June 5, 2022 Conferences | ASCO: American Society of Clinical Oncology

New England Journal of Medicine,1 drew a standing ovation during the plenary session of the 2022 Annual Meeting of the American Society of Clinical Oncology in Chicago. The findings

show that trastuzumab deruxtecan, already approved in breast cancer and certain gastric cancers, reduced the risk of disease progression or death by 50% compared with chemotherapy for HER2-low patients with both hormone receptor positive (HR+) and HR– disease.

Trastuzumab deruxtecan, jointly developed by Daiichi Sankyo and AstraZeneca, is among a group of therapies known as antibody drug conjugates (ADCs), which connect monoclonal antibodies to tumor cells with a “linker,” making the punch against cancer more targeted and potent. In this case, the well-known trastuzumab, which binds to HER2 receptors, works with deruxtecan to become embedded in the cancer cell, disrupting the cell’s DNA and leading to cell death.

DESTINY-Breast04 was a phase 3 trial of previously treated patients with metastatic HER2-low disease. It had a primary end point of PFS in patients with HR+ disease. Secondary end points included PFS based on blinded independent central review of all randomized patients, both HR+ and HR-, and OS in HR+ patients and OS in all patients.

Results from the trial showed the following:

- Of the 557 patients randomized, 494 (88.7%) had HR+ disease, and 63 (11.3%) had HR- disease.

- In the HR+ group, median PFS was 10.1 months in the trastuzumab deruxtecan group, vs 5.4 months for those taking chemotherapy (physician’s choice), for a hazard ratio (HR) of 0.51, P < .001. OS in this group was 23.9 months for the study drug vs 17.5 months for chemotherapy, HR 0.64, P = .003.

- Among all patients, median PFS was 9.9 months for trastuzumab deruxtecan and 5.1 months for chemotherapy, HR 0.50, P < .001.

- Adverse events of grade 3 or higher were lower in the study drug group, 52% vs 67.4% in the chemotherapy group.

- Of concern in patients receiving ADCs, interstitial lung disease or pneumonitis was seen in 12.1% of the study drug group; 0.8% of the patients died.

Both Shanu Modi, MD, medical oncologist at Memorial Sloan Kettering Cancer Center and the principal investigator, and experts from ASCO pronounced the results a game-changer in breast cancer.

As Modi explained during a press briefing, “We currently define the HER2 status of breast cancers in a binary model, where HER2+ breast cancers driven by the oncogene are treatable with currently available HER2+ targeted therapies and HER2- breast cancers are not.”

But, in reality, it’s not that clear cut. Within the HER2 group some patients have low levels of HER2 expression that may still be targetable, but thus far therapies have not proven effective. For this reason, these patients have been classified as HER2- for treatment.

ADCs, which Modi called next generation targeted therapies, offer a delivery system that creates a “bystander” effect, which also targets cells in the immediate vicinity of the tumor. Thus, patients with HER2-low see responses unlike any seen previously, said Modi and ASCO commenter Jane Meisel, MD, of Winship Cancer Institute at Emory University.

The experience with trastuzumab deruxtecan has been remarkable, Meisel said. “Everyone who's used it in our clinic undoubtedly has seen some patients—even with significant burdens of disease—have their cancer melt away with this agent,” she said. “What this trial does is really extend the benefits of this agent to a whole new group of patients.”

ASCO Chief Medical Officer and Executive Vice President Julie Gralow, MD, added that the pathology of breast cancer would have to be redefined, based on the findings in DESTINY-Breast04.

Modi concluded, “These results established HER2-low metastatic breast cancer is a targetable population of breast cancer, with trastuzumab deruxtecan as a new standard of care in this setting.”

Reference

Modi S, Jacot W, Yamashita J, et al. Trastuzumab deruxtecan in previously
treated HER2-low advanced breast cancer. N Engl J Med. Published online June 5, 2022. DOI: 10.1056/NEJMoa2203690