Missed Opportunity

When gemtuzumab ozogamicin re-entered the market in 2017, it was not alone: Three other drugs for AML had earned approvals that year and 4 more earned regulatory approval in the US the following year.10 The treatment space for AML was getting crowded and gemtuzumab ozogamicin, although approved, had lost its initial luster.

The recently published data from the expanded access protocol included only safety data and, like the pivotal trials that led to the drug’s 2017 approval, showed that the hepatotoxicity concerns initially revealed by the confirmatory trial could be mitigated with a lower dose.

Among the 331 patients who received gemtuzumab ozogamicin through the intermediate-size protocol — most of whom received a lower dose — only 5 had hepatotoxicity. Specifically, 4 patients had veno-occulsive disease and 1 had drug-induced liver injury.4

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A smattering of other unsurprising safety data were also reported and used to support the 2017 approval of the drug, but what wasn’t reported were any efficacy outcomes — because they weren’t widely collected.4

Expanded access protocols are not required to collect or report efficacy data. Even so, an FDA spokesperson told this publication that the expanded access regulations do not expressly prohibit the collection of such data.

While the decision to not collect efficacy data did not violate any regulatory requirements, experts were still critical. Primary study author Eunice Wang, MD, Roswell Park Comprehensive Cancer Center, Buffalo, NY, told Cancer Therapy Advisor that the “major” critique of these data when they were first presented at a medical conference and later reviewed in the manuscript was that “people really want to know the efficacy.”

Dr Wang explained that the efficacy data were not collected and reported because the drug was given at different doses — as a single agent and in combination — and to many different types of patients, making it difficult to get a “clear” efficacy signal.

Despite the limitations of analyzing data from a heterogenous population, Gustavo Rivero, MD, an assistant professor of medicine, hematology, and oncology at Baylor College of Medicine’s Dan L Duncan Comprehensive Cancer Center in Houston, Texas, told Cancer Therapy Advisor that it was a “failure” to not report efficacy data.

Even descriptive outcomes would have been helpful, allowing oncologists to parse out subgroups of patients who may benefit. For example, a subgroup of 9 patients had APL, and according to Dr Rivero, knowing how many survived beyond 3 months and reached allotransplantation would have been useful information.

Also, patients with high-risk APL often harbor FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations and are typically treated with all-trans retinoic acid, arsenic trioxide, and chemotherapy. However, exposure to chemotherapy leads to upregulation of the FLT3 ligand, which reduces treatment sensitivity. “Since CD33 is highly expressed in APL, it would be better to treat with GO [gemtuzumab ozogamicin], rather than chemotherapy, to avoid FLT3 ligand upregulation,” said Dr Rivero.

However, physicians cannot arrive at that conclusion — which would need to be confirmed in a clinical trial — without some type of efficacy data. “Efficacy data are needed,” he reiterated.

The CEO of WideTrial, Jess Rabourn, told Cancer Therapy Advisor that expanded access programs are an “opportunity” for life-science companies to learn “a lot more” about the value of their product in the targeted population than what they could in a “narrower, smaller” clinical research trial.

Although Rabourn said an expanded access protocol shouldn’t be structured in such a way that is “greedy for research-like data,” — and, if done this way, could impair the ability to treat a lot of patients — companies certainly can ask for clinical assessment data, such as a copy of lab results.

“Without putting undue strain on the health care delivery, [manufacturers] can learn a lot about the outcome[s] of these patients,” he said.


  1. Rowe JM, Löwenberg B. Gemtuzumab ozogamicin in acute myeloid leukemia: A remarkable saga about an active drug. Blood. 2013;121(24):4838-4841.
  2. Norsworthy KJ, Ko C, Lee JE, et al. FDA approval summary: Mylotarg for treatment of patients with relapsed or refractory CD33-positive acute myeloid leukemia. Oncologist. 2018;23(9):1103-1108.
  3. Center for Drug Evaluation and Research. Summary review. BLA 761060. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761060Orig1s000Orig1Orig2s000SumR.pdf. Accessed June 25, 2020.
  4. Wang ES, Aplenc R, Chirnomas D, et al. Safety of gemtuzumab ozogamicin as monotherapy or combination therapy in an expanded-access protocol for patients with relapsed or refractory acute myeloid leukemia [published online May 20, 2020]. Leuk Lymphoma. doi: 10.1080/10428194.2020.1742897
  5. Expanded access. FDA.gov. https://www.fda.gov/news-events/public-health-focus/expanded-access Accessed June 25, 2020.
  6. Young FE, Norris JA, Levitt JA, Nightingale SL. The FDA’s new procedures for the use of investigational drugs in treatment. JAMA. 1988;259:2267-2270.
  7. Subpart I—Expanded Access to Investigational Drugs for Treatment Use. 21 CFR §312 (2019).
  8. Bennett C. A new trend in drug development: Leveraging data from expanded access. Cancer Therapy Advisor. Published March 2, 2020. Accessed June 25, 2020.
  9. Polak TB, van Rosmalen J, Uyl-de Groot CA. Expanded access as a source of real-world data: An overview of FDA and EMA approvals [published online March 22, 2020]. Br J Clin Pharmacol. doi: 10.1111/bcp.14284
  10. Lai C, Doucette K, Norsworthy K. Recent drug approvals for acute myeloid leukemia. J Hematol Oncol. 2019;12(1):100.