Incorporating Generic Imatinib Into Frontline Treatment for CML

Silas Inman @silasinman
Published: Saturday, Oct 01, 2016

Dr Jerald P. Radich

Jerald P. Radich, MD

The introduction of imatinib (Gleevec) dramatically transformed the treatment paradigm for a majority of patients with chronic myeloid leukemia (CML), ushering in a new era in cancer therapy championed by targeted agents. Now, as generic imatinib enters the market, new questions focus on a renewed role for the agent in conjunction with second-generation TKIs, according to Jerald P. Radich, MD, at the 2016 NCCN Annual Congress on Hematologic Malignancies.

"We have made unbelievable changes in the natural history of this disease," said Radich, a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center. "We have a drug that hits the target, and a target where we can monitor the disease burden. If you look at the relative survival in the chronic phase for those who have the disease versus the natural history of people without CML, it's virtually within 95% confidence interval to the full population, which is absolutely astonishing."

Since the approval of imatinib, the second-generation BCR-ABL inhibitors dasatinib (Sprycel) and nilotinib (Tasigna) have also gained approval as frontline and second-line therapies for patients with CML. These agents were later joined by bosutinib (Bosulif) and ponatinib (Iclusig), which are approved as second or third-line therapies.

In most cases, selection of a frontline TKI depends on treatment goals, specifically related to achieving a major molecular remission (MMR) or a complete molecular response (CMR), comorbidities, compliance, and the possibly of discontinuing the medication in the future. With a generic version now available, cost and affordability could become another factor to consider.

At this point in time, the first approved generic version of imatinib is within a 6-month exclusivity window, resulting in a higher price compared with the future. The drug is priced at an approximate 10% discount currently, according to Radich. However, as this exclusivity window lifts and other generics enter the market, the price will continue to drop until it reaches 15% of the original price, Radich believes. Currently, second-generation TKIs are priced at $100,000 to $150,000 annually, he said.

"We should expect a pretty big drop," said Radich. "Once you get more of them out there in the marketplace, there's about a 40% reduction in costs. If there are more than 3 generics out there, then there is about a 50% drop. If there are 4 generics, it can get down to 15% to 20% of the brand cost."

Costs are not the only piece of the puzzle, however, as the second-generation agents have shown significantly greater efficacy in head-to-head comparisons with imatinib in the phase III DASISION and ENESTnd trials.1,2 Moreover, each agent has shown efficacy in the second-line setting, adding a further option to help delay progression to accelerated phase (AP) or blast crisis (BC). "Once people progress, their median survival is about 1 year," said Radich.

In the frontline setting, 5-year results from the DASISION trial1 showed a 12-month complete cytogenetic response (CCyR) rate of 77% with dasatinib and 66% with imatinib. The 5-year MMR rates were 76% versus 64% and the 5-year overall survival (OS) rates were 91% versus 90%, with dasatinib and imatinib, respectively. At 5 years, 5% of patients in the dasatinib arm had developed AP/BC CML versus 7% with imatinib.

Similarly, in 5-year findings from the frontline ENESTnd trial,2 the 12-month CCyR rate was 80% with nilotinib versus 65% with imatinib and the 5-year MMR rates were 77% and 60%, respectively. The OS rate was 94% for nilotinib versus 92% for imatinib. After 5 years, 4% and 8% of patients in the nilotinib and imatinib arms, respectively, had developed AP or BC CML. 

"The imatinib 400 mg arms are amazingly similar between studies for all of these criteria. They are surprisingly similar outcomes with imatinib,” said Radich. “Short term response is better with the second-generation drugs but overall survival is similar."

While side effects are similar across TKIs, arteriothrombotic events are lower with imatinib versus other second-generation agents. Across studies, imatinib at 400 mg was associated with an arteriothrombotic event rate of 2% to 3% versus 5% to 16% with second-generation TKIs. This may be related to a class effect and hitting BCR-ABL, noted Radich.

In a phase II study exploring a double dose of imatinib (800 mg),3 efficacy was similar for the larger dose to second-generation agents; however, there were more side effects, noted Radich. The CCyR with 800-mg imatinib was 85% and the MMR was 53%. The OS rate was 95% at 1 year.

"The imatinib at 800 mg gave almost the exact same results as a second-generation drug, and that has been seen in many trials," Radich said. "But with imatinib, once you get up to 800, you get a lot more toxicity."

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