Frontline Treatment Questions Abound as Generic Imatinib Approaches

Harry P. Erba, MD, PhD

The frontline treatment of patients with Philadelphia chromosome—positive (Ph+) chronic myelogenous leukemia (CML) continues to be debated as imatinib (Gleevec) rapidly approaches the end of its patent protection and next-generation agents continue to show efficacy in clinical trials.

Enhancing this debate is the fact that there are currently three highly effective tyrosine kinase inhibitors (TKIs) approved for the frontline treatment of patients with Ph+ chronic CML, including imatinib, and three unique therapies approved in secondary settings. Due to the depth of this armamentarium, several factors go into the decision of which therapy to utilize, including efficacy, costs, and toxicities.

In an OncLive Peer Exchange roundtable entitled “Recent Advances in MDS and CML,” moderator Harry P. Erba, MD, PhD, led a discussion on the optimal use of approved therapies across the treatment paradigm for patients with CML. The patent for the active ingredient in Gleevec expires in the United States in 2015, although other patents on certain features and processes remain in effect from 2018 to 2023, according to documents that Novartis, the drug’s manufacturer, posted on its website. Generic versions already have been launched in at least six other countries, including Canada, said Novartis.

The second-generation BCR-ABL inhibitors dasatinib (Sprycel) and nilotinib (Tasigna) demonstrated better efficacy than imatinib in the ENESTnd (Table 1) and DASISION trials (Table 2) for the first-line treatment of patients with Ph+ CML. At 24 months, the complete cytogenetic response (CCyR) rate for patients receiving dasatinib in the DASISION trial was 86%, compared with 82% with imatinib.¹ Similarly, in the ENESTnd study, the 24-month CCyR rate with nilotinib was 87% at 300 mg twice daily dosing versus 77% with imatinib at 400 mg daily.²

Table 1. Four-Year Efficacy Findings From ENESTnd

Nilotinib 300 mg BID

(n = 282)

Nilotinib 400 mg BID

(n = 281)

Imatinib 400 mg QD

(n = 283)

MMR

76% (P <.0001)

73% (P <.0001)

56%

MR4.5

40% (P <.0001)

37% (P = .0002)

23%

PFS

96.7% (P = .0497)

97.8% (P = .0074)

93.10%

OS

94.3% (P = .4636)

96.7% (P = .0498)

93.30%

BID indicates twice daily; MMR, major molecular response; MR4.5, molecular response grade 4.5; OS, overall survival; PFS, progression-free survival; QD, daily. Saglio et al. Blood. 2013;122(21; abstr 92).

Given the similar efficacy at a lower cost, imatinib remains an attractive option in the frontline setting. However, the second-generation agents are usually recommended across all settings, as a result of their increased efficacy and lesser toxicity. “I’d say that the main drivers of not using a secondgeneration TKI upfront are really economic, and I think it’s a fair discussion that’s based on limitations and things of that nature,” suggests Ruben A. Mesa, MD. “For the individual patient in the room with me, I typically advise a second-gen TKI as frontline [therapy].”

Newer Agents Prove Effective

Although there is an economic advantage with imatinib, treatment with the drug is not as well tolerated as therapy with the newer agents. Moreover, as the toxicity profile becomes more severe, patients are less likely to be compliant.

“Noncompliance leads to disease progression. And it is perfectly well established that a patient taking imatinib may not be compliant due to side effects,” explained Mark J. Levis, MD, PhD. “I can’t think of a greater reason for a patient to be noncompliant than what we would regard as, ‘Oh, it’s not that bad.’ ” To confront these conundrums, researchers have developed several strategies that involve utilizing these drugs in various patient populations or in distinct sequences. In the patient characteristic strategy, patients with high-risk disease receive treatment with the second-generation agents while imatinib is utilized primarily in the low-risk setting. In the sequencing strategy, imatinib is administered for 3 to 6 months followed by a switch to dasatinib or nilotinib; or, in a reverse approach, the second-generation agents are used as an induction therapy with imatinib as maintenance.

