Further Study Is Needed to Maximize Therapeutic Benefit in Urothelial Cancer

Rachel Narozniak, MA
Published: Friday, Mar 13, 2020

Daniel P. Petrylak, MD
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.

Boosting Benefit

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

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