In metastatic urothelial cancer, the portfolio of immunologic therapies is robust, but the treatment paradigm for these agents requires refinement.
Daniel P. Petrylak, MD, professor of Medicine and Urology, co-director, Signal Transduction Research Program, Yale School of Medicine
Daniel P. Petrylak, MD
In metastatic urothelial cancer (mUC), the portfolio of immunologic therapies is robust, but the treatment paradigm for these agents requires refinement, Daniel P. Petrylak, MD, said in a presentation during the 13th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies.
A broader selection of ICIs that can be given in the first-line setting would benefit patients with UC, particularly those who are not candidates for cisplatin chemotherapy. “The question is ‘how can we start moving these drugs earlier in the course of therapy?’” Petrylak said.
Between May 2016 and May 2017, the FDA approved 7 immune checkpoint inhibitors (ICIs) for use in UC. Most of them, including atezolizumab (Tecentriq), nivolumab (Opdivo), durvalumab (Imfinzi), avelumab (Bavencio), and pembrolizumab (Keytruda), were indicated as second-line therapies for patients with progressive disease following prior platinum-based therapy. Of the 7 immunotherapies approved by the FDA during this span, only 2—atezolizumab and pembrolizumab—have been cleared for frontline use in patients who are cisplatin-ineligible, according to Petrylak.1
Platinum-based chemotherapy is the first-line standard of care (SOC) for patients who are candidates for cisplatin. Those who cannot receive cisplatin are treated with ICIs as a frontline therapy only if they are PD-1/PD-L1-positive. Cisplatin-ineligible patients who are negative for PD-1/PD-L1 expression are typically treated with chemotherapy, which could include gemcitabine and carboplatin, or consider enrolling in a clinical trial. Single-agent anti—PD-L1/PD-1 therapy is the second-line SOC for the treatment of patients with mUC.1
Efforts to expand the stock of frontline immunotherapies are ongoing. For example, the phase III KEYNOTE-361 study (NCT02853305) is evaluating pembrolizumab with or without platinum-containing combination chemotherapy versus chemotherapy alone in patients with mUC. CheckMate-901 (NCT03036098) is a phase III trial of nivolumab in combination with ipilimumab or SOC chemotherapy versus chemotherapy alone in patients with treatment-naïve inoperable or mUC and is currently recruiting.1 Broadly, findings from these clinical investigations are pending. “The one trial that we do have some readout on is the IMvigor130 study,” Petrylak said.
Data from the phase III trial (NCT02807636) was presented at the 2019 European Society for Medical Oncology Congress and showed a progression-free survival (PFS) benefit with the addition of frontline atezolizumab to chemotherapy. At a median follow-up of 11.8 months, the median PFS was 8.2 months with atezolizumab and chemotherapy versus 6.3 months with chemotherapy alone (HR, 0.82; 95% CI, 0.70-0.96; one-sided P =.007).1
Interim median overall survival (OS) results from IMvigor130, which enrolled patients with treatment-naïve advanced UC, suggested a survival benefit with the immunotherapeutic doublet, but did not cross the prespecified interim efficacy boundary for significance, investigators said. The median OS was 16.0 months for the atezolizumab combination and 13.4 months with chemotherapy (HR, 0.83; 95% CI, 0.69-1.00).
The improvement seen in the IMvigor130 study was not replicated in the phase III DANUBE trial (NCT02516241), which compared durvalumab with or without tremelimumab versus cisplatin-based chemotherapy in unresectable mUC. DANUBE did not meet its coprimary end points of improving OS versus SOC chemotherapy for durvalumab monotherapy in patients whose tumors expressed ≥25% levels of PD-L1, or for combination durvalumab and tremelimumab regardless of patients’ PD-L1 expression.1
The full data set from DANUBE is expected to publish soon and will shed light on why, specifically, the dual immunotherapy approach failed to elicit a survival benefit in this patient population, Petrylak said.
A switch-maintenance therapeutic approach could offer another approach for achieving maximum benefit with immunotherapy in UC, Petrylak said. Findings from the phase II HCRN GU14-182 trial (NCT02500121) demonstrated that administering maintenance pembrolizumab after platinum-based chemotherapy significantly delayed disease progression in patients with mUC.
Patients who achieved a response after ≤8 cycles of chemotherapy were randomized to either placebo or maintenance pembrolizumab. The maintenance therapy conferred a PFS benefit: the median PFS was 5.4 months with the ICI versus 3.2 months with placebo (HR, 0.64; 95% CI, 0.41-0.98; log rank P =.038).1
“There was a PFS difference that favored patients treated with pembrolizumab, suggesting that giving maintenance therapy may be better than just simply observing a patient after they’ve had a response,” Petrylak said.