“I’m coming at it from the point of view of arguing that the difference in progression is the key because we might be curing patients, but what we really know is we’re preventing progression and we should use the drug that does that the best and the quickest,” said Erba. “And so that’s why I would use a second-generation [therapy upfront], everything else being equal.”

Table 2. Four-Year Efficacy Findings From DASISION

Dasatinib 100 mg QD

(n = 259)

Imatinib 400 mg QD

(n = 260)

MMR

76%

63%

MR4.5

37%

30%

PFS

90%

90%

OS

93%

92%

MMR indicates major molecular response; MR4.5, molecular response grade 4.5; OS, overall survival; PFS, progression-free survival; QD, daily. Cortes et al. Blood. 2013;122(21; abstr 653).

While limited data are available regarding sequencing strategies, Sokal score data are accessible for newly diagnosed patients with CML (Table 3). These findings suggest that patients with intermediate- to high-risk scores should receive second-generation agents first, while patients at lower risk are better served by treatment with imatinib.

“In the lower risk, sometimes I’m still willing to offer them imatinib but with the exact point that you should look earlier than 6 months. Maybe at 3 months is a better option,” suggests Rami S. Komrokji, MD. “Then the choice between the other new agent is probably also going to depend on some of the toxicity profile for those two agents, whether to select nilotinib or dasatinib.”

If costs were not a concern, the second-generation TKIs would undeniably be used in the first-line setting, panelists agreed. However, since costs are a concern, better tools are needed to determine the optimal patients for each therapy. In order to be effective, these tools would need to look at features intrinsic to each patient, such as metabolites, polymorphisms, or immune response data. This level of individualization could make research difficult.

Adding to this difficulty is the fact that outside of BCR-ABL mutations, there are not genetic alterations that facilitate the selection of frontline therapies in CML. As a result, genetic sequencing is often reserved for the detection of a possible resistance mutation, such as BCR-ABL T315I. The presence of these alterations could help determine an optimal therapy in the second-line or salvage setting.

In reference to genetic analyses, Rafael Bejar, MD, PhD, noted that he “saves that type of analysis for when patients are actually showing resistance to treatment. That’s the right time to look for these resistance mutations, and really, no other genes have been informative.”

Unfortunately, as imatinib becomes available generically, payers may not provide physicians with much of a choice when it comes to first-line therapies based on reimbursement models. If this is the case, concerns over determining the correct treatment based on patient characteristics could be an exercise in futility, Levis believes.

“I think this is going to be completely turned on its head if imatinib goes generic, and we’re going to be under tremendous pressure to not prescribe those second-generation [therapies],” Levis believes. “So everything we’re doing carefully—thinking that you really need nilotinib versus imatinib—is potentially going to go right out the window.”

Discontinuation of Therapy Difficult

The effective frontline treatment of patients with CML has dramatically changed the natural history of the disease, with the approval of TKIs that target the BCR-ABL fusion gene. However, the long-term administration of TKIs to control CML can result in a range of adverse events and financial burdens, begging the question of whether or not their administration should ever be stopped.

“For hypertension, we prescribe beta blockers forever and nobody complains of that. In CML, we need to stop therapy,” explains Elias J. Jabbour, MD. “So we’re pressured by the patient, by the society, by the financial world to stop therapy.”

Table 3. Four-Year OS by Sokal Risk in ENESTnd

Low

Intermediate

High

Nilotinib 300 mg BID (n = 258)*

97%

94%

91%

Imatinib 400 mg BID (n = 264)*

100%

91%

88%

*Patients with evaluable BCR-ABL transcripts at 3 months. Saglio G. Blood. 2013;122(21; abstr 92).

To address these concerns, the STIM1 and STIM2 trials explored the discontinuation of the TKI imatinib in patients with CML who experienced a sustained deep molecular response (DMR) for more than 2 consecutive years. In a median 12-month follow-up from the STIM² study, a molecular relapse occurred in 39% of patients following the cessation of therapy.³ However, at this point patients were able to achieve a complete molecular remission (CMR) when rechallenged with a TKI.

