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Symposium shows urothelial carcinoma at ‘forefront of practice-changing research’
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The Genitourinary Cancers Symposium showcased several very exciting studies in urothelial carcinoma.
Within the past year, two immune checkpoint inhibitors — atezolizumab (Tecentriq, Genentech) and nivolumab (Opdivo, Bristol-Myers Squibb) — received FDA approval for the treatment of locally advanced or metastatic urothelial carcinoma that progressed during or after platinum-based chemotherapy. The FDA also approved atezolizumab for the initial treatment of patients with locally advanced or metastatic urothelial carcinoma who cannot receive cisplatin.
Several clinical trials of these and other immune checkpoint inhibitors are ongoing, and investigators presented updated results at the symposium.
Below we highlight a few of these studies, but we suggest readers also review the presented data from all other valuable studies and projects.
Therapeutic advances
The large randomized KEYNOTE-045 phase 3 clinical trial compared 200 mg pembrolizumab (Keytruda, Merck) every 3 weeks with taxane or vinflunine chemotherapy in 542 patients with advanced urothelial cancer that is recurrent or progressed after platinum-based chemotherapy.
Results showed an OS benefit with the anti–PD-1 agent. Pembrolizumab may provide an additional valuable treatment option in this setting, having the highest level of evidence so far.
Another presentation included results from the entire study population of the phase 2, single-arm KEYNOTE-052 trial (NCT02335424), which included patients with advanced urothelial carcinoma ineligible for cisplatin and treated with frontline pembrolizumab.
Researchers enrolled 370 patients (median age, 74 years; 42% ECOG performance status of 2) who received 200 mg pembrolizumab every 3 weeks.
Investigators reported a 24% (95% CI, 20-29) overall response rate in all patients, and 27% ORR in patients (n = 307) who had at least 4 months follow-up. Median time to response was 2 months, and median duration of response had not been reached.
At 6 months, 67% of patients remained alive and 30% remained progression free.
Sixteen percent of patients experienced grade 3 or worse adverse events and 5% discontinued treatment due to drug-related adverse events.
These results suggest great promise for pembrolizumab in the cisplatin-ineligible frontline setting, in which there has been a significant need for safe and effective therapies.
Another presentation highlighted updated results of the phase 1/phase 2 trial of durvalumab (Imfinzi; AstraZeneca, MedImmune), an anti–PD-L1 antibody, in locally advanced/metastatic urothelial carcinoma refractory to prior platinum-based treatment (NCT01693562).
At the time of data cutoff, 103 patients who received 10 mg/kg durvalumab every 2 weeks had been followed for at least 13 weeks. Median follow-up was 7.3 months.
Twenty-one patients (20.4%) achieved response, and five (4.9%) of those achieved complete response.
Responses occurred after a median 1.4 months. Median duration of response had not been reached at the time of data cutoff, as 18 of 21 confirmed responders had ongoing responses. Importantly, researchers observed responses in both high–PD-L1 ( 25% of immune or tumor cells expressing PD-L1) and low–PD-L1 (< 25% of cells) subgroups.
Durvalumab appeared well tolerated, with a 5.2% rate of grade 3 or worse adverse events. Durvalumab received FDA accelerated approval for advanced urothelial carcinoma with progression during or after platinum-based chemotherapy given for advanced disease or within 12 months of neoadjuvant/adjuvant platinum-based chemotherapy.
A significant aspect of the clinical utility of the abovementioned compounds is the evaluation of cost and “financial toxicity.” This must be balanced against value — measured by efficacy and safety metrics, administration logistics and intervals, etc — especially in the era of cost-effectiveness and value-based care.
Researchers also updated long-term outcomes of the randomized, phase 3 BC2001 trial of chemoradiotherapy vs. radiotherapy alone — and standard radiation vs. reduced high-dose volume radiation — in muscle-invasive bladder cancer (ISRCTN68324339).
After median follow-up of 118 months, patients assigned chemoradiotherapy achieved improved locoregional control (adjusted HR = 0.59; 95% CI, 0.41-0.83) and invasive locoregional control.
Investigators observed a trend toward longer OS and metastasis-free survival with chemoradiation.
After adjustments for known prognostic factors, chemoradiation appeared associated with significantly improved bladder cancer–specific survival (HR = 0.73; 95% CI, 0.54-0.99).
