SIZE XSSIZE SMSIZE MDSIZE LG

The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


May 14, 2019–Avelumab (BAVENCIO, EMD Serono, Inc.) approved in combination with axitinib for first-line treatment of patients with advanced renal cell carcinoma (RCC) (with Pharmacist's Applications to Practice)

May 9, 2017–Avelumab (BAVENCIO®, EMD Serono, Inc.) approved for treatment of patients with locally advanced or metastatic urothelial carcinoma.

March 23, 2017–Avelumab (BAVENCIO, EMD Serono, Inc.) approved for treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC).


May 14, 2019, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761049s006lbl.pdf.

On May 14, 2019, the Food and Drug Administration approved avelumab (BAVENCIO, EMD Serono, Inc.) in combination with axitinib for first-line treatment of patients with advanced renal cell carcinoma (RCC).

Approval was based on JAVELIN Renal 101 (NCT02684006), a randomized, multicenter, open-label trial of avelumab plus axitinib in 886 patients with untreated advanced RCC regardless of tumor PD-L1 expression. Patients were randomized to receive either avelumab 10 mg/kg intravenous infusion every 2 weeks in combination with axitinib 5 mg twice daily orally or sunitinib 50 mg once daily orally for 4 weeks followed by 2 weeks off until radiographic progression or unacceptable toxicity.

The main efficacy endpoints were progression-free survival (PFS), assessed by blinded independent central review using RECIST 1.1, and overall survival (OS) in patients with PD-L1-positive tumors. Secondary endpoints were PFS and OS in the total population. A statistically significant improvement in PFS was demonstrated in patients with PD-L1-positive tumors (HR 0.61; 95% CI: 0.48, 0.79; p=0.0001). A statistically significant improvement in PFS in the total population was also demonstrated (HR 0.69; 95% CI: 0.56, 0.84; p=0.0002) at interim analysis. Median PFS in the total population was 13.8 months for patients on the avelumab plus axitinib arm and 8.4 months for patients who received sunitinib. With a median overall survival follow-up of 19 months, OS data were immature with 27% deaths in the intent-to-treat population.

The most common adverse reactions of avelumab in combination with axitinib in ≥ 20% of patients with RCC were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache. Grade 3 or 4 hepatotoxicity occurred in 9% of patients and resulted in in permanent discontinuation of avelumab or axitinib in 7%. Major cardiac adverse events occurred in 7% of patients treated with the combination.

The recommended avelumab dose for advanced RCC is 800 mg as an intravenous infusion every 2 weeks in combination with axitinib 5 mg orally twice daily.

View full prescribing information for BAVENCIO.

This application used the Assessment Aid pilot program. FDA granted this application priority review and Breakthrough Therapy designation. 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.

 

Pharmacist’s Applications to Practice

Avelumab in Combination with Axitinib for First-Line Treatment of Advanced Renal Cell Carcinoma

Author: Samantha Larson, PharmD
PGY2 Oncology Pharmacy Resident
University of Minnesota–Fairview
Minneapolis, MN

What is the potential role for avelumab in combination with axitinib in the treatment of renal cell carcinoma?

