Antibody-Drug Conjugate Impresses in Relapsed/Refractory DLBCL

Laurie H. Sehn, MD

The addition of a CD79b-targeted antibody-drug conjugate (ADC) to bendamustine and rituximab (Rituxan) more than doubled overall survival in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), updated results from a phase Ib/II clinical trial showed.¹

Patients who received polatuzumab-vedotin plus bendamustine and rituximab had a median overall survival (OS) of 12.4 months as compared with 4.7 months for patients who received the bendamustine-rituximab doublet. The 3-agent combination led to a higher rate of complete response (CR) and improved progression-free survival (PFS) and OS regardless of cell of origin or whether the disease was associated with dual expression of MYC and BCL2, as reported at the 2018 American Society of Hematology meeting in San Diego, California.

“With longer follow-up in these phase I/II cohorts, we’ve seen the original findings maintained,” said Laurie H. Sehn, MD, MPH, a medical oncologist with the British Columbia Cancer Agency Center for Lymphoid Cancer in Vancouver. “The complete response rates are higher, the progression-free survival is much higher, and surprisingly—in this very high-risk population of patients with no curative options—the OS is improved dramatically.”

“It’s probably too early to make any assumptions about plateaus on the [survival] curve, but there are many patients in this longer follow-up of 22 months who are still in complete remission with no finding of disease recurrence,” she added. “For this relapsed and refractory population, it’s quite a remarkable benefit.”

Patients with relapsed/refractory DLBCL and those who are ineligible for transplant have limited treatment options and a poor prognosis. CD79b is a component of the B-cell receptor and is expressed ubiquitously in DLBCL. Polatuzumab vedotin is an anti-CD79b antibody linked to microtubule-disrupting monomethyl auristatin E.

Preliminary results from a phase Ib trial provided evidence of the ADC’s safety and efficacy safety run-in, expansion, and randomized cohorts, as reported previously.2,3 Sehn presented updated results for all 3 patient cohorts.

The data included 6 patients from the safety cohort, 27 from the expansion phase, and 80 from the randomized comparison of bendamustine-rituximab with or without polatuzumab vedotin. Median age across the cohorts ranged from 65 to 71, and from two-thirds to three-fourths of the patients in each cohort had received 2 or more prior lines of therapy. Additionally, 20% of the patients in the randomized study had undergone a transplant.

The primary endpoint was CR as determined by independent review of positron-emission tomography—computed tomography imaging at the end of treatment. Secondary endpoints included duration of response (DOR) and PFS by independent review. Exploratory endpoints included DOR and PFS by investigator review, OS, and efficacy by cell of origin (COO) and MYC/BCL2 double-expression (DE) status.

Median follow-up was 37.6 months for the safety cohort, 27.0 months for the expansion cohort, and 22.3 months for the randomized comparison.

Three of 6 patients in the safety cohort attained CR with the polatuzumab vedotin-bendamustine-rituximab regimen. DOR, PFS, and OS could not be determined.

In the expansion cohort, 11 patients (41%) had objective responses by independent review. Median DOR, median PFS, and OS were 28.4 months, 5.4 months, and 10.8 months, respectively.

In the randomized, phase II component of the evaluation, 16 (40%) patients had CRs in the polatuzumab-vedotin arm as compared with 7 (18%) patients who received bendamustine-rituximab without the ADC (P = .026). Median DOR by independent review had yet to be reached in the polatuzumab-vedotin arm as compared with 7.7 months in the control arm (P = .0462). By investigator assessment, median DOR was 10.3 months with polatuzumab-vedotin versus 4.1 months without (P =.0321).

Median PFS by independent review was 11.1 months with the ADC and 3.7 months without (P = .0002). By investigator assessment, the median values were 7.6 versus 2.0 months without (P <.0001). Median OS was 12.4 versus 4.7 months in favor of the polatuzumab-vedotin arm (P = .0023).

Analyses by cell of origin—activated B-cell like (ABC) or germinal B-cell like (GCB)&mdash;showed consistent advantages for the addition of polatuzumab vedotin. Median PFS by investigator assessment and OS in the ABC subgroup were 10.8 months and 15.4 months, respectively, versus 2.0 and 4.7 months without polatuzumab vedotin. The GBC subgroup had inferior outcomes but still favored the ADC: 2.5 versus 1.9 months for median PFS and 7.2 versus 3.8 months for OS.

Analysis by DE status showed median PFS of 7.0 versus 1.4 months for the polatuzumab-vedotin group among patients with DE and 6.2 versus 3.1 months for those without. OS was 8.9 versus 4.6 months for the DE subgroup and 10.0 versus 4.5 months for patients without DE.

With continued follow-up, no new safety signals emerged, and the safety data remained consistent with the previous reports, Sehn said.

Given the high CR rate and long response duration, the combination of polatuzumab-vedotin, bendamustine, and rituximab might be considered for stand-alone treatment or potentially as a bridge to consolidative treatment, she and her colleagues concluded.

References

1. Sehn LH, Herrera AF, Matasar M, et al. Polatuzumab vedotin (pola) plus bendamustine (B) with rituximab (R) or obinutuzumab (G) in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): updated results of a phase (Ph) Ib/II study. Poster presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. P1683.
2. Sehn LH, Kamdar M, Herrera AF, et al. Randomized phase 2 trial of polatuzumab vedotin (pola) with bendamustine and rituximab (BR) in relapsed/refractory (r/r) FL and DLBCL. Presented at: 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 7507.
3. Matasar M, Herrera AF, Kamdar M, et al. Polatuzumab vedotin plus bendamustine and rituximab or obinutuzumab in relapsed/refractory follicular lymphoma or diffuse large B-cell lymphoma: updated results of a phase IB/2 study. Presented at: 2017 Congress of European Hematology Association; June 22-25, 2017. Abstract S468.

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