ESMO 2023 – some Tropion fears allayed

The first numerical results from AstraZeneca/Daiichi Sankyo’s Tropion-Lung01 study suggest that there was some basis for the worries triggered when the companies toplined a positive hit back in July. But fears over drug-related deaths might have been misplaced, an ESMO late-breaking abstract suggests.

The trial was the first big test of the companies’ anti-TROP2 ADC datopotamab deruxtecan, in NSCLC patients who had failed first-line targeted agents and in some cases chemo as well. Apart from the lack of reassurance on the result's clinical meaningfulness, revelation of “some grade 5 events” had wiped billions from the companies’ market caps at the time.

The extent of the grade 5 events, however, amounts to three investigator-assessed datopotamab-related deaths (a 1% rate), versus two deaths on docetaxel control, according to the abstract revealed yesterday. Interstitial lung disease, a known toxicity of the companies’ Enhertu, was seen at grade 3 or higher in just 3.4% of datopotamab patients.

This should assuage some of the biggest fears over the project. However, the ESMO late-breaker shows precisely why Astra had omitted the words “clinically meaningful” from its July press release.

The actual PFS benefit was statistically significant, with the 25% reduction in risk of progression or death versus docetaxel yielding a 0.004 p value, which cleared a 0.008 boundary. But the medians painted a far worse picture: just 4.4 months for dato, amounting to less than a month's benefit over docetaxel.

The big question doctors will want answered at ESMO on Monday is therefore whether dato has any path forward in second-line NSCLC. One hope might be patients with non-squamous histology, a subgroup whose analysis had been prespecified in Tropion-Lung01. Here the mPFS benefit amounted to nearly two months, with a 5.6-month number that Jefferies analysts said was “likely” clinically meaningful.

Breast cancer

It was perhaps because of the extremely adverse market reaction to the Tropion-Lung01 press release that Astra took a different tack with dato’s breast cancer study Tropion-Breast01 last month. Here the PFS benefit was described as clinically meaningful, with a trend on OS, and “low” rates of all-grade ILD.

Tropion-Breast01 features in a separate ESMO late-breaker, which reveals the absolute numbers for the first time. Here, 6.9 months of mPFS looks competitive with Gilead’s approved anti-TROP2 ADC Trodelvy, albeit the latter is in a slightly later-line setting. The abstract sheds no further light on ILD, but Jefferies wrote that “we understand no grade 4 or 5 ILD events were reported” in Tropion-Breast01.

Also in the mix is sacituzumab tirumotecan, an anti-TROP2 ADC Merck & Co had licensed from Kelun that had impressed in early NSCLC data at ASCO this year. A breast cancer study features in a regular ESMO abstract that had been unveiled earlier, and will no doubt prompt extensive cross-trial comparisons. 

Cross-trial comparison of anti-TROP2 ADCs in ER-positive HER2-negative breast cancer

Source: US prescribing information & ESMO.