A four-drug targeted therapy regimen proved safe and effective as the first-line treatment of diffuse large B-cell lymphoma (DLBCL), achieving a 100% response rate after four cycles, researchers from The University of Texas MD Anderson Cancer Center, Houston, reported at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition.1
Smart Stop was a phase II single-center, open-label, investigator-initiated study of newly diagnosed, treatment-naive patients with DLBCL who received lenalidomide, tafasitamab-cxix, rituximab, and acalabrutinib (LTRA) in the first-line setting. Complete responders went on to receive just two cycles of chemotherapy, whereas those with less than a complete response received the standard six cycles.
“Smart Stop has established that targeted therapy with reduced chemotherapy, and response-adapted trials with novel combinations, are feasible,” said Jason Westin, MD, Director of the Lymphoma Clinical Research Program at The University of Texas MD Anderson Cancer Center, Houston.
Rationale for Smart Stop
“For large B-cell lymphoma, CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] has been the standard of care for 47 years. But as more has been learned about the cell of origin, things have gotten complicated,” stated Dr. Westin. “We are splitting the pie into smaller and smaller subsets based on genes that are abnormal hallmark features…. Targets abound, but clinical trials have largely struggled to keep up…. Beyond the significant improvement we got with rituximab, multiple studies with great drugs and great ideas have mostly not succeeded, despite adding good drugs onto the CHOP backbone.”
Smart Stop has established that targeted therapy with reduced chemotherapy, and response-adapted trials with novel combinations, are feasible.— Jason Westin, MD
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Based on the synthetic lethality of lenalidomide and ibrutinib and their impact on immune response, Dr. Westin and his team previously conducted the Smart Start trial, testing the benefit of giving two cycles of lenalidomide and ibrutinib prior to rituximab in newly diagnosed patients with DLBCL.2 This regimen resulted in an overall response rate of 86%, a complete response rate of 36%, a 2-year progression-free survival rate of 91%, and a 2-year overall survival rate of 97%—outcomes that appeared better than historical outcomes in the non-GCB (germinal center B-cell) subtype, he noted.
“We saw more than a two-log reduction in circulating tumor DNA in a significant chunk of patients, including clinical responses in ABC [activated B-cell] and GCB patients, raising the question of whether we could do better with these targeted therapies,” Dr. Westin commented.
LTRA Regimen in Smart Stop
The researchers next aimed to improve upon the Smart Start regimen by adding two different drugs to rituximab plus chemotherapy that have shown activity in DLBCL: a more selective second-generation Bruton’s tyrosine kinase inhibitor, acalabrutinib,3 and the CD19-targeted agent tafasitamab.4 The Smart Stop study was initially restricted to patients in the non-GCB subtype, but this inclusion criterion was later removed.
KEY POINTS
- A four-drug targeted therapy regimen proved safe and effective as the initial first-line treatment of diffuse large B-cell lymphoma, achieving a 100% response rate after four cycles.
- The combination was lenalidomide, tafasitamab-cxix, rituximab, and acalabrutinib (LTRA), with just two cycles of chemotherapy administered to complete responders; those with lesser response received the standard six cycles of chemotherapy.
- The complete response rate was 63.3% after four cycles, increasing to 93.3% after six cycles.
- After almost 1 year of follow-up, no patient has experienced disease progression.
The resulting LTRA regimen was lenalidomide at 25 mg daily for days 1 to 10; tafasitamab at 12 mg/kg weekly on days 1, 8, and 15; rituximab at 375 mg/m2 given once on day 1; and acalabrutinib at 100 mg twice daily on days 1 to 21. A total of 30 patients (83% with the non-GCG subtype) received four cycles of LTRA and then underwent assessment by PET/CT. Complete responders went on to receive two cycles of CHOP chemotherapy; those with less than a complete response received the standard six cycles of CHOP. The study is still enrolling a second cohort in which complete responders will receive no chemotherapy. The primary endpoint was overall response rate after four cycles of LTRA and complete response rate at the end of treatment.
“Our hypotheses for this trial are that LTRA for four cycles will improve upon our Smart Start complete response rate of 36% and that complete responses after LTRA will allow for less or no chemotherapy and will prove durable,” Dr. Westin explained.
Key Findings
After four cycles of LTRA, all 30 patients achieved responses, for a 100% response rate. The complete response rate was 63.3% after four cycles, increasing to 93.3% after six cycles. For the GCB subtype, the complete response rate was 80%.
“We currently have 22 patients who have reached the end-of-treatment time point, and they all have had a complete response…. Of the first 10 patients, 7 received two cycles of R-CHOP [rituximab plus CHOP] and have an ongoing remission of more than 9 months. To date, no patient has experienced disease progression after a median follow-up of around 11 months, but obviously, more follow-up is needed,” Dr. Westin said.
“Limited data show a high molecular response,” he added. Circulating tumor DNA (ctDNA) was assessed for 15 patients, of whom 87% had at least a two-log reduction after four cycles (ie, a molecular response), 60% had at least a three-log reduction, and 33% had undetectable ctDNA.
Toxicity Profile
Grade ≥ 3 neutropenia was observed in 60% of patients, mostly related to the CHOP component of treatment and not resulting in treatment discontinuation. Maculopapular rash grade ≥ 3 was seen in 13% and was manageable with dose reductions and interruptions. All other grade ≥ 3 toxicities were limited to less than 10% of patients. Although 30% of patients had infections of any grade, no patients died or discontinued treatment as a result.
DISCLOSURE: Dr. Westin has served as a consultant to Novartis, Genentech, Kite/Gilead Sciences, MonteRosa, MorphoSys/Incyte, BMS, AstraZeneca, ADC Therapeutics, AbbVie, SeaGen, and Nurix.
REFERENCES
1. Westin J, Steiner RE, Chihara D, et al: Smart Stop: Lenalidomide, tafasitamab, rituximab, and acalabrutinib alone and with combination chemotherapy for the treatment of newly diagnosed diffuse large B-cell lymphoma. 2023 ASH Annual Meeting & Exposition. Abstract 856. Presented December 11, 2023.
2. Westin J, Davis RE, Feng L, et al: Smart Start: Rituximab, lenalidomide, and ibrutinib in patients with newly diagnosed large B-cell lymphoma. J Clin Oncol 41:745-755, 2023.
3. Davies A, Caddy J, Mercer K, et al: Acalabrutinib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone as first line therapy for patients with diffuse large B-cell lymphoma: The Accept phase Ib/II single arm study. 2020 ASH Annual Meeting & Exposition. Abstract 1185. Presented December 5, 2020.
4. Belada D, Kopeckova K, Bergua Burgues JM, et al: Safety and efficacy of tafasitamab with or without lenalidomide added to first-line R-CHOP for DLBCL: The phase 1b First-MIND study. Blood 142:1348-1358, 2023.
