Polatuzumab vedotin, venetoclax, and an anti‐CD20 monoclonal antibody in relapsed/refractory B‐cell non‐Hodgkin lymphoma

The Phase 2 portion of this study evaluated safety and efficacy of polatuzumab vedotin 1.8 mg/kg and venetoclax 800 mg, plus fixed‐dose obinutuzumab 1000 mg or rituximab 375 mg/m2 in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or diffuse large B‐cell lymphoma (DLBCL), respectively. Patients with complete response (CR) or partial response (PR)/stable disease (FL) or CR/PR (DLBCL) at end of induction (EOI; six 21‐day cycles) received post‐induction therapy with venetoclax and obinutuzumab or rituximab, respectively. Primary endpoint was CR rate at EOI. Safety‐evaluable populations included 74 patients (FL cohort; median age 64 years; progression of disease within 24 months on first‐line treatment, 25.7%; FL International Prognostic Index 3–5, 54.1%; ≥2 previous therapies, 74.3%) and 57 patients (DLBCL cohort; median age 65 years; International Prognostic Index 3–5, 54.4%; ≥2 previous therapies, 77.2%). The most common non‐hematologic adverse events (mostly Grades 1–2) in the FL and DLBCL cohorts were diarrhea (55.4% and 47.4%, respectively) and nausea (47.3% and 36.8%); neutropenia was the most common Grades 3–4 toxicity (39.2% and 52.6%). Efficacy‐evaluable populations included patients treated at the recommended Phase 2 dose (FL, n = 49; DLBCL, n = 48). CR rates at EOI were 59.2% (FL) and 31.3% (DLBCL); median progression‐free survival was 22.8 months (95% confidence interval [CI], 14.5—not evaluable) and 4.6 months (95% CI, 3.6–8.1), respectively. Polatuzumab vedotin plus venetoclax and obinutuzumab/rituximab had acceptable safety in patients with R/R FL or DLBCL, with promising response rates in R/R FL, including high‐risk patients.


| INTRODUCTION
Advanced-stage follicular lymphoma (FL) has recurrent relapses and is incurable with standard treatments. 1 Diffuse large B-cell lymphoma (DLBCL), although potentially curable with initial anthracycline-based chemoimmunotherapy, presents as relapsed/refractory (R/R) disease in 40% of patients. 1Therefore, novel treatment options with improved efficacy and safety are needed for these B-cell non-Hodgkin lymphoma (NHL) subtypes.
The selective BCL-2 inhibitor, venetoclax, is approved for hematologic malignancies, but its efficacy as a single agent in FL or DLBCL is limited. 2,3Polatuzumab vedotin, an anti-CD79b antibody-drug conjugate, is approved in the United States and Europe in combination with bendamustine and rituximab for R/R DLBCL and in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone for previously untreated DLBCL, based on the Phase 3 POLARIX study. 4,5Polatuzumab vedotin plus obinutuzumab or rituximab was demonstrated to be active and tolerable in early R/R NHL trials. 6,7ncurrent polatuzumab vedotin therapy may reduce resistance to venetoclax by promoting degradation of the pro-survival myeloid-cell leukemia-1 protein and enhancinge in vivo antitumor activity. 8sed on the mechanism of action of each agent, we hypothesized that polatuzumab vedotin, venetoclax, and an anti-CD20 agent may provide clinically meaningful efficacy in R/R NHL by targeting multiple disease drivers (given the genomic heterogeneity of B-cell lymphomas). 9Phase 1b dose-finding data from the GO29833 study 10 identified the recommended Phase 2 dose (RP2D) for polatuzumab vedotin as 1.8 mg/kg in combination with venetoclax 800 mg and an anti-CD20 agent (obinutuzumab or rituximab), based on a predictable and acceptable safety profile.
Here, we report updated follow-up data on the Phase 1b cohort and final safety and efficacy data from Phase 2 (data cutoff: September 30, 2022).

| Study design
This open-label, global, multicenter, non-randomized Phase 1b/2 study (GO29833; ClinicalTrials.govidentifier NCT02611323) evaluated the safety and efficacy of polatuzumab vedotin, venetoclax, and obinutuzumab in patients with R/R FL, and of polatuzumab vedotin, venetoclax, and rituximab in patients with R/R DLBCL.A doseescalation phase (Phase 1b) was followed by a dose-expansion phase (Phase 2), in which polatuzumab vedotin and venetoclax were administered at their RP2Ds.The Phase 1b study design has been published previously. 10The protocol was approved by the institutional review boards or ethics committees at participating institutions as per the International Conference on Harmonisation guidelines, including Good Clinical Practice and the ethical principles of the Declaration of Helsinki. 11,12Informed consent was provided by all patients.An internal monitoring committee reviewed safety and efficacy data.

