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FDA Alerts

Pharmacist's Applications to Practice

HOPA, through the Publications Committee, will review new drug updates and provide analysis and research on the application of these new drugs or indications.

The letters “PAP” after drugs listed below indicates that they include this additional analysis.  


September 22, 2017–Nivolumab (OPDIVO, Bristol-Myers Squibb Co.) for the treatment of hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib.(with Pharmacist's Applications to Practice.)

July 31, 2017–Nivolumab (OPDIVO, Bristol-Myers Squibb Company) for the treatment of patients 12 years and older with mismatch repair deficient (dMMR) and microsatellite instability high (MSI-H) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.(with Pharmacist's Applications to Practice.)

February 2, 2017–Nivolumab (OPDIVO, Bristol-Myers Squibb Company) for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy.(with Pharmacist's Applications to Practice.)

November 10, 2016–Nivolumab (OPDIVO Injection, Bristol-Myers Squibb Company), for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after a platinum-based therapy.(with Pharmacist's Applications to Practice.)

September 13, 2016–Nivolumab (Opdivo®) receives dosage regimen modification for the currently approved indications for renal cell carcinoma, metastatic melanoma, and non-small cell lung cancer.

May 17, 2016–Nivolumab (Opdivo®) approved for the treatment of patients with classical Hodgkin lymphoma that has relapsed.

November 23, 2015–Nivolumab (Opdivo ® Injection) approved for the treatment of advanced renal cell carcinoma in patients who received prior anti-angiogenic therapy.

October 9, 2015–Nivolumab (Opdivo ® Injection) approved for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

September 30, 2015–Nivolumab (Opdivo Injection) approved in combination with ipilimumab for the treatment of patients with BRAF V600 wild-type, unresectable or metastatic melanoma.

March 4, 2015–Nivolumab (OPDIVO) granted approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.


September 22, 2017 (with PAP)

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s041lbl.pdf

On September 22, 2017, the Food and Drug Administration granted accelerated approval to nivolumab (OPDIVO, Bristol-Myers Squibb Co.) for the treatment of hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib.

Approval was based on a 154-patient subgroup of CHECKMATE-040 (NCT 01658878), a multicenter, open-label trial conducted in patients with HCC and Child-Pugh A cirrhosis who progressed on or were intolerant to sorafenib. In addition to including patients without active hepatitis viral infection, the trial enrolled patients with either active HBV (31%) or HCV (21%) but not those with active co-infection with HBV and HCV or with hepatitis D virus infection. Patients received nivolumab 3 mg/kg by intravenous infusion every 2 weeks. The confirmed overall response rate, as assessed by blinded independent central review using RECIST 1.1, was 14.3% (95% CI: 9.2, 20.8), with 3 complete responses and 19 partial responses. Response duration ranged from 3.2 to 38.2+ months; 91% of responders had responses lasting 6 months or longer and 55% had responses lasting 12 months or longer.

Common adverse reactions occurring in greater than 20% of patients in nivolumab clinical trials include fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia. Adverse reactions occurring in patients with HCC in CHECKMATE-040 were similar to those previously reported in product labelling, with the exception of a higher incidence of elevations in transaminases and bilirubin levels. Treatment with nivolumab resulted in treatment-emergent grade 3 or 4 AST in 27 (18%) patients, grade 3 or 4 ALT in 16 (11%) patients, and grade 3 or 4 bilirubin in 11 (7%) of patients. Immune-mediated hepatitis requiring systemic corticosteroids occurred in 8 (5%) patients.

The recommended nivolumab dose for HCC treatment is 240 mg every 2 weeks.

Full dosing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s041lbl.pdf

FDA granted priority review to nivolumab for this indication. As a condition of accelerated approval, further trials will be required to verify the clinical benefit of nivolumab for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.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).


Pharmacist’s Applications to Practice – September 22, 2017

Author: Michael J. Chargualaf, PharmD
Pharmacy Clinical Specialist, Oncology
WVU Medicine Cancer Institute
Morgantown, WV

What is the potential role for nivolumab in the management of hepatocellular carcinoma (HCC)?

  • Nivolumab is the first and only checkpoint inhibitor currently approved by the U. S. food and Drug Administration (FDA) for HCC.1
    • Patients must have had disease progression on or be intolerant to sorafenib.
  • Approval was based on results from CHECKMATE-040, a multicenter noncomparative open-label phase 1/2 study.2
    • Patients could have hepatitis C or hepatitis B but not both.
    • A subgroup of 154 patients previously treated with sorafenib and Child Pugh Class A or B7 demonstrated an overall response rate of 14.3%, with 91% having a duration of response of 6 months or greater.
  • Nivolumab was recently added to the National Comprehensive Cancer Network (NCCN) guidelines on October 9, 2017, as a Category 2A treatment option for patients with disease progression on or after sorafenib (Child-Pugh Class A or B7 only).3
    • Regorafenib (Category 1) is also recommended after disease progression on or after sorafenib (Child-Pugh Class A only).
    • The RESORCE trial with regorafenib versus placebo demonstrated an 11% objective response rate for patients treated with regorafenib, compared to 4% with placebo (p = .005).4

What role can the pharmacist play in the management of patients on nivolumab?

