ASCO 2019: Targeted Therapeutics and Patient Selection in Advanced Urothelial Carcinoma

Chicago, IL (UroToday.com) Yohann Loriot, MD, MSc, provided a summary and analysis of 3 abstracts:

Abstract 4509: A phase II study of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma, Xinan Sheng
Abstract 4510: Infigratinib in upper tract urothelial carcinoma vs urothelial carcinoma of the bladder and association with comprehensive genomic profiling/cell-free DNA results, Nazli Dizman
Abstract 4511: FIERCE-22: Clinical activity of vofatamab (V) a FGFR3 selective inhibitor in combination with pembrolizumab (P) in WT metastatic urothelial carcinoma, preliminary analysis, Arlene O. Siefker-Radtke

Below, is a summary of Dr. Loriot's main analyses –  His talk focused on how we are moving from Precision Medicine 1.0 to Precision Medicine 2.0, which incorporates much more information and new technology: 

ASCO 2019_Loriot_1.png
Where before, we were limited to a dna-based evaluation in late-stage disease.

Abstract 4509:

First, Dr. Loriot reviewed Sheng et al. abstract on RC48-ADC, an antibody-drug conjugate targeting HER2 in patients with locally advanced or metastatic urothelial carcinoma. In 43 patients, they had a confirmed objective response rate (ORR) of 51.2%, DCR 90.7% and a median progression-free survival (PFS) of 7.0 months. He did note that 35% of patients discontinued therapy due to TRAEs.

He began by addressing if it was consistent with prior HER2 targeting agents in UC. And the answer is simply no – all prior efforts at targeting HER2 were unsuccessful, with no difference in survival outcomes. This was as monotherapy or in combination. This was thought to be due to the high degree of heterogeneity in HER2 in UC, suggesting it may not be a driver mutation but rather a co-driver.

So, why does RC48-ADC work where others have failed? For a few reasons, according to Dr. Loriot. First, inclusion criteria. In this study, patients had failed multiple lines of chemotherapy, thereby potentially reducing the heterogeneity. Second is molecular selection – rather than selection based on next-generation sequencing, which does not account for spatial heterogeneity within the tumor, they used IHC, which does. So, by doing so, they were able to qualify the degree of HER2 positivity in the sample (0-3). Third, the fact that it is an ADC – and specifically has cleavable linker that enables the easier release of the cytotoxic payload. This may allow for a bystander effect, where the payload actually also works on nearby cells that may not be HER2 positive or even cells that might be immune suppressive. Lastly, the payload they used was MMAE, which is a tubulin-targeting agent – and none of the patients in the study had failed prior tubulin-targeting chemotherapy, making cross-resistance less likely.

Abstract 4510:

Dizman et al. hypothesized that the molecular landscape of upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) are distinct, and therefore may have a potential association with outcomes of FGFR3 inhibitor infigratinib. Hence, they retrospectively reviewed 68 patients previously evaluated by Pal et al.1 and stratified those patients by primary tumor site (8 UTUC, 59 UCB). They found that confirmed objective response rate (ORR) was much higher in UTUC than in UCB (50% vs. 22%), albeit with a much wider range (11-84%). mPFS and mOS were also much longer in UTUC patients. The molecular landscape was also distinct between the two cohorts, and the specific mutations in FGFR3 were distinctly different:
ASCO 2019_Loriot_2.png
Again, he first addresses if it is consistent with prior studies. From a clinical standpoint, he noted that while other studies have looked at FGFR3 inhibitors in mUC, none so far have compared UTUC vs. UCB, so no comparison can be made. As the authors themselves noted, from a genomic standpoint, it is consistent with prior studies, including the evaluation by Sfakianos et al. (EU 2015). He compared it to the results of Robertson et al. (Cell 2018), which was also consistent.

If true, then what explains the differential response. He suggests the difference in FGFR3 mutations may account for this. As we saw in the earlier slide, the specific distribution of point mutations in FGFR3 in both cohorts were different – the proportion of the R248C and S249C are inversed.

Unfortunately, due to the small sample size, no strong conclusions can be drawn. Validation from other ongoing FGFR3 trials is needed. However, he does note that an adjuvant trial for infigratinib in UTUC is about to start and may provide more data prospectively.

Abstract 4511:

In the abstract by Siefer-Radtke et al. entitled FIERCE-22, they utilize Vofatamab (B-701, V), a fully human monoclonal antibody against FGFR3, in combination with pembrolizumab in 28 mUC patients who have failed at least 1 prior therapy. They noted an ORR of 36% - 33% in patients with wild type FGFR3 and 43% in patients with mut/fus FGFR3. It was generally well tolerated.

Again, he first asks if it is consistent with prior studies. First in patients with mutation FGFR3 and then in patients with wild type FGFR3. FIERCE-21 (Necchi et al. ASCO GU 2019) was a study of Vofatamab monotherapy in patients with mutations – in that study, there was poor response, ORR 11%. There are no other studies to compare it to yet, though there are other ongoing combination trials that may provide more data.

In patients with wild type FGFR3, they saw a 33% ORR. However, in other studies, it has generally been low – 20% with rogaratinib2 and <10% with pemigatinib (Necchi et al. ESMO 2018). However, this may be due to its combination with pembro, which has a response rate of 20% as monotherapy. FGFR3 inhibition may in fact be synergistic by increasing antigen expression, PD-L1 expression, etc.

In this study, they did paired biopsies before and after the 2-week lead in with vofatamab – and they found it caused upregulation of genes associated with inflammation. However, it is unclear if this accounts for the increased response seen above. More data is needed.

All of these are promising, but further analyses are needed to incorporate them into precision medicine 2.0.

Presented by: Yohann Loriot, MD, MSc, Cancer Institute, Gustave Roussy, France

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

References: 
  1. Pal et al. Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with FGFR3 Alterations. Cancer Discov. 2018 Jul;8*7):812-821. 
  2. (Joerger et al. Phase 1 experience with rogaratinib in patients with head and neck cancer selected based on FGFR and mRNA overexpression. Annals of Oncology (2018) 29 (suppl_8):viii372-viii399. 10.1093/annonc/mdy287. 
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