  • Programmed death 1 (PD-1) receptor
    • PD-1 is a protein that functions as a receptor expressed by activated T cells.
    • Programmed death-ligand 1 (PD-L1) is one of the ligands of PD-1 that is expressed on antigen-presenting cells and tumor cells.
    • PD-L1 is the ligand known to be responsible for the immunosuppressive effects of PD-1.1
  • Avelumab, a human immunoglobulin G1 (IgG1) monoclonal antibody, binds to PD-L1 and blocks the interaction between PD-L1 and PD-1.
    • When this interaction between PD-L1 and PD-1 is blocked, the inhibitory effects of PD-L1 on the immune response are released, resulting in the restoration of immune responses, including antitumor immune responses.2
  • Approval by the U.S. Food and Drug Administration (FDA) of avelumab in combination with axitinib as first-line treatment of advanced renal cell carcinoma was based on the phase 3 randomized (1:1) multicenter study JAVELIN Renal 101.3
    • Study population: 886 patients
      • 560 of 886 patients (63.2%) had PD-L1–positive tumors.
      • Patients with positive, negative, or unknown PD-L1 status were included.
      • Patients from all Memorial Sloan Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium prognostic risk groups were included.
      • 442 were assigned to receive axitinib plus avelumab.
      • 444 were assigned to receive sunitinib.
    • Intervention
      • Axitinib 5 mg orally twice daily on a continuous schedule (with possible dose increases to 7 mg and 10 mg according to safety criteria) plus avelumab intravenously 10 mg/kg every 2 weeks
      • OR Sunitinib 50 mg orally daily for 4 weeks of a 6-week cycle
    • Primary endpoints: progression-free survival (PFS) and overall survival (OS) among patients with PD-L1 positive tumors
      • PD-L1-positive tumors were defined as tumors having ≥1% of immune cells staining positive within the tumor area of the tested tissue sample.
      • PD-L1 expression was assessed at a central laboratory with the use of the Ventana PD-L1 assay.
    • Secondary endpoints: PFS and OS, irrespective of PD-L1 expression; objective response rate (ORR), adverse events, tumor-tissue biomarkers, and patient-reported outcomes
    • Efficacy results (N = 886)
      • Primary endpoint (patients with PD-L1 positive tumors)
        • PFS was longer in the axitinib plus avelumab group (13.8 months) versus sunitinib (7.2 months); hazard ratio (HR) = 0.61; 95% confidence interval (CI) = 0.47–0.79; p < .001.
        • ORR was 55.2% with axitinib plus avelumab versus 25.5% with sunitinib (odds ratio = 3.73; 95% CI = 2.53–5.37).
        • Complete response (CR) was 4.4% in the axitinib plus avelumab group versus 2.1% in the sunitinib group.
      • Secondary endpoints (patients with and without PD-L1 positive tumors)
        • PFS was longer in the axitinib plus avelumab group (13.8 months) versus sunitinib (8.4 months); HR = 0.69; 95% CI, 0.56 –0.84; p < .001).
        • ORR was 51.4% with axitinib plus avelumab versus 25.7% with sunitinib (odds ratio = 2.10; 95% CI = 2.30–4.15).
        • CR was 3.4% in the axitinib plus avelumab group versus 1.8% in the sunitinib group.
    • Safety results
      • Most common adverse events (any grade): diarrhea (62.2%), hypertension (49.5%), fatigue (41.5%), nausea (34.1%), palmar-plantar erythrodysesthesia syndrome (33.4%), dysphonia (30.6%), decreased appetite (26.3%), hypothyroidism (24.9%), stomatitis (24%), cough (23%), arthralgia (19.6%), decreased weight (19.6%), increased alanine aminotransferase (ALT) (17.1%), increased aspartate aminotransferase (AST) (14.5%), rash (14.3%).
      • Most common grade ≥3 adverse effect: hypertension (25.6%)
  • National Comprehensive Cancer Network (NCCN) lists avelumab in combination with axitinib as a category-2A treatment for relapsed or stage IV renal cell carcinoma in patients with favorable to poor prognostic factors.4 With the manageable side-effect profile and the improved PFS and high response rates irrespective of the patient’s PD-L1 status, avelumab in combination with axitinib may be a suitable option for patients with advanced renal cell carcinoma.

