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Zandelisib, a potent and selective oral PI3Kδ inhibitor, elicited a high overall response rate as a single agent in heavily pretreated patients with relapsed or refractory follicular lymphoma, according to data from the phase 2 TIDAL trial.
Zandelisib, a potent and selective oral PI3Kδ inhibitor, elicited a high overall response rate (ORR) as a single agent in heavily pretreated patients with relapsed or refractory follicular lymphoma (FL), according to data from the phase 2 TIDAL trial (NCT03768505) presented at the 2022 EHA Congress.1
In the primary efficacy population (n = 91), the ORR was 70.3% comprising a complete response (CR) rate of 35.2% and a partial response (PR) rate of 35.2%. Responses occurred early in the treatment cycle: 87.5% of all responses were achieved by the end of cycle 2 and 75.0% of CRs were achieved by the end of cycle 4. The disease control rate was 85%.
Of note, patients enrolled in TIDAL received zandelisib on an intermittent dosing schedule. “The maximum-tolerated dose was not identified [in the phase 1b study (NCT02914938)], and 60 mg was the lowest dose we analyzed and was recommended for phase 2,” Wojciech Jurczak, MD, PhD, a professor in the department of clinical oncology at Maria Sklodowska-Curie National Research Institute of Oncology in Kraków, Poland, said in a presentation of the data. “Furthermore, we developed intermittent dosing schedule with the drug given on days 1 to 7, and then 3 weeks off. This schedule was introduced to allow for Treg repopulation and to mitigate the immune-mediated adverse events [AEs] of special interest without losing the disease control.”
Specifically, patients with relapsed or refractory grade 1 to 3 FL who had progressive disease after at least 2 prior therapies including an anti-CD20 antibody and an alkylating agent, received 60 mg of zandelisib daily for two 28-day cycles. Patients received daily zandelisib on days 1 to 7 followed by 3 weeks off therapy from cycle 3 onward until progressive disease or intolerance.
Jurczak noted that the trial was initially designed to include a randomization of patients to a continuous daily dosing arm vs daily for 2 cycles in the intermittent dosing arm. The continuous dosing arm was closed after maturing data from the phase 1b study demonstrated better tolerability and a high rate of durable responses on the intermittent schedule.
The primary efficacy outcome of TIDAL is ORR in the primary efficacy population assessed by independent review committee using Lugano classification criteria, analyzed 6 months after the last patients was enrolled. Data cutoff for the presented analysis was September 30, 2021.
At baseline, among 121 patients enrolled, the median age was 64 years (range, 31-87) and 48.8% of patients were aged 65 years or older. More than half of participants were men (61.2%) and had an ECOG performance status of 0 (64.5%). Most patients had stage III/IV disease (81%).
The median number of prior therapies was 3 (range, 2-8) and 95.9% had received prior chemoimmunotherapy. Other therapies included a combination of prior anti-CD20 antibody plus lenalidomide (Revlimid) myeloablative therapy and stem cell transplant (16.5% and 23.1%, respectively). Nearly half of patients (41.3%) were refractory to their last administered therapy and 56.2% had disease progression within 2 years. Additionally, 38.8% of patients received the last therapy within 6 months of enrollment to TIDAL.
“Our baseline demographics reflected the typical relapsed or refractory FL population,” Jurczak said. “We have a majority of [individuals] with large tumor bulk—33.9% exceeding 5 cm [and] 15.7% exceeding 7 cm.”
Additional efficacy data was stratified by response to last treatment (relapsed [n = 49] vs refractory [n = 42]), number of prior therapies (2 [n = 42] vs ≥ 2 [n = 49]), and by progression of disease within 2 years (yes [n = 51] vs no [n = 40]).
The ORR for patients who had relapsed disease was 75.5% with a CR rate of 40.8% and a PR rate of 34.7% compared with a 64.3% ORR, 28.6% CR rate, and 35.7% PR rate for patients with refractory disease. For those who received only 2 prior therapies the ORR was 78.6% with a CR rate of 42.9% and a PR rate of 35.7% compared with an ORR of 63.3% and a CR rate and a PR rate of 28.6% and 34.7%, respectively, among those who were heavily pretreated. The ORR, CR, and PR for those with progression at 2 years was 66.7%, 31.4%, and 35.3%, respectively, compared with 75.0%, 40.0%, and 35.0%, respectively, among those did not have disease progression in that time frame.
“We could summarize that the efficacy of the drug was exemplary,” Jurczak noted.
The safety population included 121 patients who received zandelisib on the intermittent dosing schedule. At a median follow-up of 9.4 months (range, 0.8-24) the most common AEs were diarrhea (33%) and neutropenia (26%). Jurczak noted that only 6% of patients who reported diarrhea had grade 3 events, but that half of the reported neutropenia events were grade 4. Patients responded to treatment with growth factor support with granulocyte-colony stimulating factor therapy.
“The functional disorders of GI [gastrointestinal] tract [such as] abdominal pain, diarrhea, and constipation, were all in grade 1 and 2. Rashes were identified, but less than 2% of patients had a grade 3 [event],” Jurczak said.
At data cutoff, 16 patients (13.2%) discontinued treatment due to any AE and 12 (9.9%) discontinued due to treatment-related AE. In terms of grade 3 AEs of special interest, investigators reported the following: diarrhea (4.9%), rash (3.3%), stomatitis (2.5%), colitis (1.7%), increased aspartate transaminase (0.8%), increased alanine transaminase (0.8%), and noninfectious pneumonitis (0.8%).
“[Grade 3 AEs of special interest] were not common [and] we had no grade 4 AEs of special interest,” Jurczak said. “The cumulative incidence of grade 3 AEs did not exceed 20% and the vast majority of them—over 80%—occurred during the first 3 cycles once we had a continuous therapy.”
Five grade 5 treatment-emergent AEs included 4 cases of COVID-19, 1 case of pneumonia, and 1 case of tumor lysis syndrome. Treatment-emergent COVID-19 infections occurred in 10 patients (8.3%).
“It should be noted that all [COVID-19 deaths] were in early 2020, in a prevaccination era,” Jurczak said. “We haven’t lost any patients since the vaccination schedule was introduced and molnupiravir [Lagevrio] and Paxlovid [nirmatrelvir with ritonavir] were available.”
Excluding COVID-19 other grade 3 infections included 2 cases of pneumonia and 2 cases of febrile neutropenia, as well as 1 case each of campylobacter gastroenteritis, lower respiratory tract infection, cytomegalovirus colitis, pneumocystis pneumonia, urinary tract infection, and vestibular neuronitis.
“These data support evaluation of zandelisib on intermittent dosing as a single agent or in combination in various B-cell malignancies, both in relapsed disease and earlier lines of therapy,” Jurczak said.
Of note, another data cutoff is planned for approximately 14 months after the last patient in the primary efficacy population is enrolled. This analysis will include duration of response and more mature safety results.
A phase 3 randomized study evaluating zandelisib plus rituximab (Rituxan) vs chemoimmunotherapy in relapsed or refractory FL and marginal zone lymphoma (COASTAL; NCT04745832) is underway and actively recruiting patients.
Zelenetz AD, Jurczak W, Ribrag V, et al. Efficacy and safety of zandelisib administered by intermittent dosing (ID) in patients with relapsed or refractory (R/R) follicular lymphoma: primary analysis of the global phase 2 study TIDAL. Presented at: 2022 EHA Congress; June 9-17, 2022; Vienna, Austria. Abstract S208.