When to Use Second-Line CAR T-cell Therapy for Relapsed/Refractory DLBCL

Gilles Salles, MD

Chief of Lymphoma Service

Steven A. Greenberg Chair

Memorial Sloan Kettering Cancer Center

New York, NY

Targeted Oncology^TM: How do the National Comprehensive Cancer Network (NCCN) guidelines recommend treating patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) based on the outcomes of first-line therapy?

SALLES: [Looking at] the NCCN guidelines, for patients with the intention to proceed to autologous stem cell transplant (ASCT), second-line therapy is divided by complete responders with ASCT, partial responders [who] usually go to CAR [chimeric antigen receptor] T-cell therapy, and those with progressive disease who will go to salvage therapy or CAR T-cell therapy.¹ Patients with relapsed disease within 12 months, or primary refractory disease, should envision CAR T-cell therapy and the nontransplant candidates will go to a couple of suggested regimens.

If we go back to those patients with the intention to treat with CAR T-cell therapy, we have to think of patients a little differently from [the way one is] used to thinking. We’re used to seeing patients [in terms of being] eligible or ineligible for ASCT. [Now,] for these [patient’s relapse] early, [we have to ask if they] are eligible for CAR T-cell therapy and decide who is more [optimal] for CAR T-cell therapy. That’s probably a good discussion [to have]. In this case, we have both axicabtagene ciloleucel [axi-cel; Yescarta] and lisocabtagene maraleucel [liso-cel; Breyanzi] available for patients.

At what point can CAR T-cell therapy be used for patients with relapsed/refractory DLBCL?

Regarding their [FDA] approvals, axi-cel was approved for patients who are refractory to first-line therapy or relapse within 12 months of first-line chemoimmunotherapy.² The way we all interpret that is 12 months from the end [of first-line therapy], though initially some of the trials [did otherwise]. Liso-cel has a slightly different label: refractory disease or first-line relapse within 12 months of first-line therapy, then there is an addendum which is based on the study: refractory disease to first-line chemoimmunotherapy or relapsed after first-line chemoimmunotherapy and not eligible for ASCT.³

For axi-cel, the ZUMA-7 trial [NCT03391466] was taking patients from the time of relapse, [performing] apheresis on the patient, bridging them with steroids but not with chemotherapy, which may make [a difference].

What were the efficacy outcomes of the phase 3 trials investigating second-line CAR T-cell therapy?

[There were] 3 trials [of CAR T-cell therapy for DLBCL], ZUMA-7, BELINDA [NCT03570892], and TRANSFORM [NCT03575351].^4-6 Patients were in the range of 55 to 60 years of age [on these trials]. They had the same criteria of eligibility; all these patients [relapsed after] less than 12 months. In ZUMA-7, the only bridging therapy was steroids whereas BELINDA, the one with tisagenlecleucel [tisa-cel; Kymriah] and TRANSFORM with liso-cel were offering the possibility of 2 or 3 cycles of chemotherapy as bridging therapy.

Two-thirds to three-quarter of patients were refractory, [and approximately] 25% were relapsed [across these studies]. The median follow-up was quite different; [approximately] 2 years for ZUMA-7, 10 months for BELINDA, and 6 months at the time of publication of TRANSFORM. The complete response [CR] rate to CAR T-cell therapy in ZUMA-7 was 65%, and the CR rate with ASCT was 32%.⁴ With BELINDA there were no difference between the 2 groups, a CR of 28% [in each arm],⁵ and with TRANSFORM [the liso-cel had a] 66% CR rate which is identical to ZUMA-7 and 39% with ASCT.⁶

Two of the studies were positive, the third one is negative. If you want to know why is the third one was negative, is it a question of product, is it a question of trial design, is it a question of delays in manufacturing the product? I think there were many explanations raised. I personally think there was not one single explanation; it was a mixture of different explanations. Tisa-cel [is an effective] primary CAR T-cell therapy for children with acute lymphoblastic leukemia, so it’s a good [therapy], but in this DLBCL setting it may be inferior, and there are some data from a registry study coming from [France] suggesting that it is inferior to axi-cel.⁷

[For ZUMA-7, the PFS [progression-free survival] rate at 24 months was 46% for axi-cel versus 27% for ASCT.⁴ In BELINDA [PFS data were] not provided, [so PFS in both arms were] not reached,⁵ and [for TRANSFORM] we have a 12-month PFS rate of 50% vs 33%, so a highly significant difference for 2 [of these trials].⁶ So it’s a significant change for early relapse, and potentially for later [relapse].

_REFERENCES

_{1. NCCN. Clinical practice guidelines in oncology. B-cell lymphomas, version 2.2023. Accessed March 23, 2023. https://bit.ly/3TEXEqA}

_{2. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. News release. FDA. April 1, 2022. Accessed March 23, 2023. https://bit.ly/3ngfNPF}

_{3. FDA approves lisocabtagene maraleucel for second-line treatment of large B-cell lymphoma. News release. FDA. June 24, 2022. Accessed March 23, 2023. https://bit.ly/3TBFcPE}

_{4. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133}

_{5. Bishop MR, Dickinson M, Purtill D, et al. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022;386(7):629-639. doi:10.1056/NEJMoa2116596}

_{6. Kamdar M, Solomon SR, Arnason J, et al. 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}

_{7. Bachy E, Le Gouill S, Di Blasi R, et al. A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma. Nat Med. 2022;28(10):2145-2154. doi:10.1038/s41591-022-01969-y}