FDA Grants Priority Review to Frontline Nivolumab Plus Chemo for Unresectable or Metastatic Urothelial Carcinoma

FDA

The FDA has granted priority review to a supplemental biologics license application (sBLA) seeking the approval of nivolumab (Opdivo) plus cisplatin-based chemotherapy as a frontline treatment option for adult patients with unresectable or metastatic urothelial carcinoma.¹

The sBLA is supported by data from the phase 3 CheckMate -901 trial (NCT03036098) in which nivolumab plus gemcitabine and cisplatin (n = 304) improved overall survival (OS) vs gemcitabine plus cisplatin alone (n = 304), at a median of 21.7 months (95% CI, 18.6-26.4) and 18.9 months (95% CI, 14.7-22.4), respectively (HR, 0.78; 95% CI, 0.63-0.96; P = .0171).2 The 12-month OS rate in the nivolumab arm was 70.2% vs 62.7% in the chemotherapy-only arm; at 24 months, these rates were 46.9% and 40.7%, respectively.

The addition of the immunotherapy to chemotherapy also resulted in prolonged progression-free survival over chemotherapy alone, at a median of 7.9 months (95% CI, 7.6-9.5) by blinded independent central review (BICR) vs 7.6 months (95% CI, 6.1-7.8), respectively (HR, 0.72; 95% CI, 0.59-0.88; P = .0012). The 12-month PFS rates were 34.2% and 21.8%, respectively, and the 24-month rates were 23.5% and 9.6%, respectively.

The regulatory agency will decide on the application by April 5, 2024, under the Prescription Drug User Fee Act.¹

“The FDA’s acceptance of our application for Opdivo in combination with cisplatin-based chemotherapy represents important progress toward addressing the unmet need for options that may offer durable responses and improved survival for patients with metastatic urothelial carcinoma. There remains a clear need for efficacious first-line treatment options that may potentially help improve outcomes for patients with this hard-to-treat disease,” Dana Walker, MD, MSCE, vice president and global program lead of gastrointestinal and genitourinary cancers at Bristol Myers Squibb, stated in a press release.

CheckMate -901 enrolled patients with previously untreated unresectable or metastatic urothelial carcinoma involving the renal pelvis, ureter, bladder, or urethra who are not eligible to receive cisplatin. Patients needed to be at least 18 years of age and have an ECOG performance status of either 0 or 1.²

Study participants were randomly assigned to receive gemcitabine at 1000 mg/m2 on days 1 and 8 and cisplatin at 70 mg/m2 on day 1 with or without nivolumab at 360 mg on day 1 every 3 weeks for up to 6 cycles. Three weeks after the combination phase, those in the investigative arm entered into a monotherapy phase where they were given nivolumab at 480 mg every 4 weeks until disease progression, intolerable toxicity, withdrawal, or up to 24 months.

Patients were stratified based on tumor PD-L1 expression (≥1% vs <1%) and liver metastases (yes vs no).

OS and PFS by BICR represented the trial’s primary end points. Secondary end points included OS and PFS in those with a PD-L1 expression of 1% or higher and health-related quality of life. ORR by BICR and safety served as exploratory end points of interest.

The median age for patients in both arms was 65 years (range, 32-86). Most patients in the nivolumab/chemotherapy and chemotherapy-alone arms were male (78% vs 77%), White (69% vs 74%), and from Europe (44% vs 47%). Fifty-three percent of patients in both arms had an ECOG performance status of 0. More than half of patients in both arms (77% vs 72%) had disease in the urinary bladder at initial diagnosis. Sixty-four percent of patients in both arms had liver metastases.

Of those in the nivolumab arm, 37% had a PD-L1 expression of at least 1% and 63% had expression of less than 1% or indeterminate; in the chemotherapy-only arm, these rates were 36% and 64%, respectively.

