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Insulin-Like Growth Factor Receptor-1 Inhibitor Continues to Look Favorable in Squamous Cell NSCLC

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One of the abstracts in lung cancer that I noted as being particularly noteworthy before ASCO 2008, but which I haven’t managed to mention since, is a trial of a monoclonal antibody known as CP-751,871 that targets and inhibits insulin-like growth factor receptor-1(IGF-1R), a molecule that appears to be involved with cell growth, balance of programmed cell death, and likelihood of metastatic spread (abstract here):

IGF-1R Mechanism

This was a rather complex study, presented by Dr. Dan Karp from MD Anderson in preliminary form last year (abstract here), in which patients with previously untreated advanced NSCLC were randomized two to one to receive either carbo/taxol alone or the same chemo combination with this IGF-1R antibody at either of two doses, IV every three weeks. After randomizing 150 patients and seeing especially encouraging results in patients with squamous cancers, they then enrolled a few additional patients with squamous cancers to all receive chemo with the higher dose of the IGF-1R antibody.

The primary endpoint of the trial was objective response rate (ORR), which was a very encouraging 54% for the patients who received the IGF-1R antibody with chemo, better than the 41% ORR for chemo alone (although also definitely better than we expect to see from this regimen, so either these were unusually highly responsive patients at MD Anderson or they have more generous criteria for considering someone as having responded, or both). But the biggest intrigue centered around the exceptional 78% response rate among patients with squamous cell NSCLC on this combination ith high dose antibody:

Karp RR table

Dr. Karp presented “before and after” scans for a couple of patients who demonstrated very impressive results, and these images were met with mixed reactions. While they were certainly impressive, the comment was also made by a very respected senior member in the audience that we have also seen dramatic before & after pictures following chemotherapy as well.

The side effect profile was not particularly problematic, with the antibody slightly increasing the decrease in blood counts compared with what we see with the carbo/taxol doublet alone, and also a minority of patients with significantly elevated blood sugar levels (this is an agent that targets the insulin-like growth factor receptor that looks very similar to the insulin receptor).

Pfizer, the company that is developing CP-751,871, is barreling ahead based on these favorable results. Based on this trial, which is certainly encouraging but is really hinging on the results of just a couple of dozen patients with squamous cell NSCLC, they are in the process of launching three large randomized phase III trials. In previously untreated patients, they’ll be looking at carbo/taxol with or without CP-751,871 in a non-adenocarcinoma population, and also at cisplatin/gemcitabine with or without CP-751,871 in a broader NSCLC population, regardless of histology. In previously treated patients with advanced NSCLC, they’ll be comparing CP-751,871 to tarceva as a second line treatment in non-adenocarcinoma patients, presumably hoping to score a win where CP-751,871 may work best and tarceva is known to be far less likely to produce significant tumor shrinkage (but still appears to improve survival comparably to what you get in adenocarcinoma patients).

Although I do think it’s gutsy and aggressive to launch three concurrent phase III trials of this agent based really on a single trial, and nearly betting the farm on the idea that this agent is going to be a breakthrough for squamous cell NSCLC patients, I do think it’s terrific to have something to actually get enthused about for squamous cell NSCLC patients, who have recenty been largely excluded from other agents based on a concern about low effectiveness or greater side effect risk, or both. It would be terrific to have an effective new tool to help the third of NSCLC patients with squamous cancers.


6 Responses to Insulin-Like Growth Factor Receptor-1 Inhibitor Continues to Look Favorable in Squamous Cell NSCLC

  • CHammett says:

    I cannot begin to articulate the degree of frustration I feel over the inavailability to me of CP751,871 at a time when I have ZERO options left and now have NEW, growing mets in liver and “good” lung as well as pre-tracheal, super-clavicular, mediastinum and right hilar lymph nodes.

    Because I’ve already had first line tx (cisplatin/etoposide + 1 of 3 docetaxel) concurrent with radiation (30 of 33), later followed by Tarceva (which failed), I am ineligible for clinical trials, thus I get to die knowing that the only possibly viable option for extending my survival has been withheld from me.

    Is there absolutely NO possibility (anywhere in the world) of this tx being made available to me–including by hook or crook? :-)

    Carole Hammett

  • Dr. West says:

    Carole,

    I’m very sorry about the progression of your cancer. I can’t say whether there’s no way to get this agent, but I’m not aware of a mechanism. I would just say that although I am hopeful that it could prove to add a meaningful clinical benefit for lung cancer in general and possibly patients with squamous NSCLC tumors in particular, I don’t think it’s a true miracle. Still, I’m sorry that there doesn’t seem to be a straightforward or even potentially feasible way to get it or others in this setting.

    I ran a meeting of a clinical trial consortium for lung cancer that I and some others are starting, and we too would like to get our hands on an IGF-1R inhibitor so that we can do some research with it, but it looks like this may be a very elusive goal for us too.

    -Dr. West

  • CHammett says:

    Thanks, Dr. West, and two more questions: (1) Do you know why the pharmaceuticals don’t set up “stand alone” clinical trials for drugs such as these rather than combining them with pre-existing chemos? (2) Do you know of a Pfizer contact person/department with whom one might try to communicate?

    Carole Hammett

  • Dr. West says:

    Carole,

    To answer your second one first, I don’t know of a Pfizer contact for patients. I would check through the clinicaltrials.gov website for trials on this agent and then review the list of contact people in a nearby location.

    The answer to your first question is that they often do single agent comparison trials as well, but the standard of care in first line is a two drug platinum-based combination, so there would be a serious concern about undertreating patients if they were randomized to the single agent without chemo. Most first line trials follow the standard of “standard chemo with or without drug X”, and only in second and third line and later, where the standard is single agent treatment, do you tend to see direct comparisons of the new drug head to hear against alimta or taxotere or tarceva. In fact, many second line trials also follow the pattern of “standard drug with or without drug X” rather than a head to head comparison, probably again because some doctors and patients would be wary about being randomized to an unproven and potentially inferior new drug instead of an established second line treatment that has been shown to improve survival (and maybe also because the company isn’t that confident it could beat an established therapy in a head to head comparison). Finally, companies are less excited about becoming an established component of third or fourth line treatment rather than an add-on to first line treatment, because there are far more patients receiving first line therapy than third and fourth line treatment.

    -Dr. West

  • CHammett says:

    Dr. West:

    (1) I was able to get a Pfizer clinical trials telephone # and email address from http://www.clinicaltrials.gov and will attempt to “open a line of communication” () with them tomorrow. (2) Your explanation re how the pharmaceuticals make their choices re trials is very clear and succinct (and thus also very helpful). Thank you so very much.

    Carole Hammett

  • sunshine2gal says:

    My mother was just told she could participate in this study at the James Graham Brown Cancer Center in Louisville. I hope she is able to receive the meds and not the placebo!

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