BTK Inhibitors, CAR T-Cell Therapy Drive Paradigm Changes in Follicular Lymphoma

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The landscape of follicular lymphoma (FL) treatment is rapidly evolving, with the emergence of novel therapeutic modalities offering significant promise for patients, according to Erin Mulvey, MD.

Recent advancements in targeted therapies, including Bruton's tyrosine kinase (BTK) inhibitors and chimeric antigen receptor (CAR) T-cell therapy have demonstrated notable efficacy and improved outcomes for patients with relapsed or refractory FL–even leading to newer FDA approvals.

At the 42nd Annual Chemotherapy Foundation Symposium, Mulvey, assistant professor of medicine at Weill Cornell Medical College in New York, New York, discussed the growing landscape, with new treatment options coming down the pike for patients with relapsed/refractory FL.¹

BTK Inhibitors

In the third line, the BTK inhibitor zanubrutinib (Brukinsa) in combination with obinutuzumab (Gazyva) has recently been approved by the FDA for FL based on data from the ROSEWOOD study (NCT03332017).²

“This combination was just approved earlier this year for use in the third-line setting and beyond. Patients were eligible if they received 2 or more prior lines of therapy, including an anti-CD20 antibody and an alkylating agent, and importantly, patients who were not previously exposed to the BTK inhibitor,” said Mulvey.

The open-label, multicenter, phase 2 ROSEWOOD trial involved 217 adult patients with relapsed or refractory FL that had at lease 2 prior systemic therapies. Patients were randomly assigned 2:1 to receive zanubrutinib at a dose of 160 mg orally twice daily plus obinutuzumab at a dose of 1000 mg intravenously, or obinutuzumab alone at the same dosage and schedule. The treatment cycle was 28 days for both groups and obinutuzumab was given on days 1, 8, and 15 of cycle 1; day 1 of cycles 2 through 6; and once every 8 weeks until disease progression, toxicity, or a maximum of 2 years.

The overall response rate (ORR) was 68% in the experimental arm vs 43% in the obinutuzumab alone-arm (P = .001), and the complete response (CR) rate was 39% vs 19%, respectfully. The duration of response (DOR) was not reached in the experimental arm vs 26.5 months in the obinutuzumab alone-arm (HR, 0.5; P =.001).

The median age in the experimental arm was 63.0 (range, 31-84) and 65.5 (range, 32-88) in the obinutuzumab alone-arm. There were 21 patients from mainland China in the experimental arm vs 12 in the obinutuzumab alone-arm and 124 patients from the rest of the world vs 60 patients, respectively. Overall, the median prior lines of therapy were 3 (range, 2-11), and 211 patients had a ECOG performance score of 0 or 1.

The primary end point of the study was ORR assessed by independent central review (ICR). Secondary end points included ORR assessed by the investigator, DOR, and progression-free survival (PFS) determined by ICR and investigator review, overall survival (OS), CR rate, and cardiac magnetic resonance also assessed by ICR and investigator.

Regarding secondary end points, the DOR rate at 18 months was 70.9% in the experimental arm vs 54.6% in the obinutuzumab alone-arm, and the median PFS was 27.4 months (95% CI, 16.1-not evaluable [NE]) vs 11.2 months (95% CI, 6.5-15.7), respectively. Time to next treatment was NE (95% CI, 21.1-NE) in the experimental arm vs 12.1 (95% CI, 8.3-19.8) months, and the median OS was NE in both arms ([95% CI, 31.4-NE] vs [95% CI, 26.8–NE], respectively). The study was not powered to detect OS differences, investigators noted.

In addition to 2 or more prior lines of therapy other inclusion criterion were measurable disease, ECOG performance status score of 0 to 2, and absence of transformation to aggressive B-cell lymphoma, according to investigators.

“Toxicities were fairly predictable,” Mulvey noted. “The most common toxicities were hematologic. Not unsurprisingly, the combination was associated with more frequent grade 3 or higher adverse events [AEs]. Specifically, the more common [ AEs were] thrombocytopenia [n=22], diarrhea (n=4), pneumonia [n=14], and dyspnea [n=3]. Both arms have a relatively high incidence of grade 3 or higher,” she stated. In contrast, these grade 3 AEs in the obinutuzumab-alone arm occurred in 5, 1, 3, and 0 patients, respectively.

CAR T-Cell Therapy

Mulvey also addressed data on the 3 currently approved CAR T-cell therapies: axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (tisa-cel; Kymriah), and lisocabtagene maraleucel (liso-cel; Breyanzi).

According to data from the phase 2 ZUMA-5 trial (NCT03105336), 94% of patients with relapsed FL responded to axi-cel, including 79% with a CR, 15% with a partial response (PR), 3% with stable disease, 2% were unknown, and no patients had progressive disease. The estimated median PFS in all patients (n = 159) was 40.2 (95% CI, 28.9-NE), and the 36-month estimated PFS rate was 54% (95% CI, 45%-63%). The median OS in all patients was not reached (95% CI, NE-NE) and the rate at 36 months was 75% (95% CI, 67%-81%). “Bridging chemotherapy was permitted, but it was uncommonly used with only 3% of patients receiving it,” Mulvey noted.

For patients who had most recent exposure to bendamustine within the last 6 months prior to CAR T-cell treatment, “the 36-month estimated PFS is only 25% vs 70% for patients who had no prior bendamustine exposure,” Mulvey stated. Axi-cel was shown to improve both PFS and OS vs historic controls, she added.

For tisa-cel, the phase 2 ELARA (NCT03568461) trial showed that at a median follow-up of 17 months, the ORR was 86%, CR rate was 69%, and the 12-month PFS rate was 67%. At 29 months high response rates were confirmed in patients with high-risk disease, showing sustained response rates, Mulvey added. The probable PFS rate for all patients at 12 months was 67.2% (95%CI, 53.3%-75.9%) and at 24-month rate was 57.4% (95% CI, 46.2%-67.0%).

The TRANSCEND trial (NCT02631044) evaluating liso-cel, showed an ORR of 97% (95% CI, 91.6%-99.4%; P = .0001) in patients treated in the third line of therapy (n = 101) and a CR rate of 94% (95% CI, 87.5%-97.8%; P = .0001a). Any grade CRS occurred in 58% of patients and grade 3 CRS in 1%. In a median follow-up of 18.7 months, both the PFS and OS were not reached, regardless of which line of therapy the patient was treated in.

“This is not meant to be a direct head-to-head comparison, but to highlight some differences between these CAR T-cell therapies. From the ELARA study, using tisa-cel, there was a higher risk for both patients with the highest percentage and higher-risk scores, high tumor bulk, and lines of therapy more than the other studies. There were more patients who are refractory to axi-cel therapy, for double refractories in both CD20 antibody and alkylating agents, higher percentage of POD24 and correspondingly, more patients who received virgin therapy,” Mulvey said.

References

1. Mulvey, E. Expanded options for follicular lymphoma in 2024: a focus on BTKi, CAR-T, and bispecific antibodies. Presented at: Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® Conference; on November 13-15, 2024; New York, New York.

2. FDA grants accelerated approval to zanubrutinib for relapsed or refractory follicular lymphoma. FDA. March 7, 2024. Accessed November 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanubrutinib-relapsed-or-refractory-follicular-lymphoma