TROPION-Breast01, TROPION-Lung01 Demonstrate PFS Benefit of Datopotamab Deruxtecan in Metastatic Breast Cancer, NSCLC

In both non–small cell lung cancer (NSCLC) and in hormone receptor–positive (HR+)/HER2-negative (HER2–) breast cancer, datopotamab deruxtecan demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) compared with standard of care.

The results of TROPION-Breast01 and TROPION-Lung01 were presented at ESMO Congress 2023, held October 20-24, 2023, virtually and in person in Madrid, Spain.

In HR+/HER2– metastatic breast cancer, there is an unmet need for treatments after endocrine therapy and 1 line of systemic therapy. Currently, chemotherapy is widely used for endocrine-resistant cancer, but it has a low response rate, poor prognosis, and significant toxicity, explained Aditya Bardia, MD, MPH, associate professor of medicine, Harvard Medical School.

Research has so far shown that TROP2-directed antibody drug conjugates (ADCs) have efficacy but dose-limiting toxicities. “So, from a field perspective, there’s an unmet need both from an efficacy perspective, as well as a toxicity perspective,” he said. “We need agents that are better and less toxic.”

Datopotamab deruxtecan is a TROP2-directed agent with a stable linker payload and tumor-selective cleavable linker, which both reduce off-target toxicity. In the phase 3 TROPION-Breast01 study, patients who were previously treated with 1 to 2 lines of chemotherapy, had disease progression on endocrine therapy, or were ineligible for endocrine therapy were randomized in a 1:1 fashion to either datopotamab deruxtecan (n = 365) or investigator’s choice of chemotherapy (n = 367).

Bardia presented the efficacy analysis in the intention-to-treat population with a PFS analysis and an interim overall survival (OS) analysis. The median follow-up was 10.8 months.

At the time of the analysis, 3 times as many patients were still on datopotamab deruxtecan compared with chemotherapy (93 patients vs 39 patients). The majority of patients who discontinued had disease progression.

The median PFS was 6.9 months for datopotamab deruxtecan vs 4.9 months for chemotherapy (95% CI, HR 0.63, 0.52-0.76). The difference between PFS separated early and was not only maintained as time went on but actually increased, Bardia pointed out.

All groups derived benefit regardless of age, race, ECOG performance status, number of prior lines, and prior use of CDK4/6 inhibitors or taxane and/or anthracycline.

The confirmed objective response rate (ORR) was 36.4% for the intervention vs 22.9% for chemotherapy. In addition, datopotamab deruxtecan had some complete response, while there were none with chemotherapy. While the OS data is currently not mature, there was a trend favoring datopotamab deruxtecan. More about OS will be presented at a later date once the data have matured.

The intervention also had a lower rate of grade ≥ 3 treatment-related adverse events (TRAEs): 21% vs 45%. The rate of treatment interruption was also lower for datopotamab deruxtecan compared with chemotherapy.

“This is a bit different from most of the studies,” Bardia said. “In general, we see that the rate of adverse events is higher in the intervention arm as compared to the control arm. But here, the rate of grade 3 or higher AEs were lower with [datopotamab deruxtecan] as compared to standard chemotherapy.”

For TRAEs occurring in ≥ 15% of patients, most were grade 1 to 2 and manageable. There were no new safety signals.

“Overall, results support [datopotamab deruxtecan] as a potential new therapeutic option for patients with metastatic hormone receptor–positive breast cancer,” Bardia concluded.

Following the results in breast cancer, Aaron Lisberg, MD, assistant clinical professor of medicine, University of California, Los Angeles, presented the results of TROPION-Lung01. The standard of care in metastatic NSCLC is second-line chemotherapy, which only provides a modest benefit paired with significant toxicity.

The phase 3 study included patients with stage IIIB, IIIC, or IV NSCLC with no prior docetaxel treatment either with or without actionable genomic alterations. They were randomized 1:1 to receive either datopotamab deruxtecan (n = 299) or docetaxel (n = 305).

Similar to the results of the breast cancer study, 3 times as many patients were still on treatment at the time of analysis (18% on datopotamab deruxtecan vs 6% on docetaxel). Also of note was how long patients stayed on treatment. More than half (58%) of patients on docetaxel discontinued treatment within 3 months compared with 40% on datopotamab deruxtecan. In addition, 20% of patients stayed on datopotamab deruxtecan for more than 9 months compared with only 8% of patients on docetaxel.

There was a statistically significant improvement in PFS with a median PFS of 4.4 months for datopotamab deruxtecan vs 3.7 months for docetaxel (95% CI, HR 0.75, 0.62-0.91). The ORR was 26.4% for datopotamab deruxtecan vs 12.8% for docetaxel and the duration of response was 7.1 months for datopotamab deruxtecan vs 5.6 months for docetaxel.

While the majority of key subgroups derived a PFS benefit on datopotamab deruxtecan vs docetaxel, “the patients with nonsquamous histology are clearly deriving a PFS benefit from [datopotamab deruxtecan] while the squamous patients are not,” Lisberg explained.

Patients with nonsquamous cancer had a median PFS of 5.6 months vs 3.7 months for docetaxel, while patients with squamous cancer had a median PFS of 2.8 months vs 3.9 months on docetaxel.

The ORR was 31.2% on the intervention vs 12.8% on the control in the nonsquamous group compared with 9.2% on the intervention vs 12.7% on the control.

The median OS in the interim analysis was 12.4 months on datopotamab deruxtecan compared with 11.0 months for docetaxel. There is a trend in favor of datopotamab deruxtecan, but the results are not statistically significant as of yet. Similar to the PFS, patients with nonsquamous cancer were deriving the greatest benefit.

As in the breast cancer study, the intervention had less toxicity compared with the control. Grade ≥ 3 TRAEs occurred in 25% of patients on datopotamab deruxtecan vs 41% on docetaxel, and only 8% of patients on datopotamab deruxtecan discontinued their treatment compared with 12% on docetaxel.

“[Datopotamab deruxtecan] is the first antibody drug conjugate to demonstrate a statistically significant improvement in progression-free survival over docetaxel in patients with previously treated locally advanced or metastatic non–small cell lung cancer,” Lisberg concluded. “That said, the data makes it very clear that the PFS benefit we observed was primarily driven by patients with nonsquamous histology, both with and without actionable genomic alterations, and the patients with squamous cell lung cancer did not derive the same benefit.”