July 2017 Edition Vol.11, Issue 7

ODAC Recommends First Potential Gene Therapy and Two Biosimilars

By Megan Garlapow, PhD

Oncologic Drugs Advisory Committees (ODAC) met 4 times in 3 days the week of July 10 to make recommendations on 4 different agents. Though the FDA uses ODAC to obtain independent expert advice on whether a product should be approved, the agency is not required to follow the advice of ODAC.


First Commercially Available CAR-T Cell Therapy on the Horizon

Chimeric antigen receptor-T (CAR-T) cell therapy was big news. On July 12, 2017, ODAC reviewed Novartis Pharmaceuticals’ Biologics License Application (BLA) for intravenous CAR-T cell therapy, tisagenlecleucel-T suspension (CTL019), for the treatment of pediatric and young adult patients 3 to 25 years of age with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). ODAC voted unanimously (10-0) for CTL019, and if FDA approved, it would become the first commercially available therapy of its kind.

Data submitted to support the BLA were results from the pivotal Phase 2 ELIANA trial (NCT02435849), which showed a complete response rate of 83% in young patients with r/r ALL.1 CTL019 may offer an effective treatment option for patients for whom there exist very few therapeutics.

The FDA gave CTL019 Breakthrough Therapy designation, and the biologic is under Priority Review. Novartis intends additional filings in the United States and in the European Union via the European Medicines Agency later this year, for adults with r/r diffuse large B-cell lymphoma.

The process of CTL019 involves removing a patient’s own T cells via cryopreserved leukepheresis. The cells are then sent to the manufacturing plant where they are genetically coded to express a chimeric antigen receptor that recognizes and attacks cancer cells and B cells expressing a specific antigen. The genetically coded cells are then infused back into the patient.

Potential long-term adverse events, such as secondary cancers caused by the CAR-T cells, were a concern expressed by ODAC. Long-term monitoring of safety could require the creation of a registry for patients so that they can be followed for 15 years to evaluate subsequent malignant transformation.


“[T]isgenlecleucel is a genetically modified product that has potential for the integration of the lentiviral vector, clonal outgrowth, or neoplastic transformation of transduced host cells,” wrote the FDA in a briefing.Additionally, the adverse events can be severe for this therapy, the most prominent of which is B-cell aplasia in all treated patients, which requires long-term monitoring and therapy. Other concerning adverse events include neurological toxicity and cytokine release syndrome.1

Novartis established a Risk Evaluation and Mitigation Strategy (REMS) to address these safety concerns. The REMS includes strategies for communication with clinicians, such as a REMS factsheet, a CRS Management Algorithm, a REMS website, a Dear Healthcare Provider Letter for pediatric oncologists and for transplant specialists, and a wallet card for patients to carry.2

Nonetheless, ODAC voted unanimously in favor of CTL019, perhaps paving the way for subsequent indications for this biologic and for the whole field of CAR-T cell therapy. The FDA is expected to rule on the drug by the end of September.

Should this biologic receive FDA approval, future research should address which patients need a hematological stem cell transplant in addition to CTL019.


In the case of ABP 215

ODAC voted unanimously (17-0) to recommend approval of Amgen and Allergan’s proposed biosimilar ABP215 to its reference product Avastin [bevacizumab; Genentech].

This unanimous vote came as Amgen and Allergan seek to gain FDA approval for six indications, five of which are extrapolated, which allows an applicant to “seek licensure for one or more additional conditions of use for which the reference product is licensed.”3

Here are the indications:

  • For first- or second-line treatment of patients with metastatic colorectal cancer combined with intravenous 5-fluorouracil-based chemotherapy
  • Combined with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for the second-line treatment of patients with metastatic colorectal cancer who progressed on a first-line ABP215-containing regimen
  • Combined with carboplatin and paclitaxel for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC)
  • Combined with interferon alfa for treating patients with metastatic renal cell carcinoma
  • Combined with paclitaxel and cisplatin or paclitaxel and topotecan to treat persistent, recurrent, or metastatic cervical cancer
  • Glioblastoma with progressive disease after previous single-agent therapy

The non-extrapolated indication is for unresectable, locally advanced, recurrent or metastatic NSCLC. If the FDA approves ABP215, Amgen will still have to await the cessation of exclusivities for Avastin in platinum-resistant ovarian cancer and metastatic renal cell carcinoma and would need to submit a data package supporting the biosimilarity of ABP215 in these two indications.

