PFS With MYL-1401O Regimen Similar to Trastuzumab at 48 Weeks in HER2-Positive Metastatic Breast Cancer

Hope Rugo, MD

Hope Rugo, MD

Progression-free survival (PFS) was found to be almost identical at 48 weeks with MYL-1401O (Ogivri; trastuzumab-dkst) in combination with a taxane as initial therapy followed by MYL-1401O monotherapy as maintenance versus trastuzumab (Herceptin) in patients with HER2-positive metastatic breast cancer, according to phase III findings of the HERITAGE trial. Results of the trial were presented at the 2018 ASCO Annual Meeting.¹

This finding is consistent with the overall response rate (ORR) found in a previous report investigating MYL-1401O, a trastuzumab biosimilar, and the originator product as first-line therapy with a taxane.²

The PFS at week 48 correlated with the week 24 ORR, said Hope Rugo, MD, professor of medicine, University of California, San Francisco. Through 48 weeks, the PFS was nearly identical between the two arms at 11.1 months (P= .842) with similar CIs (MYL-1401O, 8.81-11.20; trastuzumab reference, 8.60-11.20). HR stratified by assigned taxane, tumor progression, and tumor endocrine status for 48-week PFS was 0.95 (95% CI, 0.714-1.251;P= .694).

The totality of evidence “supports biosimilarity of trastuzumab-dkst to trastuzumab and extrapolation to all indications for which trastuzumab is approved,” said Rugo. “Trastuzumab-dkst provides an additional high-quality treatment option for patients with HER2-positive cancers.”

As presented previously, the ratio of ORR at week 24 in the intent-to-treat population, the primary endpoint, was 70.0% in the MYL-1401O arm compared with 64.0% in the trastuzumab originator arm. The ORR ratio was 1.09 with a 90% CI of 0.981 to 1.218, which fell within the prespecified equivalency margins of 0.81 and 1.24.

The absolute difference in ORR was 6.0% (90% CI -1.26 to 13.11).

MYL-1401O is the first biosimilar approved in the United States for the treatment of HER2-overexpressing breast cancer and metastatic gastric or gastroesophageal junction adenocarcinoma. The FDA approved the drug in December 2017 based on phase II results from HERITAGE (NCT02472964). Rugo added that the biosimilar has been approved in 29 countries and used to treat >29,000 patients globally.

HERITAGE is a 2-part, international, multicenter, double-blind, randomized, parallel-group study that included 458 patients with measurable HER2-positive metastatic breast cancer who had not received prior chemotherapy or trastuzumab for metastatic disease. Patients were randomly assigned to MYL-1401O (n = 230) or trastuzumab (n = 228) with either docetaxel or paclitaxel at the treating institution’s discretion. Patients had to have normal left ventricular ejection fraction (LVEF) and adequate liver and bone marrow function to participate.

Patients underwent a minimum of 8 cycles in part 1 of the trial, with trastuzumab continuing until progression. Both groups received 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 trastuzumab originator as monotherapy until disease progression.

Baseline and disease characteristics were comparable between the two groups. The assigned taxane was docetaxel in 84% in each group. More than 90% of each arm was trastuzumab-naïve at baseline: 9.6% in the MYL-1401O and 7.0% in the trastuzumab arm had received prior adjuvant treatment with trastuzumab and 20.0% and 18.4%, respectively, had prior adjuvant taxane therapy. The majority of patients in both groups; 74.8% and 81.1%, respectively; had visceral metastases.

At week 24, 1.3% and 0% of patients assigned to MYL-1401O and trastuzumab originator, respectively, demonstrated a complete response (CR), and 68.3% and 64.0%, respectively, demonstrated a partial response (PR).

At week 48, an additional two patients (one per group) demonstrated CR and an additional five patients in the trastuzumab originator group demonstrated PR “which is intriguing and clearly emphasizes the importance of monotherapy as well as the importance of having alternate agents of lower cost available,” said Rugo. The confirmed ORR at 48 weeks was 70.0% and 66.7%, respectively.

Overall survival (OS) was not yet estimable and will be calculated after 240 deaths or 36 months. Based on the current data, final OS data is expected to be available in 2019.

“The OS is as yet immature, but impressive at over 80% at 52 weeks,” said Rugo.

Treatment-emergent adverse event (AEs) rates during monotherapy were similar (MYL-1401O, 54.7%; trastuzumab, 60.1%) and most were low grade. The cumulative rates of week 48 AEs were similar, with very few additional adverse events on monotherapy “as we would have expected from our experience,” she said.

There was a higher rate of arthralgia in the first 24 weeks in the MYL-1401O arm versus the originator arm (12.1% vs. 4.5%) but in monotherapy, the rates decreased substantially and were similar between the MYL-1401O and trastuzumab arms (2.8% vs. 1.2%). Only 513 of the 5015 total treatment-emergent adverse events (10%) started during monotherapy treatment.

Rates of serious AEs and AEs of special interest were comparable across treatment groups through week 48, including neutropenia (MYL-1401O, 27.5%, trastuzumab, 25.2%) and febrile neutropenia (MYL-1401O, 4.5%; trastuzumab, 4.1%). “We didn’t see any additional serious cardiac events in the monotherapy portion,” said Rugo.

Ten (4.0%) patients in the MYL-1401O arm and 6 (3.3%) in the trastuzumab arm had an LVEF <50% at least once post-baseline that showed recovery to >50% during the study. Only 3 patients in the MYL-1401O arm and 2 in the trastuzumab arm discontinued treatment because of a cardiac event.

The incidence of antidrug antibodies and antibody titers was low and similar between treatment groups. Between weeks 24 and 48, one new patient was antidrug antibody-positive in the MYL-1401O arm. The overall neutralizing antibody rate was 0.4% in the MYL-1401O arm and 1.3% in the trastuzumab arm.

References:

1. Manikhas A, Pennella EJ, Bondarenko I, et al. Biosimilar MYL-1401O monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 Heritage trial.J Clin Oncol.36, 2018 (suppl; abstr 110).
2. Rugo HS, Barve A, Waller CF, et al. Effect of a proposed trastuzumab biosimilar compared with trastuzumab on overall response rate in patients with ERBB2 (HER2)-positive metastatic breast cancer: A randomized clinical trial.JAMA.2017;317:37-47.