Relapsed/Refractory DLBCL Undergoes Rapid Evolution With CAR T-Cell Therapy, ADCs, and Bispecific Antibodies

Jeremy S. Abramson, MD, MMSc

High-dose chemotherapy and transplant remains the second-line standard of care for the majority of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL); however, CAR T-cell therapy and other novel agents, which have transformed the third-line setting, may offer alternative and more personalized second-line options in the coming years, said Jeremy S. Abramson, MD, MMSc, in a virtual presentation during the 25th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma, a program hosted by the Physicians Education Resource®, LCC.

“[My] new paradigm for managing patients with relapsed/refractory DLBCL still relies on [autologous stem cell transplant (ASCT)] in the second-line setting for patients fit for high-dose chemotherapy,” said Abramson, director of the Jon and Jo Ann Hagler Center for Lymphoma at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School. “However, I hope to replace that based on the results of [3 randomized trials comparing CAR T-cell therapy with ASCT in the second-line setting]. For patients without chemotherapy-sensitive disease, or who relapsed after an ASCT, I would take them to CAR T-cell therapy with curative intent.”

Low Responses to Chemotherapy Raises Questions Regarding Optimal Second-Line Treatment

Historically, second-line treatment selection for patients with relapsed/refractory DLBCL centered on whether a patient was fit for high-dose chemotherapy. Patients who were fit would receive salvage therapy with R-ICE [rituximab (Rituxan), ifosfamide, carboplatin, and etoposide), R-DHAP [rituximab, dexamethasone, cytarabine, and cisplatin], or R-GDP [rituximab, gemcitabine, cisplatin, and dexamethasone]. Then, they would undergo ASCT if they were sensitive to chemotherapy or receive palliative chemotherapy with R-GEMOX [rituximab, gemcitabine, and oxaliplatin] or bendamustine/rituximab (BR) if they were not sensitive to chemotherapy. Additionally, patients who were considered unfit for high-dose therapy or those who relapsed after ASCT would also receive palliative chemotherapy.

Although high-dose chemotherapy and ASCT remains the standard second-line treatment option for patients with relapsed/refractory DLBCL in the modern era, cure rates are low with this approach, and the majority of patients will have chemotherapy-refractory disease by the time they are in need of second-line therapy, Abramson explained.

Moreover, Abramson explained that patients who are refractory to chemotherapy or who relapsed 12 months or less after ASCT have low response rates to subsequent therapy, with a median overall survival (OS) of around 6 months. Those who progress on second-line therapy have an OS of approximately 4 months, he added.

“Treatment of relapsed/refractory disease must be personalized with consideration of not only the patient and disease characteristics, but also of prior therapies and the patient’s plans for future therapy to help guide optimal sequencing for that patient,” said Abramson.

CAR T-Cell Therapy Transforms the Third-Line Setting

Currently, three CD19-directed CAR T-cell therapies are approved for the treatment of patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphomas, including DLBCL. Although each of the products, axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (tisa-cel; Kymriah), and lisocabtagene maraleucel (liso-cel; Breyanzi), vary slightly in terms of regulatory indication, construct, and toxicity, complete response (CR) rates associated with the products are similar.

Regarding mechanism of action, axi-cel utilizes a CD28-directed co-stimulatory construct, whereas tisa-cel and liso-cel utilize a 4-1BB construct.

“[The 4-1BB construct] leads to differences in expansion kinetics and thus, differences in toxicity profiles,” said Abramson.

Axi-cel is the most toxic among the 3 products, with the highest rate of cytokine release syndrome and neurotoxicity compared with tisa-cel and liso-cel, explained Abramson.

The overall response rate (ORR) reported with axi-cel in the phase 2 ZUMA-1 trial (n = 101) was 83%, with a CR rate of 58%.1 With tisa-cel in the phase 2 JULIET trial (n = 111), the ORR was 52%, with a CR rate of 40%.2 With liso-cel, which is the most recently approved product, the ORR was 73%, with a CR rate of 53% as reported in the phase 1 TRANSCEND-NHL-001 trial (n = 269).³

The 1-year progression-free survival rate with axi-cel and liso-cel was 44% compared with approximately 33% with tisa-cel.^1-3

Notably, all 3 products are being evaluated in earlier lines of therapy for patients with DLBCL.

“Since DLBCL is unlikely to be cured with high-dose chemotherapy, all 3 [CAR T-cell therapies] are being compared in head-to-head randomized trials in the second-line setting versus high-dose chemotherapy, [which] may indeed alter the treatment landscape,” said Abramson.

