Optimal Biologic Dose of Ponatinib Reduces Adverse Events in CP-CML
In an interview with Targeted Oncology, Hagop Kantarjian, MD, analyzed the results of the phase 2, OPTIC and PACE trials and explained what these data mean for the future use and administration of ponatinib.
Hagop Kantarjian, MD
Determining the optimal biologic dose of ponatinib (Iclusig) may decrease toxicity and potentially improve efficacy for patients with chronic-phase chronic myeloid leukemia (CP-CML).
In the phase 2 PACE and OPTIC trials (NCT01207440, NCT02467270), Hagop Kantarjian, MD et alevaluated ponatinib in patients with CML.
PACE was a single-arm study which examined the efficacy and safety of ponatinib at 45 mg once daily in patients with CML and Philadelphia chromosome-positive acute lymphoblastic leukemia who were resistant to or intolerant of dasatinib (Sprycel) or nilotinib (Tasigna), or that has the T315I mutation.
Then, the multicenter, phase 2 OPTIC study looked at the efficacy and safety of ponatinib in this patient population. Patients were randomized to receive ponatinib at 15, 30, or 45 mg per day, and dose reductions were performed when patients achieved the primary endpoint of complete cytogenetic response.
An analysis of these 2 trials found that using the response-based dose-reduction strategy of ponatinib, as seen in the OPTIC trial, was effective. The risk for arterial occlusive events (AOEs) was about 60% lower with the response-based dose-reduction strategy.
Additionally, the OPTIC trial, which reduced the dose of ponatinib, showed the incidence of serious AOEs to decrease from 15% on the PACE trial to 4% on the OPTIC trial. The progression-free survival rates at 2 years were also higher in the OPTIC trial at close to 90% vs 60% in PACE.
“With the optimized biologic dose on the OPTIC trial, where we reduced the dose once, patients achieved a good response. With that, we had similar efficacy outcomes, and the incidence of complete cytogenetic response was the same. In fact, the rate of progression-free survival was better on the OPTIC trial where we adjusted the dose because there were less patients who stopped the treatment for adverse events,” stated Kantarjian, professor, and chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, and the Samsung Distinguished Leukemia Chair in Cancer Medicine, in an interview with Targeted OncologyTM.
In the interview, Kantarjian analyzed the results of the phase 2, OPTIC and PACE trials and explained what these data mean for the future use and administration of ponatinib.
Targeted Oncology: Can you discuss ponatinib and its mechanism of action?
Kantarjian: Ponatinib is a third-generation BCR-ABL kinase inhibitor. It is a drug that is probably more powerful than imatinib and second-generation TKIs. In the studies which are published, when we look at patients treated with ponatinib, usually patients who are resistant to tyrosine kinase inhibitors [TKIs], including resistance to a second-generation TKI, and yet we see very high response rates. It is a drug that's not only potent against the T315I mutation, but on average, regardless of the mutations, it is a BCR-ABL kinase inhibitor that's more potent than any of the currently available BCR-ABL tyrosine kinase inhibitors.
What has research already shown regarding ponatinib?
Ponatinib has shown significant activity in Philadelphia-positive ALL. When we use it at only 30 mg in combination with blinatumomab, we're getting fantastic results. I think in Philadelphia positive ALL, the tradition has been to use intensive chemotherapy with the BCR-ABL tyrosine kinase inhibitor and then move the patients to transplant, what we find is with ponatinib and blinatumomab, we're inducing the best molecular responses we've ever seen and we're reporting an estimated 3-year survival of 95% without the transplant.
This is a major inflection point in the treatment of Philadelphia-positive ALL where we are advocating for a shift in the treatment from the combination of intensive chemotherapy TKI [tyrosine kinase inhibitor] and transplant to non-chemotherapy regimens without the need of transplant, and by using 2 targeted therapies, ponatinib and blinatumomab.
Can you discuss the basis of the PACE and OPTIC trials in CML?
When we started the cancer investigations with chemotherapy, we always defined a maximum tolerated dose [MTD] and then we gave that treatment to the patient. That usually went for about 3-12 months and that kind of the concept, using the drugs at the MTD, was acceptable. In the era of targeted therapy, which started in 2000 with imatinib and then later with many other targeted treatments, we encountered a new set of problems, which is giving those treatments for several years. What we started noticing is that there are long-term side effects at the MTD. The question became, can we use a lower dose, which we now call an optimal biologic dose, and maintain the efficacy while reducing the adverse events?
