INSIDE THE BLACK BOX is an occasional column providing insight into the U.S. Food and Drug Administration (FDA) and its policies and procedures. In this installment, Martha Donoghue, MD, Supervisory Medical Officer, and Gregory Reaman, MD, Associate Director for Oncology Sciences in the Office of Hematology and Oncology Products, of the FDA discuss dinutuximab’s path to FDA approval for high-risk neuroblastoma as well as regulatory incentives for the development of future pediatric cancer drugs.
On March 10, 2015, the U.S. Food and Drug Administration (FDA) granted regular approval to dinutuximab (formerly known as chimeric 14.18 antibody; Unituxin) for use in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (retinoic acid) for the treatment of pediatric patients with high-risk neuroblastoma who achieved at least a partial response to prior first-line, multiagent, multimodality therapy. Dinutuximab is the first FDA-approved treatment specifically for patients with high-risk neuroblastoma.
Neuroblastoma Treatment Approach
What is neuroblastoma, and how is it treated?
Dr. Reaman: Neuroblastoma is a clinically and biologically unique tumor, which develops predominantly in children. It originates from primitive sympathetic ganglion cells in the adrenal medulla or, less commonly, other sites. Neuroblastoma is the most common extracranial solid tumor of childhood, and approximately 650 new cases are diagnosed each year in the United States. The median age at diagnosis is 19 months, and 90% of patients with neuroblastoma are diagnosed before the age of 5.
Gregory Reaman, MD
FDA Clinical Reviewer
Treatment and prognosis of patients with neuroblastoma depend upon multiple clinical and biologic factors, including age, stage of disease, histology, and molecular features such as MYCN amplification. Using this prognostic factor–based algorithm, children are determined to have low-risk, intermediate-risk, or high-risk neuroblastoma.
Patients with low-risk tumors have a greater than 98% chance of survival, with treatment limited to observation or tumor resection. Patients with intermediate-risk neuroblastoma also have an excellent prognosis, with a survival rate approaching 95% following receipt of a chemotherapy regimen that varies in duration and intensity depending upon clinical and biologic risk factors prior to surgical resection. In contrast, the treatment approach for patients with high-risk neuroblastoma, who number approximately 250 to 300 each year, consists of intensive multimodality therapy, which includes multiagent induction chemotherapy followed by maximum feasible surgical resection; a consolidation phase consisting of myeloablative chemotherapy followed by single or tandem autologous stem cell transplantation plus localized radiation therapy; and 6 months of immunomodulatory “maintenance therapy” comprising anti-GD2 antibody, dinutuximab treatment combined with GM-CSF and IL-2, administered in alternating cycles, and retinoic acid.
Dinutuximab and Its Path to Approval
What is dinutuximab, and why is it used to treat high-risk neuroblastoma?
Martha Donoghue, MD
FDA Clinical Reviewer
Dr. Donoghue: Dinutuximab is a chimeric (mouse/human) IgG3 monoclonal antibody that binds to the disialoganglioside, GD2. GD2 is expressed on the surface of certain cancer cells such as neuroblastoma, melanoma, and osteosarcoma, in addition to normal cells of neuroectodermal origin, including brain, spinal cord, and peripheral nerves.
Dinutuximab was approved as a component of front-line multiagent, multimodality treatment of patients with high-risk neuroblastoma based upon data from the randomized portion of Study ANBL0032, an open-label, multicenter clinical trial conducted in pediatric patients with high-risk neuroblastoma conducted by the Children’s Oncology Group (COG). Study ANBL0032 enrolled 226 pediatric patients who had achieved at least a partial response to therapy prior to autologous stem cell transplantation and who did not have evidence of disease progression at the time of enrollment. Patients were randomized on a 1:1 basis to receive either up to five cycles of the experimental antibody in combination with GM-CSF and IL-2 plus retinoic acid, followed by one cycle of retinoic acid alone (treatment arm; n = 113); or 6 months of retinoic acid alone (control arm; n = 113).
In January 2009, the seventh interim analysis of Study ANBL0032 documented a numerical improvement in the study’s primary endpoint of event-free survival, defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy, or death, in patients randomized to receive dinutuximab combination therapy vs those randomized to receive retinoic acid alone. At the time of this analysis, a total of 33 patients (29%) in the dinutuximab combination therapy arm had an event-free survival event, compared with 50 patients (44%) in the retinoic acid arm [hazard ratio (HR): 0.57 (95% CI: 0.37–0.89); P = .01].
