Novel BTK Inhibitor LP-168 Under Investigation in China for R/R Mantle Cell Lymphoma

The highly selective next-generation BTK inhibitor LP-168 is currently being investigated in the phase 2 ROCK-1 trial (NCT05716087), an open-label, single-arm, multicenter investigation evaluating the safety and efficacy of the agent given as monotherapy in the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL). Information on LP-168 and the ongoing study was shared in a poster at the 2024 ASCO Annual Meeting.¹

LP-168 has high bioavailability and potency, and the agent can act as a covalent BTK inhibitor by irreversibly inhibiting BTK wild type. Importantly, the agent could also overcome the resistance of covalent BTKs inhibitor due to its non-covalent binding and reversible inhibition of BTK C481 mutations.

“Targeting BTK has demonstrated impressive efficacy in relapsed or refractory MCL. Covalent BTK inhibitors have produced extended disease remission and durable responses in relapsed/refractory MCL,” lead study author Yuqin Song, MD, PhD, chief physician and deputy director of the Lymphoma Department at Peking University Cancer Hospital, Beijing, China, and colleagues wrote in a poster presentation overviewing the trial. “Resistance and intolerance to covalent BTK inhibitors remain the main causes of BTK inhibitor treatment failure in patients with MCL.”

The covalent BTK inhibitors ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa) have all been approved and used as treatment for patients with MCL. Notably, in January 2023, the FDA granted accelerated approval to the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) for the treatment of adult patients with relapsed or refractory MCL following at least 2 lines of systemic therapy, including a BTK inhibitor.²

ROCK-1 is enrolling patients with MCL who present with a measurable lesion and have been previously treated with a covalent BTK inhibitor. Additional eligibility criteria include disease progression or intolerance to at least 1 prior covalent BTK inhibitor; adequate bone marrow, liver, kidney, and heart function; and an ECOG performance status of no more than 2.^1,3

Exclusion criteria for enrollment onto the study include previous treatment with a noncovalent BTK inhibitor or BTK proteolysis-targeting chimeras; uncontrolled systemic disease; and central nervous system involvement.

Investigators will enroll 62 patients who meet the aforementioned criteria, and all patients will receive oral LP-168 at 150 mg once per day. Each cycle lasts 28 days, and patients will continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met.

The primary end point of the study is objective response rate (ORR) per Lugano criteria, as assessed by an independent review committee. Secondary end points include safety, quality of life, pharmacokinetics, and other efficacy parameters including investigator-assessed ORR, complete response ratio, progression-free survival, overall survival, duration of response, and time to response.³

The first patient was enrolled onto the ROCK-1 clinical trial on May 12, 2023, in China, and at present, there are 41 study sites across the country actively enrolling patients.¹

References

1. Song Y, Tang X, Cai Q, et al. An open label, single arm, multicenter phase II study of the efficacy and safety of LP-168 monotherapy for relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2024;42(suppl 16):TPS7098. doi:10.1200/JCO.2024.42.16_suppl.TPS7098.
2. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. FDA. January 27, 2023. Accessed September 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-relapsed-or-refractory-mantle-cell-lymphoma
3. A study of LP-168 in participants with relapse or refractory mantle cell lymphoma. ClinicalTrials.gov. Updated August 30, 2023. Accessed September 19, 2024. https://www.clinicaltrials.gov/study/NCT05716087