FDA Approves Third Herceptin Biosimilar

The FDA has granted an approval to Ontruzant (SB3; trastuzumab -dttb), a Herceptin (trastuzumab) biosimilar, for the treatment of patients with HER2-overexpressing breast cancer or metastatic gastric or gastroesophageal junction adenocarcinoma.

The approval is based on data sets from seven clinical trials, which demonstrated similarity in survival outcomes and safety between Ontruzant and reference Herceptin in patients with HER2-positive adjuvant and metastatic breast cancer, as well as HER2-positive metastatic gastric cancer.

Phase 3 data on the biosimilar were published in January 2018, in which the biosimilar inducted a rate of breast pathologic complete response (bpCR) similar to Herceptin in patients with HER2-positive breast cancer, and also demonstrated comparable safety outcomes.

From April 2014 to August 2015, 800 patients were randomized to eight cycles of ONTRUZANT (402 patients) or Herceptin (398 patients) concurrently with four cycles of docetaxel followed by four cycles of fluorouracil, epirubicin and cyclophosphamide. Patients then underwent surgery, followed by 10 cycles of adjuvant Ontruzant or Herceptin.

The treatment groups were well balanced for demographics and baseline disease characteristics, with no statistical differences between the two arms. The median page age was 51 years (range, 22-65). Most patients (52.8 percent) had T2 disease and clinically involved lymph nodes (79.5 percent). Estrogen receptor (ER) and progesterone receptor (PR) were negative in 40.9 percent of tumors. The mean left ventricular ejection fraction level at baseline was 65.24 percent.

Based on the study design, Ontruzant was considered equivalent for bpCR if the 95 percent CI of the ratio was within 0.785 to 1.546, or the 95 percent CI of the difference was within 13 percent.

At the time of data cutoff, the median follow-up was 337 days (range, 94-489) in the Ontruzant arm and 338 days (range, 24-475) in the Herceptin arm. Additionally, there were no relevant differences between the twp arms in the mean values for the relative dose-intensity of both investigational products and noninvestigational products.

Results showed that, in the per-protocol population, 51.7 percent of patients achieved bpCR in the ONTRUZANT arm versus 42.0 percent in the Herceptin group. The adjusted bpCR ratio was 1.259, which was within the predefined equivalence margins. Moreover, the adjusted difference was 10.70 percent, with the lower margin contained within and the upper margin outside the predefined equivalence margins.

In the intent-to-treat population, the bpCR rate was 49.0 percent in the ONTRUZANT arm and 39.7 percent in the Herceptin arm. The adjusted ratio of the bpCR rate was 1.243, and the adjusted difference in the bpCR rate was 9.59 percent. In the intent-to-treat population, total pathologic complete response rate was 45.8 percent in the ONTRUZANT arm and 35.8 percent in the Herceptin arm.

The bpCR rates were higher in estrogen receptor (ER)— and progesterone receptor (PR)–negative patients compared with ER- and/or PR-positive patients. The event-free survival and overall survival data had not matured at the data cutoff date.

Regarding safety, at leat 95 percent of patients in both arms experienced treatment-emergent adverse events (TEAEs) during the neoadjuvant period.

In the Herceptin group, the most common (20 percent or more) TEAEs were neutropenia (63.7 percent), alopecia (63.2 percent), nausea (30.4 percent) and leukopenia (24.4 percent). The most common (20 percent or more) TEAEs in the ONTRUZANT group were neutropenia (67 percent), alopecia (67 percent), nausea (31.1 percent), leukopenia (27.9 percent) and diarrhea (20.1 percent). Four deaths occurred on the study, but none were determined to be related to the study drug.

Outcomes were similar between the two arms for TEAEs of special interest. In the ONTRUZANT arm, the rate of infusion-related reaction was 8.2 percent, the rate of asymptomatic left ventricular systolic dysfunction was 0.9 percent, and rate of congestive heart failure was 0.5 percent. Those rates in the Herceptin group were 10.0 percent, 0.7 percent, and 0 percent, respectively.

Additionally, in the pharmacokinetics population, there were 161 patients in the ONTRUZANT arm and 152 in the Herceptin arm. Mean C_trough profiles from cycle 3 to cycle 8 were similar between the two treatment groups. A total of 99.2 percent of patients in the ONTRUZANT group and 97.3 percent of patients in the Herceptin group had C_troughvalues >20 µg/mL at predose cycle 8. At cycle 8, the geometric least squares mean ratio of C_trough was 110 percent, 52.535 µg/mL in the ONTRUZANT arm and 47.816 µg/mL in the Herceptin arm. The 90 percent CI was 102 percent to 119 percent, which was contained within the predefined equivalence margins.

Three patients in the ONTRUZANT arm expressed antidrug antibodies (ADAs) up to cycle 9 versus 0 in the Herceptin group. One of those 3 obtained bpCR, and none presented significant TEAEs related to immunogenicity. Investigators said the overall incidence of ADAs was too low to perform a statistical analysis of the relationship between the ADA status and efficacy or safety, but there was no significant difference between patients who were ADA positive and negative.

The European Commission approved ONTRUZANT in November 2017.

This article originally appeared on OncLive as, "FDA Approves Third Trastuzumab Biosimilar."