Ibrutinib Induces Impressive Response in DLBCL Subtype

Wyndham Wilson, MD, PhD

Ibrutinib (Imbruvica) had an overall response rate (ORR) of 37% in patients with activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), according to results from a phase II NCI-sponsored study. In contrast, patients with the germinal center B-cell-like (GCB) subtype had an ORR of only 5% with the BTK inhibitor.

BTK is a core component of B-cell receptor (BCR) signaling. According to the authors, the study results suggest that ABC—but not GCB—DLBCL may produce abnormal, BTK-activating BCR signals, which would explain ibrutinib’s enhanced efficacy in the subtype.

“This is the first clinical study to demonstrate the importance of precision medicine in lymphomas,” study co-leader Wyndham Wilson, MD, PhD, NCI Center for Cancer Research, said in statement.

“Clinical trials such as this are critical for translating basic molecular findings into effective therapies,” added study co-leader Louis Staudt, MD, PhD, NCI Center for Cancer Genomics, who discovered the role of B-cell receptor signaling in ABC DLBCL.

The open-label, nonrandomized phase II study included 80 patients with relapsed/refractory DLBCL. Gene expression profiling identified 38 tumors as ABC, 20 as GCB, 17 as unclassified, and 5 as unknown.

In the ABC cohort, the median age was 60 years (range, 34-89), 66% were male, 5% had an ECOG performance status ≥2, the medium number of prior treatment regimens was 3 (range, 1-7), and 13% had prior autologous stem cell transplant (ASCT).

In the GCB group, the median age was 65 years (range, 28-92), 70% were male, 20% had an ECOG performance status ≥2, the medium number of prior treatment regimens was 3.5 (range, 1-7), and 30% had prior ASCT. Two-thirds of patients in the ABC and GCB cohorts were refractory to their most recent chemotherapy regimen.

All patients in the study initially received 560 mg of oral ibrutinib daily in 4-week cycles until disease progression or unacceptable toxicity. The trial design allowed for dose adjustments based on certain treatment-related toxicities.

Overall, responses were observed in 25% (20/80) of patients, including 12 partial responses (PR) and 8 complete responses (CR). At a median follow-up of 11.53 months, overall survival (OS) and progression-free survival (PFS) were 6.41 and 1.64 months, respectively.

Fourteen patients (37%) with ABC DLBCL had a response compared with 1 patient (5%) in the GCB cohort (P = .0106). The median response duration was 4.83 months (range, 1.02-9.26) in the ABC arm.

ORR in the ABC group included a CR rate of 16% (n = 6). Three patients experiencing a CR in the ABC arm had ongoing responses to ibruti¬nib at 36.3, 32.7, and 52.5 months, respectively. Additionally, ORR was 22%, including one CR, among 22 ABC DLBCL patients identified as “primary refractory.”

At a median follow-up of 10.12 and 17.05 months, respectively, PFS was 2.02 months in the ABC arm compared with 1.31 months in the GCB group (P = .004). Median OS was 10.32 versus 3.35 months, respectively (P = .056).

Mutational analysis showed ibrutinib responses in 55.5% (5/9) of ABC tumors with BCR mutations, with an 80% (4/5) response rate in those patients also harboring MYD88 mutations. The authors noted, however, that the highest response in the ABC cohort occurred in BCR-negative patients (31%; 9/29). They suggested this indicates that oncogenic signaling in ABC tumors may be triggered by nongenetic mechanisms, and does not require BCR mutations.

Ibrutinib was well tolerated across patient subgroups in the study, according to the authors, with similar toxicity profiles as those observed in previous studies.

Based on the phase II outcomes, an ongoing phase III trial is examining ibrutinib combined with R-CHOP versus placebo plus R-CHOP in patients with newly diagnosed, non-GCB DLBCL (NCT01855750). Ibrutinib is being administered at the same 560-mg dose as in the phase II study. The primary outcome measure is event-free survival, with secondary endpoints including OS, PFS, and CR.

Ibrutinib currently has FDA-approved indications for chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström macroglobulinemia.

Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma [published online July 20, 2015]. Nat Med. doi: 10.1038/nm.3884.