In the STIM trials, the numbers of natural killer (NK) cells were assessed at the time of treatment discontinuation.⁴ In general, patients with sufficient levels of functional NK cells were less likely to relapse when compared with patients with low levels of dysfunctional cells. These results suggest that NK cell—related immunity may contribute to CML control after TKI cessation. However, more research is needed to discover whether NK cells could be used as a biomarker to predict relapse.

Komrokji noted that clinical developments, such as whether the patient achieved a major molecular response or the duration of remission, could help clinicians make decisions on therapy but he would not feel comfortable advising patients to stop treatment off their protocol or study.

In select circumstances, patients may request that treatment be stopped, specifically female patients wishing to become pregnant. If treatment is stopped, patients should be monitored closely for relapse, the panelists noted. Additionally, treatment with interferon alfa can be utilized, although it is uncommon. For male patients, there is not a need to stop treatment with TKIs, as teratogenic effects related to treatment are unlikely.

“What I would probably recommend in a person who is determined to stop taking the drug is very close monitoring [and] a recommendation that they see a fertility doctor so that they aren’t spending 3, 6, 9, or 12 months trying to get pregnant,” Bejar advises.

The availability of multiple effective treatments for patients with CML provides the potential to rapidly switch between therapies as a result of a perceived lack of response or toxicity. However, the panelists cautioned, the decision to change therapies should be considered in light of long-term outcomes, toxicity, and reliable clinical data.

“I do think the danger that we see nowadays with so many options is not only the premature cessation of therapy but also the willingness to jump between these therapies perhaps prematurely,” noted Mesa. “They all have their toxicity profiles, and many of these things can become better over time.”

Additional Agents Available

For patients with CML who do not respond to imatinib, dasatinib, and nilotinib, there are three additional drugs available: omacetaxine mepesuccinate (Synribo), ponatinib (Iclusig), and bosutinib (Bosulif).

Unlike the BCR-ABL TKIs, omacetaxine inhibits protein synthesis and is not a direct inhibitor of BCR-ABL. This treatment is administered as a subcutaneous injection twice daily for 2 weeks followed by one week of maintenance. In the analysis of two trials that explored omacetaxine in patients with CML, the major cytogenetic response (MCyR) rate for patients with chronicphase (CP-CML; 14 of 76 patients) was 18.4%.⁵ There were not any MCyRs in patients with accelerated-phase CML but the major hematologic response (MaHR) rate was 14.3% (5 of 35 patients).

“Our view of how we use omacetaxine is, in fact, when the T359 [mutation] crops up, when we’re out of options, when the patient is swollen with effusions and we’re not controlling it,” notes Levis. “The paradigm will be let’s use omacetaxine, let’s stabilize his disease, and let’s go to transplant.”

The main roadblock to the wider use of omacetaxine is the administration route, since it requires two daily injections for 2 weeks. As a result, researchers are investigating new schedules and even self-administration. At this point, omacetaxine is a bridge to other treatments, until different schedules or administration routes can be found.

“Omacetaxine I view as an active drug, but the expectation is this is going to be a long-term maintenance therapy,” suggests Mesa. “I don’t think we’re there yet. Perhaps it’s a different schedule. Perhaps that may change that, but clearly it seems much more of a bridge to something else.”

Ponatinib, a potent pan—BCR-ABL TKI, was granted accelerated approval by the FDA in December 2012 based on results from the phase II PACE trial. In late 2013, the FDA placed the clinical development of ponatinib on hold while it investigated an increasing frequency of serious adverse events associated with the drug. This culminated in the termination of the phase III EPIC trial that was acting as the supporting evidence for the accelerated approval. In late December 2013, the FDA reauthorized the sale of ponatinib, along with revisions to the label and a Risk Evaluation and Mitigation Strategy.⁶

At the 55th Annual Meeting of the American Society of Hematology (ASH) in December, the toxicity profile for ponatinib was updated in 2-year follow-up data from the PACE trial, which explored treatment with ponatinib in patients with CML and Ph+ acute lymphoblastic leukemia who were resistant to TKIs or who harbored the BCR-ABL T315I mutation.⁷