I presented the dose-adjusted study of ponatinib based on response and it is along the line of this concept. In this analysis, we took 2 completed studies, the PACE trial and the OPTIC trial. Those 2 studies took patients with chronic-phase chronic myeloid leukemia who were highly resistant to other tyrosine kinase inhibitors. We compare the 2 concepts.
Can you delve into the similarities and differences of the 2 trials?
In the PACE study, we gave the patients an FDA-approved dose of 45 mg daily continuously, and we reduced the dose only when we had adverse events. The second, the OPTIC trial, randomized patients to either ponatinib 45 mg, 30 mg, or 15 mg. As soon as they achieved the PCR level of less than 1%, which is a complete cytogenetic response, we reduced the dose to 15 mg. What we did then was compare the 270 patients on the PACE trialto the 94 patients on the OPTIC trial that started at 45 mg and had a dose reduction, which was mandated once they achieved the response.
What we found is with the optimized biologic dose on the OPTIC trial, where we reduced the dose once, patients achieved a good response. With that, we had similar efficacy outcomes and the incidence of complete cytogenetic response was the same. In fact, the rate of progression-free survival was better on the OPTIC trial where we adjusted the dose because there were less patients who stopped the treatment for adverse events. When we looked at the 2-year progression-free survival, it was 90% vs 67%. Then in both studies, the 2-year incidence of survival was outstanding at close to 90%. Then, we looked at the incidence of adverse events and they were lower on the OPTIC trial where we adjusted the dose based on response.
We also looked at the incidence of arterial occlusive events, which is an adverse event of concern with ponatinib. We found that by adjusting the dose once the patients had the response, it reduced the incidence of arterial occlusive events by 60%. The incidence of serious arterial occlusive event was reduced to 4% on the OPTIC trial and it was about 15%, on the PACE trial. In fact, we defined a better dose adjusted schedule of ponatinib, which is a schedule where we can start at 45 mg on average in patients with T315I mutation. We can even use a lower dose schedule or 30 mg daily in patients who don't have the T315I mutation. Then, the recommendation is to reduce the dose of ponatinib to 15 mg as soon as we get a good response, which is defined as the complete cytogenetic response or a PCR level of less than 1%.
Where do you think investigators will focus their research in the future of this space?
CML experts and patients had concerns about the adverse events with ponatinib. Now that we have a better optimized biologic dose schedule, I think we have to move ponatinib to the second-line therapy. What we would like to do is take patients who failed frontline therapy, and the failure should be failure for resistance to a second-generation TKI. A lot of the studies now are using second-generation TKIs in the frontline.
What we would like to do is rather than wait for the patients to fail multiple TKIs before we use ponatinib, what we would like to do is move it to a second-line where any patient who fails a second-generation TKI with resistance, we will treat them with ponatinib and see how the efficacy is maintained in that setting. I am confident that this will be a very good drug, a second-line therapy in patients who receive a second-generation TKI frontline and become resistant.
What was the key takeaway from these studies?
The key takeaway is with ponatinib, as with many other targeted therapies, we can look at the optimized biologic dosages which are not the same dosages that were FDA approved. This is a concept across many targeted therapies. When you look at dasatinib [Sprycel], the FDA approved dose is 100 mg but we find those of 20 mg-50 mg to be very effective. Nilotinib [Tasigna] is approved in the frontline at 300 mg twice daily. We find that once the patients achieve a good response, we can reduce them to 150 mg twice daily or 200 mg daily.
The same goes for bosutinib [Bosulif]. If we start using it, at the FDA approved dose of 400 mg, the patients encounter quite a bit of adverse events and they get discouraged and drop the treatment. Now what we do is the dose adjusted introduction. We start bosutinib at 100 mg to 200 mg daily for a week or 2, then we go to 300 mg daily for a month or 2, and then we may or may not go to 400 mg daily depending on the response and the adverse events. The general concept is that many of those targeted therapies in CML and in other diseases can be adjusted to an optimized biologic dose, which maintains the efficacy and reduces the adverse events significantly.
