Is there third line ALK inhibitor after resistance to crizotinib and LDK378 ? - 1259878

Hello,

I'm sorry to hear that you've developed resistance to crizotinib, but I hope that LDK378 will be effective for you for a long time.

Research on acquired resistance to targeted therapies such as crizotinib is such a rapidly-developing field that it would be hard to identify which agent might be appropriate if you develop resistance to your current therapy, at least until that time comes. It may also depend on how long LDK378 is effective for you. In addition, there are chemo agents other than alimta which can be used. In the U.S., taxotere and tarceva are FDA approved for second line treatment.

JimC
Forum moderator

We really don't know of any targeted therapies that are particularly effective in ALK-positive patients who have developed acquired resistance to a second generation ALK inhibitor like LDK-378. Specifically, we have no idea whether another second generation ALK inhibitor like Ariad's AP26116 or Chugai/Roche's CH5424802 will have any activity. I suspect that the activity of these agents with a remarkably similar mechanism of action will be limited after another second generation ALK inhibitor.

I'm involved with a clinical trial of a heat shock protein inhibitor from Daiichi-Sankyo, DS2248, that they're looking at in people with acquired resistance in patients with an ALK rearrangement or EGFR mutation. This class of agents has been studied in only a very small number of patients with an ALK rearrangement but has looked promising. Because it has a different mechanism of action from conventional ALK inhibitors, I'd be more hopeful that this class of agents might be effective.

Finally, as Jim noted, standard chemotherapy remains a fine choice, and there is some suggestive evidence that Alimta (pemetrexed) in particular is often effective for patients with an ALK rearrangement.

Good luck.

-Dr. West

Have not been able to get on crizotinib for more that a few weeks as WBC drop and this week not only the WBC and Neutrophils, but now ALP 311; AST 157; ALT 253. My daughter does not have NSCLC; but has tumors in pancreas and liver with sequencing showing ALK+. Not sure of next step with these new blood results - will they mean stoppage of Crizotinib?

I would say it's a matter of medical judgment rather than hard and faced rules based on any clear evidence. As I mentioned on another thread, I have a patient who has required dose reductions down to 250 mg once daily and is responding to this treatment and now finally also tolerating it much better than 250 mg twice daily (standard starting dose) or the first dose reduction to 200 mg twice daily.

Good luck.

-Dr. West

My husband had some success on Xalkori for 14 months. Upon progression, he entered a trial for an ALK+ drug, ASP3026. He has major improvement. 14 months later, he is presenting with brain metatases (doubled in size over the last 8 weeks- all around 1 cm), a large tumor in the spinal cord at C-2/3, and a new lesion on the liver. He is expected to start Zykadia in the next few weeks. Is there any evidence that this may work, as a 3rd line ALK inhibitor? Also, what kind of evidence, if any, that it penetrates the Blood/Brain barrier?

If this doesn't work, the oncologist says we may consider one of the PDL-1 immunotherapy trials. The docs consider my husband a walking miracle. He is a 8.5 year, Stage 4 survivor, still working and living life. This will be his 10th(?) line of therapy and 3rd clinical trial.

I'm sorry to hear of his progression. The second generation ALK inhibitors have all been shown to lead to a responses of brain metastases in a few patients who had them along the way, but we're really just talking about a few stray patients in these settings, not a well studied situation that could lead us to know what to expect.

Good luck.

-Dr. West

Thank you for your quick respose. I have lurked on your sites for many years and I always appreciate your knowledge and support.