  • The approved nivolumab dose for HCC is a fixed 240-mg dose administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.5 Although the 240-mg flat dose was not studied in CHECKMATE-040, this approved regimen coincides with the FDA’s recommendations for other disease states, including renal cell carcinoma, metastatic melanoma, and non-small-cell lung cancer.
  • Patients receiving treatment with nivolumab or other immunotherapy should be monitored for immune-related adverse effects (IRAEs) prior to every infusion.
  • Pharmacists have the opportunity to educate other healthcare professionals and patients on proper screening and early detection of IRAEs.
  • 19% of patients experienced a grade 3 or 4 treatment-related adverse event.2

Clinical Pearls

  • Although this is not specified in the FDA approval, the NCCN recommendation includes use of nivolumab for HCC only in patients in Child-Pugh Class A or B7.
  • Tumor programmed death-ligand 1 expression is not required.
  • Nivolumab was approved for HCC under an accelerated approval process. Verification of safety, efficacy, and clinical benefit will determine whether approval for this indication is continued.1

References

  1. U.S. Food and Drug Administration. Nivolumab (Opdivo). https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm577166.htm. Updated September 25, 2017. Accessed October 10, 2017.
  2. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-2502.
  3. Hepatobiliary Cancers. Version 4.2017. National Comprehensive Cancer Network. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed October 10, 2017.
  4. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56-66.
  5. Opdivo. [package insert]. Bristol-Myers Squibb. Princeton, NJ; September 2017.https://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed September 10, 2017.

July 31, 2017 (with PAP)

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s034lbl.pdf

On July 31, 2017, the U.S. Food and Drug Administration granted accelerated approval to nivolumab (OPDIVO, Bristol-Myers Squibb Company) for the treatment of patients 12 years and older with mismatch repair deficient (dMMR) and microsatellite instability high (MSI-H) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

The approval was based on data from Study CA209142 (CHECKMATE 142; NCT 02060188), a multicenter, open-label, single arm study conducted in 53 patients with locally determined dMMR or MSI-H metastatic colorectal cancer (CRC) who had disease progression during, after, or were intolerant to prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This was a subset of the 74 patients who received at least one prior regimen for treatment of metastatic disease containing a fluoropyrimidine with oxaliplatin or irinotecan for treatment of metastatic disease. All patients received nivolumab 3 mg/kg by intravenous infusion every 2 weeks until unacceptable toxicity or radiographic progression.

The objective response rate (ORR) as assessed by independent radiographic review committee using RECIST 1.1 was 28% (n=15) (95% CI: 17, 42) in the 53 patients who received prior fluoropyrimidine, oxaliplatin, and irinotecan. Responses lasted 6 or more months for 67% (95% CI: 38, 88) of patients. There was 1 complete response and 14 partial responses. The ORR was 32% (n=24) (95% CI: 22, 44) among the 74 patients in the overall population.

Trials of nivolumab have not been conducted in pediatric patients. 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.

The most common adverse reactions (≥20%) to nivolumab as a single agent include fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia.

The recommended nivolumab dose for this indication is 240 mg every 2 weeks.

Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s034lbl.pdf.

FDA granted this application priority review status. As a condition of accelerated approval, further studies are required to confirm clinical benefit of nivolumab for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.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).


Pharmacist’s Applications to Practice - July 31, 2017

Nivolumab for the Treatment of Patients 12 Years and Older with DNA Mismatch Repair Deficient and Microsatellite Instability–High Metastatic Colorectal Cancer

Author: Jiyeon Joy Park, PharmD
PGY-2 Oncology Pharmacy Resident
National Institutes of Health Clinical Center
Bethesda, MD

What is the potential role for nivolumab in the treatment of DNA mismatch repair deficient (dMMR) or microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC)?1-5

