Just saw this, even though it's a couple months old.
Just saw this, even though it's a couple months old. I get a little concerned when the supposed scientists are getting hyperbolic with their descriptors. Don't get me wrong; I'm all for miracle drugs. They're infrequent enough, and important enough that we definitely want serendipity to favor this. Nonetheless, it's hard enough to get rational reporting on what is and what is not a true advance, and what is and is not available to help people and their loved ones right now. It doesn't help when the researchers lose perspective, and I do think it is part of your professional responsibility to think about how you say things before you say them whenever possible.
[Most of you can't see the link, so I'm copying the article here. It's a short one, but it'll be a long g+ entry.]
Medscape Medical News > Conference News
Leukemia Drug Is 'Blessing From God,' But Trial Imperfect; Believers May Change Practice
Nick Mulcahy
June 05, 2015
CHICAGO — Like many hematologic oncologists, Asher Chanan-Khan, MD, from the Mayo Clinic in Jacksonville, Florida, is a believer in the therapeutic powers of ibrutinib (Imbruvica, Pharmacyclics) for the treatment of chronic lymphocytic leukemia (CLL).
But this week, Dr Chanan-Khan uniquely endorsed the drug, which other experts have called "transformative" and "game-changing," for patients with relapsed/refractory disease.
For "countless" CLL patients, "this drug has been a blessing from God," he said during a press conference here at the American Society of Clinical Oncology 2015 Annual Meeting.
The high praise came when Dr Chanan-Khan presented first results from the 578-patient HELIOS trial, which is the first randomized placebo-controlled phase 3 study of ibrutinib and standard therapy in relapsed/refractory disease.
He reported that ibrutinib plus bendamustine/rituximab reduced the risk for disease progression by 80%, compared with placebo plus bendamustine/rituximab. Median progression-free survival had not been reached in the ibrutinib group, but was 13.3 months in the placebo group (hazard ratio [HR], 0.20; P < 0.0001).
"This is remarkable. You cannot get a better hazard ratio than this," he proclaimed.
Progression-free survival is the study's primary end point. Median follow-up was 17 months.
The goal of therapy for CLL, which is incurable, is to induce remission and maintain remission for as long as possible, he reminded the audience.
The combination of bendamustine/rituximab has been the standard of care for patients with relapsed disease for a "very, very long time", explained Dr Chanan-Khan, who was lead author. This combination is described as immunochemotherapy, whereas ibrutinib is a novel targeted agent — a first-in-class inhibitor of Bruton's tyrosine kinase.
These results change practice in relapsed/refractory disease, with ibrutinib plus bendamustine/rituximab being the new standard, he announced.
"This becomes one of the most important changing points in the history of CLL," he prophesized.
That faith was not shared by everyone.
"This might be an advance," opined Lloyd Damon, MD, from the University of California, San Francisco, who was the meeting discussant for the HELIOS trial.
His equivocation was not with ibrutinib but with the trial design.
In his critique, Dr Damon wondered, "Did the study ask the best question?"
"Should not the question really be, 'What is the contribution of immunochemotherapy to ibrutinib?' " he challenged.
In other words, Dr Damon suggested that ibrutinib alone should have been the control group and been tested against itself plus standard immunochemotherapy. That way, it could be established whether ibrutinib monotherapy is sufficient for the treatment of these patients, and whether it is superior to the three-drug combination.
To make his point, he compared the HELIOS trial with two earlier ibrutinib studies; all were in the setting of relapsed/refractory disease. One was the single-group phase 1b trial that preceded HELIOS (Blood. 2015;125:2915), and the other was a single-group study of ibrutinib alone (Blood. 2015;125:2497).
Ibrutinib had "roughly" the same rates of response and progression-free survival in all three trials, he said.
In short, ibrutinib looked good on its own.
Dr Damon suggested that using immunochemotherapy is not ideal. Its complications include cytopenia and infection, he reported.
"Can chemotherapy be omitted as first-line treatment of CLL/SLL without damaging the long-term benefits of immunochemotherapy?" he asked.
This has been the hope — and the prediction — ever since the first results with ibrutinib in CLL were released. In a previous interview with Medscape Medical News, the principal investigator of the pivotal phase 3 RESONATE trial emphasized both the dramatic responses and the tolerability of ibrutinib.
"It's really blowing the pants off what we are standardly doing in elderly CLL patients," said John C. Byrd, MD, from the Ohio State University Comprehensive Cancer Center in Columbus. He predicted that in the near future, "we will be using ibrutinib, either alone or in combination with a monoclonal antibody, in place of chemotherapy for most CLL patients."
Adverse Events and More Efficacy Data
In the HELIOS trial, 88.9% of patients had CLL and 11.1% had small lymphocytic lymphoma (SLL), and all had failed at least one previous therapy. The patients had a performance status of 0 or 1, according to ECOG standards. The average age of participants was 64 years in the ibrutinib group and 63 years in the placebo group.
The overall response rate, assessed by an independent review committee, was significantly higher in the ibrutinib group than in the placebo group (82.7% vs 67.8%; P < .0001). And there were more complete responses in the ibrutinib group (10.4% vs 2.8%).
