FDA Grants RMAT Designation to Tisagenlecleucel in R/R Follicular Lymphoma

The FDA has granted a Regenerative Medicine Advanced Therapy (RMAT) designation to the chimeric antigen receptor (CAR) T-cell therapy, tisagenlecleucel (Kymriah), for an investigational new indication as treatment of patients with relapsed or refractory follicular lymphoma (FL), announced Novartis in a press release.

Regulatory filing with the FDA is currently expected to be completed for this indication next year. If approved, this would mark the third indication for tisagenlecleucel, which was the first FDA-approved CAR T-cell therapy and has indications in relapsed or refractory acute lymphoblastic leukemia and relapsed or refractory diffuse large B-cell lymphoma.¹

“This designation supports the advancement of Kymriah, which could potentially address an unmet need in certain patients with follicular lymphoma, as we strive to reimagine medicine at Novartis. These patients are often faced with the burden of several years of various treatments as their disease continues to progress.” said John Tsai, MD, head of Global Drug Development and chief medical officer, Novartis.

The RMAT was granted based on preliminary clinical evidence from the phase II ELARA trial, which is investigating the efficacy and safety of tisagenlecleucel in relapsed or refractory FL. The study design was presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting by Michael Dickinson, MBBS.²

ELARA is a single-arm, multicenter, open-label trial enrolling patients aged 18 years or older who have radiographically measurable grades 1, 2, or 3A relapsed or refractory FL. Patients should be refractory to second-line or later systemic therapy, which should have included a CD20-directed antibody and an alkylator. The criteria for relapse includes relapse within 6 months of completing second or later line systemic therapy, relapse within 6 month following maintenance completion, or relapsed after autologous hematopoietic stem cell transplant (HSCT). Patients are ineligible for treatment in ELARA if they have central nervous system involvement or have received prior anti-CD19 therapy, gene therapy, adoptive T-cell therapy, or allogeneic HSCT.

The primary end point of the study is complete response (CR) per Lugano classification response criteria. The study will also evaluate for secondary end points, which include overall response rate (ORR), duration of response, overall survival, cellular kinetics, immunogenicity, safety, and patient-reported outcomes. The target enrollment number is 113 patients and the study is still actively recruiting.

Prior research has shown that 20% of patients with FL relapse within 2 years of receiving frontline chemoimmunotherapy, and standard therapies like autologous and allogeneic HSCT do not improve outcomes for these individuals.

Approved targeted therapies like idelalisib (Zydelig) and copanlisib (Aliqopa) have efficacy for patients with relapsed or refractory FL, but this efficacy can be improved upon. Specifically, idelalisib achieved an ORR of 56%, which included CRs in 47% of patients and partial responses (PRs) in 14% of patients. The median progression-free survival (PFS) observed with idelalisib was 11.0 months, according to results from the phase II DELTA study (NCT01282424).³ Copanlisib demonstrated an ORR of 58% including CRs in 14% of patients and PRs in 44% of patients. The median PFS seen with copanlisib was 12.2 months, according to results from the phase III CHRONOS-3 (NCT02367040) and phase III CHRONOS-4 (NCT02626455) clinical trials.⁴

Based on the known efficacy of tisgenlecleucel shown in the 2 single-arm, pivotal, phase II clinical trials (ELIANA NCT02626455 and JULIET NCT02445248), the agent was considered likely to show activity in patients with FL. The approval of tisgenlecleucel for this indication would serve an unmet need for patients with relapsed or refractory FL.

_References

_{1. Novartis Kymriah® receives FDA Regenerative Medicine Advanced Therapy designation in follicular lymphoma [new release]. Basel, Switzerland: Novartis; April 22, 2020. https://bit.ly/2Krk2RK. Accessed April 22, 2020.}

_{2. Dickinson M, Popplewell L, Kolstad A, et al. ELARA: A phase II, single-arm, multicenter, open-label trial investigating the efficacy and safety of tisagenlecleucel in adult patients with refractory/relapsed follicular lymphoma (r/r FL). Presented at: American Society of Clinical Oncology Annual Meeting; May 31–June 4, 2019; Chicago, IL. Poster TPS7573.}

_{3. Sulles G, Schuster SJ, Gopal AK, et al. Efficacy and safety of idelalisib in patients with relapsed, rituximab- and alkylating agent-refractory follicular lymphoma: a subgroup analysis of a phase 2 study. Haematologica. 2017 102 (4): e156-e159. doi: 10.3324/haematol.2016.151738.}

_{4. Aliqopa (capanlisib) for injection [prescribing information]. Whippany, NJ: Bayer HealthCare Pharamceuticals, Inc.}