FDA grants priority review to frontline nivolumab-based regimen for urothelial carcinoma

The FDA has granted a priority review designation to a supplemental Biologics License Application (sBLA) for nivolumab (Opdivo) for use in combination with cisplatin-based chemotherapy in the first-line setting for the treatment of patients with unresectable or metastatic urothelial carcinoma, according to Bristol Myers Squibb, the developer of the immunotherapy.¹

Median OS with nivolumab plus GC was 21.7 months (95% CI, 18.6-26.4), compared with 18.9 months (95% CI, 14.7-22.4) with GC alone, reducing the risk of death by 22% (HR, 0.78; 95% CI, 0.63-0.96; P = .0171), meeting the primary end point of the study. The 12- and 24-month OS rates with the nivolumab combination were 70.2% and 46.9%, vs 62.7% and 40.7%, respectively, with GC alone.^2,3

The sBLA is supported by findings from the phase 3 CheckMate-901 trial (NCT03036098) that showed that the addition of nivolumab to frontline gemcitabine-cisplatin (GC), followed by nivolumab maintenance therapy, led to statistically significant and clinically meaningful improvements in overall (OS) and progression-free survival (PFS) compared with GC alone in patients with unresectable or metastatic urothelial carcinoma.^2,3

The FDA is scheduled to decide on the sBLA on or before April 5, 2024.

“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, global program lead, gastrointestinal and genitourinary cancers, Bristol Myers Squibb, stated in a news release.¹ “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 U.S. We want to offer a special thanks to the patients and investigators involved in the CheckMate-901 clinical trial.”

OS and PFS in CheckMate-901

Median OS with nivolumab plus GC was 21.7 months (95% CI, 18.6-26.4), compared with 18.9 months (95% CI, 14.7-22.4) with GC alone, reducing the risk of death by 22% (HR, 0.78; 95% CI, 0.63-0.96; P = .0171), meeting the primary end point of the study. The 12- and 24-month OS rates with the nivolumab combination were 70.2% and 46.9%, vs 62.7% and 40.7%, respectively, with GC alone.^2,3

OS benefit with the addition of nivolumab was also seen across the subgroup analysis, including age, sex, race, region, ECOG performance status, PD-L1 expression, liver metastases, and previous systemic anticancer therapy.

PFS by blind independent central review (BICR) was also met in the trial, with a median PFS of 7.9 months (95% CI, 7.6-9.5) with nivolumab plus GC, compared with 7.6 months (95% CI, 6.1-7.8) with GC alone, reducing the risk for progression by 28% (HR, 0.72; 95% CI, 0.59-0.88; P = .0012). The 12- and 24- months PFS rates with the addition of nivolumab were 34.2% and 23.5%, compared with 21.8% and 9.6%, respectively, in the GC-alone arm.

He noted that, for the primary analysis of PFS, patients who went on to receive subsequent anticancer therapy before disease progression were censored (nivolumab combination arm, 8% vs GC-alone arm, 24%). Immunotherapies were the most commonly used in the GC-alone arm. Therefore, since this may have impacted the primary analysis, the investigators conducted a sensitivity analysis and uncensored this patient population, finding that the median PFS with nivolumab plus GC was 7.9 months (95% CI, 7.6-9.5), compared with 7.5 months (95% CI, 6.1-7.8) in the GC-alone arm (HR, 0.74; 95% CI, 0.62-0.89).

Secondary end points

The objective response rate (ORR) in the nivolumab combination arm was 57.6% (95% CI, 51.8%-63.2%), including a complete response (CR) rate of 21.7%, partial response (PR) rate of 35.9%, stable disease (SD) rate of 25.3%, and progressive disease (PD) rate of 7.6%. The ORR in the GC-alone arm was 43.1% (95% CI, 37.5%-48.9%), including a CR rate of 11.8%, PR rate of 31.3%, SD rate of 28.3%, and PD rate of 15.8%.

When evaluating any objective response, median time to response (TTR) with nivolumab plus GC was 2.1 months (95% CI, 2.0-2.3) vs 2.1 months (2.0-2.2) with GC alone, while median duration of response (DOR) was 9.5 months (95% CI, 7.6-15.1) and 7.3 months (95% CI, 5.7-8.9), respectively. Among those who experience a CR, median TTR was 2.1 months in both arms ([95% CI, 1.9-2.2] vs [95% CI, 1.9-2.2], respectively) and median DOR was 37.1 months (95% CI, 18.1-not evaluable) and 13.2 months (95% CI, 7.3-18.4).