The development of ABP215 as 100 mg per 4 mL and 400 mg per 16 mL single-use vials is the same strength and presentations as US-licensed Avastin, with proposed instructions for administration and dosing also the same.

Results from two studies supported ODAC’s unanimous recommendation. The first study, a three-arm, single-dose pharmacokinetics study, compared ABP215 with US- and EU-approved Avastin and with results from a comparative clinical trial. In this study, 68 patients received ABP215, and 67 patients each received US- and EU-licensed Avastin. This all-male cohort all received 3 mg/kg infusions.4

The CMAX between ABP215 and US-licensed Avastin was comparable at 98.1 (90% confidence interval [CI], 93.7-102.8). Between ABP215 and EU-licensed Avastin, CMAX was comparable at 102.9 (90% CI, 98.2-107.8) and comparable between US- and EU-licensed Avastin at 104.9 (90%ci, 100.1-109.9). Additionally, the 90% CI for the ratios of geometric mean of AUC0-∞ and AUC0-t demonstrated similar pharmacokinetics across comparisons.4

Researchers conducted the second study, a comparison of ABP215 (n=328) and EU-approved Avastin (n=314) in patients with advanced or metastatic NSCLC, to provide evidence of no clinically meaningful differences in response, safety, purity, and potency between ABP215 and Avastin. Patients received an infusion of 15 mg/kg once every three weeks combined with 6 AUC carboplatin and 200 mg/m2 paclitaxel for six cycles.4

Overall response rate (ORR) was 39% in the ABP215 arm and 41.7% in the Avastin arm (risk ratio, 0.93; 90% CI, 0.8-1.09). Two complete responses occurred in each arm. In the ABP215 arm, 38.4% of patients experienced a partial response, and 41.1% of patients in the Avastin arm experienced partial response. Duration of response was 5.8 months in the ABP215 arm (95% CI, 4.9-7,7) and 5.6 months in the Avastin arm (95%CI, 5.1-6.3). Progression-free survival was not significantly different between the two arms.4

“[T]he evidence indicate that the extrapolation of biosimilarity to the indications for which the Applicant is seeking licensure is scientifically justified,” stated the ODAC brief on ABP215.



ODAC also voted unanimously (16-0) to recommend FDA approval of Mylan’s proposed biosimilar MYL-1401O to Herceptin [trastuzumab; Genentech]. Mylan presented analytical, non-clinical, and clinical data to the FDA in support of its BLA, and results indicated no clinically meaningful differences between MYL-1401O and Herceptin with regards to safety, potency, and purity. Analytical and structural similarity was also indicated.

Mylan seeks FDA approval for MYL-1401O in the following indications:

  • Combined with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
  • Monotherapy for the treatment of patients with HER2-overexpressing breast cancer who have received one or more chemotherapy regimens for metastatic disease
  • For adjuvant treatment of HER2-overexpressing node-positive or node-negative breast cancer with docetaxel and carboplatin
  • As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, or as a single agent following multi-modality anthracycline based therapy;
  • Combined with cisplatin and capecitabine or 5-fluorouracil to treat patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not undergone previous therapy for metastatic disease

This unanimous vote came even though several committee members expressed concern that MYL-1401O had not been tested with Perjeta [pertuzumab; Roche], with which Herceptin is regularly combined. Officials from Mylan emphasized that there was no need to execute such tests as Herceptin had been tested with Perjeta.

“Residual uncertainty about biosimilarity that resulted from the differences in binding kinetics is adequately addressed by data that showed no impact of these differences on ADCC [antibody-dependent cellular cytotoxicity] and PK [pharmacokinetics],” stated the ODAC meeting brief.5

Mylan presented results from Phase 3 HERiTAge (NCT02472964) to support its BLA. In the first part of HERiTAge, a two-part, double-blind, randomized, parallel-group study, patients with HER2-positive metastatic breast cancer with no prior chemotherapy or Herceptin were randomized to MYL-1401O (n=230) or Herceptin (n=228), both with a taxane.

