Faculty Bibliography

Outcomes in mature T-cell lymphomas remain poor, with previous attempts at developing mAbs compromised by limited efficacy and significant immunocompromise. Anti-killer cell lectin-like receptor G1 mAbs may have greater selectivity and specificity for malignant T cells and avoid the toxicity concerns with previous agents. See related article by Assatova et al., p. 2514.

The combination of the phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor zandelisib with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib was hypothesized to be synergistic and prevent resistance to single-agent therapy. This phase 1 study (NCT02914938) included a dose-finding stage in patients with relapsed/refractory (R/R) B-cell malignancies (n = 20) and disease-specific expansion cohorts in follicular lymphoma (FL; n = 31) or mantle cell lymphoma (MCL; n = 19). The recommended phase 2 dose was zandelisib 60 mg on Days 1-7 plus zanubrutinib 80 mg twice daily continuously in 28-day cycle. In the total population, the most common adverse events (AEs; all grades/grade 3-4) were neutropenia (35%/24%), diarrhoea (33%/2%), thrombocytopenia (32%/8%), anaemia (27%/8%), increased creatinine (25%/0%), contusion (21%/0%), fatigue (21%/2%), nausea (21%/2%) and increased aspartate aminotransferase (24%/6%). Three patients discontinued due to AEs. The overall response rate was 87% (complete response [CR] = 33%) for FL and 74% (CR = 47%) for MCL. The median duration of response and progression-free survival (PFS) were not reached in either group. The estimated 1-year PFS was 72.3% (95% confidence interval [CI], 51.9-85.1) for FL and 56.3% (95% CI, 28.9-76.7) for MCL (median follow-up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone.

BACKGROUND:Diffuse large B-cell lymphoma comprises nearly 30% of non-Hodgkin lymphoma cases and patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for stem-cell transplantation have few treatment options and poor prognoses. We aimed to determine whether the novel combination of polatuzumab vedotin in combination with rituximab and lenalidomide (Pola+R+Len) would provide a tolerable treatment option with enhanced antitumour response in patients with relapsed or refractory diffuse large B-cell lymphoma. METHODS:on day 1 and lenalidomide 10 mg/day on days 1-21 of each 28-day cycle for a maximum of 6 cycles. The primary safety objective of the dose-escalation phase was identification of the maximum tolerated dose through incidence of dose-limiting toxic effects. The primary efficacy outcome of the dose-expansion phase was Independent Review Committee-assessed complete response rate at end of induction, based on PET-CT. Analyses were conducted in the safety population, which included all patients who received at least one dose of any study drug, and the efficacy population, which included all patients who received at least one dose of any study drug at the recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02600897. FINDINGS/RESULTS:Between July 11, 2017 and Feb 3, 2020, 57 patients were enrolled (median age 71 years [IQR 60-75]; 38 [67%] were male and 19 (33%) were female; 47 [82%] were not Hispanic or Latino; and the median previous lines of therapy was 2 [IQR 1-3]). 18 participants were included in phase 1b and 39 were included in phase 2. Phase 1b confirmed a 20 mg recommended phase 2 dose for lenalidomide. After a median follow-up of 11·8 months (IQR 4·7-25·8), the complete response rate, as assessed by the Independent Review Committee, was 31% (90% CI 20-43). The most common grade 3-4 adverse events were neutropenia (35 [61%] of 57) and thrombocytopenia (eight [14%] of 57). Serious adverse events were reported in 23 (40%) of 57 patients and one patient died due to a treatment-related adverse event (neutropenic sepsis). INTERPRETATION/CONCLUSIONS:Although the combination of Pola+R+Len did not meet the prespecified activity threshold, some patients derived clinical benefit and the regimen had a tolerable safety profile in patients with relapsed or refractory diffuse large B-cell lymphoma. FUNDING/BACKGROUND:Genentech/F Hoffmann-La Roche.

