Shifting Treatment Paradigm in DLBCL Reflects Changes for CAR T-Cell Therapy, Polatuzumab

The changing treatment landscape for diffuse large B-cell lymphoma (DLBCL) now involves the use of the combination of polatuzumab vedotin (Polivy) plus rituximab (Rituxan), cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) moving into the frontline setting, as well as earlier use of chimeric antigen receptor (CAR) T-cell therapy in the second line.

The phase 3 POLARIX study (NCT03274492) evaluated Pola-R-CHP vs rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in patients with previously untreated DLBCL.¹

Findings demonstrated a higher proportion of patients who survived beyond 2 years who were treated with Pola-R-CHP, and the safety of the 2 regimens was comparable.¹

At a median follow of 28.2 months, Pola-R-CHP achieved a 27% reduction in the relative risk of disease progression, relapse, or death compared with
R-CHOP (HR, 0.73l 95% CI, 0.57-0.95;P= .02). The 24-month PFS rate observed with Pola-R-CHP was 76.7% vs 70.2% with R-CHOP (FIGURE¹).

Pola-R-CHP also led to a longer event-free survival of 86.6% vs 82.7% in the R-CHOP arm (HR 0.75; 95% CI: 0.58-0.96;P=.02). OS was also prolonged with Pola-R-CHP compared with R-CHOP (HR, 0.94; 95% CI 0.65-1.37;P= .75).

Alternative CD19-directedantibodies,antibody-drug conjugates, and bispecific antibodies seek to fill the space left when chimeric antigen receptor (CAR) T-cell therapy moved up to second-line treatment, according to Andrew D. Zelenetz, MD, PhD, who provided an overview of available treatments in diffuse large B-cell lymphoma (DLBCL) in a presentation during the 40th AnnualCFS®.²

Zelenetz is medical director of quality informatics at Memorial Sloan Kettering Cancer Center (MSK) in New York, New York.

Weighing Concerns With Available CAR T-Cell Therapies

Three CD19-directed CART-cell products are approved for use in patients with DLBCL following at least 2 prior therapies: axicabtagene ciloleucel
(axi-cel;Yescarta), tisagenlecleucel(Kymriah), and lisocabtagene maraleucel (liso-cel; Breyanzi).

Two acute toxicities that require close monitoring following infusion are cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), detailed in the TABLE².

“B-cell aplasia is an on-target effect and can result in significant immunosuppression,” Zelenetz said.

Recognition of and early intervention for these toxicities are especially important as these treatments are moved into earlier lines of therapy. All
3 agents have been evaluated in the second-line setting, but only axi-cel and liso-cel demonstrated positive results against standard of care (SOC) in
the phase 3 ZUMA-7 (NCT03391466) and TRANSFORM (NCT03575351) trials, respectively. Both trials enrolled patients with relapsed or refractory
DLBCL within 12 months of frontline therapy.

At a median follow-up of 25 months in ZUMA-7, the median event-free survival was 8.3 months with axi-cel vs 2 months with SOC; the median progression-free survival (PFS) was 14.7 months vs 3.7 months, and the overall survival (OS) was not reached vs 35.1 months, respectively.³ With
limited follow-up of 6 months in the TRANSFORM trial, the median event-free survival was 10.1 months with liso-cel vs 2.3 months with SOC; the median PFS was 14.8 months vs 5.7 months, and the OS was not reached vs 16.4 months, respectively.⁴

Both agents received FDA approval for the treatment of patients with DLBCL refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemovimmunotherapy. However, limited access, long-term toxicity, and expense may be prohibitive, Zelenetz explained. He added that high-dose therapy and autologous stem cell transplant, although typically reserved for patients in a positron emission tomography (PET) complete response, could be a suitable option for patients with PET partial response. In a case-matched Center for International Blood and Marrow Transplant Research analysis of CAR T-cell therapy and autologous stem cell transplant, patients in PET partial response demonstrated comparable outcomes.⁵

Alternative CD19-Directed Therapy

For patients who are ineligible for high-dose therapy and transplant, tafasitamab-cxix (Monjuvi) plus lenalidomide (Revlimid) may represent a potential option. The combination was evaluated in the L-MIND trial
(NCT02399085) in patients with DLBCL who received 1 to 3 prior treatment regimens.

At a follow-up of 35 months, the objective response rate (ORR) was 57.5%(95% CI, 45.9%-68.5%),the median PFS was 11.6 months (95% CI, 6.3-45.7), and the median OS was 33.5 months (95% CI, 18.3-not reached).⁶

“The PFS curve looks a lot like a CAR T-cell curve; however, there is some selection bias in this study for favorable patients, and we are awaiting further data,” Zelenetz said.

Another available option is loncastuximab tesirine-lpyl (Zynlonta). The agent was approved in April 2021 based on findings from the phase 2 LOTIS-2 trial (NCT03589469). To be eligible for enrollment in the study, patients who had relapsed or refractory large B-cell lymphoma had to have received at least 2 prior lines of therapy. Notably, patients with primary refractory disease were eligible for enrollment, as were patients who received autologous and allogeneic transplant provided it was more than 30 and 60 days from
enrollment, respectively; this population was excluded from the L-MIND trial.

