Results of Phase II mUC Trial Support Approval of Nivolumab Applications

Matthew D. Galsky, MD

Safety, efficacy, and biomarker results from the phase II CheckMate-275 trial of the PD-1 inhibitor nivolumab (Opdivo) that support FDA and European Medicines Agency (EMA) applications were reported at the 2016 ESMO Congress.

CheckMate-275 was conducted in patients with metastatic urothelial cancer who progressed on a platinum-based regimen and is the largest study of a PD-1 inhibitor in bladder cancer reported to date. Results showed that treatment with nivolumab was associated with a confirmed objective response rate (ORR) of 19.6% (95% CI, 15.0-24.9).

The response to nivolumab was rapid with a medium time to response of 1.9 months (range: 1.6-5.9). The median duration of response has not yet been reached, but responses are ongoing in 76.9% of responders, and 24.4% of 265 patients remained on therapy at a median follow-up of 7 months.

Median progression-free survival (PFS) was 2 months (95% CI, 1.87-2.63). Median PFS was 1.87 in patients with <1% PD-L1 expression (n = 143) and increased to 3.55 months in patients with PD-L1 expression of>1% (n = 122).

Median overall survival (OS) was 8.74 months (95% CI, 6.05-not estimable); median OS was 5.95 months in patients with PD-L1 <1% and 11.3 months in patients with PD-L1 expression of>1%.

Although patients with a PD-L1 expression>1% were associated with a higher ORR of 23.8% (95% CI, 16.5—32.3), patients with PD-L1 expression <1% also responded well to nivolumab and demonstrated an ORR of 16.1% (95% CI, 10.5&ndash;23.1).

In patients expressing PD-L1 &ge;5%, the confirmed ORR was 28.4% (95% CI 18.9—39.5) and 15.8% (95% CI 10.8-21.8) in patients expressing PD-L1 <5%.

&ldquo;The vast majority of patients with metastatic urothelial cancer experience disease progression despite platinum-based chemotherapy,&rdquo; said lead study author Matthew D. Galsky, MD, professor of Medicine at the Mount Sinai School of Medicine. &ldquo;Nivolumab has previously shown impressive anti-tumor activity and overall survival prolongation across multiple tumor types.&rdquo;

Galsky and colleagues conducted the open-label, single-arm, phase II study in 270 patients who received nivolumab at 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The median age was 66 years and 84.1% of patients had visceral metastases at baseline. Overall, 42.2% of patients had received 1 and 29.3% of patients underwent 2 or more prior treatment regimens in the metastatic setting.

Biomarkers were analyzed by immunohistochemistry for association between response, UC subtype via The Cancer Genome Atlas, and immune gene signature expression. The primary endpoint was ORR according to RECIST 1.1 confirmed by blinded independent review committee.

PD-L1 expression &ge;1% and &ge;5% was reported for 45.9% and 30.7% of patients, respectively.

Biomarker analyses showed that the strongest nivolumab response was associated with basal 1 (69.5%), and luminal 2 (66.3%) subtypes. The basal 1 subtype also showed the strongest interferon &gamma; gene signature expression.

Grade 3/4 treatment-related adverse events (AEs) occurred in 18% of patients; fatigue and diarrhea were the most frequently reported, each occurring in 2% of patients. There was 1 death each due to cardiovascular disease, pneumonitis, and acute respiratory failure. Three patients discontinued treatment due to treatment-related AEs.

Quality of life, assessed using the Global Health Status Scale, improved from baseline and remained stable over the course of the trial.

&ldquo;There are limited options for patients with metastatic urothelial cancer who progress on platinum-based chemotherapy,&rdquo; he said. &ldquo;Immune checkpoint blockade has become the most promising approach for these patients.&rdquo;

In June 2016, the FDA granted nivolumab a breakthrough therapy designation for the treatment of patients with unresectable locally advanced or metastatic mUC after the failure of a platinum-containing regimen. The EMA validated a type II variation application for use of nivolumab for the same indiciation in September 2016.

&ldquo;There is a significant unmet need for new treatment approaches for progressive metastatic urothelial carcinoma,&rdquo; Vicki Goodman, MD, development lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb, the manufacturer of nivolumab, &ldquo;The results from CheckMate-275 show treatment with Opdivo resulted in durable and clinically meaningful objective response of 19.6% in all-treated patients. Based on these findings, we believe Opdivo has the potential to become an important new treatment option for patients with platinum-refractory advanced bladder cancer.&rdquo;

Reference:

Galsky MD, Retz M, Siefker-Radtke AO, et al. Efficacy and safety of nivolumab monotherapy in patients with metastatic urothelial cancer (mUC) who have received prior treatment: Results from the phase II CheckMate-275 study. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA31.