Phase I/Ib Study of the Efficacy and Safety of Buparlisib and Ibrutinib Therapy in MCL, FL, and DLBCL with Serial Cell-Free DNA Monitoring

Abstract

Purpose: Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition.

Patients and methods: We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247.

Results: Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance.

Conclusions: BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma.

©2021 American Association for Cancer Research.

Figures

Figure 1.

CONSORT diagram. Of 38 consented patients, 37 were started on treatment, 36 were evaluable for adverse events, and 35 were evaluable for clinical response.

Figure 2.

Association of change in cell-free DNA variant allele frequency (VAF) with clinical outcomes. A, Heatmap of mutations observed at least twice across 24 patients with detectable ctDNA. Not assessed in tumor refers to genes that were not assessed in the baseline tumor sequencing due to differences in the gene panels used – some patients had baseline sequencing with the MSK-IMPACT assay and others with the MSK-IMPACT-Heme assay. High concordance was observed between plasma and tumor sequencing. TP53 mutations were described in baseline tumor samples in 3 MCL patients and 1 FL patient. Plasma sequencing identified an additional 2 patients with MCL and 1 DLBCL patient with TP53 mutations. B, Waterfall plot of ctDNA difference (Δ) in median VAF at cycle 3 from baseline, as plotted against patient outcomes. Decreases in median VAF in MCL correlated with initial response but could not differentiate between patients who eventually relapsed.

Figure 3.

Clinical outcomes of patients treated with ibrutinib and buparlisib. A, Swim plot of 37 patients, 35 of whom were evaluable for response. Three patients with MCL proceeded to an allogeneic stem cell transplant while in remission. B, Waterfall plot using Lugano criteria. C, Progression-free survival in each disease cohort, showing median PFS of 33 months in MCL, 1.6 months in DLBCL, and 3.7 months in FL. D, Overall survival in each disease cohort. Median OS was 6.3 months in DLBCL, and not reached in MCL and FL.

Figure 4.

Cell-free DNA and baseline sample profiles of MCL patients. Patient cfDNA samples were serially assessed using HEMEPACT. Patterns of ctDNA responses emerge corresponding to radiographic imaging. A, In a patient with early CR, the VAFs all reduced to below detectable levels. B, Detection of new mutation PLCg2 K689T with known resistance mechanism to BTK therapy in patient with partial response and subsequent progression. C, Early CR with later progression tracked by increased VAF of pre-existing mutations. An existing TP53 mutation in R248Q mutation and a newly detected more dominant TP53 S20Nfs both increased in VAF with divergent clonal representation. D, Early CR with later progression including discordant ctDNA dynamics and a potential resistance mutation. Mutations TET2 and SRSF2 known to be relevant in clonal hematopoiesis were observed without clinical association with myelodysplastic syndrome during protocol period. T, tumor; B, whole blood; N, nail; BC, buffy coat; S, saliva