CURRENT ROLE AND FUTURE DIRECTIONS
In heavily pretreated and transplantation-ineligible patients with DLBCL treated on the GO29365 trial, pola-BR resulted in an EOT ORR of 45% including CR in 40%, best ORR of 70% including CR in 58%, and median PFS, DOR, and OS of 10, 13, and 12 months, respectively. These results have established pola-BR as a new and effective option for a patient population with otherwise very limited treatment options. The incorporation of pola into the treatment paradigm of patients with relapsed/refractory DLBCL is certainly welcomed. However, there are important points about the GO29365 trial that need to be highlighted. First, the treatment the comparator arm received (BR) had very modest clinical activity (ORR and CR rate of only 18%). Furthermore, this relatively small trial was underpowered to detect the survival benefit seen with pola-BR. POLARGO (NCT04182204) is an ongoing Phase 3 clinical trial randomizing patients with relapsed/refractory DLBCL to rituximab, gemcitabine, and oxaliplatin alone or in combination with pola (Table 2). POLARGO will be an important trial to confirm the clinical activity of pola when combined with more effective chemotherapy and its role in transplantation-eligible patients. Second, the role of pola-BR in patients whose DLBCL progressed/relapsed after autologous SCT and/or chimeric antigen receptor T‐cell therapy (CAR-T) is currently undefined as only 25% of patients treated with pola-BR on GO29365 had undergone prior autologous SCT and none had received prior CAR-T. Similarly, the role of pola-BR as a bridging therapy to either autologous SCT or CAR-T is unknown, particularly the effect of prolonged treatment with bendamustine on stem cell mobilization or quality of the CAR-T product in heavily pretreated patients. Finally, it is unclear whether pola-BR is equally effective in patients with transformed FL or double- and triple-hit lymphoma as these patients were not included on GO29365.
Table 2 lists other planned or ongoing clinical trials of pola in DLBCL. As previously mentioned, the recently concluded phase 3 POLARIX trial will define if there is a role for pola in combination with chemotherapy (R-CHP) in patients with previously untreated DLBCL. NCT04231877 is a phase 1 clinical trial combining pola with dose-adjusted rituximab, etoposide, cyclophosphamide, doxorubicin, and prednisone (DA-EPCH-R) in patients with aggressive B-cell lymphoma and primary mediastinal large B-cell lymphoma (PMBL). Of note, preclinical studies show activity for pola in cell lines and xenograft models of Burkitt and PMBL.25 NCT03677141 is an ongoing phase 1b/2 clinical trial that will include a randomized comparison of mosunetuzumab (a CD20/CD3 bispecific antibody) in combination with CHOP (M-CHOP), M-CHP-pola, and R-CHP-pola in patients with previously untreated DLBCL. GO40516 (NCT03671018) is a phase 1b/2 clinical trial that investigates the combination of mosunetuzumab plus pola vs mosunetuzumab monotherapy vs pola-BR in patients with relapsed/refractory DLBCL.
There is currently no defined role for pola in FL. Pola monotherapy or when combined with rituximab resulted in short-lived remissions, and its addition to BR did not improve response rates or PFS compared with BR alone, albeit with very short follow-up. Pola has the potential to be combined with several targeted agents including lenalidomide as discussed previously. Mosunetuzumab plus pola is also being evaluated in patients with relapsed/refractory FL (GO40516, NCT03671018).
Pola is also being studied in combination with atezolizumab and RO7082859 (a CD20/CD3 bispecific antibody) in relapsed/refractory FL or DLBCL (NCT02729896, NCT03533283). Based on preclinical data showing increased BCL-XL expression as a potential resistance mechanism to pola, and that combining pola with a BCL2 inhibitor (navitoclax) enhances its in vivo activity,1 pola is being studied in combination with venetoclax plus rituximab or obinutuzumab in relapsed/refractory FL or DLBCL (NCT02611323).
Other Anti-CD79b ADCs
Iladatuzumab vedotin (DCDS0780A) is another humanized anti-CD79b antibody conjugated to MMAE that has shown clinical activity in a small phase 1b clinical trial in patients with NHL (60% ORR including 43% CR in 30 patients with relapsed/refractory DLBCL).26
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