  • Nivolumab, a programmed cell death-1 (PD-1) immune checkpoint inhibitor, was originally granted approval by the U.S. Food and Drug Administration (FDA) in December 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation–positive, a BRAF inhibitor. Since that time, nivolumab has been approved for a number of additional indications, including metastatic non-small-cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial cancer, and first-line treatment of melanoma.1
  • On July 31, 2017, an accelerated approval was granted for the treatment of patients 12 years and older with dMMR/MSI-H mCRC that has progressed after treatment with a fluoropyrimidine (fluorouracil or capecitabine), oxaliplatin, and irinotecan.2
    • dMMR/MSI-H is a genetic biomarker associated with solid tumors that have a poor prognosis. Approximately 5% of all colorectal cancer patients express dMMR/MSI-H in their tumor cells, and screening for this specific genetic mutation is now recommended for all mCRC patients.3
    • In CheckMate-142, a multicenter open-label single-arm phase-2 study (N = 74), patients were eligible if they had dMMR/MSI-H metastatic or recurrent colorectal cancer and progressed on, or were intolerant to, at least one line of therapy, including a fluoropyrimidine plus oxaliplatin or irinotecan. Patients received nivolumab 3 mg/kg by intravenous infusion every 2 weeks until unacceptable toxicity or radiographic progression.3
    • Objective response rate (ORR) per investigator was 32%, which consisted of two complete responses (CRs) and 22 partial responses (PRs). Sixty-nine percent of the patients had disease control (CR + PR + stable disease) for 12 weeks or longer.3
    • Fifty-two patients (70%) had drug-related adverse events (AEs), with the most common AEs (20% or more) being fatigue and diarrhea. Fifteen patients (20%) experienced a grade 3 or 4 drug-related AE; nine of these patients had serious drug-related AEs such as adrenal insufficiency, increased alanine aminotransferase (ALT) levels, colitis, diarrhea, gastritis, stomatitis, acute kidney injury, pain, and arthritis. Grade 3 or 4 immune-mediated AEs were also observed.
    • Over a period of 97 weeks, patient-reported outcomes related to quality of life, decrease in symptoms (e.g., fatigue, diarrhea), and functioning (e.g., emotional functioning) improved about 10% from their baseline.2
  • The National Comprehensive Cancer Network (NCCN) recommends nivolumab or pembrolizumab for dMMR/MSI-H in mCRC patients who may not tolerateintensive therapy or who have disease progression after oxaliplatin-based therapy without irinotecan, irinotecan-based therapy without oxaliplatin, previous FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) therapy, or previous fluoropyrimidine therapy without irinotecan or oxaliplatin.4
  • Pembrolizumab was approved in May 2017 for adult and pediatric patients with dMMR/MSI-H solid tumors, including mCRC. Based on five multicenter uncontrolled single-arm clinical trials, ORR was 36% in CRC patients and 46% in other types of cancer. Seventy-eight percent had responses that lasted more than 6 months. AEs were similar to those reported for nivolumab (e.g., fatigue, pruritus, rash, and immune-mediated AEs).5
  • Although no head-to-head trials have been conducted, both nivolumab and pembrolizumab show relatively similar efficacy and safety profiles in patients with dMMR/MSI-H mCRC. Pembrolizumab can also be considered in patients with non-mCRC cancers with dMMR/MSI-H.

What role can the pharmacist play in the management of patients on nivolumab?1-3,6,7

  • The manufacturer’s recommended dose is a flat dose of 240 mg given intravenously (IV) over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.1
    • The dosage for pediatric patients 12 years and older is the same as that for adults.
    • The CheckMate-142 study used 3 mg/kg IV every 2 weeks, which is different from the approved dose.3
      • Previous pharmacokinetics analyses in the population demonstrated similar drug exposure between 3 mg/kg and the 240-mg flat dose; thus the 240-mg dose is based on the FDA-approved dose for nivolumab.6
      • Flat dosing may reduce excess drug waste and provide convenience to healthcare providers.7
  • As with other indications for nivolumab, immune-mediated toxicities, depending on the severity, may necessitate withholding or permanently discontinuing the drug. These may include pneumonitis, hepatitis, colitis, endocrinopathies, nephritis, adverse skin reactions, encephalitis, and other immune-mediated adverse reactions. Consult the prescribing information for specific recommendations on toxicity management.1
    • In CheckMate-142, nivolumab was discontinued permanently if treatment was withheld for more than 6 weeks except for interruptions due to steroid tapers for treatment-related adverse events. Dose reductions were not allowed in the study.3
    • For severe or life-threatening immune-mediated toxicities such as grade 3 or 4 pneumonitis, colitis, transaminase elevations, adrenal insufficiency, rash, or grade 4 increased serum creatinine, administer corticosteroids at a dose of 1–2 mg/kg/day prednisone (or equivalent) followed by a taper.1
    • For milder immune-mediated toxicities such as grade 2 colitis, transaminase elevations, or grade 2 or 3 increased serum creatinine, consider a lower dose range of corticosteroids at .5–1 mg/kg/day prednisone (or equivalent) followed by a taper.1

Clinical Pearls3,4,8-11

  • The majority of the study population (77%) was younger than 65 years, whereas the median age of diagnosis of colon cancer is 68 in men and 72 in women.3,8
  • In contrast to the study population, which included patients (15%) who received only one regimen prior to nivolumab, the FDA-approved indication for nivolumab suggests that patients should have previously been treated with both oxaliplatin- and irinotecan-based therapy, whether given separately or combined.3
  • A subgroup analysis of tumor programmed death-ligand 1 (PD-L1) expression levels revealed that responses were observed regardless of tumor PD-L1 expression, suggesting that PD-L1 is not a useful biomarker in this patient population.3
  • NCCN recommends dMMR or MSI testing in all colorectal cancer patients regardless of their age at diagnosis.4,9 For patients with dMMR/MSI-H mCRC, PD-1 immune checkpoint inhibitors such as nivolumab or pembrolizumab can be considered after initial therapy with fluoropyrimidine-based regimens. For other solid tumors with dMMR/MSI-H, pembrolizumab is indicated.4
  • The financial burdens associated with the treatment of metastatic cancer often result in patients spending their incomes, liquidating assets, or forgoing treatment in order to meet family needs and cover life necessities.10 For an indication such as non-small-cell lung cancer, the cost of nivolumab is approximately $151,560 per quality-adjusted life year gained.11 Pharmacists may be able to assist patients in dealing with these financial burdens. Financial assistance may be available to patients who have commercial insurance or coverage in federal healthcare programs or who lack prescription drug coverage. More information can be found by contacting Bristol-Myers Squibb Access Support at 800.861.0048 or visiting www.bmsaccesssupport.bmscustomerconnect.com/opdivo/co-pay-financial-assistance.

