Molecular Oncology

Therapeutic armamentarium in urothelial carcinoma grows with understanding of tumor biology

Bladder cancer is one of the most common forms of cancer in United States, with an estimated 81,190 new cases and 17,240 deaths in 2018.

Urothelial carcinoma — the most common type of bladder cancer — can also arise from other components of the urinary tract (eg, renal pelvis, ureter, urethra). Although most patients present with nonmuscle-invasive bladder cancer (NMIBC), about a quarter present with muscle-invasive bladder cancer (MIBC), with a portion progressing to metastatic disease, which is usually fatal.

Deep understanding of the molecular underpinnings of bladder cancer has determined potential biomarkers, “drivers” and promising treatment targets.

‘Clear need’ for new therapies

Platinum (ideally cisplatin)-based chemotherapy has been the cornerstone of therapy for decades.

Petros Grivas, MD, PhD
Petros Grivas

Five immune checkpoint inhibitors have been approved for the management of platinum-refractory advanced urothelial cancer — two of them also in cisplatin-unfit patients as first-line therapy based on certain criteria — but none are approved in the localized disease setting.

Several trials are ongoing in both NMIBC and MIBC settings, with very promising data so far. Those agents can result in rapid and durable responses in a patient subset.

However, most patients do not respond, and some may have immune-related adverse events. There is a clear need for new therapies that can improve quality of life and prolong survival.

In that context, pursuit continues of agents with novel mechanisms of action, favorable toxicity profiles and significant antitumor activity. Determining appropriate combinations of checkpoint inhibitors with a spectrum of compounds that may provide additive or synergistic effects is also the objective of many clinical trials, as is evaluating relevant translational endpoints.

In the neoadjuvant setting, cisplatin-based combination chemotherapy before radical cystectomy prolongs OS compared with cystectomy alone. However, up to 50% of patients may not be fit for cisplatin, many cisplatin-fit patients may not respond, and adverse events can occur. Therefore, there is an ongoing pursuit for validated biomarkers that can help select patients who may benefit from such therapy, while sparing others from potential toxicity.

In that regard, several clinical trials in the neoadjuvant setting aim to prospectively validate the clinical relevance of DNA damage response gene mutations and other biomarkers. Similar efforts for biomarker discovery and validation are components of bladder-preservation strategies being tested in novel clinical trials; adequate accrual is critical for all trials.

Overcoming challenges in drug development

Tumor heterogeneity, genomic instability and clonal evolution have been major obstacles that may impede drug development in this disease. Further, targeted therapies have not improved outcomes in prior clinical trials, probably due to suboptimal patient selection.

However, in the era of next-generation sequencing (NGS) of tumor tissue and cell-free circulating tumor DNA (eg, plasma, urine), there is higher resolution of the genomic landscape and identification of therapeutic targets and putative biomarkers.

In April, the first targeted therapy for bladder cancer received FDA approval. Erdafitinib (Balversa, Janssen), an orally available pan-FGFR inhibitor, received accelerated approval based on a remarkable overall response rate — 40% (95% CI, 30.7-50.1), which included three complete responses — and tolerable toxicity profile in a phase 2 trial reported at last year’s ASCO Annual Meeting among patients with metastatic bladder cancer with fibroblast growth factor receptor 2/3 mutations or fusions detected by a companion diagnostic assay (RT-PCR, Qiagen).

Many additional compounds are under clinical investigation, including inhibitors of receptors and signaling pathways (eg, fibroblast growth factor receptor, human epidermal growth factor receptor, phosphatidylinositol 3-kinase/AKT/mTOR pathway), angiogenesis (eg, vascular endothelial growth factor and receptors), poly(ADP-ribose) polymerase inhibitors, cytotoxic agents (eg, chemotherapy, antibody-drug conjugates), immuno-oncology compounds, epigenetic modulators, and others.

Enfortumab vedotin (ASG-22ME; Seattle Genetics, Astellas) — an antibody-drug conjugate against Nectin-4 — has received breakthrough designation from FDA; results from a phase 2 trial were presented at this year’s ASCO Annual Meeting but were not available at the time of publication. A press release issued by the drug’s manufacturers announced positive topline results in March, with a 44% ORR.

