FDA granted priority review for nivolumab in combination with cisplatin-based chemotherapy for first-line treatment of unresectable or metastatic urothelial cancer

BMS announced that the FDA granted priority review for the supplemental BLA of nivolumab (Nivo/Opdivo; PD-1) in combination with cisplatin-based chemotherapy for first-line treatment of patients with unresectable or metastatic urothelial cancer (mUC).

The FDA has set a PDUFA date of April 4, 2024, teeing up an eventful H1 2024 as approval timeline is similar to that expected for the enfortumab vedotin (EV/Padcev; Nectin-4 ADC) + pembrolizumab (P/Keytruda; PD-1) combination for 1L all comer la/mUC (based on P3 EV-302; sBLA accepted for priority review with PDFUA of May 9, 2024 but possible approval Q1’24 under RTOR).

Key Highlights and Potential Implications:

• The application is based on results from the global P3 CheckMate-901 (CM-901) substudy in which Nivo + gemcitabine-cisplatin (GC) demonstrated survival benefit vs GC in 1L cis-eligible unresectable or mUC
  • At final analysis, Nivo-GC showed statistically significant improvements versus GC in OS (21.7 mo vs 18.9 mo; HR 0.78) and PFS (7.9 mo vs 7.6 mo; HR 0.72)
• Potential US approval in Apr’24 would make Nivo-GC the first and only immunotherapy-chemotherapy combination available in the 1L setting
  • EU approval for this regimen is also expected in ~Q3’24 based on BMS’ prior announcement that the EMA validated its Type II variation application
• Given the expected positioning of EV-P as future global 1L SoC regardless of cisplatin eligibility (pending approval and in markets where reimbursed), the Nivo-GC regimen is expected to have lower impact in the 1L cis-eligible setting while rationale for its use in 2L+ is untested
  • CM-901 data were perceived as less impressive than EV-302, leaving positioning of Nivo-GC in 1L less clear. However, if used, Trodelvy is a 2L option to this regimen but would likely continue to compete with EV
  • Platinum-based chemotherapy displaced by 1L EV-P is expected to become a key 2L treatment option and competitor to Trodelvy; however, efficacy and safety of Nivo-GC combination as a 2L option to EV-P is unknown and there is limited evidence for IO re-challenge

Additional Information

• After several 1L mUC failures involving immunotherapies (IOs), positive results for Nivo-GC supports rationale that IO combination specifically with cisplatin-based chemo (vs carboplatin) may be required for better outcomes
  • Prior P3 trials of IO-chemo combinations in 1L all-comer population did not meet the OS endpoint (e.g., P3 IMvigor130, P3 KEYNOTE-361) but exploratory analyses suggested potentially better results of IO in combination with GemCis than GemCarbo
  • The P3 CM-901 primary study of nivo + ipilimumab (CTLA-4) arm similarly did not meet the primary endpoint of OS vs SoC chemo in PD-L1+ (≥1%) 1L all-comer mUC; the primary study is ongoing in cis-ineligible pts (data expected 2024)
• Positive topline results from CM-901 sub-study were first reported in July 2023 with full results shared during a Presidential session at ESMO in October 2023 (#LBA7; outlined below), immediately following the P3 EV-302 results, and concurrently published in NEJM (389:1778-1789)
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  • Study Information:
    • P3 CheckMate-901 sub-study (NCT03036098): nivolumab (nivo) + gemcitabine + cisplatin (GC) / nivo maintenance vs GC in 1L cis-eligible unresectable or mUC
    • N=608 (Nivo-GC N=304)
    • 1EP: PFS, OS
    • 2EP: OS, PFS by PD-L1 ≥1%, HRQoL
    • Median follow up (mo): 33.6
  • Efficacy (Nivo-GC vs GC)
    • mPFS (mo): 7.9 vs 7.6 (HR 0.72)
    • mOS (mo): 21.7 vs 18.9 (HR 0.78)
    • mDOR (mo): 9.5 vs 7.3
    • cORR: 58% vs 43%
      • CR: 22% vs 12%
      • mDOcR (mo): 37.1 vs 13.2
    • HRQoL: maintained with Nivo-GC vs GC alone
  • Safety (Nivo-GC vs GC)
    • GR 3+ TRAEs: 62% vs 52%
    • Safety profile overall consistent with that of cisplatin-based chemotherapy