References

  1. Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb; July 2017.
  2. Nivolumab. U.S. Food and Drug Administration: Approved Drugs. July 31, 2017. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm569366.htm. Accessed August 31, 2017.
  3. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182-1191.
  4. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Colon cancer. V2.2017. https://www.nccn.org/. Accessed September 4, 2017.
  5. U.S. Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm. Updated May 30, 2017. Accessed September 20, 2017.
  6. U.S. Food and Drug Administration. Modification of the dosage regimen for nivolumab. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm520871.htm. Accessed September 4, 2017.
  7. Brenna Z. FDA approves modified dosing regimen for Bristol-Myers Squibb’s cancer treatment Opdivo. Regulatory Affairs Professionals Society website. www.raps.org/Regulatory-Focus/News/2016/09/15/25859/FDA-Approves-Modified-Dosing-Regimen-for-Bristol-Myers-Squibb’s-Cancer-Treatment-Opdivo/. Updated September 15, 2016. Accessed September 9, 2017.
  8. American Cancer Society. Colorectal Cancer: Facts and Figures 2017–2019. www.cancer.org. Updated 2017.
  9. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Genetic/familial high-risk assessment: colorectal. V2.2017. https://www.nccn.org/. Accessed September 11, 2017.
  10. Tefferi A, Kantarjian H, Rajkumar SV. In support of a patient-driven initiative and petition to lower the high price of cancer drugs. Mayo Clin Proc. 2015;90(8):996-1000.
  11. Kelly RJ, Smith TJ. Checkpoint inhibitors in lung cancer are not immune from cost-effectiveness analysis. J Thorac Oncol. 2016;11(11):1814-1816.

February 2, 2017 (with PAP)

http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s024lbl.pdf

On February 2, 2017, the U.S. Food and Drug Administration granted accelerated approval to nivolumab (OPDIVO, Bristol-Myers Squibb Company) for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy.

Approval was based on a single-arm study treating 270 patients with locally advanced or metastatic urothelial carcinoma who progressed during or following platinum-containing chemotherapy, or progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Patients received nivolumab, 3 mg/kg every 2 weeks, until disease progression or unacceptable toxicity. Objective response rate, confirmed by an independent radiographic review committee using Response Evaluation Criteria in Solid Tumors 1.1, was 19.6% (53/270; 95% CI: 15.1, 24.9). Seven patients had complete responses and 46 had partial responses. Estimated median response duration was 10.3 months with responses ongoing at data cutoff.

The most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, nausea, and decreased appetite. Fourteen patients died from causes other than disease progression, including four patients who died from pneumonitis or cardiovascular failure attributed to nivolumab. Adverse reactions led to dose discontinuation in 17% of patients.

The recommended dose and schedule for nivolumab for the above indication is 240 mg intravenously every 2 weeks.

FDA granted this nivolumab application breakthrough therapy designation and priority review status. This application was approved approximately one month before the goal date. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s024lbl.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).


Pharmacist's Application to Practice - February 2, 2017

Nivolumab (Opdivo) for Locally Advanced or Metastatic Urothelial Carcinoma

Author: Pete Schlickman, PharmD BCOP
Clinical Research Pharmacist, Drug Development Unit
Sarah Cannon Research Institute at HealthONE
Denver, CO

What is the potential role for nivolumab in the management of urothelial carcinoma?1,2,5

  • Nivolumab is the second anti–programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) agent approved for urothelial carcinoma after progression on a platinum agent after several decades of minimal advancement in the treatment of this disease. Prior to the two recent approvals, standard second-line therapy consisted of taxanes, gemcitabine, pemetrexed, and various cytotoxic combination regimens.
  • In a single-arm phase 2 study (CheckMate 275), nivolumab had a confirmed overall response rate (ORR) of 19.6% (RECIST v1.1) across all treated patients. Patients with PD-L1 expression >1% (via immunohistochemistry [IHC]) had a confirmed ORR of 28.4%, while those with <1% expression had an ORR of 16.1%. Overall survival (OS) results were similar in that those patients with >1% PD-L1 expression had longer OS than those with <1% expression; however, those results were not compared statistically.
  • Nivolumab and other PD-1/PD-L1 inhibitors are being explored for use in several types of cancer, including urothelial carcinoma. Current studies are exploring the use of these agents in the adjuvant and neo-adjuvant settings, as well as in combination with chemotherapy and other checkpoint inhibitors for the treatment of metastatic disease in either the first- or second-line setting.

What role can the pharmacist play in the management of patients on nivolumab?1,4, 6

  • Nivolumab is a fully human, immunoglobulin G4 (IgG4) monoclonal antibody with a low incidence (<1%) of infusion-related reactions. However, close monitoring during administration is recommended.
  • Because of the low risk of infusion reactions and minimal emetic risk, prophylactic administration of antihistamines, antipyretics, corticosteroids, and other antinausea medications is not recommended.
  • Corticosteroid use should be avoided in patients on nivolumab because of the ability to affect T-cell activation and release.
    • High-dose steroids (prednisone or equivalent 12 mg/kg daily) are recommended for any immune-mediated toxicity, including colitis, hypophysitis, and pneumonitis.

Clinical Pearls5

  • Because the CheckMate 275 study was a single-arm study, it is currently unknown how nivolumab compares to other treatment options for this disease.
  • More trials will need to be conducted to determine how best to treat patients with metastatic urothelial carcinoma in the future and to determine the significance of PD-L1 expression on patient selection and treatment response.

