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Like Gleevec for Lung Cancer: A Novel Treatment for EML4-ALK Lung Cancer
Everyone is now familiar with the success stories of targeted agents in cancer therapy. A new promising targeted agent is Pfizer drug PF02341066, the story of which may be more analogous to the development of Gleevec (imatinib)or Herceptin (trastuzumab) than to Tarceva Tarceva. Both of the former drugs were tested in selected patients, with the idea that we knew which patients were likely to benefit. This is in contrast to Tarceva, which was tested in unselected patients and found to benefit a subset; it was only afterwards that investigators identified the critical importance of EGFR mutations.
At the recent ASCO meeting, Dr. Eunice Kwak presented fascinating results of a trial in which a novel agent was tested in patients selected because of a known genetic abnormality in their lung cancers. To provide a little background, the EML4-ALK fusion gene was identified in 2007 by a group of Japanese investigators headed by Dr. Hiroyuki Mano, who identifed a novel fusion gene from a surgical specimen of a patient with lung adenocarcinoma. The EML4 gene and the ALK gene, which are normally separate from each other but both on chromosome 2, had become fused together in this patient’s cancer. This fusion results in increased activity of ALK, which was already known to be implicated in a certain type of lymphoma. The authors subsequently found that this fusion gene was present in the tumors of other patients. When they put this gene into cells and then put the cells into mice, the mice developed tumors. In the lab, they tested an inhibitor of ALK against cancer cells with this fusion gene and found that it dramatically inhibited their growth. Subsequent studies have identified that patients with the EML4-ALK fusion gene tend to be younger than the average lung cancer patient, are more likely to be light or never smokers, and have adenocarcinomas. While these clinical characteristics are also shared by patients with EGFR mutations, patients with EML4-ALK do not have EGFR mutations.
In another ASCO 2009 abstract, Dr. Alice Shaw and colleagues performed a retrospective study of the frequency of EML4-ALK in patients with these clinical characteristics. They found that 13% of the 141 patients in their sample had this fusion gene. The patients with the fusion gene were younger (average age 52 vs. 64 in those who didn’t have the mutation) and were more likely to be male. None of the patients with EML4-ALK had responded to treatment with Tarceva or Iressa. However, patients with EML4-ALK were just as likely to respond to chemotherapy and their 1-year survival was similar to other patients in the group.
In the presentation referenced above, Dr. Kwak and colleagues initially conducted a first-in-human study to determine the maximum tolerated dose of the drug. One patient in that initial group (a 49-year-old man) had an EML4-ALK lung cancer. He had a dramatic response to treatment, coming off oxygen after receiving the drug. The side effects of the drug overall were overall mild: nausea, fatigue and liver enzyme elevations the most common. The next phase of the study included only patients with ALK fusions. Out of 19 patients, over 50% had a response to treatment and 80% had either a response or stable disease. These results are especially impressive given that most of the patients had received numerous previous treatments for their lung cancers. On the basis of these promising results, a large phase III study of PF02341066 is planned to further evaluate this drug for patients with EML4-ALK lung cancer.
The story of EML4-ALK lung cancer is a new and important one, and it gives us a glimpse into a future where the idea of treating all patients with NSCLC the same way will be preposterous. This all started with an analysis of a single patient’s tumor and is one of the most elegant examples of translational research and personalized medicine that I have seen: a discovery going from a patient to the lab and back to patients, all within the space of two years.
I’m looking forward to seeing more of this. Lung cancer needs a Gleevec.
28 Responses to Like Gleevec for Lung Cancer: A Novel Treatment for EML4-ALK Lung Cancer
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Dr. Pinder -
Thank you for your description of this different approach to research on a potential treatment. It’s refreshing to read and emphasizes the point that we’ve discussed at GRACE before: There is a great need to support creative, innovative research to make some “leaps” rather than always rely on the same research pathways. I hope lung cancer meets a Gleevec.
- Catharine
Wow! I had scribbled a note to myself about EML4-ALK after reading an ASCO abstract, but I missed the others and didn’t realize how strong these relationships appear to be. As someone who has a decent chance of having EML4-ALK (male, lifelong non-smoker, under 50, with adenocarcinoma, whose best response to Tarceva was 8 months of stable disease), I have two questions:
1. What kind of tissue is needed to test for EML4-ALK?
2. Any details yet on the upcoming phase III study?
Thanks!–Neil
I’m sorry I don’t have a lot of details for you on the upcoming trial since it is still in development. I do believe that the trial would require a biopsy of tumor tissue to be sent for centralized testing for the ALK rearrangement. This test is not commercially available at this point. I do think that things are going to move pretty quickly for this drug given the impressive results seen in the above study. I will update GRACE when more details are available.
