AstraZeneca, Daiichi Sankyo build Enhertu's blockbuster case with breast cancer win against Roche's Kadcyla

Enhertu
AstraZeneca and Daiichi Sankyo's Enhertu beat Roche's Kadcyla in previously treated patients with HER2-positive, metastatic breast cancer. (Daiichi Sankyo/AstraZeneca)

AstraZeneca and Daiichi Sankyo’s Enhertu is shouldering big expectations. With a new head-to-head trial win against Roche’s Kadcyla, the companies are showing their antibody-drug conjugate could indeed disrupt the HER2 cancer market.

Enhertu outperformed Roche’s fellow antibody-drug conjugate Kadcyla at staving off tumor progression or death in patients with HER2-positive, metastatic breast cancer following initial treatment with Roche’s Herceptin and a taxane chemotherapy, AstraZeneca and Daiichi said Monday.

At a planned interim analysis in the phase 3 DESTINY-Breast03 trial, Enhertu’s advantage on that progression-free survival marker was already “highly statistically significant and clinically meaningful,” the pair added. The trial therefore hit its primary endpoint.

Results on whether Enhertu could extend the patients’ lives over Kadcyla remain immature at this point, the companies said. There was a “strong trend” in Enhertu’s favor, they said.

Enhertu’s superiority over Kadcyla in second-line HER2-positive breast cancer doesn’t come as a complete surprise given that the AZ-Daiichi drug has shown strong data that appear better than Kadcyla’s in later lines of treatment. Jefferies’ analysts recently predicted the possibility of DESTINY-Breast03 success at 100% and expect $500 million in peak sales for Enhertu in the treatment setting.

The trial marks the first global phase 3 win for Enhertu against an active control, Ken Takeshita, Daiichi’s global R&D head, noted in a statement. The drug’s initial FDA nod in third-line HER2-positive breast cancer was thanks to tumor shrinkage results from the phase 2 DESTINY-Breast01 trial. Its recent go-ahead for second-line stomach cancer came from a life extension win over chemotherapy in a phase 2 trial conducted in Japan and South Korea.

Both Enhertu and Kadcyla use trastuzumab, or Herceptin, for the antibody component. While Kadcyla carries the microtubule inhibitor DM1 as its cytotoxic payload, Enhertu adopts a topoisomerase inhibitor called deruxtecan as its own toxic payload.

Even before the head-to-head win, Enhertu was already viewed by some market watchers as a more potent HER2 drug than Kadcyla. In DESTINY-Breast01, Enhertu triggered a response in about 61% of HER2-positive breast cancer patients who had received a median six prior lines of treatments, with the response lasting a median 14.8 months at an interim analysis. By comparison, Kadcyla triggered a response in 31% of third-line-plus patients in its phase 3 TH3RESA trial. The response lasted a median 9.7 months.

The new results support “the potential of this medicine to become the new standard of care” for second-line HER2-postiive breast cancer, Takeshita said of Enhertu.

RELATED: AstraZeneca, Daiichi Sankyo push Enhertu closer to the blockbuster frontier with stomach cancer OK

Stellar efficacy aside, analysts have expressed concerns over Enhertu’s potential in earlier lines of treatment because of its serious side effect of interstitial lung disease (ILD), which currently appears as a boxed warning on the drug’s label.

In DESTINY-Breast01, 9% of Enhertu patients experienced ILD, including six deaths, or 2.6% of patients who received the medicine. As for the current DESTINY-Breast03 trial, investigators didn’t see any grade 4 or 5 treatment-related ILD events, AZ and Daiichi said.

The “encouraging safety data may open future opportunities” to bring Enhertu to earlier treatment settings, Susan Galbraith, Ph.D., AZ’s newly installed oncology R&D chief, said in a Monday statement.

RELATED: AstraZeneca, Daiichi Sankyo launch Enhertu head-to-head trial with eyes on a new breast cancer standard

Eying earlier use, AZ and Daiichi in June launched a phase 3 trial, dubbed DESTINY-Breast09, testing Enhertu in newly diagnosed HER2-positive breast cancer. The trial is comparing Enhertu—with or without Roche’s Perjeta—against the combination of Perjeta, Herceptin and chemotherapy. Another phase 3 study coded DESTINY-Breast05 is pitting Enhertu against Kadcyla as post-surgery adjuvant therapy in patients with early-stage HER2-positive breast cancer who are at high risk of disease recurrence.

Enhertu, plus two other ADCs targeting TROP-2 and HER3, is a pillar of Daiichi’s newly unveiled five-year plan. The drugmaker aims to reach over 600 billion Japanese yen ($5.4 billion) in oncology revenues by fiscal year 2025, with Enhertu taking up the bulk of the pie.

During the most recent quarter ended in June, Enhertu global sales reached 13 billion Japanese yen (about $120 million). Kadcyla, benefiting from its adjuvant nod in 2019, posted sales gains of 21% year-over-year to 481 million Swiss francs ($525 million) during the period.