Page 18 - Haematologica Vol. 109 - July 2024

EDITORIAL
Indirect treatment comparisons: how to MAIC it right?
Emmanuel Bachy
Hospices Civils de Lyon, Hematology Department, Lyon, France
As more phase II non-comparative clinical trial data are generated with new emerging treatment options, indirect cross-trial and real-life comparisons have grown exponen- tially. Sometimes they aim to provide anticipated informa- tion while waiting for ongoing phase III trials, while most often they try to substitute for head-to-head compari- sons that will never be performed by pharma companies or academic consortia. In this issue of Haematologica, Maurer and colleagues performed a matching-adjusted indirect comparison (MAIC) between patients from the Lymphoma Epidemiology for Outcomes (LEO) Consortium for Real World Evidence (CReWE) and from a phase I/II study of mosunetuzumab, a CD20xCD3 T-cell engaging bispecific antibody, as a single agent (GO29781 – clinical- trials.gov 02500497).1,2 Phase III randomized studies are of the highest quality standards for treatment comparison because random allocation can control both for measured confounders (e.g., age, sex, disease stage, treatment line, performance status) and potential unmeasured con- founders (e.g., unquantifiable belief by the physician that a particular patient would benefit from a given drug or unmeasured socio-economic determinants). Amidst both end of the spectrum ranging from basic unadjusted or unmatched comparisons and the phase III gold standard stand various statistical approaches trying to mitigate these potential biases (Figure 1A). A MAIC is usually con- sidered when individual patient data (IPD) are available for one group of patients while only aggregated data are available for the comparator (e.g., median or mean values, interquartile range). This is usually the case when trial sponsors (usually pharma companies) want to compare the outcome for patients treated with the product they develop with a competitor drug for which IPD are not available. This is also the case here where an academic consortium compares real-world IPD from a large cohort of patients to a given trial. Basically, a MAIC relies on selecting patients and pondering outcome according to their IPD characteristics to render them as close as pos- sible to aggregated data available from a trial publication
(Figure 1B).3,4 MAIC is usually considered as providing a poor confounding control as opposed to comparisons where IPD are available for both treatment groups (e.g., using propensity score-based matched comparisons or adjustments) but is usually the only option when only aggregated data are available for one treatment group. Furthermore, and like any comparison except randomized trials, MAIC cannot control for unmeasured biases that could confound the comparison of outcomes.
In follicular lymphoma, a disease still considered as incur- able for most patients, overall survival is now believed to extend beyond a median 20 years with a significant fraction of patients dying from non-lymphoma-related cause.5,6 However, disease outcome is highly heterogeneous with some patients experiencing poor survival despite the theo- retical indolent nature of the disease.7,8 Therefore, taking into account disease heterogeneity between FL patient cohorts is critical for cross-trial and other treatment comparisons. The study conducted by Maurer and colleagues shows that after careful weighting of patient data from the LEO CReWE to match clinical characteristics with those from the GO29781 study, overall (80% vs. 73%) and complete (60% vs. 53%) responses rates (ORR and CRR) were found slightly higher in the trial cohort. Despite these higher re- sponse rates, no obvious difference was observed regarding 12-month progression-free survival (PFS) (60% vs. 58% in the LEO vs. trial cohorts, respectively). However, and as stated by the authors, response status assessment differences between trial (with frequent imaging exams) and routine practice are a major bias for PFS measurement possibly penalizing response duration in the mosunetuzumab tri- al. Furthermore, 40% of patients in the LEO cohort were treated as part of a clinical trial for the selected index therapy, making it quite different from standard of care (SOC) strategies outside of specific tertiary care centers. Altogether, on one hand, prognosis is likely overestimated in the LEO cohort in contrast with routine practice be- cause of patient selection. But, on the other hand, 40% of them have probably been followed more closely to what
Haematologica | 109 July 2024
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Correspondence: E. Bachy emmanuel.bachy@chu-lyon.fr
Received: Accepted: Early view:
January 11, 2024. February 8, 2024. February 15, 2024.
https://doi.org/10.3324/haematol.2023.284534
©2024 Ferrata Storti Foundation Published under a CC BY-NC license