2014 American Society of Clinical Oncology (ASCO) meeting
The results from several important treatment studies were presented at this year’s ASCO meeting. Here is a brief summary of the results:
· Does treatment work in older people with CML?
Many trials of CML medications do not include people older than 65 even though many people who develop CML do so later in life. A treatment may be effective in a younger person, but it’s best not to assume that an older person will have the same response because of differences in drug metabolism, greater sensitivity to side effects, and so on. A new study collected data on 69 people with CML aged 66-85 years to see how well they responded to treatment (Korkmaz and colleagues. ASCO 2014; abstract 7108). Most were in chronic-phase CML but three people were in accelerated-phase. A total of 63 of 69 people were taking the standard 400 mg dose of Gleevec, while the rest were taking a bit more (600 mg per day) or a bit less (100-300 mg/day).
Overall, 46% achieved a complete cytogenetic response (CCyR) within the first six months, and 78% had a major molecular response (MMR) in the first year, so their response rates were similar to what is seen in younger people. Older individuals appeared to tolerate treatment well. Only two people stopped treatment because of side effects. In addition, 7 people didn’t respond to Gleevec and 5 people lost their initial response. So these 14 people were switched to either Sprycel or Tasigna. With the second treatment, 50% achieved MMR within 18 months. These results indicate that older people can do very well with the usual doses of Gleevec, Sprycel or Tasigna, and a majority have a very good response to therapy.
· Tasigna vs. Sprycel: 3 reports
People with CML can achieve a faster and deeper response if they’re started on a second-generation medication, such as Tasigna (nilotinib) or Sprycel (dasatinib), instead of Gleevec. This was shown in two trials: ENESTnd (using Tasigna) and DASISION (using Sprycel). How these two medication options compare was examined in two analyses (no direct comparisons have been down). In the first analysis, data from ENESTnd and DASISION were matched up using the same criteria for a response (Signorovitch and colleagues. ASCO 2014; abstract 7072). After crunching the numbers, the estimated proportion of people achieving a major molecular response at 1 year was higher if they received Tasigna rather than Sprycel. Tasigna also achieved higher rates of a deep molecular response (a 4.5-log reduction or better), and this advantage was sustained over the first 4 years of treatment.
A second analysis came to a somewhat different conclusion (Firwana and colleagues. ASCO 2014; abstract 7054). For this study, data from seven trials involving almost 3,000 people were analysed. All of the study subjects had chronic-phase CML and had not received a treatment before entering the trials. All second-generation medications (Tasigna, Sprycel and Bosulif) were better than Gleevec in achieving a faster and deeper molecular response. At 1 year, Tasigna was best at achieving a complete cytogenetic response (CCyR). But Sprycel was best at achieving MMR. Tasigna appeared to be tolerated the best, with fewer people dropping out of studies because of side effects.
And yet a third study compared the relative effectiveness of Gleevec (the standard 400 mg or a high dose of 800 mg per day), Sprycel and Tasigna (Jain and colleagues. ASCO 2014; abstract 7089). The median follow-up was about 8 years. The cumulative number of people achieving CCyR was highest with Sprycel (98%) and Tasigna (93%), and lowest with Gleevec 400 mg (85%). The cumulative rate of MMR was highest with Tasigna (94%) and Sprycel (91%), and lowest again with Gleevec (84%).
Thus, various studies have reported somewhat different findings. What this suggests is that either of the second-generation medications – Tasigna or Sprycel – can help you reach your goals more quickly than Gleevec, and the choice of one or the other will be largely determined by your response and how well you tolerate a given drug’s side effects. However, Gleevec is effective as well, and remains a good choice for someone with CML.
· Phase III results for Iclusig
A small number of people with CML will not respond to treatment because of a mutation. One problem mutation is called T315I, which blocks a drug’s ability to plug into the BCR-ABL mutation found in CML. A new drug (approved in the U.S.) is Iclusig (ponatinib), which retains its effectiveness even if the T315I mutation is present. New phase III results – the EPIC trial – were presented at ASCO (Lipton and colleagues. ASCO 2014; abstract 7023). While you might expect the drug to be tested only in people with a mutation, EPIC compared Iclusig with Gleevec as a first-choice drug. This proved overly optimistic as the trial had to be stopped early when an earlier study (called PACE) showed that people taking Iclusig were at risk of developing cardiovascular events, such as blood clots, fatal heart attacks and stroke. By the time EPIC was stopped, Iclusig had shown that it was highly effectively in CML (29% achieved MMR within 3 months), but an overall assessment couldn’t be made because of the concerns about side effects. What this means is that Iclusig is not the safest option for most people with CML. However, for people who don’t respond to treatment because of a mutation, Iclusig may be a life saver. But they’ll need to be monitored closely (and may need additional medications) to minimize the risk of developing cardiovascular complications.
. Combining Sprycel (dasatinib) with an immune agent
One of the functions of the immune system is to detect defective cells (such as cancer cells) and destroy them. Immune cells called T cells play a central role because they are able to recognize problems and signal the immune system to respond accordingly. However, to avoid immune system over-reaction (as seen in autoimmune disorders), T cells have a self-destruct switch called PD-1 (for Programmed Death-1). Some cancers are able to flip this switch with a protein called PD-L1, which destroys the T cell so that immune system is less able to attack the cancer. One way to counter this is to develop a treatment that targets PD-L1 so the self-destruct switch doesn’t get flipped.
One way to target a protein is to develop a monoclonal antibody (MAbs), a biological therapy that attacks highly specific targets. (One example of this is infliximab [Remicade], used to treat rheumatoid arthritis.) Nivolumab (also known as BMS-936558 or MDX1106) is a MAb that blocks PD-L1 from interacting with PD-1. The drug is currently in development to treat CML and a variety of other cancers. A preliminary phase I study will examine whether combining nivolumab with Sprycel is safe and effective in people with chronic-phase or accelerated-phase CML who haven’t responded to previous treatments (Porkka and colleagues . ASCO 2014; abstract TPS7119). It is an intriguing approach (and PD-1 drugs are being developed for a wide range of cancers), but no results are expected for several years.
For other ASCO news, see also How well does treatment work over the longer term?