Treatment for First Cytomegalovirus Infection Post–Hematopoietic Cell Transplant in the AURORA Trial: A Multicenter, Double-Blind, Randomized, Phase 3 Trial Comparing Maribavir With Valganciclovir
Genovefa A. Papanicolaou, Robin K. Avery, Catherine Cordonnier, Rafael F. Duarte, Shariq Haider, Johan Maertens, Karl S. Peggs, Carlos Solano, Jo‐Anne H. Young, Martha Fournier, Rose Ann Murray, Jingyang Wu, Drew J. Winston, AURORA Trial Investigators, Deepak Singhal, Joe Sasadeusz, Johan Maertans, Aspasia Georgala, Dominik Selleslag, Anke Verlinden, Tessa Kerre, Ann De Becker, Shariq Haider, Alissa Wright, Depei Wu, Radovan Vrḫovac, Catherine Cordonnier, Ana Berceanu, Sylvie François, David Michonneau, Anne Huynh, Wolfgang Bethge, Martin Kaufmann, Matthias Stelljes, Georg‐Nikolaus Franke, Timo Schmitt, Lutz Müller, Manfred Ahlgrimm, Judith Niederland, Panagiotis Tsirigotis, Ron Ram, Noga Shem‐Tov, Tsila Rosenvald-Zuckerman, Ilaria Cutini, Alessandro Busca, Francesco Onida, Cristina Tecchio, Peter Browett, Young Rok, Sung Hyun Kim, Aloysius Ho, Liang Piu Koh, Maria Lourdes Vazquez Lopez, Javier López Jiménez, Christelle Ferrà i Coll, Rafael de la Cámara, Carlos Solano, Alberto Mussetti, Juan Carlos Vallejo Llamas, Pere Barba, Manuel Jurado Chacón, Rafael F. Duarte, María Aranzazu Bermúdez Rodríguez, Nicolas J. Mueller, Hakan Özdoğu, Günhan Gürman, Adrian Bloor, Bhuvan Kishore, Kari S Peggs, Dragana Milojković, Kim Orchard, Arpad Gabor Toth, Mickey Koh, Robin K Avery, Jennifer Pisano, George Alangaden, Drew J. Winston, Genovefa Papanicolau, Benjamin E. Gewurz, Francisco M. Marty, Jo-Anne H Young, Patrick Hagen, Ran Reshef, Sameem Abedin, Paul Shaughnessy, Laura Gibson, Joan Tsiporah Shore, Carlos Bachier, Jean A. Yared, Maricar Malinis
Abstract
BACKGROUND: Neutropenia may limit the use of valganciclovir treatment for cytomegalovirus (CMV) infection following hematopoietic cell transplant (HCT). A phase 2 study indicated efficacy of maribavir with fewer treatment-limiting toxicities than valganciclovir. METHODS: In this multicenter, double-blind, phase 3 study, patients with first asymptomatic CMV infection post-HCT were stratified and randomized 1:1 to maribavir 400 mg twice daily or valganciclovir (dose-adjusted for renal clearance) for 8 weeks with 12 weeks of follow-up. The primary endpoint was confirmed CMV viremia clearance at week 8 (primary hypothesis of noninferiority margin of 7.0%). The key secondary endpoint was a composite of the primary endpoint with no findings of CMV tissue-invasive disease at week 8 through week 16. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Among patients treated (273 maribavir; 274 valganciclovir), the primary endpoint of noninferiority of maribavir was not met (maribavir, 69.6%; valganciclovir, 77.4%; adjusted difference: -7.7%; 95% confidence interval [CI]: -14.98, -.36; lower limit of 95% CI of treatment difference exceeded -7.0%). At week 16, 52.7% and 48.5% of patients treated (maribavir and valganciclovir, respectively) maintained CMV viremia clearance without tissue-invasive disease (adjusted difference: 4.4%; 95% CI: -3.91, 12.76). With maribavir (vs valganciclovir), fewer patients experienced neutropenia (16.1% and 52.9%) or discontinued due to TEAEs (27.8% and 41.2%). Discontinuations were mostly due to neutropenia (maribavir, 4.0%; valganciclovir, 17.5%). CONCLUSIONS: Although noninferiority of maribavir to valganciclovir for the primary endpoint was not achieved based on the prespecified noninferiority margin, maribavir demonstrated comparable CMV viremia clearance during post-treatment follow-up, with fewer discontinuations due to neutropenia. Clinical Trials Registration. NCT02927067 [AURORA].