Trastuzumab Duocarmazine Provides Numerical OS Benefit in Pretreated HER2+ Breast Cancer

Philippe Aftimos, MD,

Treatment with vic-trastuzumab duocarmazine (SYD985) demonstrated a trend toward numerically prolonged overall survival (OS) compared with physician’s choice of treatment in patients with pretreated HER2-positive metastatic breast cancer, according to final results from the phase 3 TULIP study (NCT03262935) presented during the 2023 ESMO Congress.¹

At a median follow-up of 35.6 months for trastuzumab duocarmazine (n = 291) and 32.0 months for physician’s choice of treatment (n = 146), the median OS was 21.0 months (95% CI, 18.1-25.0) and 19.5 months (95% CI, 14.2-23.1), respectively (HR, 0.87; 95% CI, 0.68-1.12; P = .236); however, this improvement was not found to be statistically significant. The 1-year survival estimates were 70% (95% CI, 64%-75%) and 68% (95% CI, 60%-75%), respectively.

“The final OS results confirm a trend toward a numerically prolonged OS in the trastuzumab duocarmazine group compared with the physician’s choice group,” Philippe Aftimos, MD, a medical oncologist and clinical trials development leader at the Clinical Trials Conduct Unit of Institute Jules Bordet in Brussels, Belgium, said in a presentation of the data. “Safety was aligned with the primary analysis, with no new signals identified.”

The phase 3 trial, which was conducted at 83 sites, enrolled 437 patients with HER2-positive, locally advanced or metastatic breast cancer who had previously received at least 2 therapies or ado-trastuzumab emtansine (T-DM1; Kadcyla) in the metastatic setting. Notably, those with treated brain metastases were permitted.

Study participants were randomly assigned 2:1 to receive trastuzumab duocarmazine at 1.2 mg/kg intravenously every 21 days or physician’s choice of treatment, which could have been lapatinib (Tykerb) plus capecitabine (Xeloda), trastuzumab (Herceptin) plus capecitabine, trastuzumab plus vinorelbine, or trastuzumab plus eribulin (Halaven). Treatment continued until disease progression or intolerable toxicity.

Stratification factors included region (European Union plus Singapore vs North America), number or prior treatment lines for locally advanced or metastatic disease (1 to 2 vs >2), and previous receipt of pertuzumab (Perjeta; yes vs no).

PFS by central assessment served as the trial’s primary end point. Secondary end points included PFS by investigator assessment, OS, objective response rate, and health-related quality of life.

Earlier data presented during the 2021 ESMO Congress showed that trastuzumab duocarmazine significantly improved PFS over physician’s choice of treatment in this population, at a median of 7.0 months (95% CI, 5.4-7.2) vs 4.9 months (95% CI, 4.0-5.5), respectively, translating to a 36% reduction in the risk of disease progression or death (HR, 0.64; 95% CI, 0.49-0.84; P = .002).²

Regarding safety, 96.5% of those in the trastuzumab duocarmazine arm experienced at least 1 treatment-emergent adverse effect (TEAE) vs 96.4% of those in the physician’s choice arm; these effects were grade 3 or higher for 52.4% and 48.2% of patients, respectively.

The most common all-grade TEAEs experienced by at least 15% of patients in the trastuzumab duocarmazine and physician’s choice arms, respectively, were conjunctivitis (38.2%; 2.2%), keratitis (38.2%; 8.0%), fatigue (33.7%; 29.9%), dry eye (30.2%; 10.9%), nausea (25.7%; 31.4%), alopecia (21.5%; 11.7%), reduced appetite (21.5%; 10.9%), diarrhea (20.8%; 35.8%), asthenia (20.1%; 16.8%), constipation (19.8%; 17.5%), increased lacrimation (18.4%; 1.5%), cough (16.7%; 10.2%), vomiting (12.8%; 16.8%), neutropenia (10.8%; 24.1%), pneumonitis (6.6%; 0%), interstitial lung disease (ILD; 1.0%; 0%), and Palmar-plantar erythrodysesthesia syndrome (0.7%; 23.4%).

Notably, all-grade eye toxicity was observed in 78.1% of those who received trastuzumab duocarmazine vs 29.9% of those given physician’s choice of treatment; these effects were grade 3 or higher in 21.2% of those who received trastuzumab duocarmazine. This effect resulted in dose modification or discontinuation of trastuzumab duocarmazine for 22.9% and 21.5% of patients, respectively.

All-grade ILD or pneumonitis occurred in 7.6% of those given trastuzumab duocarmazine, with 2.4% of cases being grade 3 or higher. This effect led to dose modification or treatment discontinuation for 2.1% and 5.2% of patients in this arm, respectively.

In July 2022, the FDA accepted a biologics license application (BLA) seeking the approval of trastuzumab duocarmazine for use in patients with HER2-positive unresectable locally advanced or metastatic breast cancer based on earlier data from TULIP.³ In May 2023, the regulatory agency issued a complete response letter to the BLA, requesting additional information that would require additional time and resources that extended beyond the evaluation period.⁴

A representative from Byondis, the drug developer, shared plans to evaluate the CRL and consider potential next steps for the agent in the United States.

Editor’s Note: Dr Aftimos disclosed serving in a consulting role for Boehringer Ingelheim, Macrogenics, Roche, Novartis, Amcure, Servier, G1 Therapeutics, Radius, Deloitte, and Incyte. He received honoraria from Synthon, Amgen, Novartis, Gilead, Eli Lilly, Menarini, and Daiichi Sankyo. Travel grants were provided by Amgen, MSD, Pfizer, Roche, and Daiichi Sankyo. Institutional research funding was provided by Roche.

References

1. Aftimos PG, Turner N, O’Shaughnessy J, et al. Trastuzumab duocarmazine versus physician’s choice therapy in pre-treated HER2-positive metastatic breast cancer: final results of the phase III TULIP trial. Ann Oncol. 2023;34(suppl 2):S340-S341. doi:10.1016/j.annonc.2023.09.563
2. Saura C, O’Shaughnessy J, Aftimos PG, et al. Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. Ann Oncol. 2021;32(5):1283-S1346. doi:10.1016/annonc/annonc741
3. FDA accepts Byondis’ biologics license application for [vic-]trastuzumab duocarmazine (SYD985) in HER2-positive metastatic breast cancer. News release. Byondis. July 12, 2022. Accessed November 6, 2023. https://www.byondis.com/media/press-releases/fda-accepts-byondis-biologics-license-application-for-vic-trastuzumab-duocarmazine-syd985-in-her2-positive-metastatic-breast-cancer
4. US Food and Drug Administration issues complete response letter for Byondis’ [vic-]trastuzumab duocarmazine. News release. May 15, 2023. Accessed November 6, 2023. https://www.byondis.com/media/press-releases/us-food-and-drug-administration-issues-complete-response-letter