FDA Gives Nod to T-DXd for HER2-Mutant NSCLC

The FDA has granted accelerated approval to trastuzumab deruxtecan (T-DXd; Enhertu; Daiichi Sankyo; AstraZeneca) to treat adults with inoperable or metastatic non–small cell lung cancer (NSCLC) with activating HER2 mutations who have already received a systemic platinum-based therapy. The approval is the first for a HER2-targeted therapy for lung cancer.

“This really extends the paradigm of using more targeted therapies to another oncogenic driver in lung cancer,” comments Justin Gainor, MD, of Massachusetts General Hospital in Boston.

Roughly 2% of patients with NSCLC have HER2 exon 20 insertion mutations that are targetable by T-DXd, an antibody and topoisomerase inhibitor conjugate. The approval was based on results from the phase II DESTINY-Lung02 trial, in which 52 patients were treated with 5.4 mg/kg of T-DXd delivered via intravenous infusion every 3 weeks. The confirmed objective response rate was 58%, and the median duration of response was 8.7 months.

The agency also approved Guardant Health's Guardant360 CDx, a plasma-based assay, and Life Technologies’ Oncomine Dx Target Test, a tissue-based assay, as companion diagnostics. The FDA stated that if no mutation is detected with a plasma assay, tumor tissue should then be tested.

“We now have nine distinct molecular targets in lung cancer, and I think this now means that HER2 mutation testing should be part of our standard of care for patients with advanced lung cancer,” Gainor says. Most commercially available cancer gene panels cover HER2 mutations, “and most of us have already been testing for this for several years, but this approval underscores that testing for HER2 should be a standard practice.”

Christine Lovly, MD, PhD, of Vanderbilt-Ingram Cancer Center in Nashville, TN, emphasized that the approval applies exclusively to patients with advanced or metastatic NSCLC bearing HER2 mutations.

“That is different from how we usually use HER2-directed therapies in cancer,” she says. “For example, in breast cancer they use HER2-directed therapies for HER2 amplification. This is a very important difference.”

“Would I use this drug in the proper clinical context? Yes. It has gone through rigorous trials, and the FDA has approved it,” she adds.

This is the second recent approval for T-DXd. On August 5, the FDA approved its use as a second-line therapy for patients with inoperable or metastatic HER2-low breast cancer—a newly defined subset of HER2-negative breast cancer—who have received prior chemotherapy for metastatic disease or whose cancer returned during, or within 6 months of completing, adjuvant chemotherapy.

The drug has also been greenlighted for some patients with inoperable or metastatic HER2-positive breast cancer or locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas.

In the DESTINY-Lung02 trial, adverse reactions to T-DXd occurring in at least 20% of patients included nausea; decreased white blood cell, hemoglobin, neutrophil, lymphocyte, and platelet counts; decreased albumin; elevated liver enzymes; fatigue; constipation; decreased appetite; vomiting; and alopecia. The prescribing information includes a black box warning advising health professionals about the risk for interstitial lung disease and embryo-fetal toxicity.

Gainor notes that although T-DXd may help only about 2% of patients with advanced NSCLC, the same is true for other targeted agents in lung cancer, such as drugs targeting RET or ROS1 rearrangements or the BRAF^V600E mutation.

But taken together, “many of these uncommon alterations actually affect a large number of patients when we think about the global incidence of lung cancer,” he says. —Neil Osterweil

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