OBJECTIVES: An indirect treatment comparison (ITC) involving lenvatinib plus everolimus (LEN+EVE) versus standard of care (SOC) therapy was conducted using networked data from HOPE 205, CHECKMATE-025, METEOR, AXIS and two crossover trials RECORD-1 and TARGET. Results showed superiority of LEN+EVE over EVE alone for overall survival in second-line treatment of advanced/metastatic renal cell carcinoma. No statistically significant differences in overall survival (OS) were found between LEN+EVE versus nivolumab (NIV), cabozantinib (CAB), axitinib (AXI), or placebo.

METHODS: A subsequent analysis was conducted using intention to treat (ITT) data to evaluate the impact of crossover correction on OS estimates and additionally to uncover any potential bias due to its absence. Three ITC scenarios were analyzed: A) all comparators plus placebo versus EVE; B) all comparators versus placebo; and C) LEN+EVE versus all comparators.

RESULTS: ITT data for Scenario “A” showed consistent variance in survival benefit versus crossover data by an average of 20%. OS estimates for AXI vs. EVE shifted from below null (0.98) to above null (1.27); and mortality risk (placebo vs. EVE) moved 51% further from null (1.15 vs. 1.67). ITT estimates for Scenarios “B” & “C” showed on average 9% and 14% differences in OS benefits respectively versus crossover. In Scenario “C” estimates for LEN+EVE versus Pazopanib (PAZ) or LEN+EVE versus Sunitinib (SUN) showed superiority with ITT data (0.82 or 0.75) but were inferior (1.2 or 1.09) with crossover.

CONCLUSIONS: Selection bias was observed in naive approaches when comparing survival differences between crossover non-crossover data. Failure to account for this in clinical trials may have implications on the comparative effectiveness profile and also on the cost-effectiveness results and may lead to inconsistent resource allocation decisions.