Background: Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody approved in Europe and the United States for relapsed/refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior therapies. Materials and Methods: We present interim safety data from the mosunetuzumab GO29781 (NCT02500407) phase I/II dose-escalation study in R/R non-Hodgkin lymphoma (NHL), focusing on FL. Results: Overall, 218 patients with R/R NHL, including 90 with R/R FL, received a median of eight 21-day cycles of intravenous mosunetuzumab with step-up dosing in Cycle (C) 1 (C1 Day [D] 1, 1 mg; C1D8, 2 mg; C1D15/C2D1, 60 mg; C3D1 and onwards, 30 mg). Cytokine release syndrome (CRS) was the most common adverse event (AE), occurring in 39.4% (NHL) and 44.4% (FL) of patients. Events occurred predominantly during C1 at the first loading dose; the majority were grade 1/2. CRS events were managed at the investigator's discretion with supportive care, steroids, and tocilizumab, based on protocol management guidelines. Immune effector cell-associated neurotoxicity syndrome was uncommon, reported in 0.9% (NHL) and 1.1% (FL) of patients. Neutropenia occurred in 27.5% (NHL) and 28.9% (FL) of patients (mostly grade 3/4) and could be effectively managed using granulocyte colony-stimulating factor. Tumor lysis syndrome occurred in 0.9% (NHL) and 1.1% (FL) of patients (all grade 3/4 with CRS; all resolved). Conclusion: Mosunetuzumab monotherapy as treatment for R/R B-cell NHL, including FL, was associated with low rates of severe AEs (including CRS) and is suitable for outpatient administration in the community setting. Adapted protocol guidance for the management of select AEs during mosunetuzumab treatment is included.

Relapsed/refractory aggressive large B cell lymphoma (LBCL) remains an area of unmet need. Here we report the primary analysis of a phase 1b/2 trial of outpatient mosunetuzumab (a CD20xCD3 T-cell-engaging bispecific antibody) plus polatuzumab vedotin (an anti-CD79B antibody-drug conjugate) in relapsed/refractory LBCL. The phase 2 component is a single arm of an ongoing multi-arm trial. The primary endpoint during dose expansion was independent review committee (IRC)-assessed best overall response rate. Secondary endpoints included investigator-assessed overall response rate, complete response, duration of response, progression-free survival and overall survival. At data cutoff, 120 patients were enrolled (22 dose escalation, 98 dose expansion). The primary endpoint was met during dose expansion, with IRC-assessed best overall response rate and complete response rates of 59.2% (58/98; 95% confidence interval (CI): 48.8-69.0) and 45.9% (45/98; 95% CI: 35.8-56.3), respectively (median follow-up, 23.9 months). Median duration of complete was not reached (95% CI: 20.5-not estimable (NE)). Median progression-free survival was 11.4 months (95% CI: 6.2-18.7). Median overall survival was 23.3 months (95% CI: 14.8-NE). Across dose escalation and expansion, the most common grade 3 or higher adverse events were neutropenia (25.0%, 30/120) and fatigue (6.7%, 8/120). Any-grade cytokine release syndrome occurred in 16.7% of patients. These data demonstrate that mosunetuzumab plus polatuzumab vedotin has a favorable safety profile with highly durable responses suitable as second-line therapy in transplant-ineligible relapsed/refractory LBCL. ClinicalTrials.gov identifier: NCT03671018 .

Immune checkpoint inhibitors (ICI) are increasingly used in combination. To understand the effects of different ICI categories, we characterized changes in circulating autoantibodies in patients enrolled in the E4412 trial (NCT01896999) of brentuximab vedotin (BV) plus ipilimumab, BV plus nivolumab, or BV plus ipilimumab-nivolumab for Hodgkin Lymphoma. Cycle 2 Day 1 (C2D1) autoantibody levels were compared to pre-treatment baseline. Across 112 autoantibodies tested, we generally observed increases in ipilimumab-containing regimens, with decreases noted in the nivolumab arm. Among 15 autoantibodies with significant changes at C2D1, all nivolumab cases exhibited decreases, with more than 90% of ipilimumab-exposed cases showing increases. Autoantibody profiles also showed differences according to immune-related adverse event (irAE) type, with rash generally featuring increases and liver toxicity demonstrating decreases. We conclude that dynamic autoantibody profiles may differ according to ICI category and irAE type. These findings may have relevance to clinical monitoring and irAE treatment.

