Time to Complete Response within 24 Months As a Good Surrogate Marker of 8 Year-Progression Free Survival in Extranodal Marginal Zone Lymphoma

Background: Extranodal marginal zone lymphoma (EMZL) represents the most common marginal zone lymphoma (MZL) subtype and it generally has a very indolent course, thus requiring long and costly trials to provide evidence on novel therapies. The IELSG-19 open-label phase 3 trial was conducted at 78 centers in six countries and showed the advantage of double therapy (rituximab-chlorambucil) over single therapy (rituximab or chlorambucil). Based on this trial, we assessed whether time to complete response within 24 months (TTCR24) could be a surrogate marker of progression-free survival (PFS) in EMZL.

Methods: We used a recently developed method which derives conditional survival estimates under a landmark Cox proportional hazards model. This method allows us 1) to estimate surrogacy via the proportion of treatment effect explained by surrogate information and 2) to decompose this proportion between information gathered on the true outcome and the incremental value of the surrogate outcome alone. True outcome was 8 year-PFS and candidate surrogate marker was TTCR24. For both outcomes, treatment effect was defined using restricted mean survival time difference (RMST) between the two study arms: the difference in mean progression-free survival time restricted at 8 years and the difference in mean time to CR.

Results: Among 401 patients (median follow-up: 7.4 years), 8y-PFS was not achieved in the combined therapy arm vs 8.35 years in the single therapy arm. At 2 years, TTCR24 was 83% vs 65%, while 2y-PFS was 87% vs 75%, respectively. In terms of RMST, patients under double therapy had a shorter TTCR24 by 3.8 months and a longer PFS by 11 months, compared to patients under single therapy. The estimated proportion of treatment effect on 8y-PFS explained by TTCR24 was 95% (95% CI: 0.27,1.87). When decomposed, the proportion of treatment effect on 8y-PFS was explained by PFS24 was 75% (95% CI: 0.31, 1.27) and the incremental value of TTCR24 was 20% (95% CI: -0.23,0.86).

Conclusion: We found that TTCR24 predicted 95% of the treatment effect on 8y-PFS and, when used as surrogate marker, it could reduce the needed follow-up time of a phase 3 trial by four. From this, one could conclude that a new therapy in EMZL would be effective if it offers a significantly shorter TTCR than the one obtained by rituximab-chlorambucil (5.5 months). Although this single-trial approach suffers of the lack of a trial-level evidence, there are, to date, too few MZL phase 3 trials to undertake a meta-analysis. The very strong surrogacy offered by TTCR24 could make it the most relevant surrogate marker in EMZL in the coming years.

Zucca:Celgene: Other: advisory board fees, Research Funding; Roche: Research Funding; Janssen: Research Funding; Mei Pharma: Other: advisory board fees ; Astra Zeneca: Other: advisory board fees ; Celltrion Healthcare: Other: advisory board fees ; Abbvie: Other: travel grant; Gilead: Other: travel grant, expert statements; Bristol-Myers Squibb: Other: expert statements; MSD: Other: expert statements; Incyte: Other: advisory board fee, Research Funding; BeiGene: Other: advisory board fee, Research Funding; Miltenyi Biomedicine: Other: advisory board fee. Nowakowski:Bantam Pharmaceutical: Consultancy; Blueprint Medicines Corporation: Consultancy; Celgene Corporation/Bristol Myers Squibb: Consultancy, Research Funding; Curis, Inc.: Consultancy; Daiichi Sankyo Inc: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Genentech, Inc: Consultancy, Research Funding; Incyte: Consultancy; Karyopharm: Consultancy; Kite Pharma Inc.: Consultancy; Kymera Therapeutics: Consultancy; MorphoSys US Inc: Consultancy; NanoString: Research Funding; Ryvu Therapeutics: Consultancy; Selvita: Consultancy; TG Therapeutics: Consultancy; Zai Lab: Consultancy. Cerhan:BMS/Celgene: Research Funding; Genentech: Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees, Research Funding; NanoString: Research Funding; Protagonist: Membership on an entity's Board of Directors or advisory committees. Thieblemont:Roche: Consultancy, Honoraria, Other: Travel Support; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support.