The ORR was 48.3% (95% CI, 39.9%-56.7%), the median PFS was 4.9 months, and the median OS was 9.9 months.⁷

Data have shown that CAR T-cell therapy following treatment with loncastuximab tesirine may be viable. In a small study, 10 of 10 tested patients retained CD19 expression following treatment with loncastuximab
tesirine and experienced an ORR of 50% (n = 7) with CAR T-cell therapy.⁸

Another antibody-drug conjugate that has been evaluated and approved in the relapsed/refractory setting is polatuzumab vedotin-piiq (Polivy). In the ROMULUS trial (NCT01691898),the agent was combined with rituximab (Rituxan) and displayed a best overall response rate of 56% and a median PFS of 5.5 months (95% CI, 4.3-12.8).⁹ This trial served as the basis for the randomized phase 2 trial (NCT02257567) evaluating bendamustine plus rituximab vs polatuzumab vedotin plus bendamustine and rituximab.

The best overall response rate was 70% with the triplet vs 33% with bendamustine and rituximab. The median PFS (HR, 0.31; 95% CI, 0.18-0.55;P< .0001) and OS (HR, 0.35; 95% CI, 0.19-0.67;P= .0008) favored the use of the triplet, at 6.7 months (95% CI, 4.9-11.1) vs 2.0 months (95% CI, 1.5-3.7) and 11.8 months (95% CI, 9.5-NE) vs 4.7 months (95% CI, 3.7-8.3), respectively.¹⁰

“If you overlay the results of the ROMULUS trial on the PFS curve from this trial, I would argue that they are completely identical,” Zelenetz said. “We at MSK pretty much exclusively use polatuzumab vedotin plus rituximab
without bendamustine because of the reduced toxicity and retained activity, particularly if you’re using polatuzumab vedotin to position someone to see if they’re going to be eligible for CAR T-cell therapy or even as bridging therapy after you’ve collected CAR T cells.”

Bispecific Antibodies in Development

Several promising bispecific antibodies are in development. Furthest along are glofitamab and epcoritamab, which have shown comparable activity in heavily pretreated patientswith relapsed or refractory B-cell non-Hodgkin lymphoma in phase 1/2 trials (NCT03075696; NCT03625037).

At a median follow-up of 12.6 months with glofitamab, the ORR was 51.6%, the median PFS was 4.9 months, and the median OS was 11.5 months.¹¹At a median follow-up of 10.7 months with epcoritamab, the ORR was 63.1%, the median PFS was 4.4 months, and the median OS was not reached.¹²

In both trials, patients had received a median of 3 prior lines of therapy, and 33.1% and 39% received prior CAR T-cell therapy.

Grade 3 or greater treatment-related adverse effects were seen in 41.6% of patients with glofitamab. Grade 3 or higher CRS and neurotoxicity were higher with glofitamab, and tocilizumab was more likely to be used with glofitamab vs epcoritamab. However, less than 10% of patients in both trials discontinued treatment because of AEs.

“The overall results seem to be quite similar,” Zelenetz concluded. “The drugs are given in a stepped-up manner to reduce the risk of CRS and ICANS. These drugs are not yet approved for treatment but are promising.”

REFERENCES:

1. Flowers C, Tiklly H, Morschhauser F, et al. Polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) versus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) therapy in patients with previously untreated diffuse large b-cell lymphoma (DLBCL): results from the phase III POLARIX study. Presented at: 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022); September 28-October 1, 2022; Houston TX.

2. Zelenetz AD. New landscape for relapsed or refractory (R/R) diffuse large B cell lymphoma: 2L and beyond. Presented at: 40th Annual Chemotherapy Foundation Symposium Innovative Cancer Therapy for Tomorrow®; November 9-11, 2022; New York, NY. Accessed November 22, 2022. http://bit.ly/3VhOkIS

3. Locke FL, Miklos DB, Jacobson CA, et al; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133

4. Kamdar M, Solomon SR, Arnason J, et al; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399(10343):2294-2308. doi:10.1016/S0140-6736(22)00662-6

5. Shadman M, Pasquini M, Ahn KW, et al. Autologous transplant vs chimeric antigen receptor T-cell therapy for relapsed DLBCL in partial remission. Blood. 2022;139(9):1330-1339. doi:10.1182/blood.2021013289

6. Duell J, Maddocks KJ, González-Barca E, et al. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021;106(9):2417-2426. doi:10.3324/haematol.2020.275958

7. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X

8. Thapa B, Caimi PF, Ardeshna KM, et al. CD19 antibody-drug conjugate therapy in DLBCL does not preclude subsequent responses to CD19-directed CAR T-cell therapy. Blood Adv. 2020;4(16):3850-3852. doi:10.1182/bloodadvances.2020002587

9. Palanca-Wessels MC, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol. 2015;16(6):704-715. doi:10.1016/S1470-2045(15)70128-2

10. Sehn LH, Kamdar M, Herrera AF, et al. Randomized phase 2 trial of polatuzumab vedotin (pola) with bendamustine and rituximab (BR) in relapsed/refractory (r/r) FL and DLBCL. J Clin Oncol. 2018;36(suppl 15):7507. doi:10.1200/JCO.2018.36.15_suppl.7507

11. Dickinson M, Carlo-Stella C, Morschhauser F, et al. Glofitamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and ≥ 2 prior therapies: pivotal phase II expansion results. J Clin Oncol. 2022;40(suppl 16):7500. doi:10.1200/JCO.2022.40.16_suppl.7500

12. Thieblemont C, Phillips T, Ghesquieres H, et al. Primary results of subcutaneous epcoritamab dose expansion in patients with relapsed or refractory large B-cell lymphoma: a phase 2 study. Presented at: European Hematology Association 2022 Congress; June 9-12, 2022; Vienna, Austria. Accessed November 18, 2022. http://bit.ly/3EyF4t7