Sacituzumab govitecan (IMMU-132, Immunomedics) is an antibody-drug conjugate against Trop-2, also with very promising results from a phase 1/phase 2 trial presented at Genitourinary Cancers Symposium. Evaluated in 45 patients, researchers reported an ORR of 31.1% (95% CI, 18.2-46.6), which included a complete response rate of 4% and a partial response rate of 27%. Patients with visceral involvement attained an ORR of 27%, and checkpoint inhibitor-treated patients (n = 17) had an ORR of 23%. Median PFS was 7.3 months (95% CI, 5-10.7) and OS was 16.3 months (95% CI, 9.0-31).

Relevant combinations and sequential strategies are being evaluated in several clinical trials. Prospective validation of predictive and prognostic biomarkers with clinical utility, biomarker-based patient selection, and innovative clinical trial designs are all important in this dynamic research field.

Novel NGS-based and bioinformatics assays and deeper knowledge of tumor biology, microenvironment and host immune system, along with the emergence of active promising agents, hold promise for continued growth of the therapeutic armamentarium in urothelial carcinoma.

References:

Petrylak DP, et al. Abstract LBA4505. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Siefker-Radtke AO, et al. Abstract 4503. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Tagawa ST, et al. Abstract 242541. Presented at: Genitourinary Cancers Symposium; Feb 14-16, 2019; San Francisco.

For more information:

Petros Grivas, MD, PhD, is associate professor in the department of medicine, division of oncology, and clinical director of the genitourinary cancers program at University of Washington. He also is an associate member in the clinical research division at Fred Hutchinson Cancer Research Center and medical oncologist at Seattle Cancer Care Alliance. He can be reached at pgrivas@uw.edu.

To contribute to this column or suggest topics, email Wafik S. El-Deiry, MD, PhD, FACP, at wafik.eldeiry@gmail.com.

Disclosures: Grivas reports being a co-investigator in the phase 2 trial of IMMU-132 and receiving honoraria from Seattle Genetics. He also reports financial relationships from consultant roles with AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Driver Inc., EMD Serono, Foundation Medicine, Heron Therapeutics, Janssen, Merck & Co., Pfizer, and QED Therapeutics within the last year.

Bladder cancer is one of the most common forms of cancer in United States, with an estimated 81,190 new cases and 17,240 deaths in 2018.

Urothelial carcinoma — the most common type of bladder cancer — can also arise from other components of the urinary tract (eg, renal pelvis, ureter, urethra). Although most patients present with nonmuscle-invasive bladder cancer (NMIBC), about a quarter present with muscle-invasive bladder cancer (MIBC), with a portion progressing to metastatic disease, which is usually fatal.

Deep understanding of the molecular underpinnings of bladder cancer has determined potential biomarkers, “drivers” and promising treatment targets.

‘Clear need’ for new therapies

Platinum (ideally cisplatin)-based chemotherapy has been the cornerstone of therapy for decades.

Petros Grivas, MD, PhD
Petros Grivas

Five immune checkpoint inhibitors have been approved for the management of platinum-refractory advanced urothelial cancer — two of them also in cisplatin-unfit patients as first-line therapy based on certain criteria — but none are approved in the localized disease setting.

Several trials are ongoing in both NMIBC and MIBC settings, with very promising data so far. Those agents can result in rapid and durable responses in a patient subset.

However, most patients do not respond, and some may have immune-related adverse events. There is a clear need for new therapies that can improve quality of life and prolong survival.

In that context, pursuit continues of agents with novel mechanisms of action, favorable toxicity profiles and significant antitumor activity. Determining appropriate combinations of checkpoint inhibitors with a spectrum of compounds that may provide additive or synergistic effects is also the objective of many clinical trials, as is evaluating relevant translational endpoints.

In the neoadjuvant setting, cisplatin-based combination chemotherapy before radical cystectomy prolongs OS compared with cystectomy alone. However, up to 50% of patients may not be fit for cisplatin, many cisplatin-fit patients may not respond, and adverse events can occur. Therefore, there is an ongoing pursuit for validated biomarkers that can help select patients who may benefit from such therapy, while sparing others from potential toxicity.

