IGF Inhibitor Boosts Chemo Response in NSCLC/incl. Squamous

[Barb73]

http://www.oncologystat.com/home/news/I ... er_US.html

ARTICLE:

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IGF Inhibitor Boosts Chemotherapy Response in Non–Small Cell Lung Cancer

Elsevier Global Medical News. 2008 Jul 23, F Lowry

CHICAGO (EGMN) - Adding the investigational compound CP-751871 to chemotherapy significantly increased overall responses over those to chemotherapy alone among patients with advanced non-small cell lung cancer in a phase II trial.

The overall response rate was 54% in patients given chemotherapy plus CP-751871, compared with 41% in patients treated with chemotherapy alone, Dr. Daniel D. Karp reported at the annual meeting of the American Society of Clinical Oncology.

Patients with squamous histology did particularly well. In that group, the overall response rate was 78%, said Dr. Karp of the University of Texas M.D. Anderson Cancer Center in Houston.

CP-751871 is a human monoclonal antibody directed against the insulin-like growth factor type 1 receptor (IGF1R) with potential antineoplastic activity. IGF1R is a receptor tyrosine kinase that is expressed on most tumor cells. It is involved in mitogenesis, angiogenesis, and tumor cell survival.

The investigational compound has demonstrated activity as a single agent in Ewing's sarcoma, and in combination with paclitaxel and carboplatin for first-line treatment of non-small cell lung cancer. At the 2007 ASCO annual meeting, Dr. Karp presented data on 73 patients and reported a 46% response rate for the CP-751871 arm vs. 32% for the chemotherapy-alone arm.

"There is a very strong scientific rationale for looking at the insulin axis in lung cancer," he explained. "The liver produces IGF-1, and the IGF-1 receptor has 70% homology with the insulin receptor, and controls cell and body size, growth stimulation, and inhibition of apoptosis."

This year final data were available in 150 patients and the results "continue to be encouraging," Dr. Karp said. The trial, which was sponsored by Pfizer Inc., randomized patients with untreated advanced non-small cell lung cancer (NSCLC) in a 2:1 fashion to receive paclitaxel (Taxol, 200 mg/m²) and carboplatin (AUC = 6) plus CP-751871 at either a 10-mg/kg or a 20-mg/kg dose, or to paclitaxel and carboplatin alone, every 3 weeks for up to six cycles.

Of 97 patients in the experimental arm, 52 had an objective response, for an overall response rate of 54%, vs. 22 of 53 patients in the chemotherapy alone group, which had an overall response rate of 41% (P less than .00001).

Response appeared to be dose dependent; patients who received the higher dose of CP-751871 had an overall response rate of 57% vs. 38% for those who received the 10-mg/kg dose. Similarly, median progression-free survival was 5 months for patients who received 20mg/kg of CP-751871 compared with 3.6 months for those who received the lower dose (HR .80, P = .07). In patients with squamous cell histology, progression-free survival was 5.6 months with the higher dose, and 4.3 months in the lower-dose group.

In an additional, single-arm extension of the study, 30 patients with squamous cell NSCLC received 20 mg/kg of CP-751871 and chemotherapy. Here, too, the overall response rate was 78%, Dr. Karp said.

Responses were assessed by the study investigators using RECIST criteria and independently verified by study monitors. "Responses were especially rapid and dramatic in three of the patients, whose tumors disappeared completely," Dr. Karp said.

The most frequent adverse events were grades 3 and 4 neutropenia and hyperglycemia, both of which were higher in the CP-751871 group, and grade 2 fatigue, also higher in patients who received CP-751871.

"I think it's very intuitively clear that this agent should be associated with some extra hyperglycemia. We know they are getting steroids, and they get Taxol, and we regularly see some elevations of blood sugar. Five patients had sugars over 500, but they were well managed with fluids and the usual diabetic measures. Occasional insulin was required, but this was all quite manageable," Dr. Karp said.

Three future phase III studies of CP-751871 in non-small cell lung cancer are planned, he said.

In the question and answer period that followed his talk, Dr. Karp expressed enthusiasm about the study results. "We want to be careful and not overstate it, but we think we're seeing something dramatic with this regimen. In some patients, these large necrotic tumors, these big squamous cancers, just melted in 2 to 4 weeks," he said.

"We have one patient with a 10-centimeter pancreatic mass that I can't find anymore and I've looked hard for it. One patient had a documented splenic metastasis. He had surgery and now there is no cancer left in the spleen and that patient is off treatment for 15 months. So we think we are seeing a signal in some patients."

