Tafasitamab Quadruplet Appears Safe, Feasible in Newly Diagnosed DLBCL

This study inspired investigators to ask whether better outcomes could be achieved via targeted therapies. To do this, investigators chose to examine acalabrutinib—which demonstrated more selectivity and appeared more safe/efficacious with rituximab and CHOP (R-CHOP)—and tafasitamab—which has been successfully combined with lenalidomide and yields high ORRs and CR rates in patients with non-refractory, first-line LBCL.

Treatment with a targeted combination regimen of lenalidomide (Revlimid), tafasitamab-cxix (Monjuvi), rituximab (Rituxan), and acalabrutinib (LTRA) appeared to be safe and effective as a first-line treatment for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), with the addition of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) being effective in LTRA responders, according to data from the phase 2 Smart Stop study (NCT04978584).

The investigators of the study, which was presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition, highlighted that after 4 cycles of treatment with LTRA, the overall response rate (ORR) was 100%; the complete response (CR) rate in the overall population (n = 30) was 63.3% (95% CI, 50.0%-75.2%), and 36.7% of patients achieved a partial response (PR). Among those with germinal center B-cell (GCB) disease (n = 5), the CR rate was 80% and the PR rate was 20%.

Additionally, in patients who were then treated with 6 cycles of LTRA followed by 2 cycles of CHOP, the ORR was 100%, with a CR rate was 93.3% and a PR rate of 6.7%.

“At the end of all treatment, we currently have 22 patients who have achieved this time point, all of whom have had a complete response,” lead study author Jason Westin, MD, MS, FACP, director of Lymphoma Clinical Research Program and section chief of Aggressive Lymphoma research team, Department of Lymphoma and Myeloma, at The University of Texas MD Anderson Cancer Center in Houston, said during an oral presentation on the findings. “One patient had the PET avidity but not evidence of lymphoma.”

In the phase 2 Smart Start study, rituximab, ibrutinib (Imbruvica), and lenalidomide were administered for 2 cycles before any chemotherapy treatment in patients with newly diagnosed LBCL. Previous data showed an ORR of 86% and a CR rate of 36%², according to Westing who also noted that outcomes appeared “favorable” with historical outcomes in the non-GCB subtype.

This study inspired investigators to ask whether better outcomes could be achieved via targeted therapies. To do this, investigators chose to examine acalabrutinib—which demonstrated more selectivity and appeared more safe/efficacious with rituximab and CHOP (R-CHOP)—and tafasitamab—which has been successfully combined with lenalidomide and yields high ORRs and CR rates in patients with non-refractory, first-line LBCL.

Investigators hypothesized that LTRA could improve upon the 36% CR rate seen during the piror readout of Smart Start with 4 cycles of treatment, as well as decrease or eliminate the need for chemotherapy and yield a long-lasting CR.

In the single-center, investigator-initiated, open-label study, investigators enrolled patients who had a histopathologically confirmed LBCL who had not undergone treatment previously and had measurable disease. Those with previous indolent lymphoma were permitted, provided they had not received a CHOP-based therapy, and all LBCL subtypes were eligible. Additional eligibility criteria included having a performance status of less than 3, adequate organ and bone marrow function, and no central nervous system involvement with lymphoma.

Patients were treated with 25 mg of lenalidomide daily on days 1 to 10; 12 mg/kg of tafasitamab weekly on days 1, 8, and 15; 375 mg/m2 of rituximab once on day 1; and 100 mg of acalabrutinib twice daily on days 1 to 21. Following 4 cycles of LTRA, all patients had a PET/CT scan. If patients had a CR, they then went onto arm 1A and received 2 cycles of CHOP; if they had a PR, stable disease, or progressive disease, they went onto arm 1B, they received the standard 6 cycles of CHOP. Both arms comprised an additional 6 cycles of LTRA.

The primary end point was ORR following 4 cycles of LTRA in arm 1A—which received CHOP for 2 cycles—and CR rate at the end of therapy in arm 1B—which received CHOP for 6 cycles.

Smart Stop has a second cohort (n = 30) with 2 more arms: 6 cycles of LTRA alone (arm C) and 6 cycles of LTRA plus 6 cycles of CHOP (arm D). These data were not presented at the 2023 ASH Annual Meeting; enrolled is slated to be complete in the first quarter of 2024.

The intended doses of the targeted therapies had high delivery rates for lenalidomide (92.0%), tafasitamab (92.8%), and acalabrutinib (93.0%).

The median patient age was 61 years (range, 32-84), with 30% of patients being older than 70 years of age and 7% of patients over the age of 80. Most patients had an ECOG performance status of 1 (67%), elevated lactate dehydrogenase (83%), stage III or IV disease (80%), and an International Prognostic Index score of 3 to 5 (67%). Eighty-three percent of patients had non-GCB disease.

Additionally, 7 of 10 patients who were treated with CHOP maintained ongoing remission at over 9 months. To date, no patients have progressed, although Westin emphasized that progression-free survival and overall survival data were still immature at the time of the presentation; however, he noted that the data so far appear “pretty good.”

Moreover, depth of response was assessed via circulating tumor DNA (ctDNA) analysis in a population of 15 patients. Patients with a PET response had a CR rate of 80% and 20% had a PR.

“These 15 patients, 12 of whom had a [CR] on PET, their baseline disease burden based on ctDNA...showed no difference in tumor burden,” Westin explained. “When we look at their [PhasED Seq Response] response on Smart Stop, we see that fully one-third of patients have already achieved a completely undetectable disease burden based on this ultra-sensitive assay. After the four cycles, this compares in a similar fashion to what we've seen from prior cohorts with R-CHOP. All told, 87% of patients in this early analysis have had a molecular response defined by greater than two log reduction at this time point.”

Some of the any-grade toxicities observed included anemia and neutropenia in 87% of patients, maculo-papular rash in 43%, and infections in 30%; grade 3 or higher anemia, neutropenia, maculo-papular rash, and infections occurred in 17%, 60%, 13%, and 7% of patients, respectively. In those who received LTRA alone and LTRA/CHOP, any-grade anemia in 63% and 53% of patients, neutropenia in 40% and 80% of patients, maculo-papular rash in 43% and 10%, and infections in 13% and 17%, respectively.

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. Blood. 2023;142(suppl 1):856. doi:10.1182/blood-2023-180381
2. Westin J, David RE, Feng L, et al. Smart Start: rituximab, lenalidomide, and ibrutinib in patients with newly diagnosed large b-cell lymphoma. J Clin Oncol. 2023;41(4):745-755. doi:10.1200/JCO.22.00597.