Chronic Myeloid Leukemia | Biotech Strategy Blog

ASCO 2016 Preview on Targeted Therapies

After a long lull on the targeted therapies front – outside of EGFR T790M in lung cancer – this year’s ASCO has plenty to be cheerful about with new data across multiple tumour types. We can’t cover them all here, but more will be discussed in the Daily Live Blogs starting on Saturday.

Which drugs are going to be in roaring back after a quiet period? Which ones will be having a more muted meeting?

For those of you who are working in the targeting therapy world, take heart, there is a future beyond cancer immunotherapy; it is not the universal panacea and will likely not cure every cancer, at least for now.

There’s still a market opportunity for targeted therapies in cancer, and as we mentioned in yesterday’s ASCO Preview, there is also potential for the combination of targeted therapies with immunotherapies, so long as the combined toxicity is manageable and doesn’t outweigh the benefits.

In this post we’re looking at a selection of targeted therapies in a variety of tumour types. There’s a lot to choose from at ASCO this year.

Here’s a few we think are worth highlighting upfront.

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The Evolving CML Market – which drug to give when?

One of the enduring legacies from the development of imatinib (Gleevec®/Glivec®) for the treatment of chronic myeloid leukemia (CML) is the long-term survival data from the IRIS (International Randomized Interferon versus STI571) trial that enrolled 1106 patients between June 2000 and January 2001.

Hagop Kantarjian, M.D. Professor and Chair, Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston told the 2012 Chemotherapy Foundation Symposium (also known as the Greenspan Meeting in honor of the late Ezra Greenspan, M.D.) that:

the 10 year survival rate is 85% in patients treated with imatinib, and that this rises to 90% if you exclude deaths not related to CML.

No second-generation tyrosine kinase inhibitor (e.g. nilotinib, dasatinib, bosutinib) has yet to show a superior long-term survival benefit to imatinib. Dr Kantarjian noted that “whatever comes as a new treatment in the frontline therapy has to be able to beat that time, of a 10 year survival, if there is a big cost difference.”

The IRIS trial survival data for imatinib remains the gold standard by which other tyrosine kinase inhibitors will be judged.

In other words, notwithstanding the myriad of published CML data that shows second generation TKIs offer a deeper or more rapid molecular response, there’s still no data that shows you will actually live longer if you take any of them instead of imatinib.

That’s not to say there are no benefits to the newer second generation TKIs.

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However, it is interesting that we have not seen Novartis publish an update to the IRIS trial for a while. Instead, faced with imatinib going off patent in 2014, Dr Kantarjian noted that the company has raised the price of imatinib and destroyed the price differential to nilotinib to encourage more nilotinib usage. It’s hard to compete against your own successful product!

In the short-term, this marketing strategy may promote the use of nilotinib instead of imatinib. The reality, however, is that we can expect generic imatinib to be widely used frontline once available, where cost is an issue, whether it be for out of pocket patient co-pays, or in countries where healthcare reimbursement is government funded. It will be interesting to see whether this will put some pressure on companies to lower the price of second-generation TKI’s.

In terms of current treatments for CML, Dr Kantarjian told a large audience at the Greenspan Meeting that the choice of FDA approved TKI therapy for CML in frontline is imatinib 400 mg daily, nilotinb 300 mg BID or dasatinib 100 mg daily. In second or third line therapy, the choice of TKI options is nilotinib, dasatinib, bosutinib or ponatinib (pending FDA approval in 2013).

Choice of TKI in CML

Dr Kantajarian discussed in detail the factors that clinicians need to consider when choosing a TKI for patients with CML. These include:

Efficacy – CGCR, MMR, CMR, EFS, survival
Toxicities
Disease status – frontline, salvage, tranformation
Salvage – Mutation status
Comorbidities: COPD, CHF, diabetes, pancreatitis
Cost

It’s beyond the scope of a blog post to go into detail on these. However, when it comes to efficacy, it is important to look at outcomes.

Dr Kantarjian told the audience that with second generation TKIs “so far there is no survival benefit” over imatinib and that “many patients who fail imatinib can be salvaged effectively with second TKIs.”

Important Response Categories in CML

If you are looking for an improvement in survival, you need to achieve a complete cytogenetic response, you do not have to have a major molecular response, said Kantarjian.

Table modified from Hagop Kantarjian, M.D. presentation at 2012 Chemotherapy Foundation Symposium

Dr Kantarjian noted that in a survey of 507 U.S. community oncologists: 72% had Major Molecular Response (MMR) as the desired treatment outcome with only 17% seeking a Complete Cytogenetic Response (CGCR).

The Golden Rule in CML Monitoring

Dr Kantarjian shared with the Chemotherapy Foundation Symposium audience some of his golden rules in CML monitoring, one of which was:

“Do not discard a TKI unless there is a loss of CGCR (not MMR) at the maximum tolerated adjusted dose that does not cause grade 3-4 or chronic grade 2 (affecting QOL) toxicities.”

