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Bending the Curve Trial by Trial
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LIBRETTO-431

A Study of Selpercatinib (LY3527723) in Participants With Advanced or Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer

Phase 3N = 261NCT04194944

Population
Advanced RET fusion-positive NSCLC, untreated for advanced disease (first line)
Design
Randomised phase 3 trial of first-line selpercatinib versus platinum-based chemotherapy with or without pembrolizumab (investigator's choice). Primary endpoint PFS by blinded independent central review in the intention-to-treat-pembrolizumab population (patients whose physicians planned pembrolizumab if assigned to control) and the overall ITT population. Crossover from control to selpercatinib allowed on BICR-confirmed progression. Preplanned interim efficacy analysis. Arm sizes (selpercatinib 159, control 102) are for the overall ITT population of 261; in the ITT-pembrolizumab population (212) they are 129 and 83. Interim data cutoff 1 May 2023 (full text).
Primary endpoint
PFS
Arms
  • Chemotherapy with or without pembrolizumab (control, n = 102): Platinum-based chemotherapy (pemetrexed with carboplatin or cisplatin, per the full text), with or without pembrolizumab at the investigator's discretion
  • Selpercatinib (experimental, n = 159): Selpercatinib 160 mg orally twice daily (per the full text)
People
Zhou C
PFSHR 0.46 (95% CI 0.31–0.70)Δ median PFS+13.6 monthsΔ ORR+19 points
Show the numbers
Results reported for LIBRETTO-431
EndpointAnalysisSelpercatinibChemotherapy with or without pembrolizumabEffect
PFSIntention-to-treat-pembrolizumab population (n=212)PFS assessed by blinded independent central reviewinterimZhou 2023median 24.8 monthsmedian 11.2 months (8.8–16.8)HR 0.46 (95% CI 0.31–0.70)P<0.001Selpercatinib median PFS 95% CI 16.9 to not estimable. Efficacy in the overall ITT population (261 patients) was described as similar. The ITT-pembrolizumab population included 212 patients.
ORRIntention-to-treat-pembrolizumab population (n=212)interimZhou 202384% (76–90%)65% (54–75%)Cause-specific hazard ratio for time to progression affecting the central nervous system 0.28 (95% CI 0.12 to 0.68).
Results reported for LIBRETTO-431
EndpointAnalysisSelpercatinibChemotherapy with or without pembrolizumabEffect
PFSIntention-to-treat-pembrolizumab population (n=212)PFS assessed by blinded independent central reviewinterimZhou 2023median 24.8 monthsmedian 11.2 months (8.8–16.8)HR 0.46 (95% CI 0.31–0.70)P<0.001Selpercatinib median PFS 95% CI 16.9 to not estimable. Efficacy in the overall ITT population (261 patients) was described as similar. The ITT-pembrolizumab population included 212 patients.
ORRIntention-to-treat-pembrolizumab population (n=212)interimZhou 202384% (76–90%)65% (54–75%)Cause-specific hazard ratio for time to progression affecting the central nervous system 0.28 (95% CI 0.12 to 0.68).
Hazard ratio (95% CI) by endpoint. Values below 1 favour the experimental arm.
PFS0.512◀ experimentalcontrol ▶
Data table
EndpointHR95% CI
PFS0.460.31–0.7
Illustrative — modelled from reported values, not trial data. PFS, interim.
0%25%50%75%100%0102030405060Months (modelled)
  • Chemotherapy with or without pembrolizumab (control)
  • Selpercatinib (experimental)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)
MonthsChemotherapy with or without pembrolizumabSelpercatinib
0100.0%100.0%
1637.1%63.9%
3114.7%42.0%
475.5%26.9%
622.2%17.7%
Primary publication: Zhou C, Solomon B, Loong HH, Park K, Pérol M, Arriola E, et al. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC. N Engl J Med. 2023;389(20):1839-1850. PubMedDOI

Appears in

Sources

  1. Zhou C, Solomon B, Loong HH, Park K, Pérol M, Arriola E, et al. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC. N Engl J Med. 2023;389(20):1839-1850.

    PubMedDOI