FDA Grants Priority Review to Trastuzumab Deruxtecan for Select HER2+ Metastatic Breast Cancer

FDA

The FDA has granted priority review to the supplemental biologics license application of fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti–HER2-based regimen.¹

The decision is based on findings from the phase 3 DESTINY-Breast03 trial (NCT03529110), in which the blinded independent central review (BICR)–assessed median progression-free survival (PFS) with trastuzumab deruxtecan (n = 261) had not yet been reached (95% CI, 18.5–not evaluable [NE]) vs 6.8 months (95% CI, 5.6-8.2) with trastuzumab emtansine (Kadcyla; T-DM1; n = 263), translating to a 72% reduction in the risk of disease progression or death (HR, 0.28; 95% CI, 0.22-0.37; P = 7.8 x 10-22).2 The 12-month PFS rates in the investigative and control arms were 75.8% (95% CI, 69.8%-80.7%) and 34.1% (95% CI, 27.7%-40.5%), respectively.

The median overall survival (OS) was NE in both treatment arms (HR, 0.56; 95% CI, 0.36-0.86; P = .007172). the 12-month OS rate with trastuzumab deruxtecan was 94.1% (95% CI, 90.3%-96.4%) vs 85.9% (95% CI, 80.9%-89.7%) with T-DM1.

“This regulatory review of [trastuzumab deruxtecan] in the United States marks the first time this medicine is participating in both the Real-Time Oncology Review and Project Orbis programs,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, stated in a press release. “The FDA’s prioritization of our application underscores the potential of this medicine and the continued need to expedite the availability of new treatment options, while making it possible to potentially receive approvals in several countries concurrently.”

The open-label, multicenter DESTINY-Breast03 trial enrolled patients with unresectable or metastatic HER2-positive breast cancer who received prior treatment with trastuzumab (Herceptin) and a taxane in the advanced or metastatic setting. Notably, patients with clinically stable, treated brain metastases were permitted.

Study participants were randomized 1:1 to receive either trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks or T-DM1 at 3.6 mg/kg every 3 weeks. Stratification factors comprised hormone receptor status, previous treatment with pertuzumab (Perjeta), and history of visceral disease.

The primary end point of the trial was PFS per BICR assessment and a key secondary end point was OS. Other secondary end points included objective response rate (ORR) per BICR and investigator, duration of response (DOR) per BICR, investigator-assessed PFS, and safety.

The data cutoff for the interim analysis for PFS was May 21, 2021. A total of 699 patients underwent screening, and 524 patients ended up undergoing randomization. Of the 261 patients randomized to trastuzumab deruxtecan, 257 were treated. Of the 263 patients randomized to T-DM1; 261 received treatment. The median follow-up for trastuzumab deruxtecan was 16.2 months vs 15.3 months for T-DM1.

The median age of those who received trastuzumab deruxtecan was 54.3 years (range, 27.9-83.1) vs 54.2 years (range, 20.2-83.0) in those who received T-DM1. Across the arms, most participants were female (99.6% in both arms), from Asia (57.1% vs 60.8%), had a HER2 status of 3+ per immunohistochemistry (89.7% vs 88.2%), and an ECOG performance status of 0 (59.0% vs 66.5%).

In the trastuzumab deruxtecan arm, 50.2% of patients were hormone receptor positive, 76.2% did not have brain metastases, and 70.5% had visceral disease. In the T-DM1 arm, 51.0% had positive hormone receptor status, 80.2% did not have brain metastases, and 70.3% had visceral disease.

Across the arms, most patients received previous treatment for metastatic disease. In the trastuzumab deruxtecan arm, 0.8% received no prior lines of treatment, 49.8% received 1 prior line, 21.5% had 2 prior lines, 13.4% had 3 prior lines, 5.7% had 4 prior lines, and 8.8% received 5 or more prior lines. In the T-DM1 arm, 1.1% did not have prior treatment, 46.8% had 1 prior line, 24.7% had 2 prior lines, 13.3% had 3 prior lines, 7.2% had 4 prior lines, and 6.8% had 5 or more prior lines.

Previous treatment in the investigative and control arms included trastuzumab (99.6% in both), pertuzumab (62.1% vs 60.1%), an anti-HER2 TKI (16.1% vs 13.7%), and other anti-HER2 antibodies or antibody-drug conjugate (0.8% vs 1.1%).

Additional data presented during the 2021 ESMO Congress showed that the median investigator-assessed PFS with trastuzumab deruxtecan was 25.1 months (95% CI, 22.1–NE) vs 7.2 months (95% CI, 6.8-8.3) with T-DM1 (HR, 0.27; 95% CI, 0.20-0.35; P = 6.5 x 10-24). The 12-month PFS rates in the investigative and control arms were 76.3% (95% CI, 70.4%-81.2%) and 34.9% (95% CI, 28.8%-41.2%), respectively.

Trastuzumab deruxtecan elicited an ORR of 79.7% (95% CI, 74.3%-84.4%) vs 34.2% (95% CI, 28.5%-40.3%) with T-DM1 (P < .0001). Among those who responded to the former, the complete response rate was 16.1% and the partial response rate was 63.6%; these rates were 8.7% and 25.5%, respectively, with T-DM1. The disease control rate in the investigative arm was 96.6% vs 76.8% in the control arm.

The most common grade 3 or higher treatment-related, treatment-emergent adverse effects reported with trastuzumab deruxtecan included neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%), nausea (6.6%), anemia (5.8%), fatigue (5.1%), vomiting (1.6%), increase in alanine aminotransferase (1.6%), decreased appetite (1.2%), increase in aspartate aminotransferase (0.8%), diarrhea (0.4%), and alopecia (0.4%).

Moreover, 10.5% of patients experienced interstitial lung disease (ILD) or pneumonitis associated with treatment, as determined by an independent adjudication committee. Most of these events (9.7%), were grade 1 (2.7%) or grade 2 (7.0%), although 2 grade 3 effects (0.8%) were reported. Notably, no grade 4 or 5 ILD or pneumonitis was observed.

“The review across geographies and the priority review in the United States as part of Project Orbis is so important because it speaks to the transformative potential of [trastuzumab deruxtecan] based on the unprecedented PFS benefit in this setting,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, stated in a press release.3 “The news reinforces the importance of bringing this potential new option to patients as quickly as possible.”

In October 2021, the FDA granted a breakthrough therapy designation to trastuzumab deruxtecan for use in adult patients with unresectable or metastatic HER2-positive breast cancer who previously received 1 or more anti–HER2-based regimens.4 The designation was based on data from DESTINY-Breast03.

References

1. ENHERTU granted priority review in the US for patients with HER2 positive metastatic breast cancer treated with a prior anti-HER2-based regimen. News release. Daiichi Sankyo Company, Limited; January 17, 2022. Accessed January 17, 2022. https://bit.ly/3Kjlvah
2. Cortés J, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: results of the randomized, phase 3 study DESTINY-Breast03. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741
3. Enhertu granted priority review in the US for patients with HER2-positive metastatic breast cancer treated with a prior anti-HER2-based regimen. News release. AstraZeneca; January 17, 2022. Accessed January 17, 2022. https://bit.ly/3qAN4nW
4. Enhertu granted breakthrough therapy designation in US for patients with HER2-positive metastatic breast cancer treated with one or more prior anti-HER2-based regimens. News release. AstraZeneca; October 4, 2021. Accessed January 17, 2022. https://bit.ly/3D8ZA1g