The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 16-0 to recommend approval to MYL-1401O, the trastuzumab (Herceptin) biosimilar manufactured by Mylan Pharmaceuticals.
Mylan is looking to license MYL-1401O in the U.S. as a treatment for adjuvant breast cancer, metastatic breast cancer, and metastatic gastric cancer, the same indications as trastuzumab. Genentech, the manufacturer of trastuzumab, holds an exclusive license for the metastatic gastric cancer indication. The committee discussed whether MYL-1401O was a biosimilar for that indication, but Mylan can’t market the drug for that purpose until the exclusive license expires.
The biologics license application (BLA) will now go to the FDA for final approval, with a decision expected by September 3. Mylan already sells MYL-1401O in 14 markets around the world.
I appreciate totality of evidence presented very clearly,” said Thomas S. Uldrick, MD, MS, clinical director of the HIV & AIDS Malignancy Branch at National Cancer Institute. “The agent appears highly similar and scientific justification for use in HER2-positive gastric cancer is also reasonable.”
“There was very strong evidence that [MYO-1401O was] highly similar with no clinically meaningful differences,” added Craig W. Hendrix, MD, professor of medicine and pharmacology and molecular sciences at the Johns Hopkins University School of Medicine.
Mylan submitted phase III results from HERiTAge, a two-part, multicenter, double-blind, randomized, parallel-group study to support their biologics license application (BLA). Patients with measurable HER2-positive metastatic breast cancer who had not received prior chemotherapy or trastuzumab for metastatic disease were randomly assigned to MYL-1401O (n =230) or trastuzumab with docetaxel or paclitaxel (n = 228).
Patients underwent a minimum of 8 cycles in Part 1 of the trial, with trastuzumab continuing until progression. Both forms of trastuzumab were administered with a loading dose of 8 mg/kg and a maintenance dose of 6 mg/kg every 3 weeks.
In Part 2, patients who had stable disease or better could continue with MYL-1401O or EU-trastuzumab.
The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival, overall survival, time to progression, safety, and tolerability.
MYL-1401O demonstrated an overall response rate (ORR) after 24 weeks of 69.6% among women who received the biosimilar in combination with a taxane compared with a 64% ORR for patients who took trastuzumab plus a taxane. The ratio of ORR for MYL-1401O to trastuzumab was 1.09; both 90% CI (0.974-1.211) and 95% CI (0.954-1.237). The difference in ORR between the two arms was 6.0% (90% CI: -1.3%, 13.2%). At the Week 48 cut off, the median duration of response was 9.7 months in both groups.
In the per protocol population, ORR was 70% for MYL-1401O compared with 67% for trastuzumab. The ratio of ORR was 1.06 (90% CI: 0.96, 1.18).
Progression-free survival (PFS) was nearly identical between the two groups (stratified HR, 0.95; 95% CI, 0.71-1.25). Median overall survival has not been met in either group.
Safety data also were comparable. Serious adverse events (AEs) occurred in 39.3% of the patients in the MYL-1401O arm compared with 37.0% in the Herceptin arm, with neutropenia as the most frequently reported serious AE in both arms (57.5% vs 54.1%, respectively).
Mylan also submitted two non-clinical animal studies to establish pharmacokinetic similarity, a 4-week, repeat-dose toxicity and toxicokinetic study in cynomolgus monkeys comparing MYL-14010 to EU-trastuzumab and MYL-HER-1002. MYL-HER-1002 was a single-dose, randomized, double-blind comparative pharmacokinetic (PK) study in cynomolgus monkeys comparing MYL-1401O to EU-trastuzumab, and EU-trastuzumab.
Healthy male subjects were given an infusion of 8 mg/ kg MYL-1401O (n = 42), US-approved trastuzumab (n = 37), or EU-approved trastuzumab (n = 41). The pre-defined PK endpoints were AUC0-∞, AUC0-t, and CMax.
ODAC stuff concluded there was no evidence to indicate potential clinical safety concerns associated with MYL-1401O administration, and no toxicity findings in animals treated with either MYL-1401O or EU-Herceptin. “The toxicokinetic profile of MYL-1401O was comparable to that of EU-Herceptin.”
FDA staff concluded that data from MYL-HER-1002 show that MYL-1401O demonstrated a similar PK profile with US- and EU-approved trastuzumab (see table).