Antibody-drug conjugates (ADCs) were the first topic of discussion in a presentation by Dr. Max Kates (Johns Hopkins Medicine). These anti-cancer drugs are designed to deliver a cytotoxic payload directly to target cancer cells. Two such ADCs, enfortumab vedotin (EV) and sacituzumab govitecan (SG) have recently received FDA approval for the treatment of metastatic urothelial cancer (mUC) after progression on platinum-based chemotherapy or immunotherapy. As a result of the promising results reported from initial trials of EV monotherapy, there is now interest in combining EV with other anticancer therapies. Dr. Kates highlighted the phase I EV-104 (NCT03288545) trial which is currently recruiting and will evaluate intravesical EV alone and in combination with pembrolizumab, cisplatin, carboplatin, and gemcitabine in patients with BCG unresponsive disease.
Although a useful drug development strategy in NMIBC is to assess whether therapies known to work in metastatic disease have relevance in earlier disease states, Dr. Kates explained that a paucity of preclinical evidence exists to support this approach. He proceeded to highlight work from his lab looking at the expression of ADC-specific gene targets in BCG-experienced NMIBC. Findings from this work provide a rationale for further exploration of targeted therapies for patients with NMIBC who recur after BCG. Furthermore, certain tumour groups showed upregulation of multiple gene targets with increased expression post-BCG, suggesting that combination therapy may provide additional benefit in some cohorts.
In the second talk of the session, Dr. Trinity Bivalacqua (University of Pennsylvania) discussed recombinant BCG-STING and NMIBC. The DNA sensing cGAS-STING pathway is known to play a key role in the induction of the innate immune response and its activation induces a potent type 1 interferon response in both tumour and phagocytic immune cells.2 Dr. Bivalacqua presented work from his lab demonstrating elevated expression of STING following intravesical BCG therapy in pre-clinical models of NMIBC.3
Based on these findings, Dr. Bivalacqua and his team hypothesized that BCG efficacy may be enhanced by utilizing a STING agonist to induce stronger immune responses. Using a recombinant BCG that was genetically modified to overexpress a STING agonist (BCG-disA-OE), the team tested its anti-tumour potency in urothelial cancer models. BCG-disA-OE was found to have superior anti-tumour efficacy, suggesting that complementing BCG immunotherapy with STING signaling yields an improved antitumor response. As such, recombinant BCG may hold promise as a novel intravesical immunotherapy for patients with NMIBC, and a phase 1 trial is planned to investigate this.
In the penultimate talk, Dr. Joshua Meeks (Northwestern University) explored how the anti-tumour activity of BCG may be enhanced with checkpoint inhibitors and shared insights into his own experience of using intravesical pembrolizumab and BCG combination therapy within a trial setting.
In the final talk of the session, Dr. Gary Steinberg (NYU Langone Health) provided an overview of immunotherapy delivery systems. He began by discussing oncolytic viruses such as CG0070. CG0070 targets bladder tumour cells through their defective retinoblastoma pathway, exerting both direct and indirect cytotoxic effects. Dr. Steinberg explained that the antitumour efficacy of CG0070 may be enhanced through combination with checkpoint inhibitors, and this hypothesis is being tested in the multicentre phase II CORE-001 trial (NCT04387461). The trial is currently recruiting and will evaluate the combination of pembrolizumab and intravesical CG0070 in BCG-unresponsive disease with CIS with or without Ta/T1 papillary disease.
Dr. Steinberg went on to consider other novel approaches for BCG-unresponsive disease including intravesical cytokines and targeted therapies, concluding his talk with a discussion on FGFR as a therapeutic target. Mutations and fusions in FGFR2/3 are common in patients with UC, particularly in the luminal I subtype4 and, as such, FGFR inhibition may represent a valuable therapeutic approach. Indeed, erdafitinib, a pan-FGFR inhibitor, recently received approval by the FDA for use in mUC with FGFR3 or FGFR2 alterations that have progressed on platinum-based chemotherapy. This approval has provided the impetus for a randomized phase 2 trial evaluating erdafitinib versus intravesical chemotherapy in patients with high-risk NMIBC with FGFR mutations or fusions, who recurred after BCG.5
Presented by: Molly Ingersoll, PhD, Max Kates, MD, Johns Hopkins Medicine; Joshua Meeks, MD, PhD, Northwestern School of Medicine; Trinity Bivalacqua, MD, PhD, University of Pennsylvania; Gary Steinberg, MD, NYU Langone Health
Written by: Niyati Lobo, MD, The Urology Foundation Fulbright Scholar, Twitter: @niyatilobo, with Professor Ashish Kamat, Professor of the Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Twitter: @UroDocAsh at the 7th Annual Albert Institute for Bladder Cancer Care and Research (AIBCCR) Symposium, Sept 16, 2021- Sep 18, 2021.
References:
- Ourfali S, Ohannessian R, Fassi-Fehri H et al. Recurrence rate and cost consequence of the shortage of bacillus Calmette-Guerin connaught strain for bladder cancer patients. Eur Urol Focus 2021; 7: 111-6
- Li, T. & Chen, Z. J. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J. Exp. Med. 215, 1287–1299 (2018).
- Lombardo K, Singh A, Obradovic A et al. BCG invokes superior STING-mediated innate immune response over radiotherapy in a carcinogen murine model of urothelial cancer. J Urol 2021; 206: e1131
- Haugsten EM, Wiedlocha A, Olsnes S et al. Roles of fibroblast growth factor receptors in carcinogenesis. Mol Cancer Res 2010;8:1439-1452.
- Steinberg GD, Palou-Redorta J, Gschwend JE et al. A randomized phase II study of erdafitinib (ERDA) versus intravesical chemotherapy (IC) in patients with high-risk nonmuscle invasive bladder cancer (HR-NMIBC) with FGFR mutations or fusions, who recurred after Bacillus Calmette-Guérin (BCG) therapy. J Clin Oncol 2020; 38