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

  • Pharmacists can ensure appropriate laboratory and clinical monitoring at initiation of and throughout avelumab therapy including the following:5
    • monitoring the patient’s ALT, AST, total bilirubin, serum creatinine, blood glucose, and thyroid function tests at baseline and periodically during treatment
    • monitoring for signs and symptoms of colitis, thyroid disorders, pneumonitis, adrenal insufficiency, hepatitis, hyperglycemia, other immune-related toxicities, and infusion reactions.
  • Pharmacists can ensure that appropriate dose modifications are made for avelumab-related toxicities including the following:5
    • Nephritis
      • Serum creatinine >1.5 up to 6 times the upper limit of normal (ULN): Withhold avelumab treatment. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent, followed by a taper). Resume avelumab treatment with complete or partial resolution (to grade 0 or 1) of nephritis and renal dysfunction after corticosteroid taper.
      • Serum creatinine >6 times ULN: Discontinue avelumab permanently. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper.
    • Hepatitis
      • AST or ALT ≥3 to <5 times ULN or total bilirubin ≥1.5 to <3 times ULN: Withhold avelumab (and axitinib) treatment until recovery to grade 0 or 1. If the condition is persistent (>5 days), consider systemic corticosteroids (prednisone initial dose of 0.5 to 1 mg/kg daily or equivalent), followed by a taper. After recovery, consider rechallenging with a single drug (either avelumab or axitinib) or sequential rechallenging with both avelumab and axitinib; axitinib may require a dose reduction.
      • AST or ALT ≥5 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN or total bilirubin ≥3 times ULN: Discontinue avelumab (and axitinib) permanently; consider systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent), followed by a corticosteroid taper.
    • Pneumonitis
      • Grade 2: Withhold avelumab and resume avelumab in patients with complete or partial resolution (grade 0 to 1) after corticosteroid taper
      • Grade 3 or higher: Permanently discontinue.
    •  Colitis
      • Grade 2 or 3: Withhold avelumab and resume avelumab in patients with complete or partial resolution (grade 0 to 1) after corticosteroid taper.
      • Grade 4 diarrhea or colitis or recurrent grade 3 diarrhea or colitis: Permanently discontinue.
    • Endocrinopathies
      • Grade 3 or 4: Withhold avelumab and resume avelumab in patients with complete or partial resolution (grade 0 to 1) after corticosteroid taper.
    • Other immune-related adverse effects
      • Moderate or severe clinical signs or symptoms (not described previously): Withhold treatment and evaluate. Administer high-dose systemic corticosteroids, and if appropriate, initiate hormone replacement therapy. When toxicity improves to grade 1 or less, initiate a corticosteroid taper. Resume avelumab treatment with complete or partial response to grade 0 or 1 after corticosteroid taper.
      • Life-threatening reactions (excluding endocrinopathies), recurrent severe immune-mediated reactions, or persistent grade 2 or 3 immune-mediated reactions lasting 12 weeks or longer, or requirement for ≥10 mg/day prednisone in adults (or equivalent) for >12 weeks: Discontinue permanently. If appropriate, administer high-dose systemic corticosteroids followed by a corticosteroid taper.
  • No dosage adjustments are provided in the manufacturer’s labeling for baseline renal or hepatic impairment.
  • Avelumab is administered as an intravenous infusion given over 60 minutes through a 0.2-micron sterile nonpyrogenic low-protein binding inline filter.5
    • Do not infuse other medications through the same infusion line.
  • Premedicate with an antihistamine and acetaminophen for the first four infusions and subsequently as needed.

Clinical Pearls5

  • Currently, avelumab in combination with axitinib is approved for first-line treatment of patients with metastatic renal cell carcinoma. Avelumab showed improved PFS and CR rates as compared to a single-agent vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI). It is unknown how avelumab plus axitinib compares to another approved immunotherapy and TKI combination, pembrolizumab plus axitinib, and further studies are needed to assess this question.
  • Clinical trials are ongoing to determine the efficacy of avelumab in treating metastatic renal cell carcinoma, including in combination with alternative TKIs.6
  • Avelumab has a copay assistance program through CoverOne.com.7

References

  1. Weinstock M, McDermott D. Targeting PD-1/PD-L1 in the treatment of metastatic renal cell carcinoma. Ther Adv Urol. 2015;7(6):365-377.
  2. Choueiri TK, Larkin J, Oya M, et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol. 2018;19(4):451-460. doi:10.1016/s1470-2045(18)30107-4.
  3. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103-1115.
  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Kidney Cancer. Version 2.2020 (September 3, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed September 21, 2019.
  5. Bavencio (avelumab) [package insert]. Rockland, MA: EMD Serono, Inc., and Pfizer Inc; 2017.
  6. U.S. National Library of Medicine. ClinicalTrials.gov. Avelumab ongoing clinical trials in renal cell carcinoma. Available at https://clinicaltrials.gov/ct2/results?cond=Renal+Cell+Carcinoma&term=avelumab&cntry=&state=&city=&dist=. Accessed September 21, 2019.
  7. Support for eligible patients prescribed BAVENCIO® (avelumab) and INLYTA® (axitinib). Available at https://www.bavencio.com/hcp/rcc/support

