In this presentation, Guru Sonpavde, MD, focused on the use of antiangiogenic and targeted therapies with or without PD-1/PD-L1 therapy to treat urothelial carcinoma. To address this, he first touched on what we have learned about the biology of urothelial carcinoma (UC). Our deep dive into the genomics of urothelial carcinoma have revealed important targets for future therapy. In the seminal paper by Robertson et al.2, they completed a comprehensive molecular characterization of muscle-invasive bladder cancer.
On the left, the genomic data highlights the variety of actionable targets in this disease space – some of which we are already seeing good results. We will discuss these further. On the right, the transcriptomics, from the work of a few different groups, has enabled classification into 5 distinct molecular subtypes, with differential responses to various systemic therapies.
A figure from their combined paper demonstrates that there are a wealth of targets – and we have the option of using multiple agents in selected patients.
The first targeted therapy is FGFR3 targeted agents. This is a very rational target for bladder cancer, as FGFR3 activating mutations are seen in 75% of low-grade non-muscle invasive bladder cancer (NMIBC) papillary tumors, but also 20% of muscle-invasive bladder cancer (MIBC) (protein or gene overexpression in up to 50%). Erdafitinib was the first agent assessed and has been granted accelerated approval for patients who have failed platinum-based therapy and have FGFR2/3 genetic alterations. It is a pan-FGFR (1-4) inhibitor and has demonstrated promising results in patients with metastatic urothelial carcinoma (mUC). Dr. Seifker-Radtke (ASCO 2018) presented the phase 2 BLC2001 trial – in which, of 99 patients, there was a 40% ORR and the median duration of response was 5.6 months. Importantly, the 6 patients with FGFR2 mutations did not respond. The waterfall plot of the responses is shown below:
Also important was that 22 patients had seen prior immuno-oncology (IO) therapy, and only had had any response. But, in this population, there was an OR of 59%.
Below are the ongoing trials of FGFR inhibitors:
This includes the phase 3 trial of erdafitinib, but also other more specific FGFR3 inhibitors (Rogaratinib). We eagerly await these results.
Prior experience with targeting VEGFR2 in UC has not been promising. The RANGE trial, which tested the addition of ramucirumab with docetaxel modest PFS benefit but no OS benefit. Similarly, in the Alliance 90601 trial, which tested gem/cis with or without bevacizumab, there was only mild PFS improvement but no OS benefit. However, newer agents targeting the VEGFR are being tested in various combinations. Cabozantinib and lenvatinib are more novel TKI, which also inhibit VEGFR. Dr. Apolo (GU ASCO 2018) demonstrated that adding cabozantinib with nivo/ipi for mUC resulted in ORR of 37%, and Dr. Vogelzang (ASCO-SITC 2019) demonstrated similar benefits with lenvatinib and pembrolizumab.
Below is a summary of ongoing VEGFR inhibitor trials:
Poly(ADP-ribose) polymerase (PARP) inhibitors:
PARP inhibitors are established therapies in other malignancies and include olaparib, niraparib, rucaparib, talazoparib. They specifically work in patients with DNA damage repair alterations, and these are present in ctDNA in a proportion of patients with mUC – and appear associated with worse outcomes. Tumor tissue damage by targeting this may result in improved sensitivity to immuno checkpoint inhibitors (ICIs). Preclinical data does demonstrate the efficacy of PARP inhibitors in urothelial carcinoma with DDR gene mutations.
The following are ongoing trials in this space:
Dr. Sonpavde did specifically note, however, that the ATLAS trial was suspended due to lack of efficacy at interim analysis.
HER2 Kinase inhibitors:
Dr. Sonpavde was very brief on this section as all prior experience has been disappointing in urothelial carcinoma. However, it is experiencing a resurgence, and combinations with ICI and IO are being considered.
There is also a signal of activity with mTOR inhibitors in the treatment of mUC, and so this is being pursued in the following trials:
Dr. Sonpavde ended the talk with the following conclusions:
- The first targeted agent, erdafitinib, was approved in April 2019 for post-platinum mUC who had FGFR2/3 mutations.
- Even in the era of immunotherapy, there is a role for robust investigation of targeted and antiangiogenic agents for urothelial carcinoma.
- Rational selection of patients using analytically validated biomarkers is critically important and should be informed by translational studies.
- There are going to be challenges to accrual for trials evaluating small subsets of disease.
- New targeted agents will carry the risk of new toxicity profiles and adverse events – and agents with non-overlapping toxicities should be combined.
- Large increments will probably require rational synergistic combinations of agents.
- A multidisciplinary collaboration and global approach is necessary to develop precision medicine using targeted agents.
Presented by: Guru Sonpavde, MD, Bladder Cancer Director, Dana Farber Cancer Center, Faculty, Harvard Medical School, Boston, MA
Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA
- Grivas P, Drakaki A, Friedlander TW, Sonpavde G. Conceptual Framework for Therapeutic Development Beyond Anti-PD-1/PD-L1 in Urothelial Cancer. Am Soc Clin Oncol Educ Book. 2019 Jan;39:284-300. doi: 10.1200/EDBK_237449. Epub 2019 May 17. PMID: 31099684
- Robertson et al. Comprehensive Molecular Characterization of Muscle Invasive Bladder Cancer. Cell 2017 Oct 19;171(3):540-556.e25.