References

  1. Opdivo (Nivolumab) injection [package insert]. Princeton, NJ: Bristol-Myers Squibb; February 2017.
  2. ClinicalTrials.gov Registry. National Institutes of Health. Retrieved from: www.clinicaltrials.gov. Accessed March 24, 2017.
  3. Bladder Cancer. Version 2.2017. National Comprehensive Cancer Network. Retrieved from: https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed March 27, 2017.
  4. Lexi-Drugs Online™, Hudson, OH: Lexi-Comp, Inc.; 2017; Accessed March 27, 2017.
  5. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017;18(3):312-22.
  6. Antiemesis. Version 2.2017. National Comprehensive Cancer Network. Retrieved from: https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed March 27, 2017.

November 10, 2016 (with PAP)

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125554s022lbl.pdf

On November 10, 2016, the U. S. Food and Drug Administration approved nivolumab (OPDIVO Injection, Bristol-Myers Squibb Company), for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after a platinum-based therapy.

Approval was based on data from an international, multi-center, open-label, randomized trial (CheckMate 141) comparing nivolumab with investigator’s choice (IC) of chemotherapy (either cetuximab, methotrexate, or docetaxel) in patients with recurrent or metastatic SCCHN with disease progression on or within 6 months of receiving platinum-based chemotherapy.

The trial enrolled 361 patients randomized (2:1) to nivolumab 3 mg/kg every 2 weeks intravenously (IV) (n=240) or IC (n=121) of either cetuximab 400 mg/m2 IV once, then 250 mg/m2 IV weekly (n=15), methotrexate 40 mg/m2 IV weekly (n=52), or docetaxel 30 mg/m2 IV weekly (n=54) until disease progression or unacceptable toxicity.

The trial demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) associated with the nivolumab arm (Hazard Ratio 0.7 [95% CI: 0.52, 0.92]; p=0.0101, stratified log rank test). Estimated median OS was 7.5 months (95% CI=5.5, 9.1) in the nivolumab arm and 5.1 months (95% CI=4, 6.0) for IC.

Serious adverse reactions occurred in 49% of patients receiving nivolumab. The most frequent serious adverse reactions reported in at least 2% of patients receiving nivolumab were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The most common adverse reactions occurring in more than 10% of nivolumab-treated patients and at a higher incidence than IC were cough and dyspnea. The most common laboratory abnormalities occurring in 10% or more nivolumab-treated patients and at a higher incidence than IC were increased alkaline phosphatase, increased amylase, hypercalcemia, hyperkalemia, and increased TSH.

The recommended dose and schedule for nivolumab for SCCHN is 3 mg/kg IV every two weeks.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125554s022lbl.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).


Pharmacist's Application to Practice - November 10, 2016

Nivolumab for Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Author: Carolyn Oxencis, PharmD BCOP BCPS
Clinical Oncology Pharmacist
Froedtert and the Medical College of Wisconsin Department of Pharmacy
Milwaukee, WI

What is the potential role for nivolumab in the treatment of squamous cell carcinoma of the head and neck (SCCHN)?

  • Nivolumab is an option for the treatment of patients with recurrent or metastatic SCCHN, with disease progression on or within 6 months of receiving platinum-based chemotherapy.1
  • Approval was granted for second-line treatment of SCCHN based on results from the CheckMate 141 trial2; efficacy of nivolumab was compared with investigator’s choice of cetuximab, methotrexate, or docetaxel in patients with recurrent or metastatic SCCHN.

What role can the pharmacist play in the management of patients on nivolumab?

  • Patients should be monitored carefully for immune-related adverse events, with particular attention to respiratory-related side effects and signs or symptoms of infection.
    • The most common adverse reactions occurring in more than 10% of nivolumab-treated patients were cough and dyspnea.2,3
    • The most frequent serious adverse reactions reported in at least 2% of patients receiving nivolumab were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. 2,3

Clinical Pearls

  • Currently, the FDA-approved dosing regimen of nivolumab for SCCHN is 3 mg/kg intravenously every 2 weeks.1 On September 13, 2016, the FDA modified the dosage regimen of nivolumab for previously approved indications (renal cell carcinoma, metastatic melanoma, and non–small cell lung cancer) to a fixed, non-weight-based dose of 240 mg intravenously every 2 weeks. Watch for updated dosing recommendations for SCCHN.
  • There are no recommendations based on PD-L1 expression of cells using an FDA-approved test; however, subgroup analysis of patients with confirmed PD-L1 expression and positive human papillomavirus status experienced greater benefit with nivolumab therapy.1-3

References

  1. U.S. Food and Drug Administration. Nivolumab for SCCHN. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm528920.htm. Updated November 10, 2016. Accessed January 27, 2017.
  2. Ferris RL, Blumenschein GR, Fayette J, et al. Further evaluations of nivolumab (nivo) versus investigator’s choice (IC) chemotherapy for recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): CheckMate 141. J Clin Oncol. 2016;34 (suppl; abstr 6009).
  3. Opdivo® [package insert]. Bristol-Myers Squibb Co., Princeton, NJ; December 2014. www.accessdata.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf. Accessed Jan 27, 2017.