I think this work is among the most exciting developments in lung cancer, at least for the minority of patients with this identified mutation. In some of the most recent work, it appears to be seen in only about 2-4% of patients with advanced NSCLC. For those patients, this discovery and the potential new treatment could be amazing, like finding a new Tarceva for a new mutation. I think there’s much less optimism that it offers anything for the other 96-98% of NSCLC patients. In fact, what I believe Pfizer is planning to do is move forward with a pair of trials of new agents, one being PF02341066 and the other I’m not sure of, and then screening all patients for the EML4-ALK fusion protein. Those with it would be offered/enrolled on the PF02341066 trial, and the others would be offered the trial with the other novel agent. However, to my knowledge these plans are still being sketched out.
But even as someone with a skeptical eye about hype, I think this is a very promising development.
-Dr. West
I think the immediate importance of this development is going to be the ability to help the small percentage of patients with this rearrangement. But the greater importance is the precedent it sets for drug development in lung cancer. For a large number of patients with lung cancer, we don’t know what molecular abnormality is driving their cancer. Patients with EML4-ALK previously fell into this KRAS negative, EGFR negative pool. While this could be a fluke, I suspect that there are other undiscovered abnormalities that might lend themselves to therapeutic targeting.
I agree with Dr. Pinder’s last statement (not that I don’t agree with the rest too!). While this is a very exciting development, the most important element of this story is the fact that a major pharmaceutical company (Pfizer) is willing to invest this kind of money (and by money, I mean tens of millions) into developing trials for a drug that would only potentially help 4% of NSCLC patients. This represents a sea change in pharma strategy, which has always been to try “targeted” drugs in unselected patients and hope the benefit was large enough to get wide approval of the drug.
This trial could signal a much needed change in the way we do cancer research: namely selecting patients likely to benefit, so that a much smaller number of patients is needed to see if the drug works. Theoretically this should be much cheaper, faster, and should produce results much more exciting than the usual 2-4 week improvements in survival we keep seeing in these huge international trials in unselected patients.
I salute Pfizer’s courage in designing this trial, and no they don’t pay me anything!
I am male, diagnosed at age 48, non-smoker, and Gefitinib-non-responder. I also have had many previous treatments. I should be a good candidate. I will contact my doctor about getting an eml4-alk protien assay, or working with Pfizer in their trial.
DFourer,
It may be difficult for your doctor to find a lab to do the EML4-ALK testing as it is not a commercial test at this point. As more information becomes available about the trial, I will update this post. It certainly sounds like you fit the profile of a patient who we would want to refer for this type of trial.
Dr. Pinder
After many phone calls and discussions with study coordinators, I learned today that I am excluded from this phase I study because I am HIV+. It’s disappointing news. My oncologist, Jyoti Patel, at Northwestern, was very encouraging as soon as I asked about the trial.
I tested HIV+ 24 years ago. During the 5 1/2 years I’ve been in treatment for lung cancer, I have not had any complications from HIV. Unfortunately, the study has specific criteria. I suppose the next option is something called compassionate use. I hope that if things go well, the fusion-gene test will made available to non-study-participants.
David Fourer
David,
I am sorry to hear that you are excluded because you are HIV positive. I think that one of the goals of the trial is to see if a more easily available test can be substituted for the gene fusion test with the same accuracy.
Dr. Pinder
Dr. Pinder,
I posted earlier about my exclusion from this trial (PF-02341066 phase I). Today there is an article about trials in The New York Times. It says trials are having trouble recruiting, and goes into some detail about the issues.
* Lack of Study Volunteers May Hobble Cancer Fight By GINA KOLATA, August 3, New York Times
* http://www.nytimes.com/2009/08/03/health/research/03trials.html?_r=1&hp
I’m not sure how to go about this, but I want to remind the local study site of my interest, in case new developments give me an entry into this. Either as a study participant, or some kind of expanded access.
David
I doubt that the study will change its eligibility requirements in the middle of the trial, but there is a rapidly expanding clinical program and new trials developing with this agent. I think the more feasible scenario is that a subsequent trial will be less restricted in its eligibility requirements. Otherwise, I suppose its also possible that the company will make the agent available on a compassionate use basis for patients who have the EML4-ALK mutation but don’t have access to the agent any other way. There is a new single-arm, phase II trial that is for patients with the EML4-ALK mutation who aren’t eligible for their phase III study just being initiated — I am working to get the trial open at my own center but don’t have the eligibility requirements available now and am not sure whether HIV positivity is an exclusion criterion.
