Although improvements in overall survival (OS) remain the Oncologist’s treatment goal, because effective post-trial therapy exists, true OS gains are increasingly difficult to quantify. This raises concerns as payers, unlike regulatory agencies, may be less accepting of progression-free survival (PFS) in the absence of validated relationship. Payers quantify life years gained (LYG) to determine cost per LYG; a metric used to establish cost-effectiveness. The AXIS study provides an example of this challenge.
AXIS study randomised 723 patients (361, axitinib; 362 sorafenib) with metastatic renal cell carcinoma following failure of 1 prior systemic treatment. The primary endpoint was PFS with OS as a secondary endpoint. Study treatment was continued until evidence of disease progression, intolerability or withdrawal of consent. Patients who discontinued randomised treatment could receive subsequent treatment based on investigator-opinion. Patients were followed-up until death.
From AXIS, median PFS for axitinib was 6.7 months versus 4.7 months with sorafenib (HR = 0.665, 95% CI 0.544 - 0.812; P<0.0001). Median PFS reported for axitinib-treated cytokine refractory patients was 12.1 months and median PFS 4.8 months for axitinib-treated sunitinib refractory patients. Median OS was not reached at the time of analysis as 30% of patients had died, however estimated survival probability at 12 months was similar (66% for axitinib, 67.8% for sorafenib).
Axitinib phase II trials reported 16 months median PFS for axitinib-treated cytokine refractory patients and 7 months median PFS for axitinib-treated sunitinib refractory patients. Median OS reported for axitinib-treated cytokine refractory patients was 30 months and 14 months for axitinib-treated sunitinib refractory patients.
With demonstrated PFS but diluted OS gains, post-progression survival (PPS) is scrutinised. PPS is influenced by factors like crossover and non-randomised post-progression treatments that introduce unmeasurable bias. This requires complex statistical analysis using patient level data. Further research is required in this area.
An OS gain is diluted in clinical trials due to heterogeneity in SPP. In studies with PFS as the primary endpoint a conservative estimate of OS gain can be estimated, however this is subject to bias if SPP estimations are likely based on nonrandomised, single arm studies.