A randomized, open-label, multicenter, phase 2 trial evaluating the safety and activity of pinatuzumab vedotin (DCDT2980S) in combination with rituximab or polatuzumab vedotin (DCDS4501A) in combination with rituximab and a non-randomized phase 1b/2 evaluation of polatuzumab vedotin in combination with obinutuzumab in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.

Patients aged 18 years were eligible if they had histologically confirmed R/R DLBCL (excluding transformed follicular lymphoma), received 1 prior line of therapy, had an Eastern Cooperative Oncology Group performance status of 0 to 2, and were considered transplant ineligible by the treating physician or experienced treatment failure with prior autologous SCT.

The median IRC-assessed PFS (95% CI) was 9.20 months (6.00-13.90) with pola + BR vs 3.70 months (2.10-4.50) with BR (HR, 0.39; 95% CI, 0.23-0.66); median investigator-assessed PFS was 7.50 vs 2.00 months (HR, 0.33; 95% CI, 0.20-0.56) with pola + BR and BR, respectively. Median OS (95% CI) was 12.40 months (9.00-32.00) vs 4.70 months (3.70-8.30) with pola + BR vs BR (HR, 0.42; 95% CI, 0.24-0.72). The 24-month OS probability was 38% (95% CI, 22.50-53.90) with pola + BR vs 17.0% (3.60-30.40) with BR. The 24-month PFS probability was 28.40% (95% CI, 13.9-43.0) with pola + BR vs 9.10% (95% CI, 0.00-18.90) with BR.The median DOR was 9.50 months (95% CI, 7.90-12.10) by IRC assessment and 8.70 months (95% CI, 5.90-12.10) by investigator assessment. The median IRC-assessed PFS was 6.6 months (95% CI, 5.10-9.20). Median OS was 12.50 months (95% CI, 8.20-23.10); the 12-month OS probability was 50.20% (95% CI, 40.40-60.10).

Six 28-day cycles of induction treatment with intravenous obinutuzumab 1000 mg (all cohorts), and intravenous polatuzumab vedotin and oral lenalidomide (Celgene, Summit, NJ, USA) in the following doses: 14 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 1); 18 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 2); 14 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 3); 18 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 4); 14 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 5); and 18 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 6). Polatuzumab vedotin was administered on day 1, lenalidomide on days 1-21, and obinutuzumab on days 1, 8, and 15 of cycle one and day 1 of cycles two to six of each 28-day cycle.

According to the Independent Review Committeeassessment, 29 (63.04%) of 46 patients (90% CI 50.00-75.00) had acomplete response and 35 (76.09%) patients (90% CI 64.00-86.00) had an objective response, per Modified Lugano 2014 criteria. Independent Review Committee assessment showed that 33 (71.74%) patients (90% CI59.00-82.00) had a complete metabolic response at the end ofinduction per Modified Lugano 2014 criteria.

At data cut-off (median follow-up 26.70 months [IQR 22.20-31.30]),median progression-free survival had not been reached. As determined by the investigator, theprogression-free survival was 86.00% (95% CI 75.00-96.00) at 12 months and 67.00% (95% CI 51.00-83.00) at 24 months, and 11 (23.91%) of 46 patients had an event reported at the time of this analysis.

FL patients received up to six 21-day cycles of obinutuzumab (1000 mg intravenously [IV], Day [D]1, D8, D15 of Cycle [C]1, and D1 of C26) and atezolizumab (1200 mg IV, D1 of C26) plus pola (1.40 or 1.80 mg/kg IV, D1 of C16). Subsequently, patients entered an expansion phase and received obinutuzumab and atezolizumab (same doses) plus pola at the RP2D (1.8 mg/kg). Patients who achieved at least stable disease at the end of induction (EOI; 68 weeks after D1C6) proceeded to obinutuzumab maintenance (1000 mg every 2 months) and atezolizumab (840 mg, D1 and D2 every month) for up to 2 years, or until progressive disease (PD). Unlike the FL cohort, the first seven DLBCL patients entered a safety run-in; once safety criteria were met, the cohort was expanded. All DLBCL patients received up to six 21-day cycles of rituximab (375 mg/m² IV, D1 of C16), atezolizumab (1200 mg, D1 of C26), and pola (1.80 mg/kg, D1 of C16). Patients with at least a partial response (PR) at EOI (68 weeks after D1 of C6) received rituximab consolidation (375 mg/m², D1 every 2 months) and atezolizumab (840 mg, D1 and D2 every month) for up to 8 months, or until PD.