At the time of the analysis, 90 (31%) patients from the placebo group had already crossed over to the ibrutinib group; the crossover was allowed after data from the RESONATE study indicated that the targeted therapy improved survival.
Despite the crossover, ibrutinib still showed a 37% reduction in the risk for death compared with bendamustine/rituximab (HR, 0.63; P = .059). Median overall survival has not been reached in either group, which is understandable given the long course of this disease.
The adverse events seen with the combination of ibrutinib and bendamustine/rituximab were "very tolerable" and "expected," Dr Chanan-Khan reported.
Overall, the top four adverse events — neutropenia, nausea, diarrhea, and thrombocytopenia — were "comparable" in the two study groups. In other words, the addition of ibrutinib did not worsen these adverse effects.
However, there were more infections of grade 3 or higher in the ibrutinib group than in the placebo group (28.9% vs 25.0%). There was also more bleeding of all grades with ibrutinib (31% vs 14.6%), more major hemorrhages (3.8 % vs 1.7%), and more atrial fibrillation (7.3% vs 2.8%).
The study population did not include patients with the del17p genetic aberration, which is characterized by aggressive disease. Ibrutinib is indicated for the treatment of all patients with del17p genetic aberration and of patients with relapsed/refractory disease.
The study was funded by Janssen. Dr Chanan-Khan has disclosed no relevant financial relationships. Some of the study authors are employees of Janssen.
American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA7005. Presented May 30, 2015.
[Most of you can't see the link, so I'm copying the article here. It's a short one, but it'll be a long g+ entry.]
Medscape Medical News > Conference News
Leukemia Drug Is 'Blessing From God,' But Trial Imperfect; Believers May Change Practice
Nick Mulcahy
June 05, 2015
CHICAGO — Like many hematologic oncologists, Asher Chanan-Khan, MD, from the Mayo Clinic in Jacksonville, Florida, is a believer in the therapeutic powers of ibrutinib (Imbruvica, Pharmacyclics) for the treatment of chronic lymphocytic leukemia (CLL).
But this week, Dr Chanan-Khan uniquely endorsed the drug, which other experts have called "transformative" and "game-changing," for patients with relapsed/refractory disease.
For "countless" CLL patients, "this drug has been a blessing from God," he said during a press conference here at the American Society of Clinical Oncology 2015 Annual Meeting.
The high praise came when Dr Chanan-Khan presented first results from the 578-patient HELIOS trial, which is the first randomized placebo-controlled phase 3 study of ibrutinib and standard therapy in relapsed/refractory disease.
He reported that ibrutinib plus bendamustine/rituximab reduced the risk for disease progression by 80%, compared with placebo plus bendamustine/rituximab. Median progression-free survival had not been reached in the ibrutinib group, but was 13.3 months in the placebo group (hazard ratio [HR], 0.20; P < 0.0001).
"This is remarkable. You cannot get a better hazard ratio than this," he proclaimed.
Progression-free survival is the study's primary end point. Median follow-up was 17 months.
The goal of therapy for CLL, which is incurable, is to induce remission and maintain remission for as long as possible, he reminded the audience.
The combination of bendamustine/rituximab has been the standard of care for patients with relapsed disease for a "very, very long time", explained Dr Chanan-Khan, who was lead author. This combination is described as immunochemotherapy, whereas ibrutinib is a novel targeted agent — a first-in-class inhibitor of Bruton's tyrosine kinase.
These results change practice in relapsed/refractory disease, with ibrutinib plus bendamustine/rituximab being the new standard, he announced.
"This becomes one of the most important changing points in the history of CLL," he prophesized.
That faith was not shared by everyone.
"This might be an advance," opined Lloyd Damon, MD, from the University of California, San Francisco, who was the meeting discussant for the HELIOS trial.
His equivocation was not with ibrutinib but with the trial design.
In his critique, Dr Damon wondered, "Did the study ask the best question?"
"Should not the question really be, 'What is the contribution of immunochemotherapy to ibrutinib?' " he challenged.
In other words, Dr Damon suggested that ibrutinib alone should have been the control group and been tested against itself plus standard immunochemotherapy. That way, it could be established whether ibrutinib monotherapy is sufficient for the treatment of these patients, and whether it is superior to the three-drug combination.
To make his point, he compared the HELIOS trial with two earlier ibrutinib studies; all were in the setting of relapsed/refractory disease. One was the single-group phase 1b trial that preceded HELIOS (Blood. 2015;125:2915), and the other was a single-group study of ibrutinib alone (Blood. 2015;125:2497).
Ibrutinib had "roughly" the same rates of response and progression-free survival in all three trials, he said.
In short, ibrutinib looked good on its own.
Dr Damon suggested that using immunochemotherapy is not ideal. Its complications include cytopenia and infection, he reported.
"Can chemotherapy be omitted as first-line treatment of CLL/SLL without damaging the long-term benefits of immunochemotherapy?" he asked.