Based on these results, the COG Data Monitoring Committee recommended terminating randomization in February 2009, and patients who were previously randomized to receive retinoic acid alone were allowed to cross over to dinutuximab. Subsequent patients were offered treatment with dinutuximab combination therapy in an open-label, expanded-access portion of the study. Prior to approval of dinutuximab, over 800 patients received treatment with it in the expanded-access portion of the study.
What were the FDA’s considerations for approval of dinutuximab?
Currently, there is a striking imbalance in the number of commercial development programs for treatment of adult and pediatric cancers. The FDA hopes that approvals such as this one generate more industry interest in pediatric cancer therapy development.— Martha Donoghue, MD
Dr. Donoghue: The FDA approved dinutuximab based upon the demonstrated improvement in event-free survival in patients with high-risk neuroblastoma randomized to the dinutuximab combination therapy arm. At the time of the analysis, estimated median event-free survival had not been reached in the dinutuximab-containing arm and was 1.9 years in the control arm. In addition, the FDA considered supportive analyses of overall survival that favored the dinutuximab-containing arm. In an updated analysis corresponding to a time when all patients would be evaluable for 3-year survival rates, a total of 31 patients (27%) in the dinutuximab arm had died, vs 48 patients (42%) in the control arm (HR = 0.58 [0.37–0.91]).
Because Study ANBL0032 was designed and conducted during Dr. Reaman’s tenure as Chair of the Children’s Oncology Group, and because he authorized the data transfer from the Children’s Oncology Group to the manufacturer, he recused himself from the review of the Biologics License Application for dinutuximab. In the risk-benefit assessment of the Biologics License Application, the FDA review team considered the fact that dinutuximab, when administered according to the procedures described in approved product labeling with optimal inpatient medical management including intravenous hydration as well as concomitant intravenous morphine, antipyretics, and antihistamines, is a toxic regimen. Serious risks include severe neuropathic pain, neuropathy, infusion reactions, capillary leak syndrome, hypotension, and neurologic disorders of the eye. However, given the life-threatening nature of high-risk neuroblastoma, the lack of effective alternative therapies, and the demonstrated improvements in event-free and overall survival, the review team unanimously recommended approval of the application.
Antibodies to GD2 had been investigated in patients with neuroblastoma for well over 15 years and appear to have been part of the standard of care for patients with newly diagnosed high-risk neuroblastoma for several years prior to approval of dinutuximab. Why did FDA approval take so long?
Dr. Donoghue: The FDA approved dinutuximab approximately 11 months after the Biologics License Application for dinutuximab was submitted. Although the FDA granted priority review to this Biologics License Application, review of the application required more than 10 months, because based on information provided in the Biologics License Application, the FDA determined that additional clinical and product quality data were needed to comprehensively evaluate the safety of dinutuximab. However, the time required for FDA review and approval of the Biologics License Application represented only a small fraction of the time needed for dinutuximab’s commercial development.
The lag times between the early evaluation of anti-GD2 antibodies in neuroblastoma (early 1990s), the initiation of Study ANBL0032 (2001), cessation of randomization and opening of the expanded-access phase of the study (2009), and approval of dinutuximab (2015) are a testament to the challenges of conducting clinical trials in patients with rare diseases such as pediatric cancers and the economic risks and uncertainties associated with developing new drugs to treat these diseases. These challenges can be amplified in cases such as dinutuximab, where clinical development proceeds without commercial sponsorship and when the trial supporting approval is not originally intended to be a licensing study.
Due to the relative rarity of high-risk neuroblastoma, it took 7 years (from 2001–2008) to accrue the requisite number of patients on the randomized portion of the study. Additionally, the dinutuximab clinical trials material used in the randomized portion of Study ANBL0032 and the majority of dinutuximab used to treat subsequent patients in the open-label expanded-access portion of the study were supplied by the Cancer Therapy and Evaluation Program of the National Cancer Institute (NCI). The NCI recognized the importance of finding an industry partner committed to commercially developing and manufacturing dinutuximab to ensure the long-term availability of this treatment. However, the path to commercialization was not clearly defined at first, and it took time to navigate.
In July 2010, United Therapeutics and the NCI executed a Cooperative Research and Development Agreement to collaborate on the clinical and commercial development of dinutuximab. The Cooperative Research and Development Agreement conferred to United Therapeutics exclusive access to the clinical study data derived from the studies of dinutuximab and the technical information required to support commercial manufacturing. Between the time the Cooperative Research and Development Agreement was initiated and the submission of the Biologics License Application for dinutuximab to the FDA, a number of complicated steps were required; they included development and implementation of a process for manufacturing dinutuximab on a commercial scale, conduct and analysis of a clinical trial to assess the comparability of the pharmacokinetic and safety profiles of dinutuximab and ch14.18 antibody (manufactured by the NCI) in patients with high-risk neuroblastoma, audit of the Children’s Oncology Group clinical trial data, and compilation of the data package that was subsequently submitted to the Biologics License Application.