Updated follow-up data further supported the use of fluorouracil/mitomycin-C in combination with radiotherapy as a bladder preservation approach for patients with muscle-invasive bladder cancer, including cisplatin-ineligible patients.
Biomarker studies
A study by Seiler and colleagues focused on the predictive value of molecular subtyping among patients with urothelial carcinoma who received neoadjuvant chemotherapy.
Researchers used four published models of classifying molecular subtypes — University of North Carolina (UNC), The University of Texas MD Anderson Cancer Center, The Cancer Genome Atlas (TCGA) and Lund University — on 223 pre-neoadjuvant chemotherapy transurethral resection biospecimens from patients with muscle-invasive bladder cancer. Patients received neoadjuvant chemotherapy followed by cystectomy.
Investigators compared OS for each subtype in this study with patients from a TCGA study who did not receive neoadjuvant chemotherapy.
Models generated subtype ratios similar to previously published data, and concordance for a given subtype between different methods appeared high.
Overall, luminal subtypes had the longest OS independent of neoadjuvant chemotherapy, whereas tumors classified as UNC “claudin-low” had the shortest OS regardless of treatment regimen. The benefit of neoadjuvant chemotherapy also varied among molecular subtypes. Patients with basal tumors achieved the greatest improvement in OS with the addition of neoadjuvant chemotherapy.
This study suggests decisions regarding neoadjuvant chemotherapy regimens in muscle-invasive bladder cancer may be affected by the molecular subtype of the tumor. Patients with luminal or cluster I tumors may not derive OS benefit from neoadjuvant chemotherapy and may be treated with cystectomy alone, whereas patients with claudin-low tumors potentially should be considered for alternative neoadjuvant chemotherapy protocols, as they may be resistant to cisplatin-based neoadjuvant chemotherapy.
The data require further prospective validation to assess clinical utility. The ongoing phase 2 S1314 (COXEN) trial and other neoadjuvant chemotherapy trials can provide a relevant setting and for biomarker validation and discovery.
Shifting focus to other biomarkers, another multicenter group, which included researchers from Cleveland Clinic, presented the findings of a study that assessed cell-free circulating tumor DNA (ctDNA) in advanced urothelial carcinoma. This study included 276 samples from 246 patients with urothelial carcinoma who underwent ctDNA analysis to assess potentially actionable alterations with Guardant360 (Guardant Health), a 70-gene ctDNA next-generation sequencing panel, using samples harvested from peripheral blood.
The panel detected ctDNA in 90% of samples. The most common alterations were in TP53, PIK3CA, ARID1A, FGFR2, MET, NF1, EGFR, BRAF, FGFR3, RAF1 and BRCA1/BRCA2.
These findings appeared similar to data derived from tumor tissue of unrelated cohorts of patients with muscle-invasive bladder cancer. The presence of FGFR1 alterations appeared associated with a trend toward shorter OS.
Results revealed a trend toward increased frequency of alterations in DNA repair genes among patients who underwent prior chemotherapy.
The researchers concluded that ctDNA profiling may noninvasively identify potentially actionable tumor alterations and has the potential to suggest salvage therapies in carefully selected patients, for example, through use of FGFR and PARP inhibitors.
Conclusion
All of these studies show urothelial carcinoma lies at the forefront of practice-changing research with tangible impact on outcomes.
The continual interplay between clinical and translational research is destined to inform further breakthroughs and innovative, transformative approaches in this disease.
References:
The following were presented at Genitourinary Cancers Symposium; Feb. 16-18, 2017; Orlando, Fla:
Balar AV, et al. Abstract 284.
Grivas P, et al. Abstract 334.
Hall E, et al. Abstract 280.
Powles T, et al. Abstract 286.
Seiler R, et al. Abstract 281.
Vaughn DJ, et al. Abstract 282.
For more information:
Petros Grivas, MD, PhD, is assistant professor in the department of medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and associate staff genitourinary oncologist at Taussig Cancer Institute of Cleveland Clinic. He can be reached at Cleveland Clinic, 9500 Euclid Ave., Desk CA60, Cleveland, OH 44195; email: grivasp@ccf.org.
Vadim S. Koshkin, MD, is a fellow at Cleveland Clinic. He can be reached at koshkiv@ccf.org.
Disclosure: Grivas reports consultant roles with AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Dendreon, Exelixis, Genentech and Merck. He also served as lead researcher on the study of ctDNA mentioned in this article. Koshkin reports no relevant financial disclosures.