Pola 1.80 mg/kg intravenously (IV) on day 2 of cycle 1 and day 1 of subsequent cycles; bendamustine 90 mg/m²IV on days 2 and 3 of cycle 1 and then days 1 and 2 of subsequent cycles; rituximab 375 mg/m²IV on day 1 of each cycle. Three weeks of treatment was regarded as one cycle, and patients received up to six cycles of treatment.

Seven of 12 patients who achieved CR completed six cycles of treatment. Fifteen patients (42.86%, 95% CI 26.30-60.70) achieved an overall response (12 patients CR; 3 patients PR). At a median followup of 5.40 months, median DOR, PFS, and EFS were 6.60 months, 5.20 months, and 5.10 months, respectively. Twentythree patients (65.71%) were alive, and median OS was not reached (95% CI 8.40-not evaluable [NE]).

The overall response rate (ORR) for patients with FL was 75.80%, with 57.60% of patients achieving a complete response (CR). All patients in FL cohort 6 treated at the identified RP2D dose combination achieved CR at EOI. The ORR observed for patients with DLBCL was 29.40%; 23.50% achieved CR. Similar trends were seen in the DLBCL cohorts, with higher response rates in patients treated at the RP2D (37.5% vs. 22.2%).

Patients aged 18 years were eligible if they had biopsy-confirmed R/R DLBCL (excluding transformed lymphoma) after 1 prior line of therapy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, grade 1 peripheral neuropathy (PN), and were considered transplantation ineligible by the treating physician or experienced treatment failure with prior ASCT. Double- and triple-hit lymphomas were not excluded.

CD20-positive diffuse large B-cell lymphoma (DLBCL), had not received previous treatment for lymphoma, had an Eastern Cooperative Oncology Group performance status score of 0 to 2 (on a 5-point scale, with higher numbers indicating greater disability), had a baseline International Prognostic Index (IPI) score between 2 and 5 (on a 5-level prognostic scale, with higher numbers indicating a poorer prognosis), and had adequate hematologic, renal, hepatic, and cardiac function, regardless of the cell of origin or the presence of rearrangements in MYC, BCL2, BCL6, or a combination of these.

Eight 21-day cycles of treatment were planned. During the first six cycles, patients received either pola-R-CHP or R-CHOP. On day 1 of each cycle, patients received either intravenous polatuzumab vedotin at a dose of 1.80 mg per kilogram of body weight and a placebo matching intravenous vincristine (pola-R-CHP group) or a placebo matching polatuzumab vedotin and intravenous vincristine at a dose of 1.40 mg per square meter of body-surface area (maximum of 2 mg) (R-CHOP group), plus intravenous doses of rituximab (375 mg per square meter), cyclophosphamide (750 mg per square meter), and doxorubicin (50 mg per square meter). All the patients also received oral prednisone at a dose of 100 mg once daily on days 1 through 5 of each of the first six cycles. During cycles 7 and 8, patients in both groups received rituximab monotherapy at a dose of 375 mg per square meter.

Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Among 45 patients with NHL treated at the recommended phase 2 dose of single-agent polatuzumab vedotin, median progressionfree survival was 5.70 months (95% CI 3.00-7.90) and median duration of response was 6.2 months (95% CI 3.3-14.1). In patients with diffuse large B-cell lymphoma treated at the recommended phase 2 dose of single-agent polatuzumab, median progression-free survival was 5.00 months (95% CI 2.30-6.80) and median duration of response was 5.20 months (95% CI 2.40-13.10).

Cells were inoculated subcutaneously into the flanks of female CB17 ICR severe combined immunodeficient (SCID) mice. When mean tumor size reached desired volume,the mice were divided into groups of 7 to 9 mice with the same mean tumor size and dosed intravenously via the tail vein with ADCs or antibodies. Rituximab was dosed at 30 mg/kg intraperitoneally (i.p.). Polatuzumab vedotin was administered as a single injection at 1 mg/kg.

Cells were inoculated subcutaneously into the flanks of female CB17 ICR severe combined immunodeficient (SCID) mice. When mean tumor size reached desired volume,the mice were divided into groups of 7 to 9 mice with the same mean tumor size and dosed intravenously via the tail vein with ADCs or antibodies. Rituximab was dosed at 30 mg/kg intraperitoneally (i.p.). Polatuzumab vedotin was administered as a single injection at 2 mg/kg.