Dear Doctors – my wife was diagnosed with S4 adenocarcinoma last December. She is a never smoker and received 1 Cisplatin (with complications – pulmonary emboli) followed by 6 Carboplatin/Alimta/Zometa treatments. In Feb 2009 she was put on Tarceva. She received 3 Alimta/Zometa maintenance treatments in July/Aug/Sep, however, the Aug scans showed new growth in adrenal gland. Oct scans confirmed the disease making comeback in multiple areas. She is currently on radiation therapies to spine, to be followed by radiation to hips, while the CO determines next steps. We have finally determined that she is RAS-/EGFR-, but have not been able to perform the ALK tests since it is so new. I have reached out to Mass Gen after reading your articles but am yet to schedule something with them. I would like to know if my wife might be eligible for the PF trial even after receiving Alimta as maintenance based on her genetic makeup if she turns out to be ALK+ when tested. We are in Dallas.
Also, what is the latest on this drug and the trial?
The trials are just opening up around the country, with more centers opening week by week. My understanding is that the group at Univ. of Colorado and perhaps also Mass General are able to test tissue before having someone come out to be screened, so people don’t waste time chasing down a trial that they won’t be eligible for.
In terms of eligibility, there are two trials. For the randomized one of second line therapy (one prior line of chemo, and prior EGFR inhibitor is also permitted), people shown to have an ALK mutation are randomized to PF-02341066 or Alimta, or if they received Alimta as first line therapy, they are randomized to study drug or Taxotere. If they aren’t eligible for this trial due to too many prior treatments or some other issue, most will be eligible for a single arm trial where everyone gets the study drug. This trial also allows the patients who are randomized to chemo on the larger trial to then get the study drug after that.
-Dr. West
How does one get the test for the ALK mutation? I called talked with a clinical trial screener yesterday and she said the trial wasn’t quite open yet, but they expected it to open any day. Is there somewhere else I need to be looking? I got the information from the US clinical trials site. If we ask my mom’s oncologist for the test will be be able to do it, or do we have to go Mass General or the Univ of Colorado?
I hope I can help someone with what I have been able to find so far: the test is fairly new and most places are not able to do it. We are at Dallas and my wife is being treated by Joan Schiller, one of the leaders in lung reseacrh and oncology head at UTSW, yet they were not able to find anyone locally. I have a buddy at Sloan who has told me they can do it there. I have also talked to both Mass Gen and U Col and they have both told me the same thing – that due to Pfizer’s very strict restrictions and this being a Phase I trial, their doctors will have to see the patient in person first even before testing for ALK. Besides cd’s of prior scans, at least 15-20 unstained slides or 1 block of tissues from the biopsy must be available, or a new biopsy will be required. My wife’s pathologist who did the original biopsy thinks this should not be a problem in most cases unless a lot of other tests were performed, but he will confirm shortly whether we have enough from my wife left. Both places were very interested in my wife (never smoker, 42 YR, S4 adenocarcinoma, prior chemo + EGFR agent Tarceva that did not work, confirmed RAS-/EGFR-. If you are not picky about the doctor and are willing to go with someone besides the lead authors of the paper noted by Dr. Pinder above, they can find someone in the dept to see the patient within a week. However, during the first month of the treatment us out-of-towners will have to visit every week for observations, and then every 3 weeks for treatment for as long as the drug is hopefully working and being used. At this stage the drug cannot be administered by a 3rd party like our local UTSW hospital and doctor. However, as Dr West has noted above, other clinics are coming on board. Since my wife’s health has started deteriorating fast I can’t wait, and if there are enough slides left we will try to go to one of these two places or get the test done at Sloan.
One final comment – in the paper led by Dr Shaw which I purchased from JCO, 11 out of 48 men (23%) tested ALK+, and 8/93 women (9%). However, even though this looks more promising for men, if the female patient has already tested RAS-/EGFR-, then the odds of testing ALK+ are much higher in the 30-40% range because you have already eliminated two other possibilities – it is important to remember that these 3 mutations have been mutually exclusive to date. This is also a major finding in the report. Since my wife has already tested neg for the other two, I am keeping my fingers crossed that she will test positive for ALK and be eligible to receive this drug.
Hope this helps and good luck. Thanks for the feedback to my prior question – this has been a great day of learning and a new ray of hope.
Our site (Swedish Cancer Institute in Seattle) is open and is able to coordinate sending tissue to a central lab. I understand that there is a site in Rhode Island that is open for these trials as well. Mass General and Univ. of Colorado in Denver are able to do the test, and my understanding was that University of California at Irvine was also doing much of the early work with this agent and could send the test.
In addition, Pfizer is in the process of working with many centers around the country and world to get more and more centers open in the next few weeks and months, so availability SHOULD be better very soon.