September 13, 2016

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125554s017s018lbl.pdf

On September 13, 2016, the U.S. Food and Drug Administration modified the dosage regimen for nivolumab (Opdivo®, Bristol-Myers Squibb Co.) for the currently approved indications for renal cell carcinoma, metastatic melanoma, and non-small cell lung cancer. The currently approved recommended dosage regimens were modified to 240 mg intravenously (IV) every two weeks.

The approval modifies the Dosage and Administration section of the labeling by replacing the single dose regimen of nivolumab (3 mg/kg intravenously every two weeks) with the new recommended regimen of 240 mg IV every two weeks until disease progression or intolerable toxicity for renal cell carcinoma, metastatic melanoma, and non-small cell lung cancer.

In addition, the nivolumab dosing regimen in combination with ipilimumab for melanoma will remain the same (nivolumab 1 mg/kg IV, followed by ipilimumab on the same day, every 3 weeks for 4 doses). However, after completion of ipilimumab, the recommended nivolumab dose will be 240 mg every two weeks until disease progression or intolerable toxicity. The recommended dose for classical Hodgkin lymphoma remains 3 mg/kg IV, every 2 weeks until disease progression or intolerable toxicity.

The approval was based on population pharmacokinetics analyses and dose/exposure-response analyses demonstrating the comparability of the pharmacokinetics exposure, safety, and efficacy of the proposed new dosing regimen with the previously approved regimen.

Based on simulations by the population pharmacokinetics model, FDA determined that the overall exposure at 240 mg every two weeks flat dose is similar (less than 6% difference) to 3 mg/kg every two weeks. These differences in exposure are not likely to have a clinically meaningful effect on safety and efficacy, since dose/exposure response relationships appear to be relatively flat in these three indications.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125554s017s018lbl.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).


May 17, 2016

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125554s019lbl.pdf

On May 17, 2016, the U. S. Food and Drug Administration granted accelerated approval to nivolumab (Opdivo®, marketed by Bristol-Myers Squibb) 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 (Adcetris®).

The approval was based on two single-arm, multicenter trials of nivolumab in adults with relapsed or refractory cHL. The trials enrolled patients regardless of PD-L1 expression status on Reed-Sternberg cells. The primary efficacy endpoint was objective response rate (ORR) as determined by an independent radiographic review committee. Additional outcome measures included duration of response (DOR).

Efficacy was evaluated in 95 patients previously treated with autologous HSCT and post-transplantation brentuximab vedotin. Patients had a median of 5 prior systemic regimens (range: 3, 15) and received a median of 17 doses of nivolumab (range: 3, 48). Single-agent nivolumab produced a 65% ORR (95% CI: 55%, 75%), with 58% partial remission and 7% complete remission. The median time-to-response was 2.1 months (range: 0.7 to 5.7 months). The estimated median DOR was 8.7 months.

Safety was evaluated in 263 patients with relapsed or refractory cHL. Ninety-eight per cent of patients had received autologous HSCT. Patients received a median of 10 doses of nivolumab (range: 1, 48) at the approved dose-schedule. The most common (reported in at least 20%) adverse reactions of any grade were fatigue, upper respiratory tract infection, cough, pyrexia, and diarrhea. Additional common adverse reactions (reported in at least 10%) included rash, pruritus, musculoskeletal pain, nausea, vomiting, abdominal pain, headache, peripheral neuropathy, arthralgia, dyspnea, infusion-related reactions, and hypothyroidism or thyroiditis.

Other immune-mediated adverse reactions, occurring in 1% to 5% of patients, included rash, pneumonitis, hepatitis, hyperthyroidism, and colitis. Serious adverse reactions were reported in 21% of patients. The most common SAEs, reported in 1% to 3% of patients, were pneumonia, pleural effusion, pneumonitis, pyrexia, infusion-related reaction, and rash.

A new “Warning and Precaution” was issued for complications of allogeneic HSCT after nivolumab. Transplant-related deaths have occurred, and health care professionals should follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host disease (GVHD), severe acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions. FDA has required the manufacturer to further study the safety of allogeneic HSCT after nivolumab.

The recommended dose-schedule of nivolumab is 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity.

Continued approval for the cHL indication may be contingent upon verification of clinical benefit through a randomized phase 3 trial.

This application was approved before the Prescription Drug User Fee Act (PDUFA) goal date of September 1, 2016. Nivolumab was granted Breakthrough Therapy Designation for the treatment of relapsed or refractory cHL after failure of autologous HSCT and brentuximab vedotin. Nivolumab also has Orphan Drug status for the treatment of HL. This application was granted Priority Review and was approved under FDA’s Accelerated Approval Program. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125554s019lbl.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).



September 30, 2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125554s002lbl.pdf

On September 30, 2015, the U. S. Food and Drug Administration granted accelerated approval to nivolumab (Opdivo Injection, Bristol-Myers Squibb Co.) in combination with ipilimumab for the treatment of patients with BRAF V600 wild-type, unresectable or metastatic melanoma.

Approval was based on demonstration of an increase in the objective response rate (ORR), prolonged response durations, and improvement in progression-free survival (PFS) in an international, multicenter, double-blind, randomized, two-arm, active-controlled trial in patients who were previously untreated for unresectable or metastatic, BRAF V600 wild-type melanoma.

