July 12, 2017 is a day worth remembering, no matter for Novartis, FDA or tumor immunotherapy: the marketing application of Novartis’ CAR-T therapy Tisagenlecleucel (CTL-019) evaluated by the FDA Oncologic Drugs Advisory Committee (ODAC) on this day. According to the latest news, the advisory committee of FDA unanimously (10:0) recommended approval of the BLA of Tisagenlecleucel, with indications of relapsed or refractory (r/r) pediatric and young adult patients with acute lymphoblastic leukemia (ALL). FDA will make the final review on October 3 based on the comments. This is undoubtedly an important moment as there is only the final mile for the marketing of the world’s first CAR-T. The followings are my introduction to the main discussion content of this advisory committee meeting, and sharing of the core data of this product.

Site of FDA ODAC

I. Advisory committee: most concerned about the examination of short-term and long-term safety

FDA issued a review document on July 10, 2017 which discloses the core data: Study B2202. The industry believes that the short-term and long-term safety of the product is a focus in the review of the advisory committee. A report of EvaluatePharma also shows that the clinical benefits of CTL-019 are unquestionable, and the efficacy duration, convenience, and long-term and short-term toxicity are important issues much concerned about in the industry. The concerns are summarized as follows:

1. Relapse: The relapse is a very important bug of CAR-T product, and Novartis’ data are satisfactory in this regard: according to the open review document issued by FDA, in Study B2202, among the 52/63 patients achieved remission, 29 still maintained remission in 1-year follow-up; in ELIANA trial, the relapse-free probability of patients was 75% at month 6 of ELIANA.

2. Product quality control: It is very important to control the risk and accomplish product quality control, as the preparation of CAR-T is relatively tedious.

3. Short-term and long-term toxicity: The short-term toxicity includes cytokine release syndrome and neurotoxicity, and long-term toxicity includes wrong integration of CAR, or the long-term safety after T cell modification, which Novartis shall pay attention to for a long time.

4. Clinical benefits: I mentioned previously that clinical benefits are the key for a drug to be approved, and this is also a core issue FDA is concerned about. Therefore, Novartis needs to answer the problem that what are the advantages of CAR-T product over chemotherapies or Blinatumomab.

II. Review of core data of Novartis’ Tisagenlecleucel (CTL-019): a victory of tumor immunotherapy

The cute girl Emliy Whitehead was diagnosed leukemia in a critical condition in 2012, and it was the groundbreaking clinical trial at that time, i.e., today’s CTL-019, that saved Emily, and now she is 12 years old. What a miracle the tumor immunotherapy has brought!

The typical tumor immunotherapies are PD-1 immune checkpoint inhibitor and CAR-T. The marketing application for Tisagenlecleucel (CTL-019) filed to FDA by Novartis obtained the priority review, and ELIANA clinical study (NCT02435849) was the core data supporting that application. The data showed that the complete remission of CTL-019 reached 82%, 58% of patients showed grade 3 or grade 4 cytokine storm, and there was no malignant death event. The high survival rate data from 6 months to 12 months were very important. Novartis announced the JULIET Phase II clinical study of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) during 2017 AACO annual meeting, showing 45% overall response rate and 37% complete response.

Tisagenlecleucel has now been obtained breakthrough therapy designation and priority review. We will wait the final review on October 3. In my opinion, despite its issues, Tisagenlecleucel will be successfully approved, which is for sure. However, there are many challenges facing the true commercialization of CAR-T, and I don’t know whether the treatment fee of USD 600 thousand/year is workable; in addition, I also don’t know whether CAR-T therapy can handle leukemia patients by itself or whether bone marrow transplantation is still needed.