Today we are speaking with Jorge Cortes, MD, who specializes in the treatment and clinical research of leukemia at M.D. Anderson Cancer Center in Houston, Texas, about treatment of patients with acute myeloid leukemia (AML) in the context of a new drug approval for the disease. Gemtuzumab ozogamicin (Mylotarg) an antibody drug conjugate, consisting of a recombinant, humanized anti-CD33 monoclonal antibody that linked to a cytotoxic compound, the antibiotic calicheamicin, was approved by the U.S. Food and Drug Administration (FDA) in September of this year for the treatment of adults with newly diagnosed AML whose tumors express the CD33 antigen and children aged 2 years and older with relapsed or refractory CD33-positive AML.
-Interviewed by Anna Azvolinsky
OncoTherapy Network: Gemtuzumab ozogamicin has a relatively long history of development. The antibody drug conjugate initially received an accelerated approval by the U.S. FDA in 2000 for AML patients who experienced disease relapse. However, after results of a confirmatory phase III trial were analyzed, the drug was voluntarily withdrawn from the market by its manufacturer, Pfizer. Can you talk about those initial trials and what they showed?
Dr. Cortes: The initial trial that led to the approval was a study of older patients who had received prior therapy with standard treatment and who were receiving their first salvage therapy because they had not responded to their initial treatment or they had relapsed and then received gemtuzumab ozogamicin. That study showed a benefit for these patients (30% response rate); about half the patients had complete responses and the other half had CRPs, meaning that the patient had met the criteria for CR except that platelets were not fully recovered but a transfusion was not required. That led to approval of this drug for that specific indication and patient population, but it was an accelerated approval. In essence that means the drug company commits to perform another study to confirm the benefit of the drug. However, the confirmatory study that was submitted was a front-line study in combination with standard chemotherapy, performed in a different setting and patient population. So the patients were to receive standard chemotherapy (what we call 3+7) with or without gemtuzumab ozogamicin. That study, conducted through the Southwestern Oncology Group (SWOG), ended up being a negative study mostly because of an increased mortality and worsened survival for the patients who received gemtuzumab ozogamicin with chemotherapy versus those who received chemotherapy alone. When those results came back, the confirmation was not there and that is what led to the withdrawal of this drug in 2010.
OncoTherapy Network: So then what was the reason for the renewed interest in this drug?
Dr. Cortes: I think people identified the potential benefit of gemtuzumab ozogamicin, so research continued during this time. Many other studies other than this pivotal confirmation study were being conducted around the world in different settings and populations. Shortly after the results of this confirmatory trial came out, results from other studies started to emerge and they showed different results and outcomes, many of which favored the combinations that included gemtuzumab ozogamicin. As more research was done, many other elements were clarified. One was the recognition that perhaps the initial dosing schedule that was approved was effective and generally well tolerated, particularly when used in combination with chemotherapy. However, when using gemtuzumab ozogamicin without chemotherapy, the initial dosing schedule may not have been optimal even though it met the definition for a tolerable dose. Therefore, other dosing schedules were investigated and used in combination with chemotherapy, and these subsequent studies showed benefit and that there were strategies to mitigate the risk of liver toxicity associated with this drug. As the evidence started to accumulate, it became evident that the drug was useful and perhaps the way we had initially investigated and used it was not optimal. It took us a little while to figure out the better way to use the drug, how to combine it and at what dose and sequence. As a result, the interest in getting gemtuzumab ozogamicin back to the market increased because we realized that if we utilize it properly, it does provide a clinical benefit.
OncoTherapy Network: What are the key results of the gemtuzumab ozogamicin trial that resulted in 2017 approval for newly diagnosed AML patients?
Dr. Cortes: One of the studies that I was referring to earlier was a study conducted in front-line AML, which was the main study that resulted in the approval. This study combined standard 3+7 chemotherapy with or without gemtuzumab ozogamicin. A key difference here was that the dose of gemtuzumab ozogamicin was 3 mg/m2 × 3, on days 1 through 7, while the initial schedule had been 9 mg/m2 × 3, on days 1 and 15, with optional repeat on day 21. So in this newer French study, they used a fractionated lower dose of gentuzumab ozogamicin combined with the standard doses of chemotherapy. This 3+7 chemotherapy also has a more optimal dosing than the SWOG study, but I think the key difference was the dose of gemtuzumab ozogamicin. The primary endpoint in this study was event-free survival, which was significantly improved in the arm that received the combination with gemtuzumab ozogamicin. There was also a trend for improved survival that was not statistically significant because the study was relatively small (a little over 100 patients in each arm). There was also a benefit in relapse-free survival, meaning the remissions were lasting longer. So this showed that indeed, adding this drug to standard chemotherapy would improve the long-term outcome of patients. As a result, there was a sub-analysis for the different populations and for each there was a benefit, whether the analysis was done by age or comorbidity status. An added component was a meta-analysis that was done with five randomized studies that compared chemotherapy alone versus chemotherapy plus gemtuzumab ozogamicin—different patient populations and different schedules of gemtuzumab ozogamicin, which included the negative SWOG study, this French study, and three others. This was an important meta-analysis because it was not an analysis of the published results, but rather a meta-analysis of the individual patient data. So the [authors of the meta-analysis] collected individual data for patients included in these trials and when they combined them, saw that there was a benefit for the patients that had received gemtuzumab ozogamicin, including a potential survival benefit. So those two pieces of information were the main drivers of the presentation for regulatory approval and eventual approval that made gemtuzumab ozogamicin come back to the clinic.
OncoTherapy Network: Lastly, given the other therapy options for newly diagnosed AML patients, how do you place this drug in the context of other treatments? Who are the patients for whom gemtuzumab ozogamicin is likely to be most appropriate?
Dr. Cortes: One good thing about gemtuzumab ozogamicin is that it is a targeted agent, a monoclonal antibody to CD33, and CD33 is almost universally expressed in all patients with AML. Some of the other new agents that have been approved are very powerful but very specific inhibitors, like midostaurin, for FLT3-mutated patients. Then there are the IDH inhibitors, specific for patients with IDH mutations. Gemtuzumab ozogamicin combines with chemotherapy well and leads to the benefit I described earlier, but it also has the potential to be combined with these other agents and add to the benefit of the single-agent FLT3 or IDH inhibitors. You could potentially even envision a triple combination of gemtuzumab ozogamicin plus chemotherapy plus a FLT3 inhibitor for FLT3-mutated AML patients. So I think this adds to the possibility of enhancing the anti-leukemia effect with different mechanisms of action. Of course, many of the things I am talking about are studies that need to be done, but I think it gives another foundation layer for new therapies to be developed to give us a better chance of curing AML patients.
OncoTherapy Network: Thank you so much for joining us today Dr. Cortes.
Dr. Cortes: My pleasure, thank you.