In her commentary, Dr. Angela M. Davies, senior director of clinical development at OSI Pharmaceuticals Inc., Boulder, Colo., pointed out that both the standard and experimental treatment arms produced better than expected response rates, but that the slight improvement in progression-free survival, which she called a better predictor for overall survival, was not in keeping with the "compellingly high responses" reported by Dr. Karp.

She suggested that patients with squamous cell histology would be the most appropriate to study in other phase II trials before proceeding with phase III studies.

Dr. Karp disclosed he has received research funding from Pfizer.

Dr. Davies disclosed relationships with Bristol-Myers Squibb, Eli Lilly and Co., Genentech Inc., Millenium Pharmaceuticals Inc., Sanofi-Aventis, and GlaxoSmithKline.

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(Elsevier Global Medical News, By F. Lowry, July 23, 2008)

Disclaimer:

The information contained in these articles may or may not be in agreement with my own opinions. They are not posted as medical advice of any kind.

[CaroleHammett]

Patients with squamous histology did particularly well. In that group, the overall response rate was 78%...

I have to confess that every time I read about this one, it makes me nauseous. It's bad enough knowing one's going down, but to know that there's something out there that has a 78% chance of stopping (or at least slowing) progression and that one CANNOT have access to it because the FDA says it might kill us (when we're dying anyway!).

Well, all I have to say is Arrrrrgghhh.

Actually, that's not all I have to say.

Does anyone know where this stuff is manufactured? And I do mean "where" exactly (like the specific address, including floor & room number? Oh, yes. While I'm at it, I'm also willing to accept all known information about their security system, too!)

Affectionately,

Carole "B & E" Hammett

I'd rather die while I'm living then live while I'm dead.--Jimmy Buffett

[Barb73]

Carole,

If I knew how to get more info on this to you trust me you would have it.

When I posted this, you were the on my mind.

It has been on my mind all this time.

What's with a system that doesn't make more available to those to whom it might make a huge difference?

This is the question asked by many all over the cancer world. Arrrrrghhh

Barbara

[Barb73]

Carole,

Found this article this morning, and I don't know what it means, but it mentions IGF. Maybe someone can eke out the particulars if relevant.

"Meanwhile, ImClone's pipeline of experimental drugs is gaining steam. Of particular interest is an antibody for a growth factor called IGF-1 that is related to the same biochemical pathway Erbitux hits. A half dozen IGF-1 drugs are in development. Pfizer is testing one in lung cancer; Merck, in colon cancer. But ImClone is also trying to test a newer version of Erbitux it owns entirely--a difficult prospect given Erbitux's entrenched status, but still a threat to Bristol."

http://www.forbes.com/home/2008/07/31/b ... otech.html

ARTICLE:

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BristolClone: What Took So Long?

Matthew Herper, 07.31.08, 1:03 PM ET

What took so long?

Bristol-Myers Squibb wants to buy the 83% of its biotech partner ImClone Systems it doesn't already own for $4.5 billion in cash. The news was released via a public letter to ImClone's chairman, billionaire Carl Icahn.

Shares of ImClone jumped 38% to $64 on the news, a price well above Bristol's $60-a-share offer--a sign that even though the companies have been joined at the hip since 2001 by a deal to co-promote the fast-growing colon cancer drug Erbitux, investors expect Bristol to have to raise its bid. The stage is set for a game of chicken.

"It's just amazing," says Michael Krensavage of Krensavage Asset Management. "In 2002 the stock was in the single digits. They could have bought the whole stake for nothing."

Bristol-Myers Chief Executive James Cornelius said on a conference call with reporters that the deal made more sense now than it would have two years ago. “Our confidence in the long-term future of Erbitux as an important cancer therapy has grown,” he said, “and their pipeline has advanced considerably from two years ago.”

Now Bristol's bid has larger resonance in the high-paced world of biotech investing. Last week, Roche announced it intends to buy the 40% of biotech bellwether Genentech it does not already own. Along with Takeda's earlier decision to purchase all of Millennium Pharmaceuticals, the Cambridge, Mass.-based maker of the cancer drug Velcade, the deals represent a push by large drug makers to buy smaller biotechs with fast-growing products.

But the reasons for the ImClone deal may have a lot more to do with the specific problems facing Bristol-Myers than with the larger industry landscape. Bristol may be dressing itself up for sale, it will lose its two top products (Plavix for heart disease and Abilify for mental illness) within four years, and ImClone's pipeline of experimental drugs contains two threats to Erbitux sales that ImClone controls outright.

Why did Bristol wait? One reason: It needed cash to do an all-cash deal. Bristol's stock has suffered (it trades at $21, $2 above its 52-week low), but its recent decision to offload its Convatec wound-care business for $4.1 billion should give it enough to cover the all-cash ImClone acquisition if the bid price does not rise.