May 9, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761078s000lbl.pdf

On May 9, 2017, the U.S. Food and Drug Administration granted accelerated approval to avelumab (BAVENCIO®, EMD Serono, Inc.) for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

Approval was based on data from an open-label, single arm, multi-center study that enrolled 242 patients with locally advanced or metastatic urothelial carcinoma whose disease progressed on or after platinum-based therapy or within 12 months of a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Patients received avelumab, 10 mg/kg intravenously, every 2 weeks until radiographic or clinical progression or unacceptable toxicity. All patients received pre-medication with an anti-histamine and acetaminophen prior to each avelumab administration. Confirmed overall response rate (ORR) in patients who had been followed for at least 13 weeks was 13.3% (n=30) (95% CI: 9.1, 18.4), and 16.1% (n=26) (95% CI: 10.8, 22.8) in patients who had been followed for at least 6 months. Median time to response was 2.0 months (range 1.3-11.0). The median response duration had not been reached in patients followed for at least 13 weeks or at least 6 months, but ranged from 1.4+ to 17.4+ months in both groups.

Deaths due to an adverse reaction occurred in 6% of patients. Serious adverse reactions were reported in 41% of patients. The most frequent serious adverse reactions reported in 2% or more of patients were urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestinal obstruction, and pyrexia. The most common adverse reactions that occurred in at least 20% of patients were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.

The recommended dose of avelumab is 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks. Pre-medicate with an anti-histamine and acetaminophen prior to the first four infusions of avelumab.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761078s000lbl.pdf.

FDA granted this application priority review. FDA approved avelumab for this indication approximately 3 months ahead of 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.

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 23, 2017

http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf

On March 23, 2017, the U.S. Food and Drug Administration granted accelerated approval to avelumab (BAVENCIO, EMD Serono, Inc.) for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). Avelumab is a programmed death-ligand 1 (PD-L1) blocking human IgG1 lambda monoclonal antibody. This is the first FDA-approved product to treat this type of cancer.

Approval was based on data from an open-label, single-arm, multi-center clinical trial (JAVELIN Merkel 200 trial) demonstrating a clinically meaningful and durable overall response rate (ORR). All patients had histologically confirmed metastatic MCC with disease progression on or after chemotherapy administered for metastatic disease.

ORR was assessed by an independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The ORR was 33% (95% confidence interval [CI]: 23.3, 43.8), with 11% complete and 22% partial response rates. Among the 29 responding patients, the response duration ranged from 2.8 to 23.3+ months with 86% of responses durable for 6 months or longer. Responses were observed in patients regardless of PD-L1 tumor expression or presence of Merkel cell polyomavirus.

Safety data were evaluated in 1738 patients who received avelumab, 10 mg/kg, every 2 weeks. The most common serious adverse reactions to avelumab are immune-mediated adverse reactions (pneumonitis, hepatitis, colitis, adrenal insufficiency, hypo- and hyperthyroidism, diabetes mellitus, and nephritis) and life-threatening infusion reactions. Among the 88 patients enrolled in the JAVELIN Merkel 200 trial, the most common adverse reactions were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema. Serious adverse reactions that occurred in more than one patient in the trial were acute kidney injury, anemia, abdominal pain, ileus, asthenia, and cellulitis.

The recommended dose and schedule of avelumab is 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks. All patients should receive premedication with an antihistamine and acetaminophen prior to the first four infusions of avelumab.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf.

Avelumab received orphan drug status and breakthrough therapy designation for this indication, and the application was granted priority review. As a condition of accelerated approval, an additional study is required to confirm the clinical benefit of avelumab for this indication. The approval was granted approximately two months ahead of 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.

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).

xs
sm
md
lg