Tisagenlecleucel was found to elicit clinically meaningful activity in patients with relapsed/refractory follicular lymphoma, meeting the phase 2 ELARA trial’s primary end point of complete response rate.
Tisagenlecleucel (Kymriah) was found to elicit clinically meaningful activity in patients with relapsed/refractory follicular lymphoma, meeting the phase 2 ELARA trial’s primary end point of complete response (CR) rate, according to an announcement from Novartis.1
“We are pleased that [tisagenlecleucel] is showing meaningful results and may provide a potentially definitive treatment option for patients with relapsed and refractory follicular lymphoma,” John Tsai, MD, head of Global Drug Development and chief medical officer of Novartis, stated in a press release. “These results further support our efforts to reimagine medicine in this incurable malignancy and reach this underserved patient population, who are historically burdened with several years of various treatments.”
Tisagenlecleucel was the first CAR T-cell therapy to receive FDA approval and this first CAR T-cell product to be approved in 2 distinct indications, according to Novartis. The product was developed in collaboration with the Perelman School of Medicine at the University of Pennsylvania.
In April 2020, the FDA granted a Regenerative Medicine Advanced Therapy designation to tisagenlecleucel for the treatment of patients with relapsed/refractory follicular lymphoma based on preliminary data from the multicenter, ongoing ELARA trial (NCT03568461).
The single-arm, open-label, phase 2 trial is enrolling patients aged 18 years or older with grade 1, 2, or 3A relapsed/refractory follicular lymphoma. To be eligible for enrollment, patients had to have radiographically measurable disease at the time of screening.2 If patients had central nervous system involvement or received previous treatment with an anti-CD19 therapy, gene therapy, adoptive T-cell therapy, or allogeneic hematopoietic stem cell transplantation, they could not participate.
The primary end point of the trial is complete response (CR) based on Lugano classification response criteria per independent review committee assessment.3 Key secondary end points include overall response rate (ORR), including CR rate and partial response (PR) rate, duration of response (DOR), overall survival (OS), safety, cellular kinetics, immunogenicity, and patient-reported outcomes.
The estimated enrollment for the trial is 113 patients across 14 countries. The study launched on November 12, 2018, and the estimated primary completion date is February 18, 2021. The estimated study completion date is August 24, 2022.
Data from the trial will be included in regulatory submissions, with filing in the United States projected in 2021, according to Novartis; submissions in Europe will follow. Data will also be presented at an upcoming medical conference.
In August 2017, tisagenlecleucel was approved for use in patients 25 years or younger with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse. The indication was expanded in 2018 for use in adult patients with relapsed/refractory, high-grade, B-cell lymphoma and diffuse large B-cell lymphoma (DLBCL) arising from follicular lymphoma, following 2 or more lines of systemic treatment.
The regulatory decision was based on findings from the phase 2 JULIET trial, which showed that the CAR T-cell therapy elicited an ORR of 50% (95% CI, 38%-62%) in adult patients with DLBCL.4 Furthermore, the CR rate with the product was 32%, while the PR rate was 18%. The median DOR with tisagenlecleucel had not yet been reached.
Updated data presented during the 2018 ASH Annual Meeting confirmed the durable benefit that had been observed with the CAR T-cell product.5 At a median follow-up of 19 months, the ORR was 54% (95% CI, 41%-62%) with tisagenlecleucel; this included a CR rate of 40%. Again, the median DOR had not yet been reached. Notably, 54% of patients who initially experienced a PR with the agent had converted to a CR.
At the data cutoff of May 21, 2018, a total of 167 patients were enrolled on the trial and 115 had received tisagenlecleucel at a single dose of a median of 3.0 x 108 CAR-positive T cells. The majority of patients, or 90%, had received bridging therapy and 93% had received lymphodepleting chemotherapy before CAR T-cell infusion. The median time from infusion to data cutoff was 19.3 months.
The median age of participants was 56 years and 23% were aged 65 or older. Seventy-seven percent of patients had stage III/IV DLBCL at baseline, while 17% had double or triple hit disease. Fifty-five percent of patients had the germinal center subtype and 43% had activated B-cell DLBCL. Just under half of patients (49%) underwent a prior stem cell transplant and 51% received 3 or more previous lines of treatment.
Additional data demonstrated a 6-month relapse-free survival rate of 66% (95% CI, 51%-78%); at 12 months and 18 months it was 64% (95% CI, 48%-76%). The median OS for all patients who underwent CAR T-cell infusion was 11.1 months, but it was not reached for those who achieved a CR with the agent. The 12-month OS rate was 48% (95% CI, 38%-57%), while the OS rate at 18 months was 43% (95% CI, 33%-53%).
With regard to safety, adverse effects (AEs) remained consistent between the primary analysis and the follow-up analysis, with no new deaths reported. Fifty-seven percent of participants had any-grade cytokine release syndrome; in 14% it was grade 3 and in 9% it was grade 4. Moreover, 20% of patients experienced neurological toxicities with the CAR T-cell product; 7% were grade 3 and 4% were grade 4.
Other AEs of interest included prolonged cytopenias (45%) and infection (37%). Fifteen percent of participants had febrile neutropenia and 2% had tumor lysis syndrome.