In a note to investors, Timothy Anderson at Sanford C. Bernstein called the deal "a good thing." Anderson, who went bullish on Bristol June 26, previously cited an acquisition as one likely maneuver by Bristol. He noted the deal makes Bristol "a more robust cancer company" by adding not only the rest of Erbitux but the rest of ImClone's experimental drugs, which the company built up over the past several years. He also thinks the deal could itself make Bristol more appealing to a buyer. Krensavage noted that possibility too.

Another reason for the deal may be a slight shift in priorities for Cornelius, who took over the drug company after former CEO Peter Dolan was ousted following a botched deal with a generic drug maker. Cornelius has articulated a strategy of focusing on areas like cancer or rheumatoid arthritis, which require far smaller sales forces because fewer doctors prescribe the medicines.

Great strategy, but it means Bristol gave away half the rights to a promising blood thinner to Pfizer and half the rights to two promising diabetes drugs to AstraZeneca. Meanwhile, a lot of the specialty drugs haven't really panned out.

Orencia, for rheumatoid arthritis, is expected to generate only $400 million this year, one-tenth of Abbott Laboratories' RA drug, Humira. A new skin cancer drug being developed with Medarex failed to meet its goals in a late-stage trial.

Meanwhile, ImClone's pipeline of experimental drugs is gaining steam. Of particular interest is an antibody for a growth factor called IGF-1 that is related to the same biochemical pathway Erbitux hits. A half dozen IGF-1 drugs are in development. Pfizer is testing one in lung cancer; Merck, in colon cancer. But ImClone is also trying to test a newer version of Erbitux it owns entirely--a difficult prospect given Erbitux's entrenched status, but still a threat to Bristol.

That could put Bristol-Myers Squibb in a weak position, allowing Icahn to bargain for an even higher price--even though it's unlikely any other big drug maker would want to purchase ImClone given the company's exclusive Erbitux deal with Bristol.

But it's hard to see how the specific forces pushing Bristol and ImClone into marriage affect anybody else. Whatever the odds of a Pfizer-Amgen merger are (even Pfizer and Amgen probably don't know for sure), they are the same today as they were before Bristol made its bid.

. . . . . . . . .

(FORBES, By Matthew Herper, [Robert Langreth, contributor to story], July 31, 2008)

Disclaimer:

The information contained in these articles may or may not be in agreement with my own opinions. They are not posted as medical advice of any kind.

[CaroleHammett]

In her commentary, Dr. Angela M. Davies, senior director of clinical development at OSI Pharmaceuticals Inc., Boulder, Colo., pointed out that both the standard and experimental treatment arms produced better than expected response rates, but that the slight improvement in progression-free survival, which she called a better predictor for overall survival, was not in keeping with the "compellingly high responses" reported by Dr. Karp. She suggested that patients with squamous cell histology would be the most appropriate to study in other phase II trials before proceeding with phase III studies.

Woah!!!! I am definitely losing it!

I hope it's not brain mets that explain how I managed to miss the fact that Dr. Davies is right here in my home town!

Seems to me that I'd best see about getting hold of her fast (by email or phone only because Quality of Life still prevails and I'm on my way to San Diego and Mexico this weekend NO MATTER WHAT!)

Barb: I know you would (get me whatever info is out there, including security systems no doubt! ). There were earlier postings by you on this CP-751871 last month and Greg Pawelski did some extra checking for me (not to mention explaining in layman's terms). But the earlier postings came right before my first batch of out-of-state visitors and then this one came through during the second batch (and I am so very NOT caught up with the boards yet).

I'm actually taking off today (my house sitters moved in last night), but only as far as Denver where I'll spend the night at my daughters, and then tomorrow we head for San Diego--with laptops, of course--so I'll still be around, just not as much, and I definitely think I need to do some more research on this one (I did do enough to determine that (a) I don't qualify for any of the trials because they're all 1st line in conjunction with other drugs (i.e., where the money is); and ( it's not being offered in any other countries yet (Have passport, will travel! )

Anyway, I'm logging off now for the rest of the day so I can get my bootie out of here (here being Boulder, Colorado, home of Dr. Angela Davies )

Thanks so much for these postings... back to you asap, including anything I manage to learn in the meantime, of course.

Love ya, Barb! You're the best!

Carole

Death is not nearly as frightening or tragic as stupidity.--Carole Hammett, August 2008

[Barb73]

Carole,

I will keep an eye on this subject.

However, even with my lack of the scientific, I will do my darndest to keep abreast of this.

I am very sure that more intellectual, scientific, and medically savvy contributors will jump in here to help. This site is so rich in the many who are competent and informative, thankfully.

