China-based Lupeng Pharmaceutical Ltd has enrolled the first patient in the ROCKET-CLL trial, a global Phase III study pitting rocbrutinib (LP-168) directly against Eli Lilly's Jaypirca (pirtobrutinib) in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma who have progressed after covalent BTK inhibitor therapy. The enrollment milestone, reached on May 20, 2026, at OptumCare Cancer Care Center in Las Vegas, Nevada, marks the first head-to-head test of a dual covalent and non-covalent BTK inhibitor against the current standard of care in this post-cBTKi setting.
The ROCKET-CLL trial (NCT07342478) is a randomized, open-label, multicenter Phase III study expected to enroll approximately 306 adult patients across sites in the US, EU, China, and Australia. Participants are randomized 1:1 to receive once-daily oral rocbrutinib at 200 mg or pirtobrutinib at 200 mg. The primary endpoint is progression-free survival, with overall survival designated as the key secondary endpoint. Additional secondary endpoints include overall response rate, duration of response, time to next treatment, and event-free survival. An interim analysis is planned for 2029, with full enrollment targeted for early Q4 2027.
The trial is co-led by Dr. Jennifer Woyach at Ohio State University and Dr. John Byrd at the University of Pittsburgh Medical Center, two of the more prominent investigators in the CLL field. The first site was activated on April 28, 2026, with first patient enrollment following within weeks.
The mechanism behind the LP-168 BTK inhibitor
Rocbrutinib is described by Lupeng as a fourth-generation BTK inhibitor built on the company's proprietary BeyondX platform. Its central design feature is a dual binding mechanism: the molecule can engage BTK both covalently, forming an irreversible bond, and non-covalently, maintaining reversible inhibition. The clinical rationale is that covalent BTK inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib lose activity when patients develop mutations at the C481 position of BTK, the site where those drugs bind irreversibly. Pirtobrutinib addressed that resistance gap by binding non-covalently, but resistance to pirtobrutinib itself is now being documented, driven by additional kinase domain mutations and PLCγ2 alterations.
Rocbrutinib is designed to inhibit both wild-type BTK and a broader set of resistance mutations, including C481X, T474X, and L528W substitutions. The hypothesis is that dual-mode binding reduces the likelihood that any single resistance mutation can fully abrogate drug activity — a mechanistic profile that no currently approved BTK inhibitor shares.
Phase I data informing the rocbrutinib Phase III trial design
The Phase III design draws on early evidence from a US Phase I study, data from which were presented at ASH 2025. Among CLL patients previously treated with covalent and/or non-covalent BTK inhibitors, those receiving rocbrutinib at dose levels of 200 mg per day or higher achieved an overall response rate of 78.3%. The estimated median progression-free survival for patients at doses of at least 100 mg per day was 28.1 months.