In that regard, several clinical trials in the neoadjuvant setting aim to prospectively validate the clinical relevance of DNA damage response gene mutations and other biomarkers. Similar efforts for biomarker discovery and validation are components of bladder-preservation strategies being tested in novel clinical trials; adequate accrual is critical for all trials.

Overcoming challenges in drug development

Tumor heterogeneity, genomic instability and clonal evolution have been major obstacles that may impede drug development in this disease. Further, targeted therapies have not improved outcomes in prior clinical trials, probably due to suboptimal patient selection.

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However, in the era of next-generation sequencing (NGS) of tumor tissue and cell-free circulating tumor DNA (eg, plasma, urine), there is higher resolution of the genomic landscape and identification of therapeutic targets and putative biomarkers.

In April, the first targeted therapy for bladder cancer received FDA approval. Erdafitinib (Balversa, Janssen), an orally available pan-FGFR inhibitor, received accelerated approval based on a remarkable overall response rate — 40% (95% CI, 30.7-50.1), which included three complete responses — and tolerable toxicity profile in a phase 2 trial reported at last year’s ASCO Annual Meeting among patients with metastatic bladder cancer with fibroblast growth factor receptor 2/3 mutations or fusions detected by a companion diagnostic assay (RT-PCR, Qiagen).

Many additional compounds are under clinical investigation, including inhibitors of receptors and signaling pathways (eg, fibroblast growth factor receptor, human epidermal growth factor receptor, phosphatidylinositol 3-kinase/AKT/mTOR pathway), angiogenesis (eg, vascular endothelial growth factor and receptors), poly(ADP-ribose) polymerase inhibitors, cytotoxic agents (eg, chemotherapy, antibody-drug conjugates), immuno-oncology compounds, epigenetic modulators, and others.

Enfortumab vedotin (ASG-22ME; Seattle Genetics, Astellas) — an antibody-drug conjugate against Nectin-4 — has received breakthrough designation from FDA; results from a phase 2 trial were presented at this year’s ASCO Annual Meeting but were not available at the time of publication. A press release issued by the drug’s manufacturers announced positive topline results in March, with a 44% ORR.

Sacituzumab govitecan (IMMU-132, Immunomedics) is an antibody-drug conjugate against Trop-2, also with very promising results from a phase 1/phase 2 trial presented at Genitourinary Cancers Symposium. Evaluated in 45 patients, researchers reported an ORR of 31.1% (95% CI, 18.2-46.6), which included a complete response rate of 4% and a partial response rate of 27%. Patients with visceral involvement attained an ORR of 27%, and checkpoint inhibitor-treated patients (n = 17) had an ORR of 23%. Median PFS was 7.3 months (95% CI, 5-10.7) and OS was 16.3 months (95% CI, 9.0-31).

Relevant combinations and sequential strategies are being evaluated in several clinical trials. Prospective validation of predictive and prognostic biomarkers with clinical utility, biomarker-based patient selection, and innovative clinical trial designs are all important in this dynamic research field.

Novel NGS-based and bioinformatics assays and deeper knowledge of tumor biology, microenvironment and host immune system, along with the emergence of active promising agents, hold promise for continued growth of the therapeutic armamentarium in urothelial carcinoma.

References:

Petrylak DP, et al. Abstract LBA4505. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Siefker-Radtke AO, et al. Abstract 4503. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Tagawa ST, et al. Abstract 242541. Presented at: Genitourinary Cancers Symposium; Feb 14-16, 2019; San Francisco.

For more information:

Petros Grivas, MD, PhD, is associate professor in the department of medicine, division of oncology, and clinical director of the genitourinary cancers program at University of Washington. He also is an associate member in the clinical research division at Fred Hutchinson Cancer Research Center and medical oncologist at Seattle Cancer Care Alliance. He can be reached at pgrivas@uw.edu.

To contribute to this column or suggest topics, email Wafik S. El-Deiry, MD, PhD, FACP, at wafik.eldeiry@gmail.com.

Disclosures: Grivas reports being a co-investigator in the phase 2 trial of IMMU-132 and receiving honoraria from Seattle Genetics. He also reports financial relationships from consultant roles with AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Driver Inc., EMD Serono, Foundation Medicine, Heron Therapeutics, Janssen, Merck & Co., Pfizer, and QED Therapeutics within the last year.

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