What is the potential for lead time bias in the Serena 6 trial using camizestrant (generic name: next-generation selective estrogen receptor degrader)?

Lead Time Bias in the SERENA-6 Trial Using Camizestrant

Lead time bias in the SERENA-6 trial refers to the potential artificial extension of progression-free survival that occurs when detecting ESR1 mutations early through circulating tumor DNA testing before clinical disease progression, rather than true therapeutic benefit from camizestrant.

Understanding Lead Time Bias in SERENA-6

• Lead time bias occurs when screening or early detection creates an apparent improvement in survival time that is merely due to earlier diagnosis, not actual prolongation of life 1
• In SERENA-6, patients were monitored for ESR1 mutations every 2-3 months while on first-line aromatase inhibitor plus CDK4/6 inhibitor therapy, and those with detected mutations were randomized to either continue their current therapy or switch to camizestrant 2
• The detection of ESR1 mutations before clinical progression represents a form of molecular screening that could introduce lead time bias into the assessment of progression-free survival 1

How Lead Time Bias Affects SERENA-6 Results

• The primary endpoint of SERENA-6 was investigator-assessed progression-free survival, which showed significant improvement with camizestrant (16.0 months vs 9.2 months with aromatase inhibitors; HR 0.44) 2
• This improvement could be partially attributed to detecting resistance earlier through molecular testing rather than waiting for radiographic progression 3
• By identifying ESR1 mutations before clinical progression and switching therapy early, the trial may have captured disease at an earlier timepoint in its natural history 1

Clinical Implications of Lead Time Bias

• Despite potential lead time bias, the SERENA-6 trial showed meaningful clinical benefits:
  • Significantly longer progression-free survival with camizestrant (HR 0.44; 95% CI, 0.31 to 0.60; P<0.0001) 2
  • Improved time until deterioration in patient-reported global health status and quality of life (21.0 months vs 6.4 months; HR 0.54) 2
  • Low discontinuation rates due to adverse events (1.3% with camizestrant vs 1.9% with aromatase inhibitors) 2

Mitigating Lead Time Bias in Interpretation

• To account for lead time bias, secondary endpoints like overall survival and time to second progression (PFS2) are important to evaluate the true clinical benefit 3
• Patient-reported outcomes showing delayed deterioration in quality of life suggest benefits beyond just extending time to progression 2
• The randomized design helps mitigate some bias since both arms underwent the same ESR1 mutation testing schedule 2, 3

Broader Context of Camizestrant's Efficacy

• Camizestrant has demonstrated efficacy in other trials without the same potential for lead time bias:
  • In SERENA-2, camizestrant showed superior progression-free survival compared to fulvestrant in post-menopausal women with ER-positive, HER2-negative advanced breast cancer 4
  • SERENA-1 demonstrated antitumor activity of camizestrant in combination with CDK4/6 inhibitors in heavily pretreated patients 5

Recommendations for Clinical Practice

• When interpreting SERENA-6 results, clinicians should consider the potential for lead time bias while recognizing the significant clinical benefits demonstrated with camizestrant in patients with emerging ESR1 mutations. 2, 1
• Regular monitoring for ESR1 mutations in patients on first-line aromatase inhibitor plus CDK4/6 inhibitor therapy may be beneficial for early intervention with more effective therapies 2, 3
• Consider the improved quality of life outcomes when making treatment decisions, as these are less affected by lead time bias 2