Your AI-Trained Oncology Knowledge Connection!
Andrea Necchi, MD, PhD, discusses data from GDFather-NEO evaluating nivolumab plus visugromab in cisplatin-ineligible MIBC.
Data from the blinded, exploratory phase 2 GDFather-NEO trial (NCT06059547) are positioning GDF-15 blockade as a potential strategy to deepen neoadjuvant immunotherapy activity in patients with muscle-invasive bladder cancer who are ineligible for or refused neoadjuvant cisplatin, as higher pathologic and radiographic response rates were observed with the addition of visugromab (CTL-002) to nivolumab (Opdivo) compared with nivolumab plus placebo, according to Andrea Necchi, MD, PhD, an associate professor at Vita-Salute San Raffaele University and head of genitourinary medical oncology at IRCCS San Raffaele.
Findings from GDFather-NEO presented at the
“Overall, this trial continues the path established by earlier GDFather studies in immunotherapy-resistant [solid] tumors and further supports the potential expansion of visugromab testing in urothelial cancer,” Necchi explained in an interview with OncLive®.
In the interview, Necchi outlined the rationale for the GDFather-NEO trial, the key data from the study, and future research directions for visugromab in MIBC.
Necchi: The GDFather-NEO trial was built on the [broader GDF-15 inhibition story]. GDF-15 is a member of the TGF-beta superfamily. It plays a role in fetal-maternal immune protection and immune suppression, and it is highly expressed in the placenta, for example, to protect the fetus from the maternal immune system.
It was later discovered to be one of the most highly expressed cytokines in cancer and one of the most highly expressed proteins across multiple tumor types, including lung cancer, hepatocellular carcinoma, and urothelial cancer. It is an immunosuppressive factor and represents one of the mechanisms of resistance to immune checkpoint inhibition.
Visugromab is a neutralizing antibody against GDF-15. Initial safety and efficacy data were presented in a phase 1 study [NCT04725474] across multiple tumor types, including urothelial cancer. That study was published in Nature and showed that, in urothelial cancer, a proportion of patients with immunotherapy-refractory tumors receiving nivolumab plus visugromab were effectively ‘rescued,’ meaning they were resensitized to immunotherapy after an initial failure.2
Building on that [phase 1] experience, the GDFather-NEO trial evaluated the combination of nivolumab and visugromab up-front in the neoadjuvant setting, comparing it with nivolumab plus placebo. Patients received 3 neoadjuvant cycles every 4 weeks prior to radical cystectomy. Eligible patients had MIBC with predominant urothelial histology and were either refusing or unfit for cisplatin-based chemotherapy.
The trial also allowed for bladder-sparing approaches, meaning patients could opt for transurethral resection of bladder tumor and radiotherapy instead of cystectomy, depending on response, patient preference, and shared decision-making with the treating specialist.
The primary end point presented was pCR rate, [which'] was 33.3% with the combination therapy. Pathological downstaging with nivolumab plus visugromab was observed in 66.7% of patients, which is quite a strong signal. Tolerability was favorable, with no grade 4 adverse effects [AEs] reported. There were some grade 3 AEs, largely immunotherapy-related, but these were manageable.
We also reported radiologic responses, with a 60% objective response rate [in the experimental arm vs 14.3% in the placebo arm], and nearly a 50% complete response rate [n = 7 of 15] by cross-sectional imaging with CT or MRI. Importantly, there was a good correlation between imaging response and pathological response in the nivolumab/visugromab arm.
There are ongoing studies and expansion cohorts across multiple tumor types and, hopefully, in the near future, also in bladder cancer. Based on these results, one of the most intriguing next steps—particularly when considered alongside emerging perioperative data with enfortumab vedotin-ejfv [Padcev] plus pembrolizumab [Keytruda]—would be a neoadjuvant triplet combination of enfortumab vedotin, pembrolizumab, and visugromab. Given the encouraging safety signals seen so far, combining a GDF-15–targeted agent with immune checkpoint inhibition and an antibody-drug conjugate is a potential future direction.
Patients are clearly indicating the path forward in this clinical setting. The direction is becoming clearer: we should start with systemic therapy and remain flexible rather than rigid in our treatment paradigms. Treatment decisions should adapt based on response, patient preference, and patient goals, which are often response-driven. Interim response assessments may not necessarily mandate radical surgery. Instead, we may rely more on minimally invasive tools such as biopsies, endoscopic imaging, and potentially biomarkers like urinary tumor DNA or circulating tumor DNA in the future.
This could allow us to better personalize treatment strategies, including bladder-preservation approaches in select patients who achieve deep responses and wish to preserve the bladder while still aiming for cure.