This has been the hope — and the prediction — ever since the first results with ibrutinib in CLL were released. In a previous interview with Medscape Medical News, the principal investigator of the pivotal phase 3 RESONATE trial emphasized both the dramatic responses and the tolerability of ibrutinib.
"It's really blowing the pants off what we are standardly doing in elderly CLL patients," said John C. Byrd, MD, from the Ohio State University Comprehensive Cancer Center in Columbus. He predicted that in the near future, "we will be using ibrutinib, either alone or in combination with a monoclonal antibody, in place of chemotherapy for most CLL patients."
Adverse Events and More Efficacy Data
In the HELIOS trial, 88.9% of patients had CLL and 11.1% had small lymphocytic lymphoma (SLL), and all had failed at least one previous therapy. The patients had a performance status of 0 or 1, according to ECOG standards. The average age of participants was 64 years in the ibrutinib group and 63 years in the placebo group.
The overall response rate, assessed by an independent review committee, was significantly higher in the ibrutinib group than in the placebo group (82.7% vs 67.8%; P < .0001). And there were more complete responses in the ibrutinib group (10.4% vs 2.8%).
At the time of the analysis, 90 (31%) patients from the placebo group had already crossed over to the ibrutinib group; the crossover was allowed after data from the RESONATE study indicated that the targeted therapy improved survival.
Despite the crossover, ibrutinib still showed a 37% reduction in the risk for death compared with bendamustine/rituximab (HR, 0.63; P = .059). Median overall survival has not been reached in either group, which is understandable given the long course of this disease.
The adverse events seen with the combination of ibrutinib and bendamustine/rituximab were "very tolerable" and "expected," Dr Chanan-Khan reported.
Overall, the top four adverse events — neutropenia, nausea, diarrhea, and thrombocytopenia — were "comparable" in the two study groups. In other words, the addition of ibrutinib did not worsen these adverse effects.
However, there were more infections of grade 3 or higher in the ibrutinib group than in the placebo group (28.9% vs 25.0%). There was also more bleeding of all grades with ibrutinib (31% vs 14.6%), more major hemorrhages (3.8 % vs 1.7%), and more atrial fibrillation (7.3% vs 2.8%).
The study population did not include patients with the del17p genetic aberration, which is characterized by aggressive disease. Ibrutinib is indicated for the treatment of all patients with del17p genetic aberration and of patients with relapsed/refractory disease.
The study was funded by Janssen. Dr Chanan-Khan has disclosed no relevant financial relationships. Some of the study authors are employees of Janssen.
American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA7005. Presented May 30, 2015.
I hear what you're saying, but if I got a p-value like that, then after triple checking to make sure I hadn't fucked something up in the analysis, I'd be using strong language, too.
ReplyDelete'Course I don't do drug-trials, so.
I am fine with things like "transformative" and "game-changing", or even something where you describe effects as being "like a miracle". However, "like a miracle" and "is a miracle" are quibbles I'd quibble over. When you start with the "blessing from God" stuff, you are playing on other people's professional turf, and, frankly, immediately down-playing all the work and effort of a lot of people (and suffering of a lot of people) as we just threw it up in the air and look where it landed. Be amazed, be overcome, be astonished, have your breath taken away. Think whatever you like, but watch what you say.
ReplyDeleteOne conveys incredible effect, the other conveys a lot of handwaving and magic. It's not that I don't know that a lot of science may ultimately be handwavy and magical, but the professionals are supposed to be focusing on addressing the stuff that can be addressed in a non-wavy, non-magical way. And the psychological and emotional fragility of the patients and their families, not to mention the professional care-givers doing this every day, really needs to be respected.
Yeah, "Blessing from God," is a bit over the line.
ReplyDeleteTheology aside, isn't the big question here why they use chemo if the new targeted drug alone is doing as well as the new targeted drug + chemo?
ReplyDeleteWell, yes, that is how I read the bit where one of the other debaters asked why they hadn't looked at ibrutinib alone.
ReplyDeleteThis is one of the ongoing issues with trials of these newer drugs. Is it ethical to withhold whatever treatment we are currently using, assuming we've got one, in one arm of a trial versus the new drug alone? Or for ethical reasons do we have to offer the current therapy, however ineffective, vs. the current therapy plus the new drug? And other such thorny issues in trying these things.
Always aware that at least the first few, if not all, of the trials are likely to be in people who are effectively considered without certain assistance through modern medicine (or, if you want to be politically incorrect but truthfully blunt, dead folks walking).
The cleanest trial designs you could do are often deemed unethical, and for various reasons, rightly so. Unfortunately, that means there are some questions that we simply can't answer that way. Of course, you then get into arguing the ethics of a patient's choices and autonomy to take on certain risks, but there's the undue influence of death, coercive effect of offering hope, even if it isn't real, and so forth.
Anyway, I don't think that's necessarily insurmountable here, but the culture around these trials tries to be very cognizant of the history of unethical human research, as well as rigorous science, and it sounds like they went with the most usually done design. If it's considered "safe" enough, they may go ahead with another trial of ibrutinib alone. They certainly seem to think it's doing amazing things, so far.