Study: Awaiting Erbitux Results - in NSCLC and Squamous

[Barb73]

http://www.thestreet.com/s/imclone-inve ... googlefi&c

Excerpt from article:

. . . . . . . . .

Biotech aficionados have waited since September 2007 to find out just how many weeks of survival ImClone's IMCL Erbitux can offer to patients with advanced non-small cell lung cancer, particularly a difficult-to-treat squamous subset. Those waiting for the data are now just a week away.

On May 30, the American Society of Clinical Oncology will kick off its annual meeting in Chicago. More than 30,000 people will attend, but many more will follow the data-sharing and analysis from afar.

The organization released upwards of 5,000 abstracts midmonth to be perused ahead of the event. The most highly anticipated, though -- late-breaking and plenary sessions -- are reserved for disclosure during the conference

Now a familiar topic to biotech investors, data from a study dubbed FLEX finally will be presented in Abstract #3 on June 1. FLEX is a randomized, multicenter phase III study of ImClone's Erbitux with cisplatin/vinorelbine vs. the latter chemotherapy regimen alone in previously untreated patients with advanced non-small cell lung cancer (NSCLC).

In September, the company and U.S. partner Bristol-Myers Squibb BMY surprised Wall Street by saying that the FLEX trial had succeeded in meeting its primary endpoint, an increase in overall survival. It caught investors off guard because the drug had previously failed a phase III trial, dubbed BMS CA225, when paired with a different chemotherapy regimen in July of 2007.

Although the company announced the success of the trial, the full results were held until the ASCO meeting, creating ample time for debate.

ImClone's Erbitux, which is already approved for colorectal and head and neck cancers, could be approved to treat advanced non-small cell lung cancer in 2009, and strong data would help its approval and commercial viability -- of course weak data would not. The specifics will also help to determine what sort of challenge Erbitux will present for competitor Genentech's DNA Avastin.

The primary endpoint in the FLEX study was overall survival (the amount of time the drug extends patients lives beyond treatment with just the chemotherapy regimen), with secondary endpoints of progression-free survival, response rate, disease control rate, safety and pharmacokinetics.

"We believe there is a reasonably good chance that this trial will show: a) a mediocre overall survival benefit of [about] 5 weeks (this is in-line with current consensus) that barely reaches statistical significance, no progression free survival (PFS) benefit, and c) no benefit on response rates," wrote Morgan Stanley analyst Steven Harr in a note to investors that sparked a dip in the stock mid-May.

Erbitux has better tolerability and fewer side effects than Avastin. But Avastin has an overall survival benefit closer to two months, making it hard for Erbitux -- should the four- to five-week survival benefit ring true -- to take a piece of Genentech's market share.

But, ImClone has its eye on a non-Genentech market. Avastin can't be used in about 40% to 50% of lung cancer patients, and notably that includes those with squamous lung cancer, a difficult to treat subtype. The drug is contraindicated in the squamous population primarily because of occurances of severe bleeding in a phase II study. It also isn't used for cancer that has spread to the brain and patients who have hemotysis, or are susceptible to coughing up blood from the lungs.

. . . . . . . . .

(TheStreet.com, Biotech, By Elizabeth Trotter, May 26, 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]

Thanks for finding and posting this, Barb. I have to confess that it gets a bit depressing when most of the findings seem to be helpful to adencarcinoma rather than squamous cell (with many of them even shown to be harmful to squamous cell).

I also have to admit to being more "excited" than I ought to be about the possibility that this week's ASCO conference will reveal "super-positive" findings for any of us--regardless of type.

Ah, well. Optimism may be a human failing, but it's also what keeps us going, right?

Thanks again,

Carole

[CaroleHammett]

I found an article on Erbitux from last month that I don't think(?) had been posted, which I've posted below.

One thing I note about this drug and most others of these "targeted" therapies is that the emphasis continues to be on clinical trials matching these drugs with pre-existing previously-approved chemos in hopes that the combination will result in longer survival rate rather than on trials testing these drugs as "stand alones." The recent findings on Iressa prove (to my satisfaction) that pharmaceuticals should be doing both (one has to wonder how many now-deceased adenocarcinoma patients might still be alive had Iressa been their first line treatment rather than last line or combo).

Carole

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http://www.reuters.com/article/marketsN ... 0720080423

Merck KGaA says to ask for wider Erbitux use in Q3

Wed Apr 23, 2008 6:15am EDT

By Mantik Kusjanto

FRANKFURT, April 23 (Reuters) - Merck KGaA (MRCG.DE: Quote, Profile, Research) plans to apply to the European Medicines Agency (EMEA) for its cancer drug Erbitux to be used as a first-line treatment for lung and for head and neck cancer in the third quarter of this year, the German drugs and chemicals group said on Wednesday.

The drug, which competes with Avastin made by Genentech Inc (DNA.N: Quote, Profile, Research) and Roche Holding AG (ROG.VX: Quote, Profile, Research), is vital for Germany's Merck, which is focusing on prescription drugs after selling its generic drugs business.

The planned filings follow positive outcomes of two trials unveiled last year. In September, Merck said Erbitux increased overall survival in first-line treatment of non-small cell lung cancer in a late stage study named Flex.

A separate study called Extreme showed Erbitux met the primary endpoint of increasing overall survival in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN).

Merck is set to unveil details of its Flex trial at the major ASCO cancer meeting in Chicago next month to support