The clinical trial randomized (2:1) 142 patients to receive nivolumab plus ipilimumab (n=95) or ipilimumab plus placebo (n=47). Randomization was stratified by BRAF V600 mutation status based on an FDA-approved test. Patients in the nivolumab plus ipilimumab arm received nivolumab 1 mg/kg and ipilimumab 3 mg/kg intravenously every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Patients in the ipilimumab arm received ipilimumab 3 mg/kg and nivolumab-matched placebo intravenously every 3 weeks for four doses followed by placebo. At the time of disease progression, patients on the ipilimumab arm were offered nivolumab 3 mg/kg every 2 weeks.

Of the 109 patients with BRAF V600 wild-type melanoma, the median age was 66 years and ECOG performance score was 0 (84%) or 1 (15%). Forty-six percent had M1c disease and 20% had elevated baseline LDH.

The trial demonstrated a significant improvement in ORR. The ORR was 60% [95% confidence interval (CI): 48, 71] in the nivolumab plus ipilimumab group (n=72) and 11% [95% CI: 3, 25] in the ipilimumab group (n=37), an improvement in ORR of 49% (95% CI: 31, 61; p-value <0.001). Of the 43 patients with an objective response in the nivolumab plus ipilimumab group, 9 patients (21%) with response duration ranging from 3 to 7 months have progressed after response, died, or received subsequent therapy. The remaining 34 patients (79%) had ongoing responses at the time of final analysis; in 14 patients the duration of ongoing responses is at least 6 months but less than 9 months and in 20 patients the duration of ongoing responses is at least 9 months. In addition, there was a significant improvement in PFS for the combination group compared with the ipilimumab group [HR 0.40 (95% CI: 0.22, 0.71); p-value < 0.002] with an estimated median PFS of 8.9 and 4.7 months in the nivolumab plus ipilimumab and ipilimumab groups, respectively.

Among the 140 patients with BRAF V600 wild-type or mutation-positive melanoma who received at least one dose of nivolumab or ipilimumab, serious adverse reactions (62% vs. 39%), adverse reactions leading to permanent discontinuation (43% vs. 11%) or dose delay (47% vs. 22%), and grade 3 or 4 adverse reactions (69% vs. 43%) all occurred more frequently in patients receiving the combination (n= 94) compared with those receiving single-agent ipilimumab (n=46). The most frequent serious adverse reactions in patients receiving the combination were colitis (17%), diarrhea (9%), pyrexia (6%), and pneumonitis (5%). Additional clinically significant immune-mediated adverse reactions included pneumonitis, hepatitis, endocrinopathies, nephritis/renal dysfunction, and rash.

Common adverse reactions (greater than or equal to 20%) in patients receiving nivolumab plus ipilimumab were rash, pruritus, headache, vomiting, and colitis. The most frequent grade 3 and 4 laboratory abnormalities occurring in at least 5% of patients receiving the combination were increased ALT, increased AST, increased lipase, increased amylase, hyponatremia, and lymphopenia.

When used in combination with ipilimumab, the recommended dose and schedule is nivolumab 1 mg/kg administered as an intravenous infusion over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for four doses. The recommended subsequent dose of nivolumab, as a single agent, is 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Full prescribing information is available: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125554s002lbl.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).


October 9, 2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125554s005lbl.pdf

On October 9, 2015, the U. S. Food and Drug Administration approved nivolumab (Opdivo® Injection, Bristol-Myers Squibb Co.), 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®. This approval expands the indication for nivolumab in NSCLC with progression on or after platinum-based chemotherapy to include non-squamous histologies. FDA approved nivolumab for patients with metastatic squamous NSCLC with progression on or after platinum-based chemotherapy on March 4, 2015.  

Approval was based on demonstration of an improvement in overall survival (OS) in an international, multi-center, open-label, randomized trial comparing nivolumab to docetaxel in patients with metastatic non-squamous NSCLC with progression on or after platinum-based chemotherapy.

The clinical trial enrolled 582 patients who were randomized (1:1) to receive nivolumab 3 mg/kg every 2 weeks (n=292) or docetaxel 75 mg/m2 every 3 weeks (n=290) until disease progression or unacceptable toxicity. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis.  

The trial demonstrated improvement in OS with a hazard ratio of 0.73 (95% CI: 0.60, 0.89); p <0.002. The median OS was 12.2 months in patients treated with nivolumab and 9.4 months in patients treated with docetaxel. The trial also demonstrated a significant improvement in overall response rate (19% vs 12%) in the nivolumab and docetaxel arms, respectively; the median response duration was 17 months in the nivolumab arm and 6 months in the docetaxel arm. There was no significant difference in progression-free survival.

Archival tumor specimens were evaluated for tumor PD-L1 expression (PD-L1 immunohistochemistry 28-8 pharmDx assay) following completion of the trial in 78% of the study population. Across this subgroup, 46% were PD-L1 negative (less than 1% of tumor cells expressing PD-L1) and 54% of patients had greater than or equal to 1% of tumor cells expressing PD-L1. Pre-specified subgroup analyses suggested that patients with PD-L1 positive NSCLC (PD-L1 expression in greater than or equal to 1% of tumor cells) had a larger survival treatment effect than those with PD-L1 negative NSCLC (PD-L1 expression in less than 1% of tumor cells).

