EBO February 2019 Medical World News: Regulatory Updates

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Evidence-Based Oncology, February 2019, Volume 25, Issue 2

FDA Grants Accelerated Approval to Pembrolizumab for MCC

The FDA recently granted accelerated approval1 to pembrolizumab (Keytruda) for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). The indication was approved under the accelerated approval pathway due to tumor response rate and durability of response.

The approval was based on data from the Cancer Immunotherapy Trials Network (CITN)’s CITN-09/KEYNOTE-017 trial. The phase 2, nonrandomized, multicenter, open-label trial enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy.

“Merkel cell carcinoma is an aggressive and fast-growing form of skin cancer that has historically been challenging to treat... [We] are pleased to provide an important new therapeutic option for Merkel cell carcinoma patients,” said Scott Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, in a statement.2

Patients were administered pembrolizumab 2 mg/kg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients who did not demonstrate disease progression were treated for up to 24 months. Researchers assessed tumor status at 13 weeks, followed by every 9 weeks for the first year and every 12 weeks thereafter.

The investigators found that pembrolizumab as a monotherapy demonstrated an objective response rate of 56% (95% CI, 41%-70%), with a complete response rate of 24% (95% CI, 13%-38%) and a partial response rate of 32% (95% CI, 20%-47%). Ninety-six percent of responding patients experienced a durability of response for 6 months or longer, and 54% experienced a durability of response for 12 months or longer.

“The CITN-09/KEYNOTE-017 trial demonstrates that first-line treatment with anti-PD1 therapy provides a meaningful advance for Merkel cell carcinoma patients who have historically had a poor long-term prognosis,” said Paul Nghiem, MD, PhD. “A few years ago, patients with Merkel cell carcinoma did not have treatment options beyond chemotherapy. As a practicing physician, I am pleased that this approval provides another option for patients facing this rare and challenging disease.”


  1. FDA approves pembrolizumab for merkel cell carcinoma [press release]. Washington, DC: FDA; December 19, 2018. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm628867.htm. Accessed December 21, 2018.
  2. FDA approves Merck’s Keytruda (pembrolizumab) for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic merkel cell carcinoma, a rare form of skin cancer [press release]. Kenilworth, NJ: Merck Sharp & Dohme Corp; December 19, 2018. mrknewsroom.com/news-release/oncology/fda-approves-mercks-keytruda-pembrolizumab-treatment-adult-and-pediatric-patient. Accessed December 21, 2018.

FDA Approves Third Trastuzumab Biosimilar, Ontruzant

The FDA has approved Samsung Bioepis’ Ontruzant (trastuzumab-dttb), a biosimilar trastuzumab referencing Herceptin, for the treatment of HER2- positive breast cancer and HER2-overexpressing gastric cancer.

The drug was first approved by the European Medicines Agency in November 2017, making it the first biosimilar trastuzumab to be approved in the European Union. Since the approval, Europe has seen the entry of 3 additional versions of biosimilar trastuzumab: Herzuma, Kanjinti, and Ogivri.

Ontruzant will now compete in the United States with the reference product, Herceptin, which in the third quarter of 2018, earned developer Roche an estimated $5,332,998 globally. The newly approved biosimilar will also eventually compete with 2 prior FDA-approved biosimilars: Ogivri, developed by Mylan and Biocon, and Herzuma, developed by Celltrion and Teva. To date, no trastuzumab biosimilars have launched in the United States, but Roche has reportedly reached an undisclosed agreement with Mylan concerning the launch of Ogivri in the United States.1

Under a prior agreement, Ontruzant will be commercialized in the United States by Merck.

Samsung Bioepis recently revealed safety and efficacy results for the biosimilar at 1 year.2 The results, presented in an abstract at the 2018 San Antonio Breast Cancer Symposium, held in San Antonio, Texas, from December 4-8, 2018, reported on a study of patients with HER2- positive early breast cancer or locally advanced breast cancer who were randomized to receive either the biosimilar or its reference concurrently with chemotherapy.