He went on to advise that when analyzing mutations in CML:

If CG or hematologic relapse occur, mutations studies help
No role for mutation studies pre-Rx or in imatinib responding patients

As for the choice of TKI at the MD Anderson Cancer Center, Dr Kantarjian told the audience that they currently use investigational ponatinib in both frontline and salvage settings. He noted that as an investigational drug it was free to the institution and patients.

The CML market remains one that will undergo further evolution over the next few years as new drugs such as ponatinib come to market and existing drugs such as imatinib go off patent.

It will be interesting to watch the market dynamics and whether the clinical benefits of the second-generation TKI’s justify their significantly higher cost over generic imatinib.

CML update from 2011 ASH annual meeting

The annual meeting of the American Society of Hematology (ASH) took place in San Diego this past weekend. There was a lot of interesting science, and over the next three posts I will be writing a brief summary of what caught my attention in CML, AML and the poster sessions.

Brian J. Druker & Janet D. Rowley received the Ernest Beutler prize and presented a lecture on “Chronic Myeloid Leukemia (CML): A Success Story from Chromosomes to Effective Therapy.”

As a result of the development of imatinib (originally STI571), “CML has been converted to a manageable condition”, said Druker.

He also noted that, “the next quantum improvement would be disease eradication.”

Can we aim at a cure? This question was asked by Junia Melo (Adelaide) in the excellent CML education session that also included presentations by Neil Shah (UCSF), Andreas Hochhaus (Jena).

The ASH annual meeting spends a lot of time and effort on educational programs and each year different topics are selected. In previous years I have listened to excellent presentations on AML & CLL. The session is a good way to come up to speed with an area, and usually the presenters highlight topical abstracts at the meeting that are noteworthy.

In her CML education session, Melo suggested that the concept of an “absolute cure: the eradication of the last leukemia cell from the patient’s body” was something that was almost impossible to measure. More realistic was the concept of an “operational cure: the disappearance of all signs of disease and the possibility of blastic transformation.”

Melo presented interesting research on targeting CML stem cells, and conceptual models for drug-free remission (“cure”) that involved stem cell depletion and exhaustion. This may be an area for future drug development.

FTY720 (fingolimod) inhibits self-renewal and promotes apotosis of the quiescent stem cell, said Melo. BMS-214662 was also mentioned as an interesting compound in this area.

The most newsworthy CML data presented at the meeting was on Ponatinib. Jorge Cortes (MD Anderson Cancer Center) presented the phase II results from the PACE (Ponatinib Ph+ ALL and CML Evaluation) clinical trial.

Ponatinib is being developed by Ariad and is an oral, pan-BCR ABL tyrosine kinase inhibitor (TKI) that has activity against the T315i mutation, which is not targeted by other TKIs currently on the market.

Cortes made the following conclusions about the PACE trial results:

Ponatinib has substantial anti-leukemic activity in a heavily pretreated population
Responses observed in all cohorts, regardless of mutation or disease stage
Responses improving over time
Favorable safety profile in heavily treated patients
Early efficacy signals similar to initial response results reported in the phase 1 setting
Ponatinib has the potential to become a promising new treatment option for patients with multi-refractory relapsed CML.

Dr Cortes presented several papers at the meeting, including the 24-month follow-up results from the BELA trial (Bosutinib versus imatinib in newly diagnosed Chronic Myeloid Leukemia).

In the BELA study, the data according to Cortes showed “superior rates of MMR and similar rates of CCyR for bosutinib compared with imatinib with 24 months of follow-up.”

“Bosutinib may offer a new therapeutic option for patients with newly diagnosed CP CML” he noted. Whether bosutinib can obtain regulatory approval remains to be seen given that it did not show superiority to imatinib in its primary endpoint, ie complete cytogenetic response (CCyR).

Another presentation by Dr Cortes was the phase 1 results of DCC-2036, a novel oral inhibitor of BCR-ABL1 Kinase, in patients with Ph+ leukemia including those with the T315i mutation.

DCC-2036 is a switch control inhibitor that inhibits SFK and FLT3, but spares c-KIT. It appears to be a potent inhibitor of BCR-ABL1, and BCR-ABL1 mutants, including the highly resistant T315i mutation. The Phase 1 results showed the drug was well tolerated at MTD with efficacy in refractory CML patients with multiple prior TKI treatments.

One of the benefits of attending ASH is the opportunity to meet experts from around the world. I had a very enjoyable conversation with Professor Dong-Wook Kim from Korea, who told me how he goes mountain climbing every month with his CML patients.

He runs a clinic that sees 50-60% of Korean CML patients and is the lead investigator for Radotinib, (IY5511), a new second generation TKI that is currently in phase 3 trials in Asia.

I was also delighted to note in the CML education session that Dr Hochhaus drew attention to role of CML patients’ advocates.

“The CML community is an outstanding example of global patient advocacy – not to be seen in many other cancers,” Hochhaus said.