| Patients
Eligible patients were aged ≥18 years with histologically documented CD20-positive FL or DLBCL, R/R disease after treatment with ≥1 prior chemoimmunotherapy regimen (including an anti-CD20 monoclonal antibody), Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, fluorodeoxyglucose-positron emission tomography (PET)-avid lymphoma and ≥1 bi-dimensionally measurable lesion (>1.5 cm in largest dimension).Full eligibility criteria are provided in the Supplemental data.

| Study treatment
As described previously, 10

| Endpoints and outcome measures
The primary efficacy endpoint was the CR rate at EOI per independent review committee (IRC), based on PET-computed tomography (CT) scans according to modified Lugano 2014 criteria 13

| Statistical analyses
Statistical analyses for Phase 1b have been described. 10Safety analyses were performed in the safety-evaluable population (all patients who received ≥1 dose of any study drug), and efficacy analyses in the efficacy-evaluable population (all patients who received ≥1 dose of any study drug at the RP2D).A sample size of approximately 80 patients (FL, n = 40; DLBCL, n = 40) was planned for Phase 2. Based on historical data from studies in similar settings, a PET-CT CR rate of 40% for patients with R/R FL or DLBCL was estimated for the available treatment options.A sample size of 40 patients was identified to provide adequate precision for the point estimate and for the lower bound of the prespecified two-sided 90% confidence intervals (CIs) to rule out a probability of response of <55% (not clinically meaningful), assuming an observed PET-CT CR rate of 70%.Point estimates and corresponding 90% Clopper-Pearson exact CIs were calculated to identify the true probability of a PET-or CT-defined CR at EOI. Patients without a post-baseline tumor assessment were considered nonresponders.PFS and OS were summarized using the Kaplan-Meier method.PFS data for patients without progressive disease (PD) and alive at the time of the analysis were censored at last tumor assessment.For OS, patients who were alive at the time of the analysis were censored at the date last known to be alive.Landmark estimates, with 95% asymptotic CIs, were calculated using Greenwood's formula for standard errors.S1 and S2.
(range, 0.1-9.8months).One patient with R/R DLBCL had laboratory TLS on non-protocol-specified new anti-lymphoma treatment (gemcitabine), unrelated to study drug.There was one Grade 5 (fatal) AE (pneumonia unrelated to study treatment, which occurred following disease progression and new anti-lymphoma treatment, including chimeric antigen receptor [CAR] T-cell therapy).

| R/R FL
The IRC-assessed PET-CT CR rate at EOI per modified Lugano criteria in the efficacy-evaluable population (primary efficacy endpoint) was 59.2%, and the ORR was 75.5% (  1A).Median OS was not reached.

