July 10, 2018–Ipilimumab (YERVOY, Bristol-Myers Squibb Company Inc.) for use in combination with nivolumab for the treatment of patients 12 years of age and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
October 28, 2015–(Yervoy® Injection), for the additional indication of adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.
July 10, 2018
On July 10, 2018, the Food and Drug Administration granted accelerated approval to ipilimumab (YERVOY, Bristol-Myers Squibb Company Inc.) for use in combination with nivolumab for the treatment of patients 12 years of age and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
This new use has also been added to the OPDIVO (nivolumab) labeling. Nivolumab received accelerated approval for this indication as a single agent on July 31, 2017.
The approvals were based on data from Study CA209142 (CHECKMATE 142; NCT02060188), a multicenter, non-randomized, multiple parallel-cohort, open-label study that enrolled 82 patients with dMMR or MSI-H mCRC with disease progression during or following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Assessment of dMMR or MSI-H tumor status was determined by local laboratories. All patients received ipilimumab 1 mg/kg by intravenous (IV) infusion and nivolumab 3 mg/kg IV every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg IV as a single agent every 2 weeks, until unacceptable toxicity or radiographic progression.
Among these 82 patients, the overall response rate (ORR) as assessed by an independent radiographic review committee using RECIST 1.1 was 46% (95% CI: 35,58), with 3 complete and 35 partial responses, and 89% of responding patients had response durations of ≥ 6 months. The ORR was higher than that observed in a separate cohort of 58 patients with dMMR/MSI-H mCRC with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy who received nivolumab alone, with an ORR of 28% with 67% having response durations of ≥ 6 months.
The most common adverse reactions (≥20%) in those receiving ipilimumab and nivolumab are fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, dyspnea, decreased appetite, and vomiting.
The recommended dosage regimen for this indication is nivolumab 3 mg/kg IV followed by ipilimumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks.
Efficacy for adolescent patients (12 years and older) with MSI-H or dMMR metastatic CRC is extrapolated from the results in the respective adult population.
FDA granted ipilimumab and nivolumab breakthrough therapy designations for this indication and granted priority review to these applications. As a condition of accelerated approval, further studies are required to confirm clinical benefit of ipilimumab and nivolumab for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
October 28, 2015
On October 28, 2015, the U.S. Food and Drug Administration approved ipilimumab (Yervoy® Injection), for the additional indication of adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.
The approval was based on improvement in recurrence-free survival (RFS) in a randomized (1:1), double-blind, placebo-controlled trial in 951 patients with resected Stage IIIA (lymph node >1 mm), IIIB, and IIIC (with no in-transit metastases) histologically confirmed cutaneous melanoma.
The primary efficacy endpoint was RFS determined by an independent review committee. The median RFS was 26 and 17 months in the ipilimumab (n=475) and placebo (N=476) arms, respectively [HR 0.75 (95% CI: 0.64, 0.90), p <0.002, stratified log-rank test].
Safety data was evaluated in 945 patients (median age 51 years, 62% male), who received ipilimumab 10 mg/kg (n=471) or placebo (n=474) administered as an intravenous infusion for 4 doses every 3 weeks followed by 10 mg/kg every 12 weeks beginning at week 24 up to a maximum of 3 years. Ipilimumab-treated patients received a median of 4 doses (range: 1 to 16) and 36% of patients received ipilimumab for longer than 6 months. Ipilimumab was discontinued for adverse reactions in 52% of patients.
The most common adverse reactions included rash, pruritus, diarrhea, nausea, colitis, vomiting, weight loss, fatigue, pyrexia, headache, decreased appetite, and insomnia.
Grade 3-5 immune mediated adverse reactions occurred in 41% of ipilimumab-treated patients which included enterocolitis (16%), hepatitis (11%), endocrinopathy (8%) dermatitis (4%), and neuropathy (1.7%). The five treatment-related deaths were due to immune-mediated adverse reactions of enterocolitis (3), Guillain-Barré syndrome (1) and myocarditis (1).
Patients should be assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries, including liver function tests, adrenocorticotropic hormone (ACTH) level, and thyroid function tests, at baseline and before each dose.
The recommended dose and schedule for ipilimumab for adjuvant treatment of melanoma is 10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses followed by 10 mg/kg every 12 weeks for up to 3 years. In the event of toxicity, doses are omitted, not delayed.
Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125377s073lbl.pdf
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).