Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

c-MET inhibitors are a class of drug I've been interested in and following for a little while.  All are in early development and most of the big oncology players have one lurking in their pipeline. The concept of blocking c-MET is appealing because of number of studies have shown that activated c-MET mutations may be associated with poorer prognosis and induce resistance, ie an escape route for cancer cells. 

Looking at the pathways we can see MET has a strategic position in the signalling as an upstream receptor, which makes it a good potential target, much in the way EGFR, VEGF have shown proof of concept to date:

image from www.n-of-one.com
Source: n-of-one

It was therefore interesting to see a press release this morning proclaiming:

"Biotechnology company ArQule Inc said its experimental lung cancer drug showed positive results in a mid-stage trial, sending its shares up 57 percent in pre-market trade.
The drug, ARQ 197, when used with another lung cancer drug, erlotinib, showed a 66 percent improvement in median progression-free survival (PFS) – the time without cancer growth or death – in patients with advanced, refractory non-small cell lung cancer, ArQule said."

66% improvement would normally get me very enthusiastic, but after the recent glut of promising phase II data leading to flops in phase III, I'm feeling a little more cautious and circumspect.  Especially when, on further examination it appears that:

"The median PFS was 16.1 weeks in the ARQ 197 plus erlotinib arm, compared with 9.7 weeks in the erlotinib plus placebo arm, the company said in a statement.
The company, however, said the difference in PFS between the two arms did not achieve statistical significance by applying a log-rank test."

In other words, there is no significant difference between the two groups!
Hmmm, why make a lot of noise about it then?  Perhaps that's a little harsh, but achieving significance is the sine quo non of clinical trials and that's a very black and white number.  Breathless hypey press releases do make me cringe though.

I suppose we can say that these are promising, but very early, data and more time will tell whether the approach will have any meaningful impact on survival and outcomes.  Perhaps some biomarker analysis will help determine which people with non-small cell lung cancer were most likely to respond to the combination, potentially improving the efficacy and significance.

17 Responses to “ArQule's ARQ 197 plus erlotinib has mixed early data in lung cancer”

  1. craig

    Are they playing games with numbers?
    How can one set of numbers come up with 66% positive improvement, yet, in another set of numbers with the same patient population, there is no difference at all?

  2. The Big Red Biotech Blog

    ArQule’s ARQ 197 plus erlotinib has mixed early data in lung cancer

    Readers of this blog will know that I’ve commented several times on the trials and tribulations of various treatments for non-small cell lung cancer therapies – mostly that they’ve failed to meet their endpoints in pivotal phase 3 clinical trials. Yest…

  3. The Big Red Biotech Blog

    ArQule’s ARQ 197 plus erlotinib has mixed early data in lung cancer

    Readers of this blog will know that I’ve commented several times on the trials and tribulations of various treatments for non-small cell lung cancer therapies – mostly that they’ve failed to meet their endpoints in pivotal phase 3 clinical trials. Yest…

  4. jgarnettTSC

    It would have been nice to know if these patients, who were refractory to conventional therapies, had acquired resistance initially due to the EGFR “gatekeeper” (T790M) mutation (50% of cases), Met gene amplification (20% of cases), or none of the above. It should also be determined what percentage of these patients had internal exon 19 deletions or exon 21 point mutations (eg. L858R) prior to initial resection. I think once these details have been ironed out and then statistics applied, significant figures may have come to light. All in all, I believe that we’re on a positive and exciting road towards personalized medicine with advancement in knowledge of effective kinase inhibitor cocktails.

  5. MaverickNY

    Craig,
    Very easily with an early phase clinical trial since the numbers are very small so far too early to tell much yet.

  6. MaverickNY

    Hi Jeannine,
    Excellent points.
    I don’t know how many patients had the T790M mutation and how many had MET amplification, but my basic assumption was that they would have at least MET amplification or why treat with a MET inhibitor?
    Would love to know whether the responders and non-responders could be easily identified as you suggest. It would be fascinating to see the impact of T790M on either group. Pfizer have a T790M inhibitor in very early development according to the literature although it does not appear in their current pipeline.
    Hopefully, ArQule will do some indepth analysis and more will be revealed later.

  7. jgarnettTSC

    T790M inhibitor (getting inhibition away from EGFR’s ATP-binding pocket). Perhaps the ideal inhibitor cocktail would include a pharmaceutical targeting a node downstream too; where there is a lot of cross-talk between the MAPK and PI3K cascades.
    I believe Johnson and Johnson and Pfizer have Met inhibitors that also have very high affinities and selectivity for Met. It will be interesting to see how this story unfolds.