| R/R DLBCL
In the R/R DLBCL cohort, the IRC-assessed PET-CT CR rate at EOI in the efficacy-evaluable population per modified Lugano criteria was 31.3% and the ORR was 35.4% (Table 3).Median INV-assessed PFS was 4.6 months (95% CI, 3.6-8.1;Figure 1B).Median OS was 11.0 months (95% CI, 6.9-16.8).For both the R/R FL and R/R DLBCL cohorts, secondary and exploratory efficacy results are summarized in   15 Autoimmune toxicities such as pneumonitis and colitis, while reduced with copanlisib, remain a challenge with PI3K inhibition (with several withdrawals from market), and also this agent uniquely impacts blood pressure and blood sugar in patients in addition to a cumbersome dosing schedule. 15For the two approved CAR T-cell therapies, axicabtagene ciloleucel had a third-line ORR of 94% in ZUMA-5 (median PFS not reached) 16 and tisagenlecleucel had an ORR of 86% in ELARA 17 ; however, their clinical application is likely limited by access and cost barriers. 18The approved T-cell engaging bispecific antibody, mosunetuzumab, shows an ORR of 80% 19 and emerging data from other T-cell-engaging bispecific antibodies (odronextamab and epcoritamab) and from the antibody-drug conjugate loncastuximab tesirine, show ORRs of 91%, 90%, and 79%, respectively, in R/R FL. [20][21][22] Set in this context, the combination of polatuzumab vedotin, venetoclax, and obinutuzumab appears to provide promising outcomes with overall tolerability comparable with other available agents in R/R FL, understanding that some drugs (e.g., tazemetostat 23 and mosunetuzumab 19 ) may have lower rates of AEs leading to treatment discontinuation.
Although supporting data are needed, combining polatuzumab vedotin and venetoclax with obinutuzumab excludes highly immunosuppressive agents such as bendamustine, and therefore may be suitable for patients with R/R FL who are unable to receive or fail treatment with CAR T-cell therapies and/or bispecific antibodies.It may also have potential as a regimen that does not include lenalidomide, but which has favorable efficacy compared with tazemetostat and copanlisib.Ease of administration, treatment access, and patient eligibility will dictate where this triplet combination may be sequenced for R/R FL in the future.Furthermore, the combination of polatuzumab vedotin and venetoclax with obinutuzumab may mitigate the risk of development of venetoclax-resistant BCL-2 mutations, the emergence of which has been reported in a patient with relapsed FL treated with single-agent venetoclax. 24tients with R/R DLBCL in the current study had heavily pretreated, aggressive disease (64.9% were primary refractory; approximately half had received ≥3 prior lines of therapy).Despite these adverse features, the ORR was 35.4%, with the majority of responders achieving a CR (31.3%).This compares with ORRs of 45% for polatuzumab vedotin plus bendamustine and rituximab in the R/R DLBCL registrational trial (GO29365) 4 ; 52-74% for CAR T-cell therapy (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel) in the ZUMA-1, JULIET, and TRANSCEND trials, respectively [25][26][27][28] ; 57.5% for the anti-CD19 monoclonal antibody tafasitamab plus lenalidomide in the L-MIND study (where half of patients had only one prior line of treatment) 29 ; and 28% for selinexor in the SADAL trial. 30[33] The polatuzumab vedotin, venetoclax, and rituximab regimen may benefit a subset of patients with refractory DLBCL and competent intrinsic apoptotic pathways. 10However, it is yet to be determined which biological subsets could benefit most from this triplet (e.g., germinal center B-cell DLBCL [GCB] vs. non-GCB, or high-grade lymphomas, including BCL-2 or BCL-2 and MYC expressors). 34,35In this study, as expected, response rates in patients with disease that was sensitive to the last line of treatment were better than those in in Phase 1b, patients received escalating doses of polatuzumab vedotin and venetoclax plus a fixed dose of obinutuzumab (R/R FL) or rituximab (R/R DLBCL) to determine the RP2D.In Phase 2, patients with FL received polatuzumab vedotin induction at the RP2D of 1.8 mg/kg by intravenous (IV) infusion on Day 1, and oral venetoclax 800 mg once daily on Days 1-21 of six 21-day cycles, plus obinutuzumab 1000 mg by IV infusion on Days 1, 8, and 15 of cycle 1, and on Day 1 of cycles 2-6.Patients continued to receive daily venetoclax until EOI response assessments (6-8 weeks after Day 1 of the last induction cycle).Patients who achieved a complete response (CR), partial response (PR), or stable disease (SD) at EOI received maintenance venetoclax daily for 8 months and obinutuzumab on Day 1 of every other month for 24 months.Patients with DLBCL received polatuzumab vedotin and rituximab administered on Day 1 of each induction cycle at a fixed dose of 1.8 mg/kg and 375 mg/m 2 , respectively, plus venetoclax 800 mg once daily on Days 1-21 of six 21-day induction cycles.Patients achieving CR or PR following induction were eligible for consolidation therapy (venetoclax daily and rituximab on Day 1 of every other month for 8 months).Prophylactic treatment, premedication, and supportive care measures are described in the Supplemental data.