Are there any unanswered questions regarding how dinutuximab can help treat pediatric patients with neuroblastoma?
Recognizing the challenges in developing treatments for rare diseases, we welcome early and frequent communication with stakeholders involved in developing new treatments for pediatric cancers.— Gregory Reaman, MD
Dr. Reaman: Several important questions relating to the use of dinutuximab in the front-line treatment of high-risk neuroblastoma remain unanswered. Although the Study ANBL0032 treatment arm including dinutuximab, GM-CSF, IL-2, and retinoic acid demonstrated improvement in event-free and overall survival compared with retinoic acid alone, the contributions of the individual components were not isolated in this trial, and additional information needed to be considered. Nonclinical data have shown that dinutuximab alone can induce tumor lysis, and clinical data indicate that GM-CSF or IL-2 at the doses administered in Study ANBL0032 do not have antitumor activity. There are nonclinical data indicating that tumor lysis can be enhanced with the addition of these cytokines in vitro; however, the clinical importance of this effect is uncertain. Furthermore, it is clear that the addition of IL-2 and GM-CSF carries the risk of further adverse reactions.
Preliminary results from an ongoing European clinical trial in children with high-risk neuroblastoma being conducted by the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) suggest that comparable event-free survival can be achieved with a similar chimeric antibody without the addition of cytokines. Results of the final analysis of this trial may help to address this question and may provide guidance to the U.S. pediatric oncology community regarding the role of IL-2 and GM-CSF in dinutuximab therapy in high-risk neuroblastoma.
Additional questions exist about the optimal infusion rate of anti-GD2 antibodies with respect to both efficacy and increased tolerability. This question is also being evaluated in clinical trials outside the United States. The role of additional therapy following dinutuximab-based treatment to further improve event-free survival rates in this disease is also under consideration. To assess whether dinutuximab may play a role earlier in the management of high-risk neuroblastoma, the Children’s Oncology Group is conducting a small, randomized trial to evaluate the antitumor activity of irinotecan and temozolomide in combination with dinutuximab or temsirolimus (Torisel) in children with relapsed or refractory neuroblastoma. Evaluation of the antitumor activity of dinutuximab in other GD2-expressing pediatric tumors such as osteosarcoma is also in progress.
Regulatory Incentives for Pediatric Drug Development
Developing new therapies to treat rare cancers such as neuroblastoma is expensive and associated with risk. How do regulations support the development of pediatric cancer drugs?
Dr. Donoghue: There are laws that support the development of drugs for rare diseases in both adult and pediatric patients as well as laws that specifically focus on the development of drugs for diseases occurring in pediatric patients that can be leveraged to support pediatric cancer drug development. These laws include the Orphan Drug Act, the Best Pharmaceuticals for Children Act, and the Pediatric Research Equity Act. More recently, in 2012, the Food and Drug Administration and Safety Act added Section 529 to the Federal Food, Drug, and Cosmetic Act, which instituted the Rare Pediatric Disease Priority Review Voucher Program.
The Best Pharmaceuticals for Children Act provides a mechanism for incentivizing companies to study therapies in children that are under investigation (or already approved) for a different adult indication. Its counterpart, the Pediatric Research Equity Act, requires that pharmaceutical companies developing new products for use in a specific clinical condition also study the product in children with that condition. However, the requirements of the Pediatric Research Equity Act are typically waived for drugs approved for adult cancers because such cancers usually do not occur in children (eg, breast and lung cancers). In addition, drugs with Orphan Drug designation for an indication are exempt from the requirements under the Pediatric Research Equity Act, even when that indication occurs in both adults and children.
The Orphan Drug Act provides for granting special status, “Orphan Drug designation,” to a drug that is aimed at diagnosing or treating a disease or condition that affects fewer than 200,000 persons in the United States, upon request of a sponsor. The Orphan Drug designation provides incentives for companies to develop therapies to treat rare diseases, including all pediatric cancers, such as potential eligibility for the Orphan Products Grants Program, waiver of New Drug applications or Biologics License application fees, and prolonged market exclusivity.
Additionally, the FDA has implemented programs to expedite the development and approval of therapies to treat serious and life-threatening illnesses such as pediatric cancers. These programs include the Fast Track designation, Priority Review designation, Accelerated Approval, and Breakthrough Therapy designation.
How did these regulations impact the development of dinutuximab?
