“Very Compelling” Results for ADC in TNBC Trial

In a phase I trial, the antibody–drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd; Daiichi Sankyo/AstraZeneca) demonstrated encouraging response rates and manageable toxicity in patients with advanced/metastatic triple-negative breast cancer (TNBC) that has recurred after, or is resistant to, multiple therapies. But which patients are most likely to respond remains unclear.

Ian Krop, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, presented findings from the TNBC cohort of the ongoing TROPION-PanTumor01 study at the 2021 San Antonio Breast Cancer Symposium, held in Texas, December 7–10.

Dato-DXd consists of three components: a humanized antitrophoblast cell-surface antigen 2 (TROP2) IgG mAb attached to a topoisomerase I inhibitor, a derivative of exatecan, with a tetrapeptide-based cleavable linker. High TROP2 expression is an unfavorable prognostic factor for overall survival.

Researchers enrolled 44 patients with advanced/metastatic relapsed or refractory TNBC in the trial. Thirty patients (68%) had previously received at least two therapies, including taxanes, platinum-based chemotherapy, immunotherapy, PARP inhibitors, or another topoisomerase I inhibitor, such as the ADC sacituzumab govitecan (Trodelvy; Gilead).

After receiving Dato-DXd for a median of 7.6 months, 15 patients (34%) experienced a complete or partial response; 17 more experienced stable disease (SD).

However, “because a full 30% of patients in the study had had a prior topoisomerase I inhibitor ADC, and that is the same class of payload as Dato-DXd, there is a possibility of cross resistance,” explained Krop. Thus, researchers assessed responses in 27 participants naïve to these therapies. After a median of 8.8 months, 14 patients had responded, and nine more had SD.

The median duration of response was not reached at the time of data cutoff, and responses were ongoing for 13 of 15 patients, which Krop called “highly encouraging.”

Although 98% of patients experienced treatment-emergent adverse events (TEAE), about half were grade 1 or 2. The most common TEAEs were nausea and stomatitis, predominantly grade 1 or 2.

Lisa Carey, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, noted that the number of patients in the trial was small and just “an early look at activity,” but she deemed the study findings “very compelling.”

As with the phase III ASCENT trial of sacituzumab govitecan, patients enrolled in the trial were not tested for TROP2 expression because it is expressed across all breast cancer subtypes. Also, because this was the first trial of Dato-DXd, researchers didn't know the minimum level of TROP2 expression likely to generate responses. “It was felt prudent to allow an unselected group of patients on this initial study, and then retrospectively assess if there was a clear relationship between level of TROP2 expression and effectiveness,” Krop explained.

That's data that Sherene Loi, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, Australia, would like to see. “It is always better to have a good predictive biomarker, especially given [that] other ADCs are [or] will be available in the near future, and the side effect profile may not be tolerable for some patients,” she said.

“These promising results warrant further investigation … in phase III clinical trials,” said Leisha Emens, MD, PhD, of the University of Pittsburgh Hillman Cancer Center in Pennsylvania. To that end, researchers are planning a phase III trial in TNBC. In the meantime, they have launched BEGONIA, an ongoing trial in TNBC to evaluate the efficacy and safety of Dato-DXd plus durvalumab (Imfinzi; AstraZeneca), and TROPION-Breast01, a phase III trial in HR-positive/HER2-negative breast cancer. –Suzanne Rose