The GDFather trial was a phase II study, a proof of concept study, that allocated patients to receive a combination of nivolumab and the GDF-15 neutralising antibody visugromab or nivolumab and placebo for three courses every four weeks before radical cystectomy. Proof of concept study because it was not aimed to get an assessment of the comparison between the two arms, just to get an assessment of the clinical data and biomarker data from the initial patient population.

15 patients were allocated in both arms or an additional patient was put in the visugromab/nivolumab combination, so 16 and 15 patients respectively. The primary endpoint was the pathological complete response rate with also the radiological response as another endpoint.

GDF-15 is an emerging target in solid tumours. GDF-15 is an immunosuppressive factor, one of the most highly secreted cytokines in cancer, and highly expressed in urothelial cancer. Visugromab data, in combination with nivolumab, had already been presented in an immunotherapy refractory patient population in a phase I study published in Nature a few months ago, including a urothelial cancer cohort. Updated data from this study have been also presented at this year’s meeting.

The GDFather-NEO trial is the first trial to put visugromab in immunotherapy naïve patients. We saw that the pathological complete response rate with the combination therapy, with nivolumab and visugromab, was 33% and the pathological downstaging to non-muscle invasive disease was 67%. So a very high proportion of patients benefited, with major response to neoadjuvant therapy. The same was for radiological response, so it was four times higher than the radiological response seen with nivolumab monotherapy. There was a pretty good association between major response with imaging with radiology and major response assessed with cystectomy or with TURBT. Importantly, the study allowed the possibility to skip the radical cystectomy and to undergo re-TURBT, so radical resection, endoscopic resection and resection of the tumour, depending on patient preference and the patient’s decision after informed consent post-treatment.

Initial biomarker data also put in on the baseline analysis of baseline samples, blood samples and tumour tissues, showed that there was no baseline difference between the two arms with regards to secreting cytokines, circulating GDF-15 levels and the GDF-15 expression by the tumour cells or enrichment of T-cells in the tumour. So nothing that could have provided the kind of justification for the difference between the two arms in terms of pathCR and radiological response.

So, overall, quite promising data, a very new target in this field. The tolerability was pretty good with very, very few grade 3 side effects, no grade 4 side effects. So it’s an ideal situation in which we could envision the possibility to get a third drug, a third combination therapy with maybe an ADC-IO and visugromab in the neoadjuvant space, maybe with a bladder preservation strategy.