In HER2+ MBC, Trastuzumab Deruxtecan Slashes Risk of Disease Progression, Death by 72% vs T-DM1

Trastuzumab deruxtecan, the HER2-directed antibody drug conjugate (ACD) sold as Enhertu (AstraZeneca/Daiichi Sanyko), tripled progression-free survival (PFS) over trastuzumab emtansine (T-DM1) in HER2-positve metastatic breast cancer (MBC), according to interim results of a phase 3 trial that showed a 72% reduction in the risk of disease progression or death.1

The prespecified analysis of DESTINY-Breast03 opened a Presidential Symposium September 18, during the European Society of Medical Oncology (ESMO) 2021 Virtual Congress, with the study’s lead author predicting a new standard of care and a commentator calling the results “startling.”

“Patients with previously treated HER2-positive metastatic breast cancer will typically experience disease progression in less than a year with available HER2-directed treatments,” said Javier Cortés, MD, PhD, head, International Breast Cancer Center (IBCC), Barcelona, Spain, who presented the results. He pointed to the “high and consistent benefit” seen in both the efficacy end points and key subgroups.2

“DESTINY-Breast03 is remarkable and supports the potential of [trastuzumab deruxtecan] to become the new standard of care for those who have previously been treated for HER2-positive metastatic breast cancer,” Cortés said.

Taking note of the PFS curves, with a hazard ratio (HR) of 0.28, commentator Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center said, “I don't believe I've seen a hazard ratio like this in HER2 breast cancer before.”

Despite progress in prevention and treatment over the past 2 decades, breast cancer remains the most common cancer in women after skin cancer, and the second-leading cause of cancer death in women worldwide. More than 2 million patients with breast cancer were diagnosed in 2020, and 685,000 patients died.3

About 1 in 5 patients with breast cancer is HER2-positive4 (HER2+), which means their disease is triggered by the HER2 protein, a tyrosine kinase receptor that can cause aggressive tumor growth in breast, gastric, lung, and colorectal cancers. Patients with HER2+ MBC will often see their disease progress even after treatment with trastuzumab and chemotherapy drugs called taxanes, such as paclitaxel.

Trastuzumab deruxtecan (T-DXd) was approved in December 2019 for patients with unresectable or metastatic HER2-positive breast cancer with 2 or more prior anti-HER2-based regimens in MBC, based on results of the open-label phase 2 study, DESTINY-Breast01,5 for which Modi was the lead author. The drug has also received approval in gastric cancer, and positive results for lung cancer were presented during ESMO 2021 and published in the New England Journal of Medicine.6

The other ADC, T-DM1, is indicated for the adjuvant treatment of HER2+ patients with breast cancer who have residual invasive disease after being treated with trastuzumab and taxane, or who have disease recurrence within 6 months. Thus, DESTINY-Breast03 was designed to compare the 2 ADC therapies head-to-head.

The trial randomized 524 patients in North America, Asia, Europe, South America, and Oceania 1:1 to receive either T-DM1 or T-DXd. The primary end point was PFS as determined by blinded independent central review. Secondary end points include overall survival (OS), objective response rate (ORR), duration of response, and safety.

Results show the following:

• Median age was 54 years, with a range of 20 to 83 years.
• With a data cutoff of May 21, 2021 for the interim analysis, the HR for PFS was 0.2840 (P = 7.8 x 10-22). Median PFS was not reached for T-DXd vs 6.8 months for T-DM1.
• The estimated 12-month OS event rates were 94.1% (95% CI, 90.3-96.4) for T-DXd and 85.9% (95% CI, 80.9-89.7) for T-DM1; HR: 0.5546 (95% CI, 0.3587-0.8576. Data are not considered mature, and P = 0.007172 did not cross pre-specified boundary for significance.
• Confirmed ORR were 79.1% (95% CI, 74.3-84.4) for T-DXd vs 34.2% (95% CI, 28.5-40.3); P < 0.0001.
• Treatment-emergent adverse events (TEAEs) were similar in both arms. There were no drug-related deaths. Adjudicated drug-related interstitial lung disease (ILD) occurred in 10.5% of patients with T-DXd , with most (9.7%) grade 1/2; vs 1.9% with T-DM1 (all grade 1/2).

Modi had presented updated phase 2 results from DESTINY-Breast01 during the Miami Breast Cancer Conference in March 2020 and highlighted the “landmark” 18-month OS of 74%,7 but she still seemed surprised by the size of the benefit relative to T-DM1. One question now, she said, is whether T-DM1 will work for patients after T-DXd.

“I do believe that the DESTINY-03 data support T-DXd as a new second-line option for HER2+ metastatic breast cancer,” Modi said. “In particular, there is a clear benefit for the population of patients who have brain metastases. Most importantly, T-DXd delivered in this early-line setting was associated with less lung toxicity, resetting the risk benefit analysis in its favor.”

“Today’s results are ground-breaking,” said Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca. “Enhertu tripled progression-free survival as assessed by investigators, and provided a disease control rate exceeding 95% compared to 77% for T-DM1.”

Taken together with the safety results, “These unprecedented data represent a potential paradigm shift in the treatment of HER2-positive metastatic breast cancer,” she said.

References

1. Cortés J, Kim SB, Chung WP, 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: European Society for Medical Oncology 2021 Virtual Congress. September 16-21, 2021; virtual. Abstract LBA1.
2. Enhertu significantly improved progression-free survival in DESTINY-Breast03 head-to-head trial vs. trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer. News release. AstraZeneca and Daiichi Sankyo Company; August 9, 2021. Accessed September 18, 2021. bit.ly/3tRh5zG
3. Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 10.3322/caac.21660.
4. Ahn S, et al. HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation. J Pathol Transl Med. 2020; 54(1): 34-44.
5. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610-621. DOI: 10.1056/NEJMoa1914510
6. Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer. N Engl J Med. Published online September 19, 2021. DOI: 10.1056/NEJMoa2112431
7. Helwick C. Miami Breast Cancer Conference: Updated DESTINY-Breast01 results show trastuzumab deruxtecan-nxki delivers durable responses. The ASCO Post. Published March 9, 2021. Accessed September 19, 2021. https://bit.ly/3tVTC0u