Both arms underwent 8 cycles, with administration of MYL-1401O or Herceptin at a loading dose of
8 mg/kg and a maintenance dose of 6 mg/kg once every three weeks until progression. In the second part of HERiTAge, patients continued with MYL-1401O or Herceptin if they had stable disease, partial response, or complete response.5

ORR, the primary endpoint, was similar between the two arms. At 24 weeks, ORR in the MYL-1401O was 69.6% vs. 64% in the Herceptin arms. The ratio of ORR for MYL-1401O to Herceptin was 1.09 (95% CI, 0.95-1.24). Median duration of response was 9.7 months in both arms at the 48-week cut-off. Progression-free survival and safety data were also comparable between the two arms. Median overall survival had not been reached in either arm.5

If the FDA approves MYL-14101O, cost and drug access could improve in the United States, according to Mylan’s president, Rajiv Malik.


Mylotarg for CD33-positive AML

On July 11, 2017, ODAC reviewed the BLA for Mylotarg [gemtuzumab ozogamicin; Wyeth Pharmaceuticals Inc] indicated for IV use in combination with daunorubicin and cytarabine for the treatment of adult patients with previously untreated, de novo acute myeloid leukemia (AML); Wyeth is a subsidiary of Pfizer.

ODAC voted in favor of Mylotarg (6-1), indicating a favorable risk-to-benefit profile for the drug at a dose of 3 mg/m2 on days one, four, and seven added to chemotherapy in patients with de novo CD33-positive AML. The FDA’s decision on whether it approves Mylotarg is expected by September 2017. Mylotarg was originally approved in 2000, via the FDA’s accelerated approval program, to treat patients with CD33-positive AML who had experienced a first relapse and were 60 years or older.

Pfizer voluntarily withdrew Mylotarg in 2010 after SWOG S0106, a Phase 3 confirmatory trial (NCT00085709), showed a significantly higher rate of death due to treatment-related adverse events in the Mylotarg arm, and Mylotarg showed no clinical benefit.

A lower dosing schedule of Mylotarg in ALFA-0701 (NCT00927498), a Phase 3, multi-center, open-label trial in patients 50 to 70 years of age in France, showed decreased toxicity. It also demonstrated improvement in two-year, event-free survival (EFS) in the 139 analyzed patients who received Mylotarg (40.8%) vs. the 139 analyzed patients who received standard-of-care (17.1%; hazard ratio 0.58, 0.43-0.78; P = .0003),6 a factor which ODAC considered heavily when making its recommendation.

Mylotarg is an antibody-drug conjugate composed of calicheamicin, a cytotoxic agent, attached to a monoclonal antibody that targets CD33. CD33 is an antigen expressed on the surface of myeloblasts in over 90% of patients with AML. The antibody component of Mylotarg allows it to attach to these CD33-expressing cells. Mylotarg is then internalized, and calicheamicin causes cell death.7



  1. Grupp SA, Laetsch TW, Buechner J, et al. Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Presented at American Society of Hematology 58th Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA.
  2. FDA Briefing Document. Oncologic Drugs Advisory Committee Meeting. BLA 125646: Tisagenlecleucel. July 12, 2017. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM566166.pdf
  3. Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009; Guidance for Industry. April 2015. https://www.fda.gov/downloads/drugs/guidances/ucm444661.pdf
  4. FDA Briefing Document. Oncologic Drugs Advisory Committee Meeting. BLA 761068: ABP215, a proposed biosimilar to Avastin (bevacizumab). July 13, 2017. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM566365.pdf
  5. FDA Briefing Document. Oncologic Drugs Advisory Committee Meeting. BLA 761074: MYL-1401O, a proposed biosimilar to Herceptin (trastuzumab). July 13, 2017. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM566369.pdf
  6. Castaigne S, Pautas C, Terré C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012 Apr 21. https://www.ncbi.nlm.nih.gov/pubmed/22482940
  7. Mylotarg Label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021174s020lbl.pdf

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