FDA Grants Breakthrough Therapy Designation to Trastuzumab Deruxtecan for Select HER2+ Metastatic Breast Cancer

The FDA has granted a breakthrough therapy designation to trastuzumab deruxtecan-nxki (Enhertu) for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received 1 or more anti–HER2-based regimens.¹

The designation is based on findings from the phase 3 DESTINY-Breast03 trial (NCT03529110), which showed that the median progression-free survival (PFS) per blinded independent central review (BICR) was not yet reached (95% CI, 18.5–not evaluable [NE]) with the antibody-drug conjugate (ADC) vs 6.8 months (95% CI, 5.6-8.2) with ado-trastuzumab emtansine (Kadcyla; T-DM1) in patients with HER2-positive metastatic breast cancer (HR, 0.28; 95% CI, 0.22-0.37; P = 7.8 x 10^-22).²

“This is an important step in bringing [trastuzumab deruxtecan] as a potential new option in earlier lines of treatment for HER2-positive metastatic breast cancer, given the urgent need to improve outcomes,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, stated in a press release. “This recognition by the FDA underscores the transformative possibility of [trastuzumab deruxtecan] seen with the remarkable DESTINY-Breast03 results presented at ESMO just 2 weeks ago.”

The open-label, multicenter phase 3 trial enrolled patients with unresectable or metastatic HER2-positive breast cancer who had previously received treatment with trastuzumab (Herceptin) and a taxane in the advanced or metastatic setting. Notably, patients were allowed to have clinically stable, treated brain metastases.

A total of 524 participants were randomized 1:1 to receive either trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 261) or T-DM1 at 3.6 mg/kg every 3 weeks (n = 263). They were stratified by hormone receptor status, previous treatment with pertuzumab (Perjeta), and history of visceral disease.

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

At a median follow-up of 16.2 months for trastuzumab deruxtecan and 15.3 months for T-DM1, 125 patients on the investigative arm had discontinued treatment. The most common reason was disease progression (n = 66), followed by toxicities (n = 35), patient withdrawal (n = 13), death (n = 3), physician decision (n = 2), or another reason (n = 2). A total of 214 patients discontinued on the control arm. Of these patients, 158 discontinued because of progressive disease, 17 did so because of toxicity, 11 did so because of patient withdrawal, 8 due to physician decision, 5 for another reason, and 3 due to death.

Across the treatment arms, the median age of participants was 54.3 years, 99.6% were female, and the majority were from Asia and had HER2 status of 3+ per immunohistochemistry. Moreover, 59.0% of those on the investigative arm and 66.5% of those on the control arm had an ECOG performance status of 0, and 50.2% and 51.0%, respectively, had hormone receptor positivity. Moreover, 23.8% of those on the trastuzumab deruxtecan arm had brain metastases vs 19.8% of those on the T-DM1 arm; 70.5% and 70.3%, respectively, had visceral disease.

Ninety-two percent of those on the investigative arm and 89.0% of those on the control arm had previously received treatment for metastatic disease. In the investigative arm, 0.8% had no prior treatment, 49.8% had 1 prior line, 21.5% had 2 prior lines, 13.4% had 3 prior lines, 5.7% had 4 prior lines, and 8.8% had 5 prior lines. In the control 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% 4 or more prior lines.

The previous anticancer therapies received in the investigative and control arms included trastuzumab (99.6% vs 99.6%, respectively), pertuzumab (62.1% vs 60.1%), an anti-HER2 TKI (16.1% vs 13.7%), and another anti-HER2 antibody or ADC (0.8% vs 1.1%).

Additional data presented during the 2021 ESMO Congress showed that the 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 median OS had not yet been reached in either the investigative or control arms (HR, 0.56; 95% CI, 0.36-0.86; P = .007172). The 12-month OS rates in the trastuzumab deruxtecan and T-DM1 arms, respectively, were 94.1% (95% CI, 90.3%-96.4%) and 85.9% (95% CI, 80.9%-89.7%), respectively.

Moreover, trastuzumab deruxtecan elicited a confirmed 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 trastuzumab deruxtecan, 16.1% achieved a complete response, 63.6% had a partial response, 16.9% had stable disease, and 1.1% experienced disease progression. The disease control rates in the investigative and control arms were 96.6% vs 76.8%, respectively.

The median treatment duration was 14.3 months (range, 0.7-29.8) with trastuzumab deruxtecan vs 6.9 months (range, 0.7-25.1) with T-DM1. Any drug-related treatment-emergent adverse effects (TEAEs) occurred in 98.1% of those on the investigative arm vs 86.6% of those on the control arm; 45.1% and 39.8% of patients, respectively, experienced drug-related TEAEs that were grade 3 or higher in severity. Serious drug-related TEAEs were experienced by 10.9% of those who received trastuzumab deruxtecan vs 6.1% of those given T-DM1.

Moreover, 12.8% of those on the investigative arm (n = 257) experienced drug-related TEAEs that resulted in discontinuation vs 5.0% of those on the control arm (n = 261); 21.4% and 12.6% of patients, respectively, experienced drug-related TEAEs that required dose reductions. No patients on either arm experienced a drug-related TEAE that resulted in death.

The most frequently experienced TEAEs associated with treatment discontinuation for trastuzumab deruxtecan was interstitial lung disease (ILD) or pneumonitis (8.2%) and thrombocytopenia (2.7%) for T-DM1. The most common TEAEs linked with dose reductions in the investigative arm included nausea (6.2%) and neutropenia (3.5%); this was thrombocytopenia (4.2%) and alanine and aspartate aminotransferase increase (2.7%, each), with T-DM1.

Most treatment-related TEAEs were gastrointestinal or hematological in nature. Any-grade ILD/pneumonitis occurred in 10.5% and 1.9% of those on the investigative and control arms, respectively. No grade 4 or 5 adjudicated drug-related ILD/pneumonitis events were reported with trastuzumab deruxtecan. Additionally, reduction in the left ventricular ejection fraction occurred at any grade in 2.7% of those who received trastuzumab deruxtecan and 0.4% of those who were given T-DM1.

“By granting a fourth breakthrough therapy designation to [trastuzumab deruxtecan], the FDA continues to recognize the significant potential of this medicine against multiple HER2-targetable tumors,” Ken Takeshita, global head of R&D, at Daichi Sankyo, added in the press release. “With the unprecedented data recently reported from the DESTINY-Breast03 trial, we look forward to working closely with the FDA to bring [trastuzumab deruxtecan] to patients who have been previously treated for HER2-positive metastatic breast cancer as soon as possible.”

References

1. 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 October 4, 2021. https://bit.ly/3D8ZA1g
2. Cortés J, Kim S, Chung W, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): results of the randomized phase III DESTINY-Breast03 study. Presented at: 2021 ESMO Congress; September 18, 2021; Virtual. https://bit.ly/2ZVjSgu