Polatuzumab vedotin 30mg powder for solution for infusion vials

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. METHODS: We conducted a double-blind, placebo-controlled, international phase 3 trial to evaluate a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL. Patients 18 to 80 years of age were randomly assigned in a 1:1 ratio to receive six cycles of either pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival and safety. RESULTS: Overall, 879 patients underwent randomization: 440 were assigned to the pola-R-CHP group and 439 to the R-CHOP group. After a median follow-up of 28.2 months, the percentage of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% [95% confidence interval (CI), 72.7 to 80.8] vs. 70.2% [95% CI, 65.8 to 74.6] at 2 years; stratified hazard ratio for progression, relapse, or death, 0.73 by Cox regression; 95% CI, 0.57 to 0.95; P = 0.02). Overall survival at 2 years did not differ significantly between the groups (88.7% [95% CI, 85.7 to 91.6] in the pola-R-CHP group and 88.6% [95% CI, 85.6 to 91.6] in the R-CHOP group; hazard ratio for death, 0.94; 95% CI, 0.65 to 1.37; P = 0.75). The safety profile was similar in the two groups. CONCLUSIONS: Among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP. (Funded by F. Hoffmann-La Roche/Genentech; POLARIX ClinicalTrials.gov number, NCT03274492.).

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PURPOSE Patients with transplantation-ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) fare poorly, with limited treatment options. The antibody-drug conjugate polatuzumab vedotin targets CD79b, a B-cell receptor component. METHODS Safety and efficacy of polatuzumab vedotin with bendamustine and obinutuzumab (pola-BG) was evaluated in a single-arm cohort. Polatuzumab vedotin combined with bendamustine and rituximab (pola-BR) was compared with bendamustine and rituximab (BR) in a randomly assigned cohort of patients with transplantation-ineligible R/R DLBCL (primary end point: independent review committee [IRC] assessed complete response [CR] rate at the end of treatment). Duration of response, progression-free survival (PFS), and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression methods. RESULTS Pola-BG and pola-BR had a tolerable safety profile. The phase Ib/II pola-BG cohort (n = 27) had a CR rate of 29.6% and a median OS of 10.8 months (median follow-up, 27.0 months). In the randomly assigned cohort (n = 80; 40 per arm), pola-BR patients had a significantly higher IRC-assessed CR rate (40.0% v 17.5%; P = .026) and longer IRC-assessed PFS (median, 9.5 v 3.7 months; hazard ratio [HR], 0.36, 95% CI, 0.21 to 0.63; P < .001) and OS (median, 12.4 v 4.7 months; HR, 0.42; 95% CI, 0.24 to 0.75; P = .002; median follow-up, 22.3 months). Pola-BR patients had higher rates of grade 3-4 neutropenia (46.2% v 33.3%), anemia (28.2% v 17.9%), and thrombocytopenia (41% v 23.1%), but similar grade 3-4 infections (23.1% v 20.5%), versus the BR group. Peripheral neuropathy associated with polatuzumab vedotin (43.6% of patients) was grade 1-2 and resolved in most patients. CONCLUSION Polatuzumab vedotin combined with BR resulted in a significantly higher CR rate and reduced the risk of death by 58% compared with BR in patients with transplantation-ineligible R/R DLBCL.

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Polatuzumab vedotin (polatuzumab vedotin-piiq; Polivy™) is an antibody-drug conjugate comprising a monoclonal antibody against CD79b (a B cell receptor component) covalently conjugated to the anti-mitotic cytotoxic agent monomethyl auristatin (MMAE) via a cleavable linker. After binding to CD79b on the B-cell surface, polatuzumab vedotin is internalized and the linker is cleaved, releasing MMAE into the cell, where it inhibits division and induces apoptosis. Polatuzumab vedotin is being developed by Genentech (a subsidiary of Roche) for the treatment of haematological malignancies. In June 2019, the US FDA granted accelerated approval to polatuzumab vedotin, in combination with bendamustine plus rituximab, for the treatment of adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have received at least two prior therapies. Use of the compound in combination with bendamustine plus rituximab is also under regulatory review for relapsed/refractory DLBCL in the EU and is in ongoing phase 1b/2 development in this setting or relapsed/refractory follicular lymphoma (FL) in several countries. Various other polatuzumab vedotin combination therapy regimens are also in phase 1b/2 development for relapsed/refractory non-Hodgkin lymphoma (NHL) [including DLBCL and FL] or in phase 2 or 3 development for previously untreated DLBCL, while polatuzumab vedotin monotherapy has been in phase 1 development for relapsed/refractory B-cell NHL in Japan. This article summarizes the milestones in the development of polatuzumab vedotin leading to this first approval for its use in combination with bendamustine plus rituximab for relapsed/refractory DLBCL.

