Bavencio (Avelumab) Approved for Metastatic Merkel-Cell Carcinoma and for Urothelial Carcinoma

March 2018, Vol 11, Ninth Annual Payers' Guide - FDA Approvals, News & Updates
Lisa A. Raedler, PhD, RPh
Medical Writer

Merkel cells are hormone-producing cells in the skin epidermis that relay touch-related information to the brain.1 Merkel-cell carcinoma is characterized by uncontrolled growth of skin cells with Merkel-cell features. Although the incidence of Merkel-cell carcinoma has increased sharply in the past few decades, Merkel-cell carcinoma remains a rare condition; approximately 2000 new cases are diagnosed annually in the United States.2

Unlike melanoma, another aggressive skin cancer that is associated with sun exposure and immunosuppression, patients with Merkel-cell carcinoma are often infected with Merkel-cell polyomavirus.3-5 Other risk factors for Merkel-cell carcinoma include fair skin, long-term sun exposure, weakened immune system, and age >65 years.3 The median survival of patients with Merkel-cell carcinoma is approximately 9.6 months after an initial metastasis.6

Urothelial carcinoma is the most common subtype of bladder cancer, accounting for more than 90% of bladder cancer diagnoses in the United States.7 In 2017, more than 79,000 cases of bladder cancer will be diagnosed, and nearly 17,000 people will die from this disease.8

The prognosis associated with bladder cancer is favorable for patients with localized disease: 70% of patients are alive at 5 years.8 This rate decreases to 5% for patients with distant bladder cancer.8

Bavencio Approved for Skin and Bladder Cancers

On March 23, 2017, the US Food and Drug Administration (FDA) used its accelerated process to approve avelumab (Bavencio; EMD Serono/Pfizer) injection for the treatment of patients aged ≥12 years with metastatic Merkel-cell carcinoma, including those who have not received chemotherapy.9,10 Avelumab, a monoclonal antibody that inhibits programmed-cell death ligand-1 (PD-L1), is the first drug approved for this indication in the United States.9,10

On May 9, 2017, avelumab received a second accelerated approval from the FDA, for the treatment of patients with locally advanced or metastatic urothelial carcinoma that progressed during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.10,11 Both approvals will require additional evidence to complete the FDA review.

Mechanism of Action

Expressed on tumor cells and on tumor-infiltrating immune cells, PD-L1 can affect the antitumor immune response in the tumor microenvironment. The binding of PD-L1 to T-cells and antigen-presenting cells results in the suppression of cytotoxic T-cell activity and proliferation, and cytokine production.10 Avelumab binds PD-L1 and inhibits interactions between PD-L1 and its receptors, PD-1 and B7.1. This interaction results in the restoration of immune responses, including antitumor activity. In vitro evidence suggests that avelumab induces antibody-dependent cell-mediated cytotoxicity.10

Dosing and Administration

The recommended dose and schedule for avelumab is 10 mg/kg via intravenous (IV) infusion for 60 minutes every 2 weeks.10 Patients should receive premedication with an antihistamine and acetaminophen before the first 4 infusions of avelumab. Subsequently, premedication should be given based on the presence or the severity of previous infusion reactions.10

Clinical Trials
JAVELIN Merkel 200

The FDA approval of avelumab for metastatic Merkel-cell carcinoma was based on JAVELIN Merkel 200, an open-label, single-arm, multicenter study of 88 patients with histologically confirmed metastatic Merkel-cell carcinoma that progressed during or after chemotherapy.9,12 Patients received avelumab 10 mg/kg IV every 2 weeks until disease progression or until unacceptable toxicity.10

The major efficacy outcome measures were confirmed overall response rate (ORR) as assessed by a blinded independent review committee (IRC) every 6 weeks, and the IRC-assessed duration of response. All patients completed 12 months of follow-up.10

The patients’ median age was 73 years (range, 33-88 years), and their Eastern Cooperative Oncology Group (ECOG) performance score was 0 (56%) or 1 (44%). All patients had received ≥1 previous therapies for metastatic Merkel-cell carcinoma; 52% had evidence of Merkel-cell polyomavirus.10 The ORR was 33% (95% confidence interval [CI], 23.3-43.8; Table 1).10 Responses were seen regardless of tumor PD-L1 expression or the presence of Merkel-cell polyomavirus.10

Table 1

The median duration of exposure to avelumab was 4 months (range, 2 weeks-21 months); 14% of patients received treatment for >1 year.10

JAVELIN Solid Tumor

The FDA approval of avelumab for advanced urothelial carcinoma was based on data from a cohort of 242 patients with previously treated advanced urothelial carcinoma who were enrolled in the JAVELIN Solid Tumor clinical trial, an open-label, single-arm, multicenter study.11

Patients received avelumab 10 mg/kg IV every 2 weeks until disease progression or until unacceptable toxicity. The primary outcome measures were IRC-assessed ORR every 6 weeks, and the duration of response.10