  8. jgarnettTSC

    Yes! I didn’t think of that. With about 70% of all treatment refractory NSCLC cases having either Met amplified or EGFR-T790M, it makes perfect sense to develop a T790M inhibitor that can be used in combination with a highly selective and specific Met inhibitor. Perhaps a better kinase inhibitor cocktail will also include a target downstream at a node of the PI3K and MAPK pathways (ERK?).
    I believe that Johnson and Johnson and Pfizer also have highly selective Met inhibitors, and so it will be interesting to see how this particular story unfolds.

  9. DrWestGRACE

    I don’t believe that the trial required c-MET amplification. It may have required tissue submission, but it didn’t require presence of an activating EGFR mutation or any particular mechanism of acquired resistance to be present.
    I’m hopeful that we’ll get a lot more insight from the actual presentation of the data. And though I’ve said that I don’t think too much should be made from phase II work, I do find the differences impressive, particularly in the adenocarcinoma population, in whom there was a near doubling of PFS.
    I agree that statistical significance (or lack thereof) is an issue, but that’s not the same as clinical significance. There are some trials that just miss statistical significance but show a very impressive absolute difference (such as docetaxel as maintenance therapy in Fidias, JCO 2009) that is still arguably very relevant, while there are other trials that show statistical significance but marginal clinical significance (such as cetuximab on FLEX). And as you point out, clinical trials may miss statistical significance due to a lack of effect or perhaps largely due to the trial being underpowered.
    We’ll have to see what the curves look like, and especially what the molecular markers tell us, but I’m actually hopeful that there’s something really there. Even so, it may well be similar to the ALK rearrangement story of being very relevant, but only to a small minority of people with lung cancer.

  10. DrWestGRACE

    I don’t believe that the trial required c-MET amplification. It may have required tissue submission, but it didn’t require presence of an activating EGFR mutation or any particular mechanism of acquired resistance to be present.
    I’m hopeful that we’ll get a lot more insight from the actual presentation of the data. And though I’ve said that I don’t think too much should be made from phase II work, I do find the differences impressive, particularly in the adenocarcinoma population, in whom there was a near doubling of PFS.
    I agree that statistical significance (or lack thereof) is an issue, but that’s not the same as clinical significance. There are some trials that just miss statistical significance but show a very impressive absolute difference (such as docetaxel as maintenance therapy in Fidias, JCO 2009) that is still arguably very relevant, while there are other trials that show statistical significance but marginal clinical significance (such as cetuximab on FLEX). And as you point out, clinical trials may miss statistical significance due to a lack of effect or perhaps largely due to the trial being underpowered.
    We’ll have to see what the curves look like, and especially what the molecular markers tell us, but I’m actually hopeful that there’s something really there. Even so, it may well be similar to the ALK rearrangement story of being very relevant, but only to a small minority of people with lung cancer.

  11. MaverickNY

    I think you’re right about c-MET amplification, Jack. I found this trial, which looks like it might be the one:
    http://clinicaltrials.gov/ct2/show/NCT00777309?term=arq+197&rank=14
    It seems a tissue sample was needed for eligibility, so we can hope that the in-depth analysis before and after treatment will be illuminating:
    “Confirmed availability of archival pathology samples (10 unstained paraffin-embedded slides) or tissue block suitable for subsequent analysis of KRAS, EGFR, and c-Met.”
    16 vs 10 weeks is indeed encouraging and I look forward to a robust analysis. I’m just a bit jaded after the recent raft of phase III trials not doing well in cancer trials after exciting data in phase II.
    Let’s hope for some initial thoughts at ASCO, they certainly will be eagerly awaited!

  12. MaverickNY

    I think you’re right about c-MET amplification, Jack. I found this trial, which looks like it might be the one:
    http://clinicaltrials.gov/ct2/show/NCT00777309?term=arq+197&rank=14
    It seems a tissue sample was needed for eligibility, so we can hope that the in-depth analysis before and after treatment will be illuminating:
    “Confirmed availability of archival pathology samples (10 unstained paraffin-embedded slides) or tissue block suitable for subsequent analysis of KRAS, EGFR, and c-Met.”
    16 vs 10 weeks is indeed encouraging and I look forward to a robust analysis. I’m just a bit jaded after the recent raft of phase III trials not doing well in cancer trials after exciting data in phase II.
    Let’s hope for some initial thoughts at ASCO, they certainly will be eagerly awaited!

  13. ATL PlasticSurgery

    Thanks for the update.Lung cancer is a hard one to cure.There is extensive procedures and follow ups that keep making you feel sick.But knowledge to the cure is also a very important thing.

  14. Ckowit

    My husband has the EGFR mutation but with a rare s768i mutation 20th exon of the gene. Should he be on Tarceva alone or go on the trial with ARQ197?

    • maverickny

      Hi there, I’m not a physician so it would be hard for me to advise you on that but I can highly recommend Dr West’s GRACE site where you can ask questions like this in the lung cancer forum and usually a specialist will be able to help you.

      Here is the link: http://cancergrace.org/forums/

Comments are closed.

error:
error: Content is protected !!