With the prospect of generic imatinib in 2015, companies with CML products in development may be in a race against time to seize the market opportunity. It will be interesting to watch the market dynamics over the next few years.

Patient advocacy session at European Hematology Association EHA 2011 Congress shows impact of drug adherence on outcome

The patient advocacy session at the recent 16th Congress of the European Hematology Association in London focused on adherence to cancer treatments, and was filled to capacity, with the many attendees having to watch it from an overflow area.

Dr David Marin, Reader in Onco-Haematology at Imperial College, London presented research published last year in the Journal of Clinical Oncology that dramatically demonstrated how adherence to chronic myeloid leukemia (CML) therapy is the critical factor for achieving molecular responses.

In a study of 87 CML patients taking imatinib (Glivec®/Gleevec®) for a median period of 91 days, Dr Marin showed that no major molecular response (MMR) was observed when adherence was ≤ 80% and no complete molecular responses (CMR) were observed when adherence was ≤ 90%. The graphical figure that he presented from his paper, dramatically shows how missing only a few doses of drug can have a major impact on outcome:

Although the work by Marin and colleagues at the Hammersmith Hospital was undertaken with CML patients taking imatinib, the paper notes that adherence problems

“may apply equally to patients receiving second-generation tyrosine kinase inhibitors.”

Imatinib is the only TKI approved in the UK, thus that’s the only one available for studies there to date.

What made this data so compelling was the study rationale that used an electronic pill container, the medical event monitoring system (MEMS™) from the Aardex Group. This product contains a microchip that records the date and time it is opened.

Dr Marin’s study showed that “lack of adherence is underestimated by conventional methods.” Self-reporting of adherence and pill counts are inaccurate compared to electronic data capture using MEMS (study subjects were unaware of the micro-chip in the pill bottle).

When psychologists at the Hammersmith Hospital subsequently interviewed patients who missed doses of drug, they found intentional and non-intentional adherence reasons.

A few excepts of patient quotes from Dr Marin’s presentation:

Intentional non-adherence:

“Oh I can’t be bothered tonight, it’s not going to kill me [to miss a dose]”

“I thought there was no way I was going [on holiday] and being tired.”

Unintentional non-adherence:

“And sometimes you just forget”

“[the pharmacy] had no medication for me, so I went for nearly a week with no medication.”

Other speakers in the excellent patient advocacy session chaired by Jana Pelouchová (European Cancer Patient Coalition, Czech Republic) and Jan Geissler (CML Advocates Network, Germany) included Giora Sharf (Israeli CML patient’s Organization and CML Advocates Network, Israel) and Professor Rudolf Schoberberger (Medical University of Vienna, Austria).

Professor Schoberberger focused on the impact of drug packaging on compliance, particularly in elderly patients, and presented compelling research on how “child-proof” equals “age-proof.” Sally Church in her video blog from EHA also discusses the patient advocacy session and how pharma/biotech companies could improve drug packaging.

The issue of adherence is a personal choice that every patient taking a chronic therapy makes. However, as Sally notes on Pharma Strategy Blog more patient and physician education is needed so that patients know there may be dramatic consequences from missing only a few doses per month.

Not only may adherence have a major impact on patient outcome, but as one questioner from France pointed out at the end of the EHA patient advocacy session, “for a statistician it is a nightmare.” Poor adherence in clinical trials “means that the true effect of a drug is not well known. Efficacy may be under-estimated if adherence is low.”

More monitoring of adherence in clinical trials through the use of MEMS technology may, therefore, be necessary to ensure that clinical trial data shows the true efficacy and adverse event profile of a drug.

I hope that the European Hematology Association (EHA) will make a webcast of this informative patient advocacy session publicly available online as it raised issues of considerable importance to patients, physicians and biotech/pharma companies alike.

Marin, D., Bazeos, A., Mahon, F., Eliasson, L., Milojkovic, D., Bua, M., Apperley, J., Szydlo, R., Desai, R., Kozlowski, K., Paliompeis, C., Latham, V., Foroni, L., Molimard, M., Reid, A., Rezvani, K., de Lavallade, H., Guallar, C., Goldman, J., & Khorashad, J. (2010). Adherence Is the Critical Factor for Achieving Molecular Responses in Patients With Chronic Myeloid Leukemia Who Achieve Complete Cytogenetic Responses on Imatinib Journal of Clinical Oncology, 28 (14), 2381-2388 DOI: 10.1200/JCO.2009.26.3087

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Posts tagged ‘Chronic Myeloid Leukemia’

ASCO 2016 Preview on Targeted Therapies

This content is restricted to subscribers

The Evolving CML Market – which drug to give when?

Choice of TKI in CML

Important Response Categories in CML

The Golden Rule in CML Monitoring

CML update from 2011 ASH annual meeting

Patient advocacy session at European Hematology Association EHA 2011 Congress shows impact of drug adherence on outcome