Non-CAR T-Cell Therapies Offer Additional Third-Line Options

Although chemoimmunotherapy with R-GEMOX or cytarabine- and platinum-containing therapy is still widely utilized in the second-line setting for patients with relapsed/refractory DLBCL, newer options, including polatuzumab vedotin-piiq (Polivy) plus BR, tafasitamab-cxix (Monjuvi) plus lenalidomide (Revlimid), selinexor (Xpovio), brentuximab vedotin (Adcetris) in patients with CD30-positive disease, ibrutinib (Imbruvica) in patients with non–germinal center B-cell and activated B-cell disease, and pembrolizumab (Keytruda) in patients with primary mediastinal large B-cell lymphoma, have entered the third-line setting.

Polatuzumab vedotin, an antibody-drug conjugate targeting CD79b, plus BR, was approved in June 2019 for the treatment of patients with relapsed/refractory DLBCL who received at least 2 prior lines of therapy. Updated results from the phase 1b/2 study (NCT02257567) that led to the regulatory decision demonstrated an ORR of 45% with polatuzumab vedotin plus BR (n = 40) vs 17.5% with BR alone (n = 40).⁴ The CR rates were 40.0% and 17.5%, respectively.

Adverse effects (AEs) observed with this regimen included cytopenias, nausea, diarrhea, peripheral neuropathy, fatigue, and pyrexia.

“Relative to polatuzumab and BR, I would be cautious about using this regimen in a patient who I might ultimately consider taking to CAR T-cell therapy because bendamustine really does deplete T cells and may make it harder to generate a CAR T-cell product,” said Abramson.

In June 2020, the FDA approved the XPO1 inhibitor selinexor for patients with relapsed/refractory DLBCL, not otherwise specified, based on findings from the phase 2 SADAL trial. The results of the study revealed an ORR of 29% and a CR rate of 13% in 134 patients evaluated.⁵ Moreover, responses were retained for at least 6 months in 38% of patients who achieved a partial response or CR and for at least 12 months in 15% of these patients.

AEs such as fatigue, nausea, diarrhea, decreased appetite, weight loss, constipation, vomiting, and pyrexia were commonly reported with selinexor.

More recently, in July 2020, the FDA approved the combination of tafasitamab and lenalidomide for the treatment of patients with relapsed/refractory DLBCL, not otherwise specified. The regulatory decision was based on findings from the phase 2 L-MIND trial. Updated results of the study, which were presented during the 2020 ASH Annual Meeting and Exposition, revealed that the combination induced an ORR of 57.5%, a CR rate of 40.0%, and a median duration of response of 34.6 months in 80 evaluable patients with relapsed/refractory DLBCL.⁶

Commonly reported toxicities with the combination included cytopenia, diarrhea, pyrexia, and asthenia; 51% of patients required a dose reduction of lenalidomide.

Bispecific Antibodies Positioned to Push the Paradigm Further

Notably, bispecific antibodies, including mosunetuzumab, odronextamab, epcoritamab, and glofitamab, are a promising treatment modality for patients with DLBCL. Early data with these agents reported ORRs ranging from 37% to 76% and CR rates ranging from 19% to 54%.^7-10

“Ultimately, we will continue to add to [the DLBCL] armamentarium with the likely next addition being bispecific T-cell engaging antibodies targeting CD20 and CD3. Hopefully [these will] provide an off-the-shelf immunotherapy available in real time for patients with relapsed/refractory disease,” concluded Abramson.

References

1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. doi:10.1056/NEJMoa1707447

2. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980

3. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0

4. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172

5. Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e522. doi:10.1016/S2352-3026(20)30120-4

6. Maddocks KJ, Duell J, González-Barca E, et al. Long-term subgroup analyses from L-Mind, a phase II study of tafasitamab (MOR208) combined with lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Blood. 2020;136(suppl 1):19-21. doi:10.1182/blood-2020-140314

7. Schuster SJ, Bartlett NL, Assouline S, et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell (CAR-T) therapies, and is active in treatment through multiple lines. Blood. 2019;134(suppl 1):6. doi:10.1182/blood-2019-123742

8. Bannerji R, Allan JN, Arnason JE, et al. Odronextamab (REGN1979), a human CD20 x CD3 bispecific antibody, induces durable, complete responses in patients with highly refractory B-cell non-Hodgkin lymphoma, including patients refractory to CAR T therapy. Blood. 2020;136(suppl 1):42-43. doi:10.1182/blood-2020-136659

9. Hutchings M, Mous R, Clausen MR, et al. Subcutaneous epcoritamab induces complete responses with an encouraging safety profile across relapsed/refractory B-cell non-Hodgkin lymphoma subtypes, including patients with prior CAR-T therapy: updated dose escalation data. Blood. 2020;136(suppl 1):45-46. doi:10.1182/blood-2020-133820

10. Hutchings M, Carlo-Stella C, Bachy E, et al. Glofitamab step-up dosing induces high response rates in patients with hard-to-treat refractory or relapsed non-Hodgkin lymphoma. Blood. 2020;136(suppl 1):46-48. doi:10.1182/blood-2020-136044