Exploratory end points

Median DOR by BICR with the addition of nivolumab was 9.5 months (95% CI, 7.6-15.1), compared with 7.3 months (95% CI, 5.7-8.9) with GC alone. The 12- and 24-month DOR rates with nivolumab combination therapy were 46.2% and 35.0%, compared with 29.2% and 12.6%, respectively, with GC alone.

More patients in the GC-alone arm went on to receive subsequent immunotherapy (60 vs 8), compared with the nivolumab arm. The proportion of patients receiving non-immunotherapy subsequent therapy, including surgery, radiotherapy, and/or platinum-based chemotherapy, was similar in both arms.

Any-grade treatment-related adverse events (TRAEs) occurred in 97% of the nivolumab combination arm, compared with 93% of the GC-alone arm, with 62% and 52%, respectively, being grade 3 or higher. The most common grade 3 or higher TRAEs in the nivolumab combination and GC-alone arms included anemia (22% vs 18%, respectively), neutropenia (19% vs 15%), decreased neutrophil count (14% vs 11%), decreased platelet count (8% vs 5%), decreased white blood cell count (10% vs 4%), thrombocytopenia (7% vs 5%), and leukopenia (2% each).

Lastly, health-related quality of life (HRQoL) was stable in both arms on the study.

Treatment exposure

The median duration of study therapy was 7.4 months (range, 0.0-47.9) in the nivolumab combination arm, compared with 3.7 months (range, 0.0-14.3) with GC alone. In total, 74% of patients treated with nivolumab and 55% of those treated with GC alone completed 6 cycles of treatment per the study protocol. Treatment discontinuation occurred as a result of disease progression (7% vs 17%, respectively) and study drug toxicity (8% each).

Of those treated with nivolumab plus GC in the combination phase, 244 went on to receive nivolumab monotherapy maintenance therapy, with 20 (8%) completing treatment and 23 (9%)still on therapy at data cutoff.

Study Design

Overall, the global, open-label, randomized phase 3 trial, patients were randomized 1:1 to receive either 360 mg nivolumab plus 1000 mg/m² gemcitabine and 70 mg/m² cisplatin every 3 weeks for up to 6 cycles (n = 304) or the gemcitabine/cisplatin regimen alone (n = 304). Patients treated with nivolumab in the combination phase then went on to receive 480 mg nivolumab every 4 weeks until disease progression, unacceptable toxicity, withdrawal, or up to a maximum of 24 months of maintenance therapy.

OS and PFS per BICR served as the primary end points, while the secondary end points included OS and PFS by PD-L1 of 1% or greater and HRQoL. The key exploratory end points were ORR per BICR and safety.

Patients were eligible for the trial if they were 18 years of age or older; had previously untreated, unresectable, or metastatic urothelial carcinoma involving the renal pelvis, ureter, bladder, or urethra; were cisplatin eligible; and had an ECOG performance status of 0 to 1.

The investigators stratified patients by tumor PD-L1 expression and liver metastases.

Median follow-up was 33.6 months (range, 7.4-62.4).

At baseline, patients in the nivolumab arm were a median age of 65 years (range, 32-86), while the majority were male (78%), White (69%), and had an ECOG performance status of 0 (53%). At initial diagnosis, 77% of patients had urinary bladder disease, 11% had renal pelvis disease, and 12% with other. In total, 37% of patients in this arm had PD-L1 expression of 1% or more vs 63% with less than 1%. Lastly, 21% of patients had liver metastases.

References

1. U.S. 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... Published online and accessed December 5, 2023. https://news.bms.com/news/corporate-financial/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 G, Powles T, et al. Nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone for previously untreated unresectable or metastatic urothelial carcinoma: Results from the phase III CheckMate 901 trial. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA7.

3. van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus Gemcitabine–Cisplatin in Advanced Urothelial Carcinoma. N Eng J Med. Published: October 22, 2023. doi:10.1056/NEJMoa2309863