In the pre-novel agent era, the median postprogression overall survival (PPS) of patients with classic Hodgkin lymphoma (cHL) who progress after autologous stem cell transplant (ASCT) was 2 to 3 years. Recently, checkpoint inhibitors (CPI) and brentuximab vedotin (BV) have improved the depth and durability of response in this population. Here, we report the estimate of PPS in patients with relapsed cHL after ASCT in the era of CPI and BV. In this multicenter retrospective study of 15 participating institutions, adult patients with relapsed cHL after ASCT were included. Study objective was postprogression overall survival (PPS), defined as the time from posttransplant progression to death or last follow-up. Of 1158 patients who underwent ASCT, 367 had progressive disease. Median age was 34 years (range, 27-46) and 192 were male. Median PPS was 114.57 months (95% confidence interval [CI], 91-not achieved) or 9.5 years. In multivariate analysis, increasing age, progression within 6 months, and pre-ASCT positive positron emission tomography scan were associated with inferior PPS. When adjusted for these features, patients who received CPI, but not BV, as first treatment for post-ASCT progression had significantly higher PPS than the no CPI/no BV group (hazard ratio, 3.5; 95% CI, 1.6-7.8; P = .001). Receipt of allogeneic SCT (Allo-SCT) did not improve PPS. In the era of novel agents, progressive cHL after ASCT had long survival that compares favorably with previous reports. Patients who receive CPI as first treatment for progression had higher PPS. Receipt to Allo-SCT was not associated with PPS in this population.

To date, mAbs have had limited success in improving outcomes for patients with T-cell lymphomas. Preclinical data suggest that anti-T-cell receptor Vβ-segment mAbs are a novel therapeutic strategy for patients with T-cell lymphomas that avoid several limitations of current therapies. See related article by Lucero et al., p. 4230.

Rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is the current standard therapy for patients with diffuse large B-cell lymphoma (DLBCL) and is curative in ∼60% of patients. Atezolizumab is a humanized immunoglobulin G1 monoclonal antibody that targets programmed death-ligand 1 and has previously shown anti-tumor activity in several tumor types. In a phase 1b/2 trial (NCT02596971) we evaluated the safety and efficacy of atezolizumab in combination with R-CHOP (atezo-R-CHOP; for 6 to 8 cycles) in patients with previously untreated DLBCL. Patients achieving a complete response at the end of induction received consolidation therapy with atezolizumab on Day 1 of each 21-day cycle for an additional 17 cycles. Overall, 42 patients with DLBCL were included in this analysis. The primary endpoint, complete response rate at end of induction, as assessed by an independent review committee (IRC; modified Lugano 2014) was 77.5% (95% confidence interval [CI], 64.0-87.7; n = 40). Investigator-assessed progression-free survival and overall survival at 3 years were 77.4% (95% CI, 59.7-88.0) and 87.2% (95% CI, 71.9-94.5), respectively. All treated patients experienced ≥1 adverse event (AE; 32 patients [76.2%] had a Grade 3-4 AE). One patient had a fatal AE (unconfirmed progressive multifocal leukoencephalopathy), that was considered related to atezolizumab and rituximab, and 17 (40.5%) patients experienced atezolizumab-related AEs of special interest. In previously untreated patients with DLBCL, atezo-R-CHOP demonstrated encouraging clinical efficacy and a safety profile consistent with the known toxicities of the individual drugs.