Asco-GU – confirmatory Padcev trial throws a curveball

Subgroup analysis of a confirmatory US study in bladder cancer suggests no benefit in female patients.

Seagen/Astellas’s bladder cancer drug Padcev is expected to be selling nearly $4bn in five years’ time, according to EvaluatePharma sellside consensus, but its confirmatory EV-301 study has thrown doctors a curveball.

The data, being presented today at the Asco-GU meeting, appear to show that the drug does not work in women. However, the companies can probably shrug off this post hoc subgroup analysis and, even if doctors now shy away from prescribing Padcev to female patients, women comprise a relatively minor portion of this cancer type.

Padcev, an anti-nectin-4 antibody-drug conjugate, received US accelerated approval for urothelial bladder cancer after failure on PD-(L)1 blockade and chemo, just over a year ago. This was on the basis of the single-cohort EV-201 study, which showed a striking 44% overall remission rate in patients not preselected for nectin-4 expression.

To convert the early green light into full US approval the companies want to use the phase III EV-301 study, which tests a similar second or later-line setting to EV-201, but compares Padcev against chemotherapy. This was stopped early for efficacy last September, but the data are only now being presented at Asco-GU.

Across the 608-strong intent-to-treat population Padcev’s median overall survival benefit is 3.9 months, the 30% reduction in risk of death yielding a p value of 0.001. Risk of progression or death, a secondary endpoint, was reduced by 38% (p<0.001).

So far so good. But subgroup analyses reveal a worrying sign: among EV-301’s 138 female subjects survival favoured chemotherapy, with women given Padcev being at a relative 17% increased risk of death.

Deaths in selected EV-301 subgroups. Adapted from Dr Thomas Powles's presentation at Asco-GU.

Of course, such a post hoc finding has to be treated with caution. It concerns less than a quarter of EV-301’s population, reflecting the demographic profile of advanced urothelial carcinoma, and until it is explored prospectively it remains just a signal in a subgroup.

Still, the analysis will come as a surprise. EV-201 had not suggested a lack of responses in female patients, and Padcev’s label makes no mention of such a possibility. What it does do, however, is warn of embryo-fetal toxicity and say women given the drug should take contraception, as well as citing risk of adverse reactions in the child of a breastfeeding mother on Padcev.

Taken together such risk factors, and suggestion of no benefit versus chemo, might make urologists wary of prescribing Padcev to women. Should EV-301 lead to full US approval these data would be obvious to doctors reading Padcev’s updated label.

On the plus side, overall serious adverse events were balanced across EV-301’s two cohorts, though treatment-related rash, peripheral neuropathy and hyperglycaemia were elevated with Padcev.

From a business perspective, even eliminating female patients as a target population entirely might not cause too big a dent to Padcev’s sales forecasts, since women make up a minority of this cancer type.

And it is still unclear whether such a sex imbalance in benefit might also be seen in the much more important first-line setting. EV-302, the trial supporting this use, is still some way off yielding data, but forecasts no doubt bake in a significant contribution from the front-line setting.

Selected Padcev studies in urothelial bladder cancer
Trial Setting Data Relevance
EV-201 ≥2L (post PD-(L)1), single-cohort ORR 44% (CR 12%) Ph2 study that secured US accelerated approval
EV-301 ≥2L (post PD-(L)1), vs chemo mOS 12.9mth vs 9.0mth (HR=0.70, p=0.001) Ph3 study to convert accelerated US approval to full approval
EV-103 1L & 2L, uncontrolled Keytruda combo: mPFS 12.3mth; ORR 85% in PD-L1-high, 67% in PD-L1-low Ph1/2 study of various combos
EV-302 1L, Keytruda combo, vs chemo None (started enrolling Mar 2020) Ph3 study to support 1L approval
Source: company reports & Asco-GU.

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