-Dr. West
Hello Dr. Pinder, thank you for your very informative post regarding ELM4-ALK Mutation. I am a Territory Manager with Genzyme Genetics and our company is currently testing ALK by FISH for Vanderbilt University for this clinical trial in NSCLC. We will have ALK in NSCLC available commercially in the first quarter 2009. I hope this helps. Joy
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Thanks for the great post Dr. Pinder. Unfortunately my mother’s doctor doesn’t know or believe that Gleevec is having this type of effect on NSCLC patients—unfortunately she is a patient. I’m a web developer in my mid thirties and therefore pretty savvy with the web. It seems that the ability to use the web to its potential in itself could truly give people an advantage in helping to cure them of certain cancers/disease in general. The other advantage that maybe a younger generation has is having a better idea of when to be your own doctor and seek second opinions —not just trusting one doctor’s opinion until the end. I’m sure a lot of others out there are struggling with the same issues I am at the moment. Even after forwarding your great post onto my mom, I have an idea of the outcome. Since she has Mayo Clinic’s healthcare plan there is no way of getting another opinion—at least not outside of Mayo without paying out of pocket. Isn’t it interesting how it always comes down to money and our country’s messed up healthcare ways. I’m sure some people out there are probably thinking “well, Mayo’s the best isn’t it?”. Maybe they are at certain things but nobody is “the best” at treating something as specific as my mother’s cancer unless they are willing to try everything. I could ramble forever, but if anybody out there has any advice as to what to do in our situation to try and get another opinion and or try and get a Gleevec trial going, I’m all ears. Thanks again for the great post!
mendicott,
I’m afraid there’s a bit of confusion here, perhaps from the title of Dr. Pinder’s article. Gleevac is not being used for NSCLC (it is used for leukemia and some other cancers). Instead she was analogizing the development of Gleevac, one of the first “targeted” therapies, with the development of an investigational drug for NSCLC, PF02341066, which has now been given the name crizotinib. It is therefore not surprising that your mother’s oncologist would doubt the use of Gleevac in her situation.
For some of the most recent news on crizotinib, you can read Dr. West’s recent post: http://cancergrace.org/lung/2010/06/09/alk-talk/
Jim
Thanks, Jim, for clarifying. Sorry for the confusion, Mendicott. Your mother’s oncologist is correct – we do not have any indication that Gleevec is an active drug in lung cancer.
-Dr. Pinder
Thanks for catching that Jim, after re-reading I think I better understand. On the other hand, it seems like there are a couple clinical trial using Gleevec with other drugs to treat NSCLC. Here are a couple links I found:
http://utm-ext01a.mdacc.tmc.edu/dept/prot/clinicaltrialswp.nsf/Index/2004-0726
http://clinicaltrials.gov/ct2/show/NCT00222144
Is this not legit?
Thanks,
Mike
Sorry, though, for misspelling Gleevec. Of all the tough drug names and medical terms, I can’t handle “Gleevec”? ::)
Mike,
No, those are reasonable questions to be asking, but they’re clinical trials, reflecting that the role of Gleevec is only investigational. It’s fair to be studying it in clinical trials, and if this line of research is favorable, perhaps it will find its way into more standard use. However, there have been many other trials with it in lung cancer that haven’t been especially encouraging, so I am not as optimistic about it as some other lines of clinical research in lung cancer.
Mike,
You’re absolutely right about the trials, and I have even more egg on my face than I thought from just misspelling “Gleevec” in my post. Before posting yesterday, I went to clinicaltrials.gov to search for trials but by searching for “Gleevac NSCLC” not surprisingly I came up empty. (If you search for “Gleevac” one trial does come up; must have been written up by a relative of mine).
Anyway, I’m glad you got a clarifying response from Dr. West; I didn’t see your follow-up post until now.
Jim
Dr. Pinder,
Thanks for the background and perspective on the developments in targeted therapies. I am trying to educate myself as well as possible in the month since me diagnosis of stage 4 adenocarcinoma of one lung and pleural tissues. My reason for writing is that testing of the biopsy material showed both the EML4-ALK and AGFR mutations. During my second opinion yesterday at Dana-Farber the oncologist indicated that nobody there had seen such both mutations in the same patient. I asked about the possibility of lab error, but he thought it is unlikely to be an error by Genzyme. My local oncologist is baffled, as am I. Since Tarceva is available (and Crizotinib is restricted to clincial trials (for which my condition would be an excluding criterion) that is going to be my initial course of treatment. My question is, has anyone heard of testing positive for both mutations before?
thanks,
Brian L. Werner
Brian,
There have been some responses to your question here:
http://cancergrace.org/forums/index.php?topic=4598.msg34094#msg34094
and here:
http://cancergrace.org/forums/index.php?topic=4598.msg34108#msg34108
Best wishes,
Joe S.