PI3K Inhibitors and CAR T-Cell Therapy Find Their Niche in Indolent B-Cell Lymphomas

In relapse/refractory follicular lymphoma (FL), promising results have been observed with PI3K inhibitors and are encouraging because of the less than optimal outcome associated with Bruton's tyrosine kinase inhibitors (BTK). ^1,2 PI3K inhibitors, such as copanlisib (Aliqopa) and umbralisib (Ukoniq), the EZH2 inhibitor tazemetostat (Tazverik), and axicabtagene ciloleucel (axi-cel; Yescarta), have shown favorable results.

These third-line regimens and their treatment activity updates were presented at the National Comprehensive Cancer Network (NCCN) Annual Conference 2022 by Ann S. LaCasce, MD, MMSc, director of the Mass General Brigham Fellowship in Hematology and Oncology at the Dana-Farber Cancer Institute and associate professor at the Harvard Medical School.³

PI3K Inhibitors

Copanlisib was studied in a phase 2 trial (NCT01660451) in 142 patients with relapsed or refractory indolent lymphoma.⁴ Patients received 60 mg intravenously on days 1, 8, and 15 of a 28-day cycle. The overall response rate (ORR) was 59%, the complete remission (CR) rate was 14%, and the median progression-free survival (PFS) rate was 11.2 months (95% CI, 0.2-24.0). Copanlisib had a manageable safety profi le in these patients; the most common any grade adverse events (AEs) reported were hypertension (61%), hyperglycemia (50%), and diarrhea (34%).

A subsequent study compared rituximab (Rituxan) plus copanlisib vs placebo plus rituximab in patients with relapsed/refractory indolent lymphoma (NCT02626455).⁵ Investigators randomly assigned patients 2:1 to receive the copanlisib combination (n = 307) or the placebo combination (n = 151). About 60% of patients in both cohorts had follicular lymphoma (n = 184 and n = 91, respectively). The median PFS of patients with FL was 22.2 months (95% CI, 17.8-33.1) in the copanlisib arm vs 18.7 months (HR, 0.58; 95% CI, 10.2-21.1; P = .0014). Benefit was also seen in the copanlisib combination in patients with other forms of indolent lymphoma.

Umbralisib, the other beneficial PI3K inhibitor, was tested in 208 patients with indolent lymphoma, 56% (n = 117) of whom had FL. Investigators in this multicohort, open-label, phase 2b study (NCT02793583) administered 800 mg of umbralisib orally once daily until disease progression, unacceptable toxicity, or study withdrawal.⁶ Those in the FL cohort experienced an ORR of 45%, a CR of 6%, and a median PFS of 10.6 months (95% CI, 7.2-13.7). Forty-three patients (37%) had more than 3 prior regimens. Any grade neutropenia and diarrhea occurred in 16% and 59% of patients, respectively. Grade 3 neutropenia was found in 12% and grade 3 diarrhea was found in 10%.

EZH2 Inhibitor

LaCasce spotlighted EZH2 mutations and how they are present in approximately 20% of patients with FL. Investigators found tazemetostat was active in both EZH2-mutant and EZH2–wild-type lymphomas (TABLE7 ).

In an open-label, single-arm, phase 2 trial (NCT01897571), tazemetostat was given in 800 mg doses orally twice per day in 28-day cycles to patients who had EZH2- mutant (n = 45) or EZH2–wild-type (n = 54) FL.⁷ Assessed by an independent radiology committee, 31 patients (69%; 95% CI,53%- 82%) in the EZH2-mutant arm had an objective response rate compared with 19 patients (35%; 95% CI, 23%-49%) in the EZH2–wildtype arm.

CR occurred in 6 patients (13%) in the mutant group and in 2 patients (4%) in the wild-type group. The median PFS was comparable between the 2 arms. The EZH2-mutant arm had a median PFS of 13.8 months (95% CI, 10.7-22.0) vs the EZH2–wild-type arm, which had a median PFS of 11.1 months (95% CI, 3.7-14.6).

LaCasce commented: “This is a very well tolerated drug. It has a significantly favorable toxicity profile. So this is a very good option in patients who are elderly, or those who do not have bulky or rapidly progressive disease, particularly those with wild-type EZH2 who may be able to do well with stable disease for some period of time.”

CAR T-Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy is active and has changed the field in aggressive B-cell lymphoma in the relapsed refractory setting, LaCasce said. In the ZUMA-5 trial (NCT03105336), a single-arm, multicenter, phase 2 trial, investigators enrolled 153 patients with indolent lymphoma who underwent leukapheresis and axi-cel.⁸

At the data cutoff, 148 patients received an infusion of axi-cel, and 124 (84%) had follicular lymphoma. The ORR was 94% of patients with FL, and the complete remission rate was 8%. Median PFS was not reached in patients with FL.

Any grade neurological events occurred in 56% of patients, and any grade cytokine release syndrome (CRS) occurred in 78% of patients. Grade 3 or higher neurological events appeared in 6%, and grade 3 or higher CRS appeared in 15%.

“Although we need longer follow-up, there is the possibility of durable remission making this a very appealing option for young patients,” LaCasce said.

REFERENCES

1. Gopal AK, Schuster SJ, Fowler NH, et al. Ibrutinib as treatment for patients with relapsed/refractory follicular lymphoma: results from the open-label, multicenter, phase II DAWN study. J Clin Oncol. 2018;36(23):2405-2412. doi:10.1200/JCO.2017.76.8853

2. Davids MS, Roberts AW, Seymour JF, et al. Phase I fi rst-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35(8):826-833. doi:10.1200/ JCO.2016.70.4320

3. LaCasce, AS. Updates to the management of patients with relapsed/refractory indolent B-cell lymphomas: follicular lymphoma. Presented at: NCCN Annual Conference 2022; March 31-April 2, 2022; Orlando, FL. Accessed April 13, 2022. https://nccn.digitellinc. com/nccn/sessions/565/view

4. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017;35(35):3898-3905. doi:10.1200/JCO.2017.75.4648

5. Matasar MJ, Dreyling M, Leppä S, et al. Feasibility of combining the phosphatidylinositol 3-kinase inhibitor copanlisib with rituximab-based immunochemotherapy in patients with relapsed indolent B-cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2021;21(11):e886-e894. doi:10.1016/j.clml.2021.06.021

6. Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib, a dual PI3Kδ/ CK1ε inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol. 2021;39(15):1609-1618. doi:10.1200/JCO.20.03433

7. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433- 1442. doi:10.1016/S1470-2045(20)30441-1

8. Jacobson CA, Chavez JC, Sehgal AR, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022;23(1):91- 103. doi:10.1016/S1470-2045(21)00591-X