The Crown study is a randomized, ongoing Phase III clinical trial that is comparing the efficacy of Pfizer’s Lorbrena/Lorviqua (lorlatinib) versus Pfizer’s Xalkori (crizotinib) in the first-line (1L) setting for ALK+ non-small cell lung cancer (NSCLC) patients. An interim analysis of CROWN presented at the virtual European Society for Medical Oncology (ESMO) 2020 annual conference on September 19–21 showed that Lorbrena/Lorviqua greatly extended progression-free-survival (PFS) compared with Xalkori.

The CROWN study randomized a total of 296 ALK+ patients. As assessed by independent review, the PFS was 9.3 months with Xalkori, but it was not estimable with Lorbrena/Lorviqua, at a hazard ratio (HR) of 0.28. At 12 months, 39% of patients with Xalkori and 78% of patients with Lorbrena/Lorviqua maintained PFS, while the median overall survival (OS) was not reached by the time of analysis for either agent. Importantly, Lorbrena/Lorviqua was found to be far more efficacious than Xalkori at reducing brain lesions due to better central nervous system (CNS) activity, and also resulted in improved quality of life as a patient-reported outcome.

Xalkori received FDA accelerated approval for ALK+ NSCLC in 2011, achieving one of the shortest timeframes from target discovery to clinical use for oncology R&D programs and rapidly becoming the 1L standard of care (SoC). Later, Novartis’ Zykadia (ceritinib) was approved for use after Xalkori. Roche’s Alecensa (alectinib) was approved in 2015 in the same setting, and in 2017 became the SoC in the 1L setting based on results from the ALEX Phase III study. Takeda’s Alunbrig received approval with the same labels in 2017 and 2020, at which time Alecensa had consolidated its position as the market leader. As such, it is unfortunate that Lorbrena/Lorviqua was not compared with 1L Alecensa, but the field has moved so quickly that the ALEX results had not yet been made public at the time the CROWN study was initiated. This leaves physicians with the uncertainty of relying on cross-trial comparisons of PFS to choose their 1L preferred option. Unlike other oncology indications, long-term OS data from the CROWN study will not give a clear answer, as patients will have been treated with other ALK inhibitors on progression, making PFS the best estimate of each agent’s benefit.

ALK mutations are infrequent, occurring in 3–5% of NSCLC patients, but the large incidence of NSCLC results in a market value of over $1B globally. In 2019, Alecensa achieved sales of $882M and Xalkori achieved sales of $531M globally, but a portion of these sales is attributed to their use for other driver mutations in NSCLC. Alunbrig and Zykadia have struggled to find a place in this market, achieving far lower sales than Xalkori.

GlobalData estimates that while the CROWN data are not enough to unequivocally set Lorbrena/Lorviqua as the new SoC, they are enough to achieve significant 1L market penetration. Furthermore, if Pfizer demonstrates Lorbrena/Lorviqua’s superiority, the company will have two anti-ALK agents in the market that can reclaim market dominance together.

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