Polatuzumab and the progression‐free survival (pfs) predicament: a comparative analysis of health technology assessment agency (hta) reviews

As more cancer drugs are approved based on changes in surrogate measures such as PFS, greater controversy surrounds their clinical benefit and economic value. In the POLARIX trial for untreated diffuse large B cell lymphoma (DLBCL), polatuzumab (Polivy), as part of the PolaRCHP regimen, achieved superior PFS than RCHOP (76.7% vs. 70.2%) with no difference in overall survival (OS) – challenging the 20-year standard of care. We examined reviews of PolaRCHP by international HTAs to understand how international expert organizations view a new cancer drug that marginally improves PFS without OS benefit. Methods: We searched NAVLIN (Eversana, Milwaukee, WI), a global HTA database, to determine which HTA organizations have reviewed polatuzumab in untreated DLBCL. We then extracted key summary documents from each group’s website to investigate the rationale provided. Results: Among 14 HTAs that reviewed pola, 5 assessed its use in frontline DLBCL. HTAs in Germany and the UK recommended reimbursement, while those in France and Australia did not. The UK was willing to tolerate an uncertain impact on OS due to acceptable cost effectiveness, while a “hint” of non-quantifiable benefit was sufficient to earn reimbursement in Germany (Table). Conversely, Australia and France emphasized that unchanged overall and complete response rate undermined the PFS benefit (suggesting that PolaRCHP may neither achieve more responses nor deeper responses among responders), as well as the uncertain impact on OS, given the aggressive nature of DLBCL. HTAs considered price differently: the UK found pola’s incremental cost-effectiveness ratio (ICER) acceptable while Australia considered its budget impact too high. France and Germany did not factor price into assessments. Conclusions: Polatuzumab offers insights into how HTAs value PFS: in some countries, a marginal PFS benefit in the absence of OS benefit was sufficient to warrant reimbursement, while other HTAs felt the difference in PFS was undermined by lack of improvement in response rate and depth and OS. Our study is limited by undisclosed negotiated discounts, which may influence reimbursement decisions in different jurisdictions. Understanding how HTAs interpret trial results is essential to ensure optimal design of future clinical trials and improve patient access to effective novel agents. The research was funded by: Arnold Ventures Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies Conflicts of interests pertinent to the abstract E. R. S. Cliff Research funding: Arnold Ventures A. J. N. Raymakers Consultant or advisory role Adam Raymakers reports serving as a member of the pan-Canadian Oncology Drug Review Expert Review Committee (pERC) with the Canadian Agency for Drugs and Technologies in Health (CADTH).