ONCAlert | Upfront Therapy for mRCC

Case 1: Targeted Therapy in FLT3+ AML

Targeted Oncology
Published Online:12:35 PM, Wed June 19, 2019


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Naval G. Daver, MD: In the interest of time, we’ll move on. Dr McCloskey, if you could give a brief overview of the FLT3 data you have. Thank you.

James K. McCloskey II, MD: I’m happy to. As we mentioned, it’s been an exciting couple of years in AML [acute myeloid leukemia], but the RATIFY trial looking at the addition of midostaurin to induction in a consolidation chemotherapy in newly diagnosed patients was really the study that resulted in our first FDA approval. Again, this was de novo AML patients between the ages of 18 and 60 with a confirmed FLT3 mutation. Patients on this trial were risk-stratified according to their FLT3 mutations, but it did accrue patients with TKD [tyrosine kinase domain] mutations, as well as ITD [internal tandem duplication] mutations. They were then further risk-stratified based on allelic burden. In this case, the cutoff for risk for high or low was .7.

This trial was a tremendous effort on the part of many investigators, and over 3000 patients were screened, with eventually 717 patients being randomized in a double-blind fashion to either midostaurin or placebo. Midostaurin was combined with induction cytarabine and daunorubicin, with midostaurin being added on days 8 through 21 at 50 mg twice daily. For any patient who achieved a CR [complete remission], they were then eligible to proceed with a stem cell transplant when that was available. Likewise, until that point, they continued with consolidation with high-dose cytarabine in combination with midostaurin added days 8 through 21 at 50 mg twice daily.
 
Importantly, I think after this, patients were eligible for a maintenance arm of the study. Patients were not randomized to maintenance. In this context, midostaurin was administered 50 mg twice daily continuously days 1 through 28.

If we look at the breakdown of the characteristics of the patients accruing to this trial, patients had a median age around 47, in keeping with the patient that we just discussed. They were well-stratified, as we discussed, in accordance to their subtype of FLT3, whether it be ITD, TKD, or a low or high allelic ratio.

When we broke down responses in those patients, we did not see a difference in CR during the first 60 days. CR rate was just over 50% in both arms. When we expanded to look at CR during induction or consolidation, including patients that subsequently achieved a CR after coming off study, there was a favor. The trial did favor midostaurin with a 66% CR rate compared to 59% in the placebo arm with a P value of .045.

This improved CR rate and the use of midostaurin resulted in improvement in median overall survival to 74 months in the midostaurin arm, compared to 25 months in the placebo arm. Again I think, especially at the time, this was super exciting data. It took us decades to move those curves. Lots of things added to 7+3 [cytarabine/daunorubicin] had failed to separate those curves over the preceding decades.

Many patients treated on the study did proceed to stem cell transplant, and that remains our standard approach for these folks. If we look at outcomes based on those patients who underwent stem cell transplant, we saw that the greatest benefit to stem cell transplant and survival in the midostaurin group was really seen in those patients who went to transplant in CR1 [first complete remission].

This gets at our question about how we approach these patients with FLT3 mutations based on the allelic ratio, and midostaurin is a pan-tyrosine kinase receptor. We talked about it inhibiting FLT3, but it actually hits a variety of other receptors, as well, so I think it’s particularly relevant to our discussion about thinking about the type of FLT3-mutated patients we might select. The bottom line is that all patients on this study really benefited from midostaurin. If we looked at survival based on subgroup, TKD patients benefit, as did patients with a low allelic burden. I think based on that, we really can’t yet use allelic burden to decide whether midostaurin should be added to those folks as frontline therapy.

The other thing that was really exciting about this study was that it demonstrated that we could safely add something to 7+3 [cytarabine/daunorubicin] without getting a lot of unexpected toxicities. If we looked at grade 3 and 4 or 5 adverse events, we didn’t see a significant increase in infectious complication or myelosuppression. The only thing that fell out of that was an increased risk of rash, which most of us who treat AML feel comfortable with if we’re getting an improved efficacy.

With that in mind, we’ll touch briefly on another FLT3 inhibitor, gilteritinib. Currently, in our commercial use of this drug, it is for patients with relapsed and refractory disease, but I think we’re going to continue to see expanding indications for the FLT3 inhibitors in both upfront and the relapsed setting.

The ADMIRAL study was a phase III randomized study looking at patients with FLT3-mutated AML who were relapsed or refractory. Just over 300 patients accrued to this study, and they were randomized in a 2-to-1 fashion to gilteritinib versus salvage chemotherapy. There were a variety of chemotherapy options for that standard arm. We included low-dose cytarabine, or hypomethylators for patients who were more frail, as well as intensive salvage therapy, including cytarabine-based regimens like FLAG-IDA [fludarabine/cytarabine/G-CSF/idarubicin] or MEK [inhibitors].  

Again, the primary endpoint of interest in this study was CR rate and overall survival. At any point, a patient who had a remission and appropriate donor could proceed to stem cell transplant.
I think this is an interesting model because it raises the potential for us to use a targeted agent in salvage instead of high-dose chemotherapy, and in fact, when we looked at the results in this phase III study, we show that they favored the use of a molecularly targeted therapy. The response rates were almost double for the gilteritinib group compared to salvage chemotherapy. If we look at responses, the CR rate in the gilteritinib group was 21% compared to 11% in the salvage chemotherapy group.

Response rates of CR and CRh [complete response with partial hematologic recovery] were 34% compared to 15%, and more patients treated in the gilteritinib arm were able to proceed to stem cell transplant—26% compared to 15%. All of these improved responses translated to an improvement in median overall survival in the gilteritinib group—9.3 months compared to 5.3 months. Again, I think it’s an exciting era where we’re talking about a molecularly targeted therapy with a significantly more appealing [adverse] effect profile than chemotherapy.