Combining PD-1/PD-L1 blockade with CTLA4 inhibition in the second-line might be another way to improve ICI therapy in UC, Petrylak added. Data from the phase I/II CheckMate 032 study (NCT01928394) of nivolumab with or without ipilimumab followed by maintenance nivolumab supports this notion, Petrylak said.
Investigators observed an objective response rate of 38% among the patients who received nivolumab with 1 mg/kg of ipilimumab. The OS and PFS were also superior in this cohort, at 15.3 months and 4.9 months, respectively. The ORR was 27% in the group that was treated with nivolumab and 3 mg/kg of ipilimumab, and 26% in the nivolumab monotherapy arm.1
“This is an indication that more intense new therapy may improve outcomes in the second-line setting,” Petrylak said. This approach might also afford an advantage in the frontline treatment of UC, he added.
Beyond switch-maintenance therapy and combinations consisting of both PD-1/PD-L1 and CTLA4 inhibition, adjuvant regimens are another avenue for “moving treatments upfront or improving immunotherapy,” Petrylak said.
At present, 2 adjuvant trials are completing and 1, the AMBASSADOR trial (NCT03244384), is currently accruing patients, according to Petrylak. AMBASSADOR investigators will evaluate the efficacy of pembrolizumab monotherapy after surgery for localized muscle-invasive bladder cancer (MIBC) and locally advanced UC. AMBASSADOR will enroll up to 739 patients.
Several studies are also investigating the value of ICI therapy in the neoadjuvant setting. Among them is BLASST-1, an ongoing phase II trial (NCT03294304) of nivolumab, cisplatin, and gemcitabine prior to SOC radical cystectomy in patients with MIBC. Another phase II study (NCT02690558) will evaluate the same neoadjuvant triplet therapy before cystectomy in approximately 39 patients with MIBC.
“We encourage you to put patients in these studies,” Petrylak said.
Targeted Treatment Options
In UC, biomarker testing is critical to deriving therapeutic benefit from a targeted treatment regimen, particularly because multiple pathways can be involved in kinase signaling, such as FGFR3, ERBB2, EGFR, TSC1, and TSC2.1
“We don’t really see any 1 dominant pathway. We see that there are multiple pathways, but none of them are particularly dominant. They are all at most [found in] about 25% of our patients and this is why molecular profiling of our patients is going to be so important to selecting these patients in the future,” Petrylak said.
Currently, there are 2 targeted agents indicated for the treatment of UC. With the April 2019 FDA approval of erdafitinib, an oral FGFR kinase inhibitor indicated for patients with locally advanced or metastatic bladder cancer harboring activating FGFR2/3 mutations or fusions, the UC armamentarium gained its first precision therapy.2
The second precision therapy arrived in December 2019, when enfortumab vedotin-ejfv received FDA approval for patients with locally advanced or mUC who were previously treated with a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant, adjuvant, locally advanced, or metastatic setting. Enfortumab vedotin-ejfv is an antibody drug conjugate (ADC) that targets nectin-4, a protein that is highly expressed in urothelial carcinoma.3
“Nectin-4 is expressed in practically all urothelial carcinoma specimens and the FDA indication [states] that you don’t need to check nectin-4 expression for a patient to go on enfortumab vedotin-ejfv,” Petrylak said.
In contrast to nectin-4 expression, clinicians should assess FGFR3 expression in all patients with mUC, Petrylak said. Enfortumab vedotin and IMU132 have promising activity in patients who experience disease progression on ≥2 therapies. FGFR mutations present in 20% to 60% of urothelial carcinomas. FGFR3 alterations, which are associated with the development of higher-grade, invasive disease, are uncovered in about 15% of patients with mUC.4
Importantly, FGFR3-mutant tumors are thought to confer resistance to immunotherapy, increasing the importance not only of erdafitinib’s approval but also of developing agents from other drug classes for the treatment of this disease.3 FGFR inhibitors and anti—FGFR ADCs are currently under clinical investigation and will continue to be a focus of subsequent trials in advanced UC, Petrylak said.
Infigratinib (BGJ398125) and rogaratinib are 2 of the experimental FGFR inhibitors in development and will expectedly be tested as monotherapies and in combination with other agents, Petrylak said. Doublet regimens consisting of targeted therapies and immunotherapy will also be a focus of future clinical investigations in UC, he added.1