LUGANO, SWITZERLAND – A combination of the Bruton’s tyrosine kinase (BTK) ibrutinib (Imbruvica) and the pan-phosphoinositide 3-kinase (PI3K) inhibitor buparlisib showed clinical activity superior to that of single-agent ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL).
In a phase I/IB dose escalation study and expansion cohort testing the combination in patients with diffuse large B cell lymphoma (DLBCL), follicular lymphoma, and MCL, the overall response rate (ORR) among patients with MCL was 100%, consisting of complete responses (CR) in 8 of 11 patients, and partial responses (PR) in 3 patients, reported Connie Lee Batlevi, MD, of Memorial Sloan Kettering Cancer Center in New York.
In contrast, the response rate to ibrutinib monotherapy among patients with relapsed MCL is around 20%, she said.
Preclinical studies have demonstrated synergism between BTK inhibitors and PI3K inhibitors in B-cell non-Hodgkin lymphoma (NHL), prompting the investigators to look into the combination in patients with relapsed or refractory DLBCL, follicular lymphoma (FL), and MCL.
They enrolled 25 patients (9 with DLBCL, 5 with FL, and 11 with MCL). The patients received escalating doses of once daily ibrutinib and buparlisib in three dose levels (ibrutinib 420-560 mg; buparlisib 80-100 mg). Dose level 3, consisting of ibrutinib 560 mg and buparlisib 100 mg, was selected for dose expansion based on one of six patients developing a dose-limiting toxicity.
Using the Lugano Response Criteria, the overall ORR (all histologies) was 52%. Among nine patients with DLBCL, the ORR was 11%, with one CR and no PR. Among five patients with FL, the ORR was 20%, consisting of one CR and no PR.
Among 11 patients with MCL, however, the ORR was far more impressive, at 100%, including eight CR and three PR. No patients with MCL had either stable or progressive disease.
Under the RECIL (International Working Group) criteria, the ORR was 48% including one CR each for DLBCL and FL, and eight CR and two PR for patients with MCL.
In the safety analysis, there were two dose-limiting toxicities in the lowest and highest dose groups, but none at dose level 2 (ibrutinib 560 mg and buparlisib 80 mg).
Grade 3 or greater adverse events occurred in 63% of patients. The most common events were hyperglycemia and rash in 19% each, and diarrhea, anorexia, and neurologic changes in 11% each,
The grade 3 neurologic changes included depression, agitation, mood swings, confusion and memory impairment, all of which resolved after buparlisib was withdrawn.
Dr. Batlevi showed scans of two patients with representative clinical responses in MCL. One 55-year-old man with blastoid MCL who had relapsed 18 months after frontline therapy with ofatumumab and bendamustine had near total clearance of lesions after two cycles of ibrutinib and buparlisib. He remains in CR after 12 months on the combination.
A second patient, a 77-year-old man with MCL that relapsed 10 years after R-CHOP and rituximab maintenance followed by autologous stem cell transplant, showed a complete response upon restaging after two cycles of ibrutinib/buparlisib.
The investigators are currently enrolling patients for phase IB expansions, with the goal of better estimating the safety and efficacy of the combination.
Memorial Sloan Kettering Cancer Center sponsored the study, with support from Janssen and Novartis. Dr. Batlevi reported no conflicts of interest.