are needed.2
"Once urothelial carcinoma progresses after treatment with chemotherapy, the five-year survival rate is alarmingly low," said Dr. Andrea Apolo, National Cancer Institute, Bethesda, MD, US. "Until recently, there had been limited innovation in urothelial carcinoma, and this approval gives us another treatment to help battle this aggressive disease."
The efficacy and safety of BAVENCIO was demonstrated in the urothelial carcinoma cohorts (N=242) of the JAVELIN Solid Tumor trial, a Phase I, open-label, single-arm, multicenter study of BAVENCIO in the treatment of various solid tumors. The urothelial carcinoma cohorts enrolled patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. These data will be presented at an upcoming medical congress.
The warnings and precautions for BAVENCIO include immune-mediated adverse reactions (such as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis and renal dysfunction and other adverse reactions), infusion-related reactions and embryo-fetal toxicity. The most common adverse reactions (reported in at least 20% of patients) in patients with locally advanced or metastatic urothelial carcinoma were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%) and urinary tract infection (21%).1 For more information, please see Important Safety Information for BAVENCIO below.
BAVENCIO is designed to potentially engage both the adaptive and innate immune systems. By binding to PD-L1, BAVENCIO is thought to prevent tumor cells from using PD-L1 for protection against white blood cells, such as T cells, exposing them to anti-tumor responses.1 BAVENCIO has also been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.1
The alliance is committed to providing industry-leading patient access and reimbursement support through its CoverOne program in the United States. This program provides a spectrum of patient access and reimbursement support services intended to help patients receive appropriate access to BAVENCIO in the United States.
About Urothelial Carcinoma Cohorts in JAVELIN Solid Tumor Trial
The efficacy and safety of BAVENCIO was demonstrated in the urothelial carcinoma cohorts of the JAVELIN Solid Tumor trial, a Phase I, open-label, single-arm, multicenter study that included 242 patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen who were treated with BAVENCIO.
Patients with active or a history of central nervous system metastasis; other malignancies within the last five years; an organ transplant; conditions requiring therapeutic immune suppression; or active infection with HIV, hepatitis B or C were excluded. Patients with autoimmune disease, other than type 1 diabetes, vitiligo, psoriasis, or thyroid disease that did not require immunosuppressive treatment, were excluded. Patients were included regardless of their PD-L1 status. Patients received BAVENCIO at a dose of 10 mg/kg intravenously over 60 minutes every two weeks until disease progression or unacceptable toxicity. Tumor response assessments were performed every six weeks, as assessed by an Independent Endpoint Review Committee (IERC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Efficacy outcome measures included confirmed overall response rate (ORR) and duration of response (DOR). Efficacy measures were evaluated in patients who were followed for a minimum of both 13 weeks and 6 months at the time of data cut-off.
Out of the total 226 patients evaluable for efficacy, 44% had non-bladder urothelial carcinoma, including 23% of patients with upper tract disease; 83% of patients had visceral metastases; 34% of patients had liver metastases. Nine patients (4%) had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Forty-seven percent of patients only received prior cisplatin-based regimens, 32% received only prior carboplatin-based regimens, and 20% received both cisplatin and carboplatin-based regimens.
The international clinical development program for avelumab, known as JAVELIN, involves more than 30 clinical programs, including nine Phase III trials, and more than 5,200 patients across more than 15 tumor types.
In December 2015, Merck and Pfizer announced the initiation of a Phase III multicenter, multinational, randomized, open-label, parallel-arm study (JAVELIN Bladder 100) of BAVENCIO plus best supportive care versus best supportive care alone as a maintenance treatment in patients with locally advanced or metastatic urothelial carcinoma whose disease did not progress after completion of first-line platinum-containing chemotherapy. This trial is currently enrolling patients.
IMPORTANT SAFETY INFORMATION and INDICATIONS
BAVENCIO can causeimmune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% (21/1738) of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.
BAVENCIO can causeimmune-mediated hepatitis, including fatal cases.Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis was reported in 0.9% (16/1738) of patients, including two (0.1%) patients with Grade 5 and 11 (0.6%) with Grade 3.
BAVENCIO can causeimmune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis and permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon re-initiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including seven (0.4%) with Grade 3.
BAVENCIO can causeimmune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.
Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% (8/1738) of patients, including one (0.1%) with Grade 3.
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life- threatening (Grade 4) thyroid disorders. Thyroid disorders including hypothyroidism, hyperthyroidism, and thyroiditis were reported in 6% (98/1738) of patients, including three (0.2%) with Grade 3.
Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer anti-hyperglycemics or insulin in patients with severe or life-threatening (Grade ≥ 3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients, including two cases of Grade 3 hyperglycemia.
BAVENCIO can causeimmune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment.Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% (1/1738) of patients.
BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation.For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO: myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.
BAVENCIO can causesevere (Grade 3) or life-threatening (Grade 4)infusion-related reactions.Patients should be premedicated with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% (439/1738) of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.
BAVENCIO can causefetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.
The most common adverse reactions (all grades, ≥ 20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).
Selected treatment-emergent laboratory abnormalities (all grades, ≥ 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).
The most common adverse reactions (all grades, ≥ 20%) in patients with locally advanced or metastatic urothelial cancer (UC) were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%) and urinary tract infection (21%).
Selected laboratory abnormalities (grades 3-4, ≥ 3%) in patients with locally advanced or metastatic UC were hyponatremia (16%), gamma-glutamyltransferase increased (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).
INDICATIONS
BAVENCIO is indicated for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC).
BAVENCIO is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
These indications are approved under accelerated approval based on tumor response and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.
Avelumab has not yet been approved for any indication in any market outside of the US. As announced on October 31, 2016, the European Medicines Agency (EMA) has validated for review Merck’s Marketing Authorization Application for avelumab, for the proposed indication of metastatic Merkel cell carcinoma.
About BAVENCIO(avelumab)
BAVENCIO is a human programmed death ligand-1 (PD-L1) blocking antibody indicated in the US for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy, as well as for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma.1 These indications are approved under accelerated approval based on tumor response and duration of response. Continued approval for these indications is contingent upon verification and description of clinical benefit in confirmatory trials.
BAVENCIO is not approved for any indication in any market outside the US.