ORLANDO, FL, USA (UroToday.com) - Andrea Apolo, MD began the session by expressing what an exciting time it currently is for systemic therapy in bladder cancer. [yee_row column-size="md-column" boxed_layout="yee-container-fluid" padding_layout="" style_detail="" theme_options="flattern" border_color="" border="none" background_image_options="none" background_image="" background_color_options="none" background_color="" responsive_column_reset="no" vacolumns="top" ex_class="" id="" visiable="1"][yee_column width="1/1" ors="" column-size="md-column" xs-column="0" xs-hidden="" sm-column="0" sm-hidden="" md-column="0" md-hidden="" lg-column="0" lg-hidden="" hidden-print="visiable" background_image="" background_color="" ex_class="" visiable="1"][yee_text_block css_animation="no" ex_class="" style_detail="" yee-widget-theme="default" border_color="" border="none" visiable="1"]{textblock_content}
Despite all of the failures with targeted systemic therapies in the recent past, a paradigm shift towards utilizing genomic profiling and immunotherapy in the treatment of metastatic bladder cancer has resulted in promising early trial results. Dr. Apolo emphasized the importance of the genetic characterization of bladder cancer by the TCGA, which identified 32 significantly mutated genes, including potential therapeutic targets like FGFR3, TSC1 and PIK3CA. She highlighted that a large proportion of the muscle-invasive tumors utilized in the TCGA study had mutations in chromatin regulatory genes, resulting in epigenetic alterations that are also potentially targetable. She then pointed to trials in development utilizing this new genetic data to stratify patients to specific treatments including the ATLANTIS trial (androgen receptor-positive patients to enzalutamide, FGFR3 patients to an FGFR inhibitor, and all others to cabozantinib), the MATCH-UP trial (stratification based on multiple mutations including in FGFR3, PIK3CA, and TSC1), and COXEN (secondary therapy determination based on genomic profiling of tumor).
Dr. Apolo then transitioned to a discussion about the use of immunotherapy in bladder cancer. Immune checkpoint targeting has resulted in significant responses in multiple different types of solid tumors. Urothelial carcinoma (UC) is a prime candidate for this type of therapy given its high expression of PD-L1, which has been shown to correlate with pathologic stage as well as overall survival. The use of PD-L1/PD-1 binding by UC results in immunosuppression, inhibiting T-cell migration and proliferation, and attenuating T-cell cytotoxic response. Early trials targeting PD-L1 with the agent MPDL3280A and PD-L1 with pembrolizumab have demonstrated significant radiologic responses in patients with platinum-resistant metastatic UC, including complete responses in a small proportion of patients. Dr. Apolo discussed questions which have arisen as a result of these trials. Regarding whether or not PD-L1 status should be used to select patients for these therapies, Dr. Apolo stated that it should not, as a small proportion of patients that were PD-L1-negative demonstrated a radiographic response to MPDL3280A. She proposed that the presence of infiltrating immune cells in the tumor may better predict which patients are likely to respond to immune checkpoint targeting, but at this point its reliability as a biomarker in comparison to PD-L1 is unclear. In addressing the question of whether PD-L1 status may be changed, she presented evidence that PD-L1 status is dynamic. Examination of tissue pre- and post-PD1-inhibitor therapy in a patient with radiologic response demonstrated an increase in infiltrating immune cells following therapy as well as an upregulation of PD-L1.
Dr. Apolo then focused on ways in which to enhance the immune response via combination of immune checkpoint targeting with secondary agents like vaccines, CTLA-4 inhibitors, and tyrosine kinase inhibitors. She pointed to increased rates of radiologic tumor response in melanoma and renal cell carcinoma when nivolumab (PD-1 inhibitor) was used in combination with ipilimumab (CTLA-4 inhibitor) or sunitinib compared to when it was utilized alone. She also discussed that combination therapy may be a way to overcome PD1 tumor status. In the trial with nivolumab alone, response in patients whose tumors were PD-L1-positive were significantly more likely to respond to therapy, but in combination studies, responses in PD-L1-positive and negative tumors were similar. Cabozantinib has immunomodulatory properties which act to reverse tumor-induced immunosuppression and thus represents another prime candidate for combination therapy. She warned, however, that while combination therapies appear to result in increased response rates, they are accompanied by higher rates of adverse events including rash, diarrhea, and acute renal failure.
Dr. Apolo concluded by outlining the immune checkpoint clinical trials currently ongoing in bladder cancer. Multiple trials exist in the metastatic setting in patients who are either cisplatin ineligible or refractory using immune checkpoint inhibition both alone and in combination, and many others are in development in all stages of the disease. She highlighted a trial in the non-muscle invasive setting looking at PD-L1 inhibition in combination with BCG therapy in patients with high grade or BCG-refractory disease.
Presented by Andrea Borghese Apolo, MD at the 2015 Genitourinary Cancers Symposium - "Integrating Biology Into Patient-Centric Care" - February 26 - 28, 2015 - Rosen Shingle Creek - Orlando, Florida USA
National Cancer Institute at the National Institutes of Health, Bethesda, MD USA
Reported by Timothy Ito, MD, medical writer for UroToday.com
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