Dr. Reaman: The development program for dinutuximab leveraged a few regulatory incentives. In 2010, the FDA granted Orphan Drug status to dinutuximab for the treatment of neuroblastoma, and in 2013, the FDA’s Office of Orphan Products Development designated neuroblastoma a “rare pediatric disease.” As a result, upon the approval of dinutuximab, United Therapeutics received a Rare Pediatric Disease Priority Review Voucher. Finally, following receipt of the Biologics License Application for dinutuximab, the FDA granted priority review to the application, which shortens the goal review time line by 4 months.
Why is the approval of dinutuximab important, and what does it mean for the future development of new therapies to treat pediatric patients with cancer?
Dr. Donoghue: Foremost, the approval of dinutuximab is important because the data submitted to support the approval of any drug provides assurance of the safety and effectiveness of using this drug. Dinutuximab has demonstrated a clinical benefit in the first-line treatment of pediatric patients with high-risk neuroblastoma in the setting of minimal disease burden following intensive multimodality therapy. Additionally, it provides an example of how public-private partnerships can successfully address an unmet medical need. Finally, this approval illustrates the power of regulatory incentives for the commercial development of new drugs to treat pediatric cancers. Currently, there is a striking imbalance in the number of commercial development programs for treatment of adult and pediatric cancers. The FDA hopes that approvals such as this one generate more industry interest in pediatric cancer therapy development.
One lesson from the dinutuximab clinical development program is the importance of early planning when the outcome of a clinical trial may impact the future treatment of patients with pediatric cancer. When clinical trials have the potential to provide substantial evidence of safety and effectiveness, it is best to have a strategy in place as early as possible to ensure the availability of effective experimental therapies to treat future patients. This could potentially include a plan to provide expanded access for tens to hundreds of patients, so their medical needs are addressed prior to approval, and formation of strategic partnerships as early in development as possible to shorten the time line for commercial development and approval of safe and effective therapies.
Historically, the development of pediatric cancer drugs has lagged behind that of therapies to treat adult cancers. What is the FDA doing to help expedite the development of pediatric cancer drugs?
Dr. Reaman: The approval of dinutuximab represents an approval of a Biologics License Application for a product specifically submitted to seek a pediatric cancer indication. This is, unfortunately, an unusually rare approach to product development for pediatric cancers. As most pediatric cancer drug development currently leverages the discovery and development of drugs for adult cancers, the FDA is committed to identify those drugs that may have relevance to one or more cancers occurring in childhood as early in the development time line as possible to maximize the legislative authority provided by the Best Pharmaceuticals for Children Act. There are now over a dozen pediatric oncologists in the Office of Hematology and Oncology Products who meet on a regular basis to discuss areas of opportunity for development of pediatric drugs that are under investigation for treatment of adult cancers and have potential applicability in pediatric patients. The FDA also holds meetings of the Pediatric Subcommittee of the Oncologic Drugs Advisory Committee at least annually and the Best Pharmaceuticals for Children Act Pediatric Oncology Working Group meetings on a quarterly basis to assess interest by key opinion leaders in the evaluation of new pediatric drugs and biologics and discuss novel trial designs to expedite their evaluation. These activities can result in the issuance of Written Requests for pediatric studies, even prior to approval for their adult indication.
Additionally, the FDA has an active outreach program that includes public meetings with stakeholders and involvement in internal and external working groups to foster communication and promote the development of new therapies. The Office of Hematology and Oncology Products also participates in monthly pediatric cluster calls with the representatives of the European Medicines Agency and other international regulatory agencies to facilitate a coordinated approach to global pediatric cancer drug development.
The FDA encourages companies and sponsor investigators to consider enrolling children in adult trials of new cancer drugs when appropriate. The FDA also encourages early discussion between sponsors and pediatric oncology clinical investigators when the mechanism of action of a new drug, particularly for molecularly targeted agents, may be relevant for one or more pediatric cancers. Recognizing the challenges in developing treatments for rare diseases, we welcome early and frequent communication with stakeholders involved in developing new treatments for pediatric cancers. Finally, the FDA exerts flexibility in the consideration of novel trial designs and sources of data needed to establish safety and effectiveness in New Drug or Biologics License applications for drugs for pediatric cancers and other rare diseases. Examples of this flexibility can be found in reviews leading to the approval of everolimus (Afinitor) for the treatment of subependymal giant cell astrocytoma, denosumab (Xgeva) in adolescent patients with giant cell tumor of the bone, imatinib in children with chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia, and pegaspargase (Oncaspar) for the treatment of patients with acute lymphoblastic leukemia, among others. ■
Disclosure: Drs. Donoghue and Reaman reported no potential conflicts of interest.
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