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PURPOSE Prognosis for patients with refractory/relapsed large B-cell lymphoma (LBCL) considered ineligible for curative-intent therapy is poor. The combination of mosunetuzumab, a T-cell–engaging bispecific antibody, and polatuzumab vedotin, an antibody-drug conjugate (Mosun-Pola), represents a novel fixed-duration outpatient therapy. METHODS In the phase III SUNMO trial, patients with refractory/relapsed LBCL who were ineligible for autologous stem-cell transplant were randomly assigned (2:1) to receive Mosun-Pola or rituximab, gemcitabine, and oxaliplatin (R-GemOx). Dual primary end points were centrally assessed overall response rate (ORR) and progression-free survival (PFS). Overall survival was a key secondary end point. RESULTS A total of 208 patients were randomly assigned to receive Mosun-Pola (n = 138) or R-GemOx (n = 70). At a median follow-up of 23.2 months, the primary analysis of SUNMO demonstrated that the median PFS was significantly longer with Mosun-Pola than with R-GemOx (11.5 months [95% CI, 5.6 to 18] v 3.8 months [95% CI, 2.9 to 4.1]; hazard ratio for progression or death, 0.41 [95% CI, 0.3 to 0.6]; P < .0001). ORR was significantly greater with Mosun-Pola versus R-GemOx (70% v 40%; P < .0001), with complete response rates of 51% and 24%, respectively. In the Mosun-Pola group, the rate of grade ≥2 cytokine release syndrome (CRS) and usage of tocilizumab occurred in <5% of patients and patient-reported outcomes were improved compared with R-GemOx. CONCLUSION Mosun-Pola demonstrated superior efficacy versus R-GemOx, with significant improvements in both ORR and PFS, and infrequent CRS events with a manageable safety profile.

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PURPOSE: An unmet need remains for more effective therapies for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), especially high-grade B-cell lymphoma (HGBCL). We present the primary analysis of a phase Ib/II study (ClinicalTrials.gov identifier: NCT03533283) investigating efficacy and safety of glofitamab plus polatuzumab vedotin (Glofit-Pola) in patients with R/R LBCL, including HGBCL and those who received previous chimeric antigen receptor (CAR) T-cell therapy. METHODS: Patients received 1,000 mg obinutuzumab on Cycle (C)1 Day (D)1 (once daily). Polatuzumab vedotin (1.8 mg/kg) was given on C1D2 and D1 of C2-6 (21-day cycles; once daily). Glofitamab was given as step-up doses in C1 (D8, 2.5 mg; D15, 10 mg) followed by 30 mg on D1 of C2-12 (21-day cycles; once daily). Polatuzumab vedotin was given for six fixed-duration cycles, and glofitamab for 12. RESULTS: As of September 2, 2024, 129 patients with LBCL (HGBCL; n = 44, 34.1%), received ≥1 dose of study treatment. The median age was 67 years (range, 23-84), and 63.6% were male. Patients had received a median of 2 (range, 1-7) previous lines of treatment (previous CAR T-cell therapy, n = 28, 21.7%). The independent review committee-assessed overall response rate was 78.3% (complete response rate, 59.7%). The median progression-free survival and overall survival (OS) were 12.3 and 33.8 months, respectively (median OS follow-up time, 32.7 months). The most common adverse event (AE) was cytokine release syndrome (43.4%; grade 1-2: 41.9%; one grade 5 event). Grade 3-4 AEs occurred in 58.9% of patients; 9.3% had grade 5 AEs, and 14.7% discontinued treatment because of AEs. CONCLUSION: Glofit-Pola demonstrated high efficacy and durable responses, with manageable safety, in heavily pretreated patients with R/R LBCL, including patients with HGBCL and previous CAR T-cell therapy failure.

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The efficacy and safety of polatuzumab vedotin combined with rituximab, cyclophosphamide, doxorubicin, and prednisolone (pola-R-CHP) in patients aged ≥ 80 years with untreated diffuse large B-cell lymphoma (DLBCL) remain largely unexplored. In this study, we administered a reduced-dose pola-R-CHP regimen to 38 patients with DLBCL aged > 80 years. Extending the findings of the POLARIX trial in this older individuals' cohort, we conducted a retrospective analysis to assess the efficacy and safety of the treatment in a real-world clinical setting. After 12 months, the overall and progression-free survival rates were 86.2% (95% confidence interval [CI]: 70.0-94.0) and 78.5% (95% CI: 59.2-89.5), respectively. Although the incidence of febrile neutropenia was relatively high (32%), an increased risk was observed in patients with an average relative dose intensity of < 70%, even with reduced treatment intensity. Notably, none of the patients required a dose reduction of polatuzumab vedotin owing to peripheral neuropathy. Therefore, our findings indicate that a reduced-dose pola-R-CHP regimen may be a viable and effective treatment option for older patients newly diagnosed with DLBCL.

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