HONG KONG – Japan's Daiichi Sankyo Co. Ltd. has moved its HER2-targeting antibody-drug conjugate (ADC), DS-8201 ([fam-] trastuzumab deruxtecan), into a pivotal program, including a study that pits it against Roche Holding AG's Kadcyla (ado-trastuzumab emtansine, TDM-1), an ADC first approved in 2013 that's expected to hit blockbuster status this year.

The recently launched Destiny-Breast03 and Destiny-Breast02 are designed as global, randomized, active-controlled, open-label, multicenter and two-arm phase III trials. Destiny-Breast03 will enroll about 500 patients at 150 sites in North America, Asia and Europe. It seeks to compare the safety and efficacy of DS-8201 with Kadcyla in patients with HER2-positive unresectable and/or metastatic breast cancer, who received treatment with trastuzumab and a taxane chemotherapy. The primary endpoint is progression-free survival (PFS).

Up to 600 patients will participate in the Destiny-Breast02 trial, across the company's 160 sites in North America, South America, Europe and Asia. That trial is comparing the safety and efficacy of DS-8201 with either trastuzumab plus capecitabine or lapatinib plus capecitabine in patients with HER2-positive unresectable and or metastatic breast cancer who have been treated previously with HER2 therapies, including Kadcyla, also with a primary endpoint of PFS.

"We are currently in discussions with the EMA and other regulatory authorities worldwide to determine next steps for the overall development of [fam-] trastuzumab deruxtecan," Jennifer Brennen, spokesperson for Daiichi Sankyo, told BioWorld.

Kadcyla has been an important compound in Roche's anti-HER2 portfolio. Full-year 2017 sales totaled $928.4 million, with consensus estimates predicting sales just topping $1 billion for 2018, according to Cortellis.

ADCs deliver cytotoxic chemotherapy to cancer cells through a linker attached to a monoclonal antibody that binds to a specific target on cancer cells. Daiichi Sankyo has said DS-8201 can carry a greater cytotoxic payload, which makes it a more potent ADC that pairs the anti-HER2 antibody with a topoisomerase inhibitor, rather than Kadcyla's tubulin inhibitor.

Daiichi also has an ongoing phase II trial, Destiny-Breast01, testing DS-8201 in patients with HER2-positive metastatic breast cancer that is resistant or refractory to TDM-1. It is an open-label, global, multicenter and two-part study.

"Accrual into Destiny-Breast01 was completed in September 2018. We are targeting to submit the results of Destiny-Breast01 to the FDA in FY2020," said Brennen. "We anticipate a confirmation of the timing for biologics license application filing in the fourth quarter of FY2018."

DS-8201 is also sought to treat other types of cancer. Destiny-Gastric01, targeting HER2-positive advanced gastric cancer resistant or refractory to trastuzumab, is in phase II. The candidate is also undergoing a phase II trial for HER2-expressing advanced colorectal cancer.

A phase II trial in metastatic nonsquamous HER2-overexpressing or HER2-mutated non-small-cell lung cancer, and a phase I study in combination with Opdivo (nivolumab, Bristol-Myers Squibb Co.) for HER2-expressing metastatic breast and bladder cancers also are ongoing.

The oncology drug was granted breakthrough therapy designation by the FDA for treating patients with HER2-positive locally advanced or metastatic breast cancer. Those patients had been treated previously with trastuzumab and Perjeta (pertuzumab, Roche) and had disease progression after Kadcyla.

The FDA also granted it fast track designation for the treatment of HER2-positive unresectable and metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies, including Kadcyla.

In Japan, the Ministry of Health, Labour and Welfare (MHLW) granted it Sakigake designation, similar to the U.S. breakthrough designation, for treatment of HER2-positive advanced gastric or gastroesophageal junction cancer.

For HER2-positive metastatic breast cancer, the combination of trastuzumab, pertuzumab and a taxane as first-line therapy is recommended. If the cancer progresses after the treatment, Kadcyla is an anti-HER2 agent approved for second-line therapy. If those two do not work, there is currently a lack of specific standard of care. Patients can then choose to go for standard chemotherapy, with or without continued anti-HER2 therapy, or opt for palliative care.

In September, Daiichi entered a clinical trial collaboration agreement with MSD, a subsidiary of Merck & Co. Inc. to evaluate the combination of DS-8201 and Keytruda (pembrolizumab) in HER2-expressing or metastatic breast cancer and HER2-expressing or HER2 mutant non-small-cell lung cancer.

Also in the cancer pipeline is Daiichi's drug targeting FLT3-mutated acute myeloid leukemia (AML), quizartinib, which was granted orphan drug designation by the MHLW in early September. The FLT3 inhibitor also bagged the FDA's breakthrough therapy designation in August.

Quizartinib is currently in phase III trial for relapsed or refractory FLT3-ITD AML in the U.S. and EU, and newly diagnosed FLT3-ITD AML in the U.S., EU and Japan. It is in phase II development for relapsed or refractory FLT3-ITD AML in Japan.