Zydelig® (idelalisib): The Force to Fight CLL and FL

Interview with Dr Dominique Tonelli, Regional Senior Medical Affairs Director for Gilead, by Kelly Llewellyn, Assistant Editor for EMJ.

THE BACKGROUND

After the European Commission granted the marketing authorisation for Gilead’s Zydelig® (idelalisib), a first-in-class oral treatment for chronic lymphocytic leukaemia (CLL) and follicular leukaemia (FL), the European Medical Journal held an exclusive interview with Dr Dominique Tonelli, Regional Senior Medical Affairs Director for Gilead.

CLL is the most common type of adult leukaemia (occurring in people around the age of 60), but unfortunately to date it remains an incurable disease, and around 3,000 cases are diagnosed every year in the UK alone; FL is the most common type of indolent non-Hodgkin lymphoma.

Dr Tonelli commented: “I think we can be proud to potentially have the opportunity to make a difference of those patients. We will continue working and providing new information and new data for those CLL and FL patients who have very limited treatment options; it is a significant milestone for us. I hope that it will make a difference for many more patients than only those with limited treatment options.”

THE STUDIES

The marketing authorisation of idelalisib for use in CLL and FL patients was supported primarily by data from a randomised, placebo-controlled, Phase III trial, named Study 116, and a single-arm Phase II trial, Study 101-09. The studies included patients in the most negative situation and who had tried and exhausted previous therapies.

The previous Phase I and II studies were to establish: “1) what the best regime is and also how to administer this drug. Those trials, which were published, established that the drug should be administered orally, continuously every day, twice daily; 2) to define what the recommended dose to be used is. The dose is 150 mg twice a day, so it is a tablet of 150 mg, it is quite a small tablet so it is easy to swallow; 3) assess any insult activity in this population; and 4) [to] evaluate the safety profile. All those elements together formed the basis to move to combination trials to see whether the drug is combinable with other agents,” explained Dr Tonelli.

After the Phase I trial it was established that in CLL and FL the recommended dose of Zydelig as a single agent is 150 mg twice daily, continuously, as an oral tablet,” highlighted Dr Tonelli. “Then we move to Phase II in combination, with Zydelig plus rituximab, Zydelig plus chemotherapy and rituximab, and later on, we have also started trials of Zydelig in combination with ofatumumab and other agents. But basically, first of all, the two main drugs, rituximab and chemotherapy [were used] to see whether our drug could be combined [and] what the dose will be. The research of those combination trials established that, in fact, whenever Zydelig is administered as a single agent, or in combination, the regimen and the dose to be used are the same. Which means, in fact, that the safety profile of the drug is very much combinable with either an immunotherapy or chemotherapy.”

In the Phase I study it was found that the objective response rate was dramatically increased without increasing the safety profile, this provided a strong rational that this drug was beneficial in CLL patients, but it is more beneficial when combined with rituximab. Dr Tonelli said: “The right way to use Zydelig for CLL patients who have been previously treated, will be in fact to use it in combination with rituximab.”

The primary endpoint of the Phase III studies included disease progression, progression-free survival, and quality of life (QoL). A data safety committee, who looked at the data in a blind manner “observed that there was a dramatic difference between the two groups; a dramatic difference in term of progression free survival,” emphasised Dr Tonelli.

The data monitoring committee “decided to stop the study and to un-blind it because it was not ethical to keep continuing including patients because there was one arm which reached the median [5.5 months].

So they un-blinded, and what they saw was that, in fact, it was the arm of rituximab only that was doing badly compared to the other arm [rituximab plus idelalisib]. That is what happened for the Phase III trial which was used and reviewed by the authorities when we submitted the dosage for registration in the European Union, and was the basis for the approval in [pre-treated] CLL patients,” said Dr Tonelli.

It has been said that chemotherapy may no longer be needed for CLL patients, do you think this could lead to chemotherapy being completely redundant in these cancers?

There is no reason to change the standard treatment which is a combination of chemotherapy and immunotherapy, there is no reason to change it if it controls 90-95% of the patients, or if it cures patients, or if it has a perfect safety profile. The reason there is a need to develop, and continue to develop, in order to see whether potentially we can avoid chemotherapy there would be, to me, two main reasons; 1) nowadays, those treatments are very effective, however, they do not prevent patients from relapsing sometimes; 2) these patients have a median age of 70, and the bone marrow and reservoir of red blood cells and platelets etc. are not the same as when you are 20 years old… those patients may not be able to receive chemotherapy, or if they can receive chemotherapy they may not be able to receive chemotherapy for many lines of treatment, when we know in advance that we will have to treat them for a long time.

Yes there is a need to think about a way to avoid chemotherapy, but just not for the pleasure to avoid chemotherapy,” answered Dr Tonelli.

Dr Tonelli continued: “There is still a lot of progress needed in unmet medical needs, either in terms of efficacy, because those patients will relapse sometimes, or in terms of safety.” However, for patients who cannot receive further chemotherapy there is now an alternative.

WHAT BENEFITS WILL IT BRING TO PATIENTS?

Some patients who have CLL are inflicted with genetic alterations, such as a chromosome 17 deletion – del (17p), or a mutation in the TP53 gene, both of which have been linked to poor prognosis and predictive of more rapid disease progression; moreover, patients with these alterations have a worse prognosis compared to patients without them.

There was a trial in first-line CLL patients… that were treated with rituximab and Zydelig. We established that when those patients have 17p deletion in first-line, they perform as well as if they have no alterations, meaning that… to add Zydelig to rituximab for those patients erases the fact that they have 17p deletion, in terms of prognosis,” explained Dr Tonelli.

Age in these patients is a factor which needs to be taken into consideration since comorbidities could be a potential problem, as could co-treatments because they may not be able to receive chemotherapy. “Having a treatment which can help patients who cannot, or [can no longer] receive chemotherapy… is important. This is one element which will be very important for patients who are not chemotherapy eligible any more, and also for patients who have a poor prognosis, such as genetic alteration,” highlighted Dr Tonelli.

Dr Tonelli continued: “What is impressive in the drug, which has been reported, is the measure of objective response and the measure of the QoL reported outcome; the response is reached very quickly and patients feel it, in terms of decreased lymph nodes, which decrease rapidly inside. What is interesting in the QoL is that it is not worsening while on treatment; when it is an effective treatment it stabilises the QoL in these patients,” so if they were not treated their QoL would worsen.

But does the patient feel different?” Dr Tonelli asked, “the answer is yes, and this has been demonstrated with QoL questionnaires, which were validated, and I think that this was a critical element for these patients.

Have you received any positive feedback from oncologists or any healthcare professionals currently using the drug?

Yes, we have received positive feedback. We also received that from clinical investigators during the trial. Their highlights were the one key element – the time to response – the fact that the patient responds very quickly to the treatments and the treatment has very rapid effects in terms of lymph node shrinkage and in terms of QoL improvement,” Dr Tonelli emphasised. 

 

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