In these data, 46% of the participants remained in the trial at 2 years, with 20% discontinuing due to progression and 13% as a result of adverse events (4% thrombocytopenia). The investigator-assessed rates of all-cause serious cardiovascular, cerebrovascular, and peripheral vascular adverse events were 6%, 3%, and 2%, respectively. FDA reports and warnings seemed to indicate a higher rate for these events. “I think there should be concerns about the cardiovascular risk and efforts made to try to see what is the most effective way to prophylax against those, but I do think that’s a very important part of the armamentarium,” said Mesa. The benefits gained from treatment with ponatinib are significant, specifically in patients with the secondary T315I resistance mutation. The side effect profile of ponatinib can be managed by considering risk factors, such as dyslipidemia, smoking, and past cardiovascular events.

“I think we’ve seen a safety signal that clearly is of concern, but I think, for many of us, we’re looking at a group of individuals in the indication who really have a difficult problem,” Mesa said. “This is not upfront chronic- phase CML. These are individuals who have already declared themselves as having more refractory disease.”

The optimal sequence and overall outcomes for the PACE trial were presented in several analyses at ASH. In one of these analyses, patients with CP-CML treated with imatinib and dasatinib, followed by nilotinib (n = 68) achieved an MCyR rate of 46% and a CCyR rate of 40%. The duration of MCyR was 90% at 12 months.⁸ In the second analysis, patients who received imatinib, nilotinib, and then dasatinib (n = 46) had MCyR rates of 44% and CCyR rates of 33% with 87% of patients responding at 12 months.⁹

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The dual SRC and ABL inhibitor bosutinib represents the third option available for patients with resistant or intolerant Ph+ CML. This TKI gained approval from the FDA in September 2012 for treatment following progression on prior therapies. The agent is effective in some resistant patients, except those with the T315I mutation. In general, the panelists consider this agent as a treatment option following nilotinib, imatinib, and dasatinib only if the T315I mutation is not present. Click to view the videos.

References

1. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION) [published online December 9, 2011]. Blood. 2012;119(5):1123-1129.
2. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial [published online August 17, 2011]. Lancet Oncol. 2011;12(9):841-851.
3. Mahon F-X, Nicolini FE, Noël M-P, et al. Preliminary report of the STIM2 study: a multicenter stop imatinib trial for chronic phase chronic myeloid leukemia de novo patients on imatinib. 2013 Annual Meeting Abstracts. Blood. 2013;122(21; abstr 654).
4. Rea D, Dulphy N, Henry G, et al. Low natural killer (NK) cell counts and functionality are associated with molecular relapse after imatinib discontinuation in patients (pts) with chronic phase (CP)-chronic myeloid leukemia (CML) with undetectable BCR-ABL transcripts for at least 2 years: preliminary results from immunostim, on behalf of STIM investigators. 2013 Annual Meeting Abstracts. Blood. 2013;122(21;abstr 856).
5. FDA approval for omacetaxine mepesuccinate. National Cancer Institute website. http://www.cancer.gov/cancertopics/druginfo/fda-omacetaxinemepesuccinate. Updated July 3, 2013. Accessed April 4, 2014.
6. ARIAD announces U.S. resumption of marketing and commercial distribution of Iclusig (ponatinib) in refractory Philadelphia-positive leukemias [press release]. Cambridge, MA: ARIAD Pharmaceuticals, Inc; December 20, 2013.
7. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. Ponatinib in patients (pts) with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL mutation: 2-year follow-up of the PACE trial. 2013 Annual Meeting Abstracts. Blood. 2013;122(21; abstr 650).
8. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. Efficacy and safety of ponatinib following failure of nilotinib in patients with chronic phase chronic myeloid leukemia (CP-CML) in the PACE trial. 2013 Annual Meeting Abstracts. Blood. 2013;122(21; abstr 2738).
9. Hochhaus A, Cortes JE, Kim D-W, et al. Efficacy and safety of ponatinib following failure of dasatinib in patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) in the PACE trial. 2013 Annual Meeting Abstracts. Blood. 2013;122(21; abstr 1498).