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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Insulin-Like Growth Factor Receptor-1 Inhibitor Continues to Look Favorable in Squamous Cell NSCLC
Wed, 08/06/2008 - 21:19
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

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.

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