Patients underwent surgery, then received treatment with either SB3 (Ontruzant) or its reference. Afterward, 367 patients—181 treated with the reference trastuzumab and 186 treated with the biosimilar—were enrolled.

Within the group of patients treated with the reference, 126 had been exposed to lots of trastuzumab, with expiry dates from August 2018 to December 2019, that had a lower antibody-dependent cell-mediated cytotoxicity (ADCC) than other lots of the reference product. The remaining 55 patients given the reference therapy were unexposed to these lots. After 30.1 months of treatment with the biosimilar and 30.2 months of treatment with the reference, there was no statistically significant difference in event-free survival between the biosimilar arm (96.7%) and the patients unexposed to the lower-ADCC activity lots of the reference (98.2%) (HR, 1.19; 95% CI, 0.23-6.18; P = .8376).


  1. Davio K. FDA accepts BLA for Samsung Bioepis’ trastuzumab biosimilar. The Center for Biosimilars® website. centerforbiosimilars.com/news/fda-accepts-bla-for-samsung-bioepis-trastuzumab-biosimilar?rel=0. Published December 20, 2017. Accessed January 16, 2017.
  2. Pegram MD, Pivot X, Cortes J, et al. Event-free survival by ADCC status from a follow-up study compar- ing SB3 (trastuzumab biosimilar) with reference trastuzumab for HER2 positive breast cancer in neoad- juvant setting. Presented at the 2018 San Antonio Breast Cancer Symposium, December 4-8, 2018; San Antonio, Texas. Abstract P6-17-09. abstracts2view.com/sabcs18/view.php?nu=SABCS18L_1224&terms=.

Mylan and Biocon's Trastuzumab Biosimilar Gains European Marketing Authorization

Mylan and Biocon have received final approval from the European Commission to market their trastuzumab biosimilar, Ogivri, referencing Herceptin. The drug earned authorization for the treatment of HER2- positive early breast cancer, metastatic breast cancer, and metastatic gastric cancer as either monotherapy or combination therapy.

The companies announced1 the receipt of the marketing authorization, which applies to all 28 EU member states and the European Economic Area, after having received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use in October 2018.

The positive opinion was based on a data package that included analytical data as well as preclinical and clinical studies. The results from the studies show there were no clinically meaningful differences between the reference trastuzumab and the biosimilar, and findings from the phase 3 HERITAGE clinical trial underscored the similarity of the 2 molecules.

The HERITAGE trial,2 a multicenter, double-blind, randomized, parallel-group study, is evaluating the efficacy and safety of the biosimilar in comparison with the reference trastuzumab

in combination with a taxane as first-line therapy in patients with HER2-positive metastatic breast cancer. Patients were randomized to receive either the biosimilar or the reference with a

taxane every 2 weeks. After 24 weeks, patients with responding or stable disease were given trastuzumab as monotherapy. They were followed through 48 weeks for progression-free

survival and 36 months for overall survival (OS). The primary end point was overall response rate.

Of the 230 patients treated with the biosimilar, 70% achieved a response, compared with 64% of the 228 treated with reference trastuzumab at week 24, with 1.3% of those in the biosimilar group and 0% of those in the reference group demonstrating complete response and 68.3% and 64%, respectively, demonstrating partial responses. As assessments are currently ongoing, OS will be calculated after either 36 months or 240 deaths.

Ogivri is also approved in the United States, where it received FDA authorization in December 2017. The drug is not yet marketed in the United States, however, and Mylan and Biocon have not yet announced a launch date for their product in either the US or European market.


  1. Biosimilar trastuzumab co-developed by Biocon receives approval in the EU [press release]. Bengaluru, India: Mylan and Biocon; December 19, 2018. biocon.com/191218_Biocon_Company_Statement_SE.asp. Accessed December 20, 2018.
  2. Rosenberg J. New directions in oncology biosimilars. The Center for Biosimilars® website. centerforbiosimilars.com/conferences/asco-2018/new-directions-in-oncology-biosimilars Published June 7, 2018. Accessed December 20, 2018.