Sunday, December 23, 2012

ASH 2012: 189 The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Promotes High Response Rate, Durable Remissions, and Is Tolerable in Treatment Naïve (TN) and Relapsed or Refractory (RR) Chronic Lymphocytic Leukemia (CLL) Including Patients with High-Risk (HR) Disease

Let's look in more detail at some of data on ibrutinib (PCI-32765) presented at ASH 2012.

There were many papers on ibrutinib, but I am going to start with #189 that looks at data in CLL/SLL that now goes out almost two years ("beyond 22 months") using the drug as single agent therapy.

Five cohorts were studied. Remember only patients needing treatment could enrolled in the trial.

For those for whom ibrutinib would be their first therapy ever for CLL, 26 got 420 mg and 5 got 820 mg. These were the treatment naive (TN) cohorts and all were older than 65.

The 820 cohort was closed before full accrual when it became apparent the lower dose had comparable activity and safety in the relapsed and refractory patients. What I believe this is saying is that once the target (the BTK pathway) is saturated with drug and fully blocked, there is no advantage to adding more drug.

In the relapsed and refractory (RR) groups, there were two cohorts. 27 and 34 patients respectively got 420 or 820 of ibutinib daily. All these patients had had to have failed at least two prior therapies  including a purine analog, usually fludarabine. As I said, before the different dosages made no difference in the outcomes.

The fifth cohort consisted of 24 addition high risk (HR) patients who had either 17p del or had relapsed in less than two years after FCR or an equivalent chemo-immunotherapy.They all received 420 mg daily.

In the combined two TN group, three patients had complete remissions (CR), nineteen had partial remissions (CR), three had PR with the now expected lymphocytosis, four patients had stable disease, and two patients could not be evaluated. In all, 29 of 31 patients and 100% of all evaluated patients were still on the trial drugs because it was helping them after almost two years.

That's a strong result, but let's look at the hard to treat patients, the RR and HR cohorts. This is the real test and where there is the greatest need for improved outcomes.

In the RR groups one patient out of 61 progressed. In the HR group, where seven were 17p del and eight were 11q del, one of 24 progressed. A detailed breakdown of the responses and all the data is available online here.

True in these two groups, there were only two CRs, but the results are better than the last interim report with more remissions. I bet there will be more CRs reported at ASH 2013 (in New Orleans) when we have yet another year of follow-up for this study. The data may be getting better the longer patients are on therapy.

Adverse events were usually not serious with diarrhea in 54% across cohorts being far and away the most common. That percent falls to about 3% after 6 months. Serious blood and infection issues can occur, but are very rare. Remarkably, IGA (an immunoglobulin used to fight infections especially in the mucus membranes) levels actually increased and IGM and IGG stayed stable. 7 of 116 patients quit the study due to side effects of the drug. All the problems seem to get less frequent after the first six months of treatment.

Drilling down into the data, the authors (my doctor, John Byrd was lead author) report that response rates were the similar for those with bad prognostics including 17p, high b2M, multiple prior therapies, and advanced disease stage.

This is a revolutionary change. Is it saying that the dreaded 17p del or having failed multiple therapies or being RAI stage IV makes no difference in our response rate? Seems so.

Old treatments in these tough to treat groups would be lauded if half the patients were doing OK after two years, but with ibrutinib, only two of 85 patients are reported as having progressed. And there are no significant side effects.

The Kaplan Meier curve tells it all. On the Y or vertical axis is the number of us still alive. On the X or horizontal axis is time. A flat line near the top is ideal. These results are nothing short of stunning.

Those old charts that showed a 45 degree or greater rush to mortality will soon be banished to the dustbin of medical history along with bloodletting for a sore throat or skull trephining for headaches.

We are living longer. And feeling better. Say goodbye soon to chemo for most of us. That's not just this wild-eyed patient talking. That is the emerging consensus from the CLL gurus.

Studies on ibrutinib were reported at last year's ASH, but the buzz has grown exponentially, not because the data is so much better which it is, but because it is looking as if this could be a durable treatment with no unexpected side effects and no growing issues of resistance so far.

I have been going to ASH meetings long enough to have seen more than one promising drug turn out to be a one hit wonder that makes big news one year and disappears the next, but ibrutinib is beginning to emerge as a solid therapy.

Hence the phase 3 trials. That's the acid test, the real proof.

Two years is too soon to close the book on CLL, but the data is way better than what we had last year, but we need bigger numbers and longer follow-up.

The phase 3 trials that are up and running already will tell us so much more. The sooner those are fully enrolled, the sooner I believe this game changing drug will be available to all of us who might need it.

If you are needing to consider therapy soon, I encourage you to check out clinical to see if something there makes sense for you.

The life you save might be your own.

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Anonymous Anonymous said...

Great post. It's sometimes hard to decipher the true gem therapies from the bucket bc the researchers and pharma need to be measured when they talk about new drugs.

Of those in the know, when do they think Ibrutinib will be FDA approved?

January 12, 2013 at 2:24 AM  

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