ESMO: Datroway, Trodelvy lay claim to frontline TNBC therapy

Two TROP2-targeting antibody-drug conjugates, Datroway and Trodelvy, have new data suggesting they could become options for previously untreated patients with triple-negative breast cancer (TNBC).

AstraZeneca and Daiichi Sankyo's Datroway (datopotamab deruxtecan) came out of the blocks strongly at the ESMO congress with results from the TROPION-Breast02 trial, which achieved a 43% reduction in the risk of disease progression or death compared to chemotherapy when used first-line for TNBC patients in whom immunotherapy was not an option.

That positive result on progression-free survival (PFS) – a median of 10.8 months versus 5.6 months in the chemo group – was backed up by a 21% reduction in the risk of death versus chemo, which equated to an extra five months of life. Median overall survival (OS) came in at 23.7 months and 18.7 months, respectively.

There was a similar outcome for Gilead Sciences' Trodelvy (sacituzumab govitecan) on PFS in the ASCENT-03 trial, with a 38% improvement in median PFS (9.7 months vs 6.9 months with chemo). OS data are still immature, according to the investigators, but show a very slight 2% trend in favour of Trodelvy. The data have also been published in the New England Journal of Medicine.

TNBC accounts for about 15% of all breast cancer cases and is often difficult to treat, with a five-year survival rate of only about 15% for patients diagnosed with advanced, metastatic disease.

Moreover, around 60% of patients with metastatic TNBC have tumours that do not express PD-L1, making them less likely to respond to PD-1/PD-L1 checkpoint inhibitors, and both Datroway and Trodelvy – if approved – offer an alternative to chemo in this group. The two ADCs are already on the market to treat previously treated metastatic HR-positive, HER2-negative breast cancer.

TROPION-Breast02 lead investigator Rebecca Dent of the National Cancer Centre Singapore said the results of the study are "remarkable…considering the trial included a subset of patients with highly aggressive disease who are often excluded from research in this setting."

AZ and Daiichi have trumpeted the OS result as differentiating their ADC, while Gilead is pointing to the combined evidence from ASCENT-03 and previously reported ADSCENT-04, which tested the drug alongside MSD's PD-1 inhibitor Keytruda (pembrolizumab) in previously untreated, PD-L1-positive metastatic TNBC.

"With two positive phase 3 trials, Trodelvy has potential as the first and only ADC to be a backbone standard of care for all first-line metastatic TNBC patients, regardless of PD-L1 status," it said in a statement.

Neither AZ/Daiichi Sankyo nor Gilead have said yet when they intend to file for approval of their drugs as first-line TNBC therapies.

With an eye on extending the label of Datroway even further, AZ and Daiichi are running the TROPION-Breast05 study in PD-1/PD-L1-eligible advanced TNBC patients, with or without AZ's PD-L1 inhibitor Imfinzi (durvalumab), as well as TROPION-Breast04 and TROPION-Breast03 in neoadjuvant and post-neoadjuvant treatment of earlier-stage TNBC.

Gilead, meanwhile, is running the ASCENT-05 study of Trodelvy plus Keytruda in TNBC patients with residual disease after surgery and neoadjuvant therapy.

BioNTech is also testing its PD-L1xVEGF bispecific pumitamig, with and without chemo, in a PD-L1-ineligible TNBC population in the ROSETTA Breast-01 trial, but data from that isn't expected for a couple of years.

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