Cells were inoculated subcutaneously into the flanks of female CB17 ICR severe combined immunodeficient (SCID) mice. When mean tumor size reached desired volume,the mice were divided into groups of 7 to 9 mice with the same mean tumor size and dosed intravenously via the tail vein with ADCs or antibodies. Rituximab was dosed at 30 mg/kg intraperitoneally (i.p.). Polatuzumab vedotin was administered as a single injection at 0.1 mg/kg.

Cells were inoculated subcutaneously into the flanks of female CB17 ICR severe combined immunodeficient (SCID) mice. When mean tumor size reached desired volume,the mice were divided into groups of 7 to 9 mice with the same mean tumor size and dosed intravenously via the tail vein with ADCs or antibodies. Rituximab was dosed at 30 mg/kg intraperitoneally (i.p.). Polatuzumab vedotin was administered as a single injection at 4 mg/kg.

Cells were inoculated subcutaneously into the flanks of female CB17 ICR severe combined immunodeficient (SCID) mice. When mean tumor size reached desired volume,the mice were divided into groups of 7 to 9 mice with the same mean tumor size and dosed intravenously via the tail vein with ADCs or antibodies. Rituximab was dosed at 30 mg/kg intraperitoneally (i.p.). Polatuzumab vedotin was administered as a single injection at 0.5 mg/kg.

Cells were inoculated subcutaneously into the flanks of female CB17 ICR severe combined immunodeficient (SCID) mice. When mean tumor size reached desired volume,the mice were divided into groups of 7 to 9 mice with the same mean tumor size and dosed intravenously via the tail vein with ADCs or antibodies. Rituximab was dosed at 30 mg/kg intraperitoneally (i.p.). Polatuzumab vedotin was administered as a single injection at 8 mg/kg.

Cells were inoculated subcutaneously into the flanks of female CB17 ICR severe combined immunodeficient (SCID) mice. When mean tumor size reached desired volume,the mice were divided into groups of 7 to 9 mice with the same mean tumor size and dosed intravenously via the tail vein with ADCs or antibodies. Rituximab was dosed at 30 mg/kg intraperitoneally (i.p.). Polatuzumab vedotin was administered as a single injection at 1 mg/kg.

Cells were inoculated subcutaneously into the flanks of female CB17 ICR severe combined immunodeficient (SCID) mice. When mean tumor size reached desired volume,the mice were divided into groups of 7 to 9 mice with the same mean tumor size and dosed intravenously via the tail vein with ADCs or antibodies. Rituximab was dosed at 30 mg/kg intraperitoneally (i.p.). Polatuzumab vedotin was administered as a single injection at 12 mg/kg.

Cells were inoculated subcutaneously into the flanks of female CB17 ICR severe combined immunodeficient (SCID) mice. When mean tumor size reached desired volume,the mice were divided into groups of 7 to 9 mice with the same mean tumor size and dosed intravenously via the tail vein with ADCs or antibodies. Rituximab was dosed at 30 mg/kg intraperitoneally (i.p.). Polatuzumab vedotin was administered as a single injection at 1.5 mg/kg.

Cells were inoculated subcutaneously into the flanks of female CB17 ICR severe combined immunodeficient (SCID) mice. When mean tumor size reached desired volume,the mice were divided into groups of 7 to 9 mice with the same mean tumor size and dosed intravenously via the tail vein with ADCs or antibodies. Rituximab was dosed at 30 mg/kg intraperitoneally (i.p.). Polatuzumab vedotin was administered as a single injection at 16 mg/kg.

Cells were inoculated subcutaneously into the flanks of female CB17 ICR severe combined immunodeficient (SCID) mice. When mean tumor size reached desired volume,the mice were divided into groups of 7 to 9 mice with the same mean tumor size and dosed intravenously via the tail vein with ADCs or antibodies. Rituximab was dosed at 30 mg/kg intraperitoneally (i.p.). Polatuzumab vedotin was administered as a single injection at 2 mg/kg.

Cells were inoculated subcutaneously into the flanks of female CB17 ICR severe combined immunodeficient (SCID) mice. When mean tumor size reached desired volume,the mice were divided into groups of 7 to 9 mice with the same mean tumor size and dosed intravenously via the tail vein with ADCs or antibodies. Rituximab was dosed at 30 mg/kg intraperitoneally (i.p.). Polatuzumab vedotin was administered as a single injection at 4 mg/kg.