Brigatinib

Japan-based Chugai Pharmaceutical Co., Ltd. (TSE: 4519) has registered a first-in-human Phase I clinical trial of AQUA07, an oral investigational drug whose mechanism has not been publicly disclosed, in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) who have progressed on at least one prior ALK inhibitor. The AQUA07 clinical trial is notable for its parallel-arm structure: one arm evaluates AQUA07 as monotherapy, while a second tests it in combination with lorlatinib, Pfizer’s third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI). The design suggests Chugai may be positioning AQUA07 to address resistance mechanisms that emerge after exposure to later-generation ALK inhibitors — a setting where durable options remain limited. The Phase I, open-label, multicenter study (NCT07617337) is expected to enroll approximately 102 adults with locally advanced unresectable or metastatic ALK-positive NSCLC, according to the trial record. Patients must have received at least one prior ALK TKI, though those treated exclusively with crizotinib — the first-generation agent — are excluded, effectively enriching the population for individuals who have progressed on second- or third-generation inhibitors such as alectinib, brigatinib, or lorlatinib itself. The study is structured in two parallel dose-escalation parts: Part A evaluates AQUA07 monotherapy, and Part B evaluates AQUA07 in combination with lorlatinib, with each arm seeking to establish the recommended Phase II dose and maximum tolerated dose. Recruitment is anticipated to begin in Q3 2026, with primary completion targeted for August 2030. Secondary endpoints include pharmacokinetic profiling of both AQUA07 and lorlatinib, as well as preliminary efficacy measures — objective response rate, progression-free survival, and duration of response — assessed per RECIST v1.1. The biological rationale for AQUA07 cannot be fully characterized from available public sources; Chugai has not disclosed the compound’s molecular target or mechanism of action ahead of trial initiation, which is consistent with the company’s practice for early-stage internal programs. The oral route of administration and classification as a small-molecule drug are confirmed by the trial record, suggesting a kinase inhibitor-type modality, though this remains an inference. The decision to pair AQUA07 with lorlatinib in a dedicated dose-escalation arm — rather than simply evaluating monotherapy activity — implies the compound may act on a pathway distinct from or complementary to direct ALK kinase inhibition, potentially addressing bypass signaling or resistance mutations that limit the durability of ALK TKI monotherapy. Chugai has prior expertise in ALK-positive NSCLC through its development of alectinib (Alecensa), a second-generation ALK inhibitor now widely used as a first-line standard of care. In the post-lorlatinib resistance setting, the competitive field is sparse but active. The most advanced program is Nuvalent‘s neladalkib (NVL-655), a brain-penetrant next-generation ALK inhibitor designed to overcome a broad range of resistance mutations, including compound mutations that can emerge following sequential ALK TKI treatment. The agent is currently under US FDA review following positive pivotal data from the ALKOVE program. Chugai’s decision to evaluate AQUA07 both as monotherapy and in combination with lorlatinib suggests a potentially differentiated strategy, although the absence of a disclosed molecular target makes direct comparisons premature. Trial identifier: NCT07617337. Sponsor: Chugai Pharmaceutical Co., Ltd. Status: Not yet recruiting. This article was generated with AI assistance and reviewed and edited by the AllSci editorial team Explore more at AllSci News: https://allsci.com/news/ Your email address will not be published. Required fields are marked * Comment * Name * Email * Website Privacy Terms About Us Copyright © 2026. AllSci Corp. All rights reserved.

Pfizer (NYSE: PFE) reported seven-year follow-up data from the Phase III CROWN trial showing that 55% of previously untreated ALK-positive non-small cell lung cancer patients receiving lorlatinib (Lorbrena) remained alive without disease progression — a landmark in a disease where durable control at this timepoint has not previously been documented. The CROWN trial is a randomized, open-label, Phase III study that enrolled 296 patients with previously untreated ALK-positive advanced or metastatic NSCLC, randomized 1:1 to lorlatinib (n\=149) or Pfizer’s Xalkori (crizotinib) (n\=147). The seven-year analysis, an unplanned post-hoc assessment prompted by the fact that median progression-free survival remained unreached at both the three- and five-year marks, was based on investigator tumor assessment and presented at the 2026 ASCO Annual Meeting (Abstract #8502), with simultaneous publication in Annals of Oncology. At seven years, the probability of remaining alive without progression was 55% (95% CI: 46–63) with lorlatinib versus 3% (95% CI: 1–8) with crizotinib. Investigator-assessed median PFS was not reached in the lorlatinib arm, with a hazard ratio of 0.19 (95% CI: 0.13–0.26), representing an 81% reduction in the risk of progression or death. The intracranial data were similarly striking: lorlatinib reduced the risk of intracranial progression by 94% (HR 0.06; 95% CI: 0.03–0.12), with no new intracranial progression events observed after the first 30 months. At the time of analysis, 44% of patients in the lorlatinib arm remained on treatment, compared with 3% in the crizotinib arm. The safety profile was consistent with prior analyses. Grade 3/4 adverse events occurred in 77% of lorlatinib patients versus 57% with crizotinib, though treatment-related discontinuations were low and comparable — 5% versus 6%, respectively — with no new permanent discontinuations due to treatment-related adverse events after the first 26 months on lorlatinib. Lorlatinib is a third-generation ALK/ROS1 tyrosine kinase inhibitor engineered specifically to overcome resistance mutations that limit earlier-generation agents and to penetrate the blood-brain barrier — properties that appear central to the durability seen in CROWN. The first-line ALK-positive NSCLC space now includes several approved oral agents: Roche’s Alecensa (alectinib), Takeda’s Alunbrig (brigatinib), Novartis’s Zykadia (ceritinib), and, most recently, Xcovery’s Ensacove (ensartinib), approved in December 2024. Cross-trial comparisons are limited by differences in patient populations, follow-up duration, and analytical methods, but no other agent in this class has reported a median PFS that remains unreached at seven years. Overall survival data from CROWN remain immature, and those results will be the next material readout for the program. Your email address will not be published. Required fields are marked * Comment * Name * Email * Website Privacy Terms About Us Copyright © 2026. AllSci Corp. All rights reserved.