Have a wonderful, adventurous vacation and fill it with fun-loving memories. As they say, "You go, girl."

Keep that attitoode, Carole. It's what I most love about you (among other fantastic qualities).

Much love to you, and hope always,

Barbara

[CaroleHammett]

Hi, Barb.

I'm sure that everyone has figured out by now that we are members of a mutual admiration society! But your seniority (as you so firmly pointed out to me recently) gives you certain advantages, one of them being (in my humble, junior opinion) that you're automatically more admirable!

Thanks for keeping an eye out and also for the well wishes. So far the trip goes well; i.e., I am posting from the airport while waiting for our plane! (I just LOVE computers and the internet!).

At some point over the next few days (in between sun and fun), I will do an "in depth investigation" of "our" Dr. Angela Davies of Boulder Colorado and in the meantime, you have a great weekend!

Love,

Carole

Life is not measured by the number of breaths we take, but by the moments that take our breath away.--George Carlin'

[Shelley (MLC)]

Hi Barb (and Carole) Thanks so much for the info on the study. I am very interested in this as well. My mom also has Squamous Cell (stage IV) and just like you Carole, I wish the drug was available for everyone NOW. Shelley

[Barb73]

Hi Shelley,

I hope, as you do, that this study will be successful and available soon for all of those who would benefit.

Barbara

[CaroleHammett]

Hi, Barb and Shelley.

I haven't done any further research yet--been too busy having fun (See http://www.lungevity.org/l_community/viewtopic.php?p=367076#367076), but if I get a break in between and for sure after I get back, I'm going to be on this one big time!

Love ya bunches,

Carole of the Sea

[Barb73]

Carole of the Sea,

You keep taking journal notes on that fab vacation. I tell you, Carole, you made me laugh right out loud with that "sea" thingy.

Love you,

Barbara

[CaroleHammett]

Hi, all.

A middle of the night post from Mission Bay, San Diego preparatory to dozing back off so as to be able to jump on "Mexican Riviera" cruise ship tomorrow...

1. Dr. West at cancergrace.org has posted on the subject of CP751871 (see also my frustrated comment there) at http://cancergrace.org/lung/2008/08/06/igf-1r-for-squam-nsclc/

2. See also http://lungevity.org/l_community/viewtopic.php?t=37534 for my posting of 2008 ASCO abstract (referenced above).

3.. More research shows that the above-referenced Dr. Angela M. Davies probably criticized the proposed CP751871 clinical trials (for which I am ineligible) due to the fact that she's pushing Tarceva (at least one of the three trials will be comparing CP751871 to Tarceva) so she's not a CP751871 resource.

Having a great time... wish you were all here!

With Mucho Love and Affection,

Carole "Quality of Life Prevails" Hammett

[CaroleHammett]

Just a quick note to let you know that Dr. West did reply to my query (see above link), but basically said, Sorry, but no banana.

I suppose I could try contacting Pfizer directly, but it appears that the problem is not limited to Pfizer, but extends to FDA as well; i.e., a no-hoper.

Will keep you posted if anything new, but the good news in the meantime is that despite spread, I'm still feeling great!

Carole

Dream as if you'll live forever; live as if you'll die tomorrow.--James Dean

[Barb73]

Because I am following your posts on this, the Topic link was in my email this morning.

Thank you, Carol, for updating us on this subject.

The links you provided regarding commentaries between you and Dr. West are very helpful. They provided a clearer understanding of the mechanisms through which a new drug may enter clinical trials.

Appreciatively,

Barbara

[CaroleHammett]

Barb: "...The links... provided a clearer understanding of the mechanisms through which a new drug may enter clinical trials."

Hi, Barb.

I, too, benefited from Dr. West's explanation re clinical trials, including drawing the inescapable conclusion that the pharmaceuticals are far more interested in getting the biggest bang for the buck than saving the most lives.

Affectionately,

Carole

[Barb73]

far more interested in getting the biggest bang for the buck than saving the most lives.

Yes, precisely.

Barbara

[CaroleHammett]

Hi, Barb, Shelley et al

Just wanted to let you know that I contacted Pfizer, but was told (as expected) that I was ineligible for their clinical trials on CP751,871 and that they had no other mechanism for supplying me with this therapy.

This puts me back in the position of asking whether anyone knows where CP751,871 iis manufactured (not just specific address, but floor and room #). All information regarding Pfizer's security system would also be appreciated.

With love and affection,

Carole

PS to all: I continue to be so behind in my emails, PMs, message boards, etc. that I'm not even bothering to try to be organized or catch up. I confess to being tired, but I've been so busy chasing my own tail since getting home that I can't even blame it on cancer fatigue!