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

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The application is based on results from the phase 3 CheckMate-901 trial.

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

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

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