Among the 226 patients who were followed for at least 13 weeks, the median age was 68 years (range, 30-89 years), and the ECOG performance score was 0 (34%) or 1 (66%). Overall, 47% of patients received only cisplatin-based regimens, 32% received only carboplatin-based regimens, and 20% received cisplatin- and carboplatin-based regimens.10 The ORR for patients with ≥6 months of follow-up was 16.1% (95% CI, 10.8-22.8; Table 2).10 No clear difference was seen in response rates based on PD-L1 expression. The median duration of exposure to avelumab was 12 weeks (range, 2-92 weeks).10

Table 2

Adverse Reactions

Of the 88 patients with metastatic Merkel-cell carcinoma, the most common (≥20%) adverse reactions were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema.10 Avelumab was discontinued in 7% of patients because of adverse reactions, including ileus, transaminitis, creatine kinase elevation, tubulointerstitial nephritis, and pericardial effusion.10 Serious adverse reactions in >1 patient included anemia, abdominal pain, ileus, asthenia, and cellulitis.10

Among the 242 patients with advanced urothelial carcinoma, the most common (≥20%) adverse reactions with avelumab were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection. Fourteen (6%) patients who received avelumab died secondary to events that included respiratory failure, sepsis, cerebrovascular accident, and gastrointestinal events.

Avelumab was permanently discontinued because of adverse reactions in 12% of patients. The most common (≥3%) grade 3 or 4 adverse reactions included anemia, fatigue, hyponatremia, hypertension, urinary tract infection, and musculoskeletal pain.10

Avelumab has no contraindications.10

Use in Specific Populations

Women of childbearing potential should use effective contraception during treatment with avelumab and for at least 1 month after the last dose.10

Nursing women should be advised not to breastfeed during treatment with avelumab and for at least 1 month after the last dose.10

The safety and efficacy of avelumab have been established in pediatric patients aged ≥12 years with metastatic Merkel-cell carcinoma.10

Clinical studies of avelumab in Merkel-cell carcinoma did not include sufficient patients aged ≥65 years to determine whether they respond differently from younger patients. No overall differences in the safety or efficacy of avelumab were reported between elderly patients and younger patients with urothelial carcinoma.10

Warnings and Precautions

Avelumab can cause life-threatening immune-mediated reactions, including pneumonitis, colitis, nephritis, and hepatitis.10

Immune-mediated endocrinopathies, including adrenal insufficiency during and after treatment; thyroid disorders; and type 1 diabetes, including diabetic ketoacidosis, have been reported with avelumab.10

To prevent severe or life-threatening infusion-related reactions, patients should receive premedication with an antihistamine and acetaminophen before the first 4 infusions of avelumab.10

Conclusion

Avelumab, a PD-L1 inhibitor, is the first drug approved in the United States for patients with metastatic Merkel-cell carcinoma, a rare and aggressive skin cancer. This approval provides the first treatment option available for patients with this rare but aggressive disease. The efficacy and safety of avelumab were established in a phase 2 clinical trial for metastatic Merkel-cell carcinoma and in a phase 1 clinical trial for advanced urothelial carcinoma. Both approvals were done under the FDA’s accelerated review process. Final approval of both indications is contingent on confirmatory evidence from clinical trials.

References
1. merkelcell.org. What is a Merkel cell? Merkel cells are found in the skin, where they function mainly as touch receptors. http://merkelcell.org/about-mcc/what-is-a-merkel-cell/. Accessed June 11, 2017.
2. merkelcell.org. What is Merkel cell carcinoma? Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with roughly 2,000 new cases per year in the United States. https://merkelcell.org/about-mcc/what-is-merkel-cell-carcinoma/. Accessed June 11, 2017.
3. merkelcell.org. Causes of Merkel cell carcinoma: learn more about who is at elevated risk for developing Merkel cell carcinoma and what we know about the causes of this cancer. https://merkelcell.org/about-mcc/causes-of-merkel-cell­carcinoma/. Accessed June 11, 2017.
4. Grabowski J, Saltzstein SL, Sadler GR, et al. A comparison of Merkel cell carcinoma and melanoma: results from the California Cancer Registry. Clin Med Oncol. 2008;2:327-333.
5. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319:1096-1100.
6. Miller NJ, Bhatia S, Parvathaneni U, et al. Emerging and mechanism-based therapies for recurrent or metastatic Merkel cell carcinoma. Curr Treat Options Oncol. 2013;14:249-263.
7. National Cancer Institute. Bladder cancer treatment (PDQ)–health professional version. Updated June 5, 2017. www.cancer.gov/types/bladder/hp/bladder-treatment-pdq. Accessed June 11, 2017.
8. National Cancer Institute. SEER cancer stat facts: bladder cancer. http://seer.cancer.gov/statfacts/html/urinb.html. Accessed June 11, 2017.
9. US Food and Drug Administration. FDA approves first treatment for rare form of skin cancer. March 23, 2017. www.fda.gov/newsevents/newsroom/pressannouncements/ucm548278.htm. Accessed June 11, 2017.
10. Bavencio (avelumab) injection [prescribing information]. Rockland, MA: EMD Serono; May 2017.
11. US Food and Drug Administration. FDA grants accelerated approval to avelumab for urothelial carcinoma. May 9, 2017. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm557162.htm. Accessed June 11, 2017.
12. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma. Lancet Oncol. 2016;17:1374-1385.

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