3 | RESULTS 3 . 1 |
Patient population Between March 9, 2016 and January 31, 2020, 131 patients were enrolled and treated.Patient disposition is shown in Figure S1A,B, and demographics and baseline clinical characteristics are detailed inTable 1.In the FL cohort (n = 74) median age was 64 years, 86.5% of patients had Ann Arbor Stage III-IV disease, 54.1% had a FL International Prognostic Index (FLIPI) of 3-5, and 74.3% had received ≥2 previous therapies.In the DLBCL cohort (n = 57) median age was 65 years, 82.5% of patients had Ann Arbor Stage III-IV disease, 54.4% had an IPI of 3-5, and 77.2% had received ≥2 previous therapies.3.1.1 | R/R FL The safety-evaluable population included 74 patients (Phase 1b doseescalation, n = 33; Phase 2 dose-expansion, n = 41; median follow-up 40.5 months [range, 11.0-76.2]).The efficacy-evaluable population comprised 49 patients (median follow-up 37.4 months [range, 11.0-51.0]).Sixty-six patients (89.2%) completed induction and 31 patients (41.9%) completed maintenance therapy.Nineteen patients (25.7%) discontinued from the study prior to completion; four patients were lost to follow-up, one patient withdrew from the study, and 14 patients died (six due to PD, two due to unknown cause [one reported as cardiac arrest], and one death each due to COVID-19 pneumonia, pneumonia, end-stage pulmonary disease, acute pulmonary edema, sepsis and respiratory failure following allogeneic stem cell transplant, and multiorgan failure secondary to graft versus host disease post-allogenic stem cell transplant).

( 5 .
4%), and infusion-related reactions (5.4%).The incidence of peripheral neuropathy was 45.9% (Grade 1, n = 20; Grade 2, n = 14), with resolution in 20 patients at data cutoff; four (5.4%) patients required polatuzumab vedotin dose reduction and three (4.1%)patients discontinued treatment.Median time to peripheral neuropathy onset was 2.6 months (range, 0-28 months) and median time to resolution was 5.7 months (range, 0.4-32.9months).Two patients (2.7%) had tumor lysis syndrome (TLS; one laboratory, one clinical) during the first cycle; both recovered with supportive care and temporary interruption of polatuzumab vedotin and venetoclax.Two patients with R/R FL experienced a Grade 5 (fatal) AE (one with pneumonia while receiving maintenance obinutuzumab at Day 336; one with COVID-19-related pneumonia at Day 609 in a patient starting a new therapy following disease progression).T A B L E 1 Patient demographics and baseline clinical characteristics.
patients with refractory disease (90.0% and 21.1%, respectively).It is encouraging to note that the two patients who had relapsed following CAR T-cell therapy as a prior treatment were able to achieve a response at EOI with this regimen.The additional 8 months of consolidation treatment with rituximab and venetoclax did not result in an improvement in response for the patients who achieved a PR at EOI.Given the relative resistance of refractory DLBCL to chemo-immunotherapy, concerns regarding the impact of bendamustine prior to CAR T-cell therapy apheresis for T cell collection, and uneasiness about CD19-targeted regimens prior to CD19-directed CAR T-cell therapy, polatuzumab plus rituximab (dropping bendamustine) has been a common bridging regimen applied based on limited prospective data.The polatuzumab vedotin, venetoclax, and rituximab regimen could also be utilized as a potential bridging therapy prior to CAR T-cell therapy as it is associated with a lower cumulative incidence of Grade 3 or higher cytopenias than the polatuzumab vedotin, bendamustine, and rituximab regimen and has meaningful CR rates.In summary, this study demonstrated the acceptable safety of polatuzumab vedotin and venetoclax plus obinutuzumab or rituximab in R/R FL and DLBCL, respectively, with promising EOI response rates in R/R FL, including patients with high-risk disease features.Due to the limitations of a non-randomized single-arm study design and a heavily pretreated patient population with high-risk features, understanding the toxicity and response rates in various patient subgroups may provide insights for future use of these regimens.
Adverse event summary for patients with relapsed/ refractory (R/R) follicular lymphoma and R/R diffuse large B-cell lymphoma.
5.3%).The overall incidence of peripheral neuropathy was 22.8% (Grade 1, n = 10; Grade 2, n = 3), with resolution in seven patients at data cutoff.Two (3.5%) patients required polatuzumab vedotin dose reduction and no patients discontinued due to peripheral neuropathy.Median time to peripheral neuropathy onset was 2.0 months (range, 0-3.4 months) and median time to resolution was 0.9 months Abbreviations: CI, confidence interval; CT, computed tomography; DLBCL, diffuse large B-cell lymphoma; EOI, end of induction; FL, follicular lymphoma; INV, investigator; IRC, independent review committee; NE, not evaluable; PET, positron emission tomography; PR, partial response; PFS, progression-free survival; RP2D, recommended Phase 2 dose; R/R, relapsed/refractory; SD, stable disease.a Patients treated at the RP2D.b Two cases of PET-PR were downgraded to SD by IRC due to not meeting CT-PR requirements, per modified Lugano criteria.T A B L E 2

Table 3 ;
post hoc subgroup analyses by baseline characteristics are shown in Figure S2A,B.