Trodelvy Gets Full Green Light From FDA

Nod from FDA comes as drugmakers are withdrawing indications for cancer drugs that were also approved an accelerated basis.

A year after granting accelerated approval to Trodelvy (sacituzumab govitecan-hziy), the FDA has granted to full approval to the antibody–drug conjugate as a treatment for triple-negative breast cancer, according to its maker, Gilead Sciences.

The approval comes against the backdrop of other agents and indications similarly approved on an accelerated basis by the FDA coming off the market after they didn’t met post-marketing standards. The agency is reportedly conducting a broad evaluation of indications approved on an accelerated basis, so more withdrawals may be in the offing.

In early March, Merck withdrew the metastatic small cell lung cancer indication for its Keytruda (pembrolizumab), a blockbuster drug several times over. In February, AstraZeneca withdrew the metastatic bladder indication for Imfinzi (durvalumab).

According to the April 7 press release from Gilead, the FDA approved Trodelvy as a treatment for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer who have received two or more prior systemic therapies, at least one of them for metastatic disease. The press release says the approval was based on data from the ASCENT study, a phase 3 trial that showed Trodelvy extended median progression-free survival to 4.8 months compared with 1.7 months with standard chemotherapy. The ASCENT results also showed the agent as extending median overall survival to 11.8 months versus 6.9 months with standard therapy, according to the Gilead press release.

Triple-negative breast cancer accounts for between 10% and 15% of all breast cancers, according to the American Cancer Society. The term “triple negative” refers to the breast cancer cells lacking estrogen or progesterone receptors and little, if any, HER protein.

Trodelvy is a monoclonal antibody, sacituzumab, linked to a topoisomerase inhibitor, SN-38. Other approved antibody-conjugates include Adcetris (brentuximab vedotin), Besponsa (inotuzumab ozogamicin ) and Kadcyla (trastuzumab emtansine). In simplified terms, antibody-conjugates are scout-soldier combinations: the monoclonal antibody part of the antibody-conjugate scouts out and recognizes a telltale feature of the cancer cell, typically a receptor of some kind on its surface, and latches on. An agent that is toxic to the cancer, the soldier, is linked to the antibody. Once the antibody is attached in some way, that link is broken and the toxic agent is set loose so it can critically damage cancer cells. In Trodelvy’s case, sacituzumab is the scouting antibody that recognizes the Trop-2 receptor, a protein frequently expressed on triple-negative breast cancer cells and other types of epithelial tumors, according to the Gilead press release. High expression of the Trop-2 receptor is associated with poor survival and relapse, the company said. The SN-38 that is attached to sacituzumab interacts topoisomerase I; the resulting DNA damage triggers apoptosis, killing off the cancer cells.

Investors and the media that cover the biotech industry have been following Trodelvy closely. The drug was developed by Immunodemics, a Morris Plains, New Jersey, biotech company. When Gilead acquired Immunodemics for $21 billion last year, most of the media reports on the deal said the purchase and its high price were predicated on strong sales for Trodelvy.

“The antibody-conjugate needs more indications both in earlier lines of treatment and beyond breast cancer before Gilead can get a return on its $21 billion investment,” Fierce Pharma reported analysts as saying this week when Gilead announced the full FDA approval, which will presumably make some oncologists more open to prescribing the drug.

Triple-negative breast cancer is more common in women younger than age 40, who are African-American, or who have a BRCA1 mutation, according the cancer society. It tends to grows and spread faster than other types of breast cancer, says the cancer society's website, and there are fewer treatment options for women with triple-negative breast than those with tumors with breast cancer cells that have estrogen or progesterone receptors or an abundance of the HER protein.

“Women with triple-negative breast cancer have historically had very few effective treatment options and faced a poor prognosis,” said Aditya Bardia, M.D., M.P.H., the study chair of the ASCENT trial and director of the breast cancer research program at Mass General Mass General Cancer Center in Boston, in the Gilead press release. “Today’s FDA approval reflects the statistically significant survival benefit seen in the landmark ASCENT study and positions sacituzumab govitecan-hziy as a potential standard of care for pre-treated TNBC.”