Transcript edited for clarity.
 


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Naval G. Daver, MD: In the interest of time, we’ll move on. Dr McCloskey, if you could give a brief overview of the FLT3 data you have. Thank you.

James K. McCloskey II, MD: I’m happy to. As we mentioned, it’s been an exciting couple of years in AML [acute myeloid leukemia], but the RATIFY trial looking at the addition of midostaurin to induction in a consolidation chemotherapy in newly diagnosed patients was really the study that resulted in our first FDA approval. Again, this was de novo AML patients between the ages of 18 and 60 with a confirmed FLT3 mutation. Patients on this trial were risk-stratified according to their FLT3 mutations, but it did accrue patients with TKD [tyrosine kinase domain] mutations, as well as ITD [internal tandem duplication] mutations. They were then further risk-stratified based on allelic burden. In this case, the cutoff for risk for high or low was .7.

This trial was a tremendous effort on the part of many investigators, and over 3000 patients were screened, with eventually 717 patients being randomized in a double-blind fashion to either midostaurin or placebo. Midostaurin was combined with induction cytarabine and daunorubicin, with midostaurin being added on days 8 through 21 at 50 mg twice daily. For any patient who achieved a CR [complete remission], they were then eligible to proceed with a stem cell transplant when that was available. Likewise, until that point, they continued with consolidation with high-dose cytarabine in combination with midostaurin added days 8 through 21 at 50 mg twice daily.
 
Importantly, I think after this, patients were eligible for a maintenance arm of the study. Patients were not randomized to maintenance. In this context, midostaurin was administered 50 mg twice daily continuously days 1 through 28.

If we look at the breakdown of the characteristics of the patients accruing to this trial, patients had a median age around 47, in keeping with the patient that we just discussed. They were well-stratified, as we discussed, in accordance to their subtype of FLT3, whether it be ITD, TKD, or a low or high allelic ratio.

When we broke down responses in those patients, we did not see a difference in CR during the first 60 days. CR rate was just over 50% in both arms. When we expanded to look at CR during induction or consolidation, including patients that subsequently achieved a CR after coming off study, there was a favor. The trial did favor midostaurin with a 66% CR rate compared to 59% in the placebo arm with a P value of .045.

This improved CR rate and the use of midostaurin resulted in improvement in median overall survival to 74 months in the midostaurin arm, compared to 25 months in the placebo arm. Again I think, especially at the time, this was super exciting data. It took us decades to move those curves. Lots of things added to 7+3 [cytarabine/daunorubicin] had failed to separate those curves over the preceding decades.

Many patients treated on the study did proceed to stem cell transplant, and that remains our standard approach for these folks. If we look at outcomes based on those patients who underwent stem cell transplant, we saw that the greatest benefit to stem cell transplant and survival in the midostaurin group was really seen in those patients who went to transplant in CR1 [first complete remission].

This gets at our question about how we approach these patients with FLT3 mutations based on the allelic ratio, and midostaurin is a pan-tyrosine kinase receptor. We talked about it inhibiting FLT3, but it actually hits a variety of other receptors, as well, so I think it’s particularly relevant to our discussion about thinking about the type of FLT3-mutated patients we might select. The bottom line is that all patients on this study really benefited from midostaurin. If we looked at survival based on subgroup, TKD patients benefit, as did patients with a low allelic burden. I think based on that, we really can’t yet use allelic burden to decide whether midostaurin should be added to those folks as frontline therapy.

The other thing that was really exciting about this study was that it demonstrated that we could safely add something to 7+3 [cytarabine/daunorubicin] without getting a lot of unexpected toxicities. If we looked at grade 3 and 4 or 5 adverse events, we didn’t see a significant increase in infectious complication or myelosuppression. The only thing that fell out of that was an increased risk of rash, which most of us who treat AML feel comfortable with if we’re getting an improved efficacy.

With that in mind, we’ll touch briefly on another FLT3 inhibitor, gilteritinib. Currently, in our commercial use of this drug, it is for patients with relapsed and refractory disease, but I think we’re going to continue to see expanding indications for the FLT3 inhibitors in both upfront and the relapsed setting.

The ADMIRAL study was a phase III randomized study looking at patients with FLT3-mutated AML who were relapsed or refractory. Just over 300 patients accrued to this study, and they were randomized in a 2-to-1 fashion to gilteritinib versus salvage chemotherapy. There were a variety of chemotherapy options for that standard arm. We included low-dose cytarabine, or hypomethylators for patients who were more frail, as well as intensive salvage therapy, including cytarabine-based regimens like FLAG-IDA [fludarabine/cytarabine/G-CSF/idarubicin] or MEK [inhibitors].  

Again, the primary endpoint of interest in this study was CR rate and overall survival. At any point, a patient who had a remission and appropriate donor could proceed to stem cell transplant.
I think this is an interesting model because it raises the potential for us to use a targeted agent in salvage instead of high-dose chemotherapy, and in fact, when we looked at the results in this phase III study, we show that they favored the use of a molecularly targeted therapy. The response rates were almost double for the gilteritinib group compared to salvage chemotherapy. If we look at responses, the CR rate in the gilteritinib group was 21% compared to 11% in the salvage chemotherapy group.

Response rates of CR and CRh [complete response with partial hematologic recovery] were 34% compared to 15%, and more patients treated in the gilteritinib arm were able to proceed to stem cell transplant—26% compared to 15%. All of these improved responses translated to an improvement in median overall survival in the gilteritinib group—9.3 months compared to 5.3 months. Again, I think it’s an exciting era where we’re talking about a molecularly targeted therapy with a significantly more appealing [adverse] effect profile than chemotherapy.

Transcript edited for clarity.
 
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