The most common (greater than or equal to 20%) grade 1-4 adverse reactions in the nivolumab arm included fatigue, musculoskeletal pain, cough, decreased appetite, and constipation. The most common (greater than or equal to 2%) grade 3-4 adverse reactions were dyspnea, fatigue, pneumonia, pulmonary embolism, pleural effusion, hyperglycemia, respiratory failure, and pain. The most common (greater than or equal to 2%) grade 3-4 laboratory abnormalities included lymphopenia, hyponatremia, anemia, increased AST, and increased ALT.

Serious adverse events were reported in 47 of patients receiving nivolumab. The most common serious adverse events were pneumonia, pulmonary embolism, dyspnea, and pleural effusion. Immune-mediated adverse events that occurred in patients treated with nivolumab included hypothyroidism/thyroiditis, rash, pneumonitis, diarrhea/colitis, hyperthyroidism, hepatitis, nephritis, limbic encephalitis, and polymyalgia rheumatica.

The recommended dose and schedule for nivolumab is 3 mg/kg intravenously every two weeks.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125554s005lbl.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).


March 4, 2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125527s000lbl.pdf

On March 4, 2015, the U. S. Food and Drug Administration granted approval to nivolumab (OPDIVO, Bristol-Myers Squibb Co.) for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Nivolumab was previously approved in December, 2014 for the treatment of previously treated unresectable or metastatic melanoma. Nivolumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway-mediated inhibition of the immune response, including anti-tumor immune response.

Approval was based on superior overall survival (OS) for patients who were randomly allocated to either nivolumab or docetaxel in an open-label, multicenter, multinational randomized trial in patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum-based chemotherapy regimen. Patients received nivolumab (n=135), 3 mg/kg intravenously every 2 weeks, or docetaxel (n=137) 75 mg/m2 intravenously every 3 weeks. The major efficacy outcome was OS.  

Nivolumab demonstrated a statistically significant improvement in OS as compared with docetaxel at the protocol pre-specified interim analysis. Median OS was 9.2 months (95% CI: 7.3, 13.3) for patients assigned to nivolumab and 6 months (95% CI: 5.1, 7.3) for those assigned to docetaxel [Hazard Ratio 0.59% CI: 0.44, 0.79, p=0.00025].

Approval was supported by a single-arm, multinational, multicenter trial in patients with metastatic squamous NSCLC who had progressed after receiving a platinum-based therapy and at least one additional systemic regimen. Patients (n=117) received nivolumab, 3 mg/kg intravenously every 2 weeks. The major efficacy outcome measure was confirmed objective response rate (ORR) measured by independent review committee using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The ORR was 15% (95% CI: 9, 22) All were partial responses. At the time of analysis, 10 of the 17 responding patients (59%) had response durations of 6 months or longer.

The most common (greater than or equal to 30%) adverse reactions among the 117 patients receiving nivolumab in the above single-arm trial were fatigue, dyspnea, musculoskeletal pain, decreased appetite, and cough. The most frequent grade 3 and 4 adverse drug reactions observed in at least 5% of patients treated with nivolumab were dyspnea, fatigue, and musculoskeletal pain. Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, nephritis/renal dysfunction, hypothyroidism, and hyperthyroidism.

The recommended dose of nivolumab is 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125527s000lbl.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).


November 23, 2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125554s012lbl.pdf

On November 23, 2015, the U. S. Food and Drug Administration approved nivolumab (Opdivo ® Injection, Bristol-Myers Squibb Co.) for the treatment of advanced renal cell carcinoma in patients who have received prior anti-angiogenic therapy.  

The approval was based on a randomized study in which patients with advanced renal cell cancer who had received prior anti-angiogenic therapy received either nivolumab 3 mg/kg intravenously every 2 weeks (N=410) or everolimus 10 mg orally once daily (N=411).

The primary endpoint was overall survival. Median overall survival was 25.0 and 19.6 months in the nivolumab and everolimus arms, respectively [HR 0.73 (95% CI: 0.60, 0.89); p=0.0018]. Confirmed response rate was 21.5% (95% CI: 17.6, 25.8) in the nivolumab arm and 3.9% (95% CI: 2.2, 6.2) in the everolimus arm. The median response duration was 23.0 months in the nivolumab arm and 13.7 months in the everolimus arm. Median progression-free survival was 4.6 and 4.4 months with nivolumab and everolimus arms, respectively [HR 0.88 (95% CI: 0.75, 1.03); p=0.11].

Safety was evaluated in 406 patients who had previously received at least one anti-angiogenic therapy. The most common (greater than or equal to 20%) adverse reactions included asthenic conditions, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. The most common (greater than or equal to 30%) laboratory abnormalities which have worsened compared to baseline included increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, elevated triglycerides, and hyperkalemia.

Serious adverse events were reported in 47% of patients. The most common serious adverse events (greater than or equal to 2%) were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. Nineteen deaths were reported within 30 days of the last nivolumab dose. Fifteen were attributed to progressive disease and four due to pneumonia, suicide, heart failure, and myocardial infarction. Immune-mediated adverse events (e.g., pneumonitis, diarrhea/colitis, hepatitis, nephritis, endocrinopathies, and encephalitis) have been reported.

The recommended dose and schedule for nivolumab is 3 mg/kg by intravenous infusion over 60 minutes every two weeks.

This application was granted Breakthrough Therapy Designation, Fast Track, and Priority Review. It was approved prior to the Priority Review deadline of March 15, 2016. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125554s012lbl.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).


 

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