Trastuzumab Deruxtecan DESTINY for Some Cancers

Evidence is mounting that trastuzumab deruxtecan (Enhertu; AstraZeneca/Daiichi Sankyo), which is approved for certain HER2-positive breast cancers, may be effective in other solid cancers. In a randomized phase II trial of HER2-positive gastric and gastroesophageal junction (GEJ) cancers, trastuzumab deruxtecan significantly extended overall survival (OS) and progression-free survival (PFS) compared with standard chemotherapy. The agent also elicited high response rates in single-arm phase II trials of HER2-mutant non–small cell lung cancer (NSCLC) and HER2-positive colorectal cancer. Findings were presented at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting, May 29–31.

An antibody–drug conjugate, trastuzumab deruxtecan consists of the anti-HER2 monoclonal antibody trastuzumab connected by a cleavable linker to deruxtecan, a topoisomerase I inhibitor. The antibody binds to HER2 on tumor cells and the agent is internalized, at which point the linker is cut, releasing deruxtecan—which causes DNA damage and apoptosis. The agent is particularly potent due to a high drug to antibody ratio.

Approximately 15% to 20% of patients with gastric or GEJ cancers have HER2-positive disease, and their treatment options are limited after their cancer worsens on standard chemotherapy plus trastuzumab. At the ASCO meeting, researchers reported results from the phase II DESTINY-Gastric 01 trial (N Engl J Med 2020 May 29 [Epub ahead of print]).

Researchers in Japan and South Korea randomly assigned 163 patients with advanced HER2-positive gastric cancer and 24 patients with GEJ cancer in a 2:1 ratio to receive trastuzumab deruxtecan or chemotherapy. Patients had received a median of two prior therapies; all had been previously treated with trastuzumab or a biosimilar. Patients treated with trastuzumab deruxtecan had an objective response rate (ORR) of 51.3%, a median OS of 12.5 months, and a median PFS of 5.6 months, compared with 14.3%, 8.4 months, and 3.5 months, respectively, in patients who received chemotherapy.

Overall, 69.2% of patients on the experimental arm experienced grade 3 or higher adverse events, compared with 53.2% of patients on the chemotherapy arm. The most common severe side effects in both arms were a decreased neutrophil count and anemia. Interstitial lung disease and pneumonitis occurred in 6.4% of patients.

“These results are striking and likely to be practice changing,” said Adam Bass, MD, of Dana-Farber Cancer Institute in Boston, MA, who was not connected to the trial. Second-line therapy for HER2-positive gastroesophageal cancer “has been a vexing problem, as the therapies that have proven successful in breast cancer have consistently failed,” he added.

One possible reason for this failure is the heterogeneity of gastroesophageal tumors, which may lead to outgrowths of HER2-negative subclones that cause trastuzumab resistance. Thus, he said, an important question is whether the drug is actually superior to HER2-targeted agents such as ado-trastuzumab emtansine (T-DM1/Kadcyla; Genentech) that haven't worked, or whether investigators were more careful to select patients with HER2-positive tumors at resistance—information that would inform clinical practice.

“The results of the study are quite outstanding,” agreed Daniel Catenacci, MD, of the University of Chicago Medicine in Illinois, who was also not involved, noting that patients do not usually respond to third-line therapy. He noted, however, that the trial was conducted in Asia where most such patients have gastric cancer, whereas most such patients in Western countries have proximal GEJ or esophageal cancers—and poorer responses. Thus, the findings must be confirmed in a Western population.

Catenacci also expressed concern about interstitial lung disease and pneumonitis—side effects that may make it difficult to prescribe the drug earlier in treatment. “However, when one gets to third or later lines of therapy where options are limited,” he said, “the risk/benefit profile changes and this would be a welcome option.”

Trastuzumab deruxtecan has also shown promise in other solid cancers. Following encouraging phase I results, the phase II DESTINY-Lung 01 trial tested the agent in patients with inoperable, metastatic, nonsquamous HER2-mutant NSCLC who relapsed or became resistant to standard treatments but had not received HER2-targeted agents other than pan-HER tyrosine kinase inhibitors (Cancer Discov 2020;10:688–701). In total, 26 of 42 patients responded, and 12 more experienced stable disease. The median PFS was 14 months; median OS has not been reached.

“This drug does appear to have the highest response and the most meaningful PFS—and seems to be the best drug that I've been able to evaluate or look at for HER2-mutated lung cancer,” said discussant Benjamin Levy, MD, of Johns Hopkins University in Baltimore, MD.

In the phase II DESTINY-CRC01 trial, the drug elicited an ORR in 24 of 53 patients with inoperable and/or metastatic HER2-positive colorectal cancer who did not have RAS or BRAF mutations and who had received at least two prior therapies, which could have been anti-HER2 agents. Patients had a median PFS of 6.9 months; median OS has not been reached. Side effects in the lung and colorectal cancer trials were similar to those seen in DESTINY-Gastric 01.

“I would say without a doubt that this trial is clinically relevant,” said Autumn McRee, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, who discussed DESTINY-CRC01. However, randomized trials comparing trastuzumab deruxtecan to standard-of-care therapies are needed.

Research on trastuzumab deruxtecan in these diseases will continue: The single-arm DESTINY-Gastric 02 trial will test the agent in patients with gastric and GEJ cancers in North America and Europe. DESTINY-Lung 01 will explore the drug in patients with HER2-expressing disease, whereas DESTINY-Gastric 01 and DESTINY-CRC 01 will test it in HER2-low patients. –Catherine Caruso

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