Page 17 - Haematologica Vol. 107 - September 2022

EDITORIAL A.R. Mato and L.E. Roeker Novel-agent combination therapies in chronic
lymphocytic leukemia: the law of relative contributions
Anthony R. Mato and Lindsey E. Roeker
Memorial Sloan Kettering Cancer Center, New York, NY, USA E-mail: Matoa@mskcc.org
doi:10.3324/haematol.2021.280217
In this issue of Haematologica, Moreno et al.1 present the final analysis of the randomized, phase III iLLUMINATE trial. In this study, the combination of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (administered in a treat- to-progression, continuous fashion) plus the anti-CD20 monoclonal antibody obinutuzumab was compared to time-limited chlorambucil plus obinutuzumab in the front-line setting. Now with a median of 45 months of fol- low-up, the data confirm an impressive progression-free survival (PFS) advantage of ibrutinib plus obinutuzumab over chlorambucil plus obinutuzumab (median PFS not reached for ibrutinib plus obinutuzumab vs. 22 months for chlorambucil plus obinutuzumab, hazard ratio=0.25, 95% confidence interval: 0.16-0.39, P<0.0001) without a clear advantage in overall survival (hazard ratio=1.08, P=0.793), although it should be noted that treatment crossover was allowed. For ibrutinib plus obinutuzumab, the overall response rate, complete response rate and rate of undetectable minimal residual disease were also impressive at 91%, 42% and 38%, respectively. The iLLUMI- NATE trial also allowed enrollment of patients with chro- mosome 17p deletion [(del17p)] providing efficacy data for ibrutinib-based therapy in this high-risk population of pa- tients.
Taken in the context of the current treatment landscape, these data from iLLUMINATE should trigger important considerations regarding the relative contributions of drugs. While the ibrutinib plus obinutuzumab combination is unequivocally superior to the chlorambucil-based con- trol arm in terms of PFS, we do not gain insight into how obinutuzumab adds to the already herculean activity of ibrutinib in the front-line setting as this trial did not in- clude an ibrutinib monotherapy arm. In the current pan- demic, assessing the contribution of obinutuzumab is particularly relevant given that the addition of an anti- CD20 monoclonal antibody will blunt or eliminate humoral responses to SARS-Cov-2 mRNA vaccines (all risk without a proven reward). Additionally, lessons learned from re- cent randomized trials in chronic lymphocytic leukemia (CLL) remind us that only with proper assessment of relative contributions can one determine the true risk ver- sus benefit of a combination. For example, two prior ran- domized clinical trials compared ibrutinib to ibrutinib with the anti-CD20 monoclonal antibody rituximab and did not demonstrate a PFS or overall survival advantage for ibruti- nib plus rituximab over ibrutinib alone.2,3 Based on these
trials which provided clarity on the relative contribution of rituximab to ibrutinib, nearly all clinicians favor ibrutinib monotherapy over ibrutinib plus rituximab combination therapy. In the ELEVATE-TN study the second generation BTK inhibitor acalabrutinib was compared alone and in combination with obinutuzumab to chlorambucil plus obi- nutuzumab in the front-line setting.4 In this three-arm, randomized, phase III, clinical trial, Sharman et al. dem- onstrated a PFS advantage for the combination of acala- brutinib plus obinutuzumab over acalabrutinib monotherapy. The ELEVATE-TN study design should be celebrated, as it allowed clinicians to examine the benefit of adding obinutuzumab to acalabrutinib and supports the use of the novel agent-based combination acalabrutinib plus obinutuzumab. Given differences in patient popu- lations, clinical trial designs, and biases inherent to cross- trial comparisons of different agents, data from ELEVATE TN should not be freely extrapolated to other BTK in- hibitors plus obinutuzumab combinations. This body of literature catalyzes careful consideration of how to design future novel agent combination studies in CLL to ad- equately assess the relative safety and efficacy contribu- tions of individual components of a multi-agent combination regimen.
As future efforts to optimize treatment of CLL focus on novel agent-based doublet and triplet therapy, we must consider the relative contributions of each component. Phase I/II studies examining combination therapies have demonstrated safety and efficacy, leading to the devel- opment of phase III studies exploring the combinations. Rational phase III study design requires consideration of whether the combination is absolutely required to achieve the desired clinical outcome. For example, in the recently reported GLOW trial, the combination of ibrutinib and venetoclax demonstrated superior PFS to the chlorambu- cil plus obinutuzumab regimen.5 While the GLOW study is undoubtedly positive with regard to its primary PFS end- point, the trial does not allow us to determine the relative contributions of the components of the ibrutinib plus venetoclax combination to safety or efficacy. With the current data, we cannot determine whether the combina- tion is better than monotherapy or a single novel agent in combination with obinutuzumab. Novel agent monother- apy control arms are noticeably absent in many of the currently accruing trials examining novel agent-based doublet and triplet therapies, so assessment of the
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