Investigators Working to Improve Cure Rate in DLBCL

Thomas E. Witzig, MD

Despite decades of drug development and a deepening understanding of the biology of diffuse large B-cell lymphoma (DLBCL), physicians haven’t seen much improvement in cure rates, Thomas E. Witzig, MD, said during a presentation at the 2018 SOHO Annual Meeting.

The history of DLBCL care is littered with promising treatments that did not pan out, and after years of research, the standard of care remains 6 cycles of R-CHOP-21.

“We are still stuck . . . on this idea that we’re only curing 60% to 80% of patients,” said Witzig, a hematologist-oncologist with Mayo Clinic in Rochester, Minnesota. “Studies [from the early 2000s] showed that R-CHOP was better than CHOP and we’ve been trying for the past 15 years to move on from that.”

The standard could change, however, pending the results of studies combining R-CHOP with ibrutinib (Imbruvica) or lenalidomide (Revlimid). In the meantime, Witzig said data from recent trials show just how challenging getting past that 80% threshold has been.

Findings from the phase III GOYA trial (NCT01287741) showed that the addition of obinutuzumab (Gazyva) to CHOP (G-CHOP) did not significantly improve progression-free survival (PFS) compared with R-CHOP in patients with treatment-naïve DLBCL. Patients were assigned to eight 21-day cycles of obinutuzumab (n = 706) or rituximab (Rituxan; n = 712) followed by 6 or 8 cycles of CHOP.

At a median follow-up of 29 months, the estimated 3-year PFS was 69.6% for G-CHOP versus 66.9% for R-CHOP (HR, 0.92; 95% CI, 0.76-1.11;P= .3868).¹

Findings from the REMARC trial published last year showed that maintenance therapy with lenalidomide may not provide much benefit for patients with DLBCL. Following 6 to 8 cycles of R-CHOP, patients aged 60 to 80 years with treatment-naïve DLBCL or another aggressive B-cell lymphoma were randomly assigned to 25 mg daily lenalidomide maintenance (n = 323) or placebo (n = 327) for 21 days of every 28-day cycle for 24 months.²

At a median follow-up of 39 months, the median PFS was not reached for the experimental group compared with 58.9 months for placebo (HR, 0.708; 95% CI, 0.537-0.933;P= .013). The result was consistent among subgroups including sex, age-adjusted International Prognostic Index (IPI) score, age younger than 70 versus ≥70 years, response after induction, and PET status at assignment.

However, the median overall survival (OS) was similar between the 2 arms (87% vs 89%; HR, 1.218; 95% CI, 0.861-1.721;P= .26) at a median follow-up of 52 months.

“That was the first study that showed a PFS advantage,” Witzig said. “But for reasons that weren’t clear, this did not translate into an overall survival advantage. This is somewhat of a positive study, but it may not be practice changing because it did not translate into an overall survival benefit.”

The mTOR inhibitor everolimus (Afinitor) demonstrated single-agent efficacy and a small OS benefit in the phase III PILLAR-2 trial (NCT00790036). The trial included 742 patients with an IPI score ≥3 who were at increased risk for relapse following a complete response (CR) while on R-CHOP. Patients were randomly assigned to adjuvant everolimus (n = 372) or placebo (n = 370).³

Everolimus did not significantly improve disease-free survival (DFS). The 2-year disease-free survival (DFS) rate was 77.8% (95% CI, 72.7%-82.1%) with everolimus versus 77.0% (95% CI, 72.1%-81.1%) with placebo. Everolimus was associated with a slight OS benefit at 2 years (90.7% vs 88.3%; HR, 0.75; 95% CI, 0.51-1.01), but the trial did not meet the statistical criteria showing significant improvement.

Investigators are awaiting results of large trials looking at activated B cell-like (ABC) and non-germinal center B-cell (GBC) DLBCL. Data have not yet been released from the phase III PHOENIX trial (NCT01855750) comparing ibrutinib/R-CHOP versus R-CHOP, but a press release from Janssen Pharmaceuticals released in July said the trial did not meet its primary endpoint for DFS for newly diagnosed GBC DLBCL.

Lenalidomide/R-CHOP (R²CHOP) induced an overall response rate (ORR) of 98%, with a CR rate of 80%, among 60 patients with DLBCL in phase II findings from Nowakowski et al. At 24 months, the EFS rate was 59% (95% CI, 48%-74%) and the OS rate was 78% (95% CI, 68%-90%). The 24-month PFS for patients with non-GCB disease treated with R-CHOP was 28% compared with 64% for GCB patients (P<.001) and the 24-month OS was 46% versus 78% (P<.001), respectively. There was no difference in 24-month PFS or OS in patients treated with R²CHOP.⁴

Although there was some controversy surrounding the use of immunohistochemistry to identify subtypes and the potential effect of possible errors in subtyping may have had on results, the trial proceeded to phase III based on these findings.

Witzig said physicians are also awaiting results from ECOG 1412 (NCT01856192) and ROBUST (NCT02285062).

&ldquo;Those are going to be key studies released probably this year or next year that will tell us whether any of these strategies, ibrutinib or lenalidomide will make a difference,&rdquo; Witzig said.

ECOG 1412 is a randomized phase II trial comparing R²CHOP with R-CHOP in patients with newly diagnosed ABC or GBC DLBCL. The primary endpoint is PFS and secondary endpoints include response rate, CR rate, and OS.

ROBUST is a randomized, double-blind, global, phase III trial comparing R²CHOP with R-CHOP-21 in patients with previously untreated ABC-type DLBCL. The primary endpoint is PFS and secondary endpoints include OS, response rate, and health-related quality of life.

Findings from the Nowakowski paper and the phase II REAL07 trial led to ROBUST. REAL07 showed that R²CHOP induced an ORR of 92% (95% CI, 81%-97%) and a CR of 86% among 49 elderly patients with untreated stage II-IV DLBCL or grade 3b follicular lymphoma.⁵

References:

1. Vitolo U, Trněn&yacute; M, Belada D, et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-Cell lymphoma.J Clin Oncol.2017;35(31):3529-3537. doi: 10.1200/JCO.2017.73.3402.
2. Thieblemont C, Tilly H, Gomes de Silva M, et al. Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.J Clin Oncol. 2017;35(22):2473-2481. doi: 10.1200/JCO.2017.76984.
3. Witzig TE, Tobinai K, Rigacci L, et al. Adjuvant everolimus in high-risk diffuse large B-cell lymphoma: final results from the PILLAR-2 randomized phase III trial.Ann Oncol. 2018;29(3):707-714. doi: 10.1093/annonc/mdx764.
4. Nowakowski GS, LaPlant B, Macon WR, et al. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma: a phase II study.J Clin Oncol.2015;33(3):251-257.
5. Vitolo U, Chiappella A, Franceschetti S, et al. Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial.Lancet Oncol. 2014;15(7):730-7. doi: 10.1016/S1470-2045(14)70191-3.