The median follow-up for the final analysis was 33.6 months (range, 7.4-62.4). The median duration of treatment on the nivolumab arm was 7.4 months (range, 0.0-47.9) vs 3.7 months (range, 0.0-14.3) in the chemotherapy-alone arm. Seventy-four percent of patients in the nivolumab arm completed 6 cycles of treatment per protocol vs 55% of those in the chemotherapy arm. A total of 244 patients went on to receive single-agent nivolumab and 8% completed treatment; 28% were still on therapy at the time of the database lock.

Additional data showed that the addition of nivolumab to chemotherapy resulted in an objective response rate (ORR) of 57.6% (95% CI, 51.8%-63.2%), which included a complete response (CR) rate of 21.7% and a partial response (PR) rate of 35.9%; 25.3% of patients had stable disease (SD) and 9.5% had progressive disease (PD). The median time to response (TTR) was 2.1 months (95% CI, 2.0-2.3) and the median duration of response (DOR) was 9.5 months (95% CI, 7.6-15.1). Moreover, the median time to CR (TTCR) was 2.1 months (95% CI, 1.9-2.2) and the median duration of CR (DOCR) was 37.1 months (95% CI, 18.1-not evaluable).

Chemotherapy alone resulted in an ORR of 43.1% (95% CI, 37.5%-48.9%), which was comprised of a 11.8% CR rate and a 31.3% PR rate. In this group, the SD and PD rates were 28.3% and 12.8%, respectively. In this group, the median TTR was 2.1 months (95% CI, 2.0-2.2) and the median DOR was 7.3 months (95% CI, 5.7-8.9). The median TTCR was 2.1 months (95% CI, 1.9-2.2) and the median DOCR was 13.2 months (95% CI, 7.3-18.4).

Regarding safety, any-grade treatment-related adverse effects (TRAEs) were experienced by 97% of patients in the nivolumab/chemotherapy arm vs 93% of those in the chemotherapy-alone arm; these effects were grade 3 or higher for 62% and 52% of patients, respectively. Any-grade TRAEs led to treatment discontinuation for 21% of those in the nivolumab arm and 17% of those in the chemotherapy-alone arm.

The most common any-grade TRAEs reported in all-treated patients in the nivolumab and chemotherapy-alone arms were anemia (57% vs 48%), nausea (47% vs 48%), neutropenia (31% vs 30%), decreased neutrophil count (25% vs 21%), fatigue (24% vs 24%), decreased appetite (22% vs 16%), decreased platelet count (22% vs 15%), decreased white blood cell count (21% vs 14%), vomiting (18% vs 17%), asthenia (15% vs 16%), thrombocytopenia (15% vs 12%), pruritus (14% vs 3%), constipation (14% vs 14%), rash (13% vs 3%), diarrhea (13% vs 9%), hypothyroidism (13% vs 0%), increased blood creatinine (13% vs 12%), and leukopenia (13% vs 11%).

“We look forward to working with the FDA throughout the review of this application and hope to bring the first immunotherapy-chemotherapy combination to these patients in the United States,” Walker added in the news release.¹ “We want to offer a special thanks to the patients and investigators involved in the CheckMate -901 clinical trial.”

References

1. US Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for Opdivo (nivolumab) in combination with cisplatin-based chemotherapy for the first-line treatment of adult patients with unresectable or metastatic… News release. Bristol Myers Squibb. December 5, 2023. Accessed December 5, 2023. https://news.bms.com/news/details/2023/U.S.-Food-and-Drug-Administration-Accepts-for-Priority-Review-Bristol-Myers-Squibbs-Application-for-Opdivo-nivolumab-in-Combination-with-Cisplatin-Based-Chemotherapy-for-the-First-Line-Treatment-of-Adult-Patients-with-Unresectable-or-Metastatic/default.aspx
2. van der Heijden MS, Sonpavde GP, Powles TB, et al. LBA7 nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone for previously untreated resectable or metastatic urothelial carcinoma: results from the phase III CheckMate 901 trial. Ann Oncol. 2023;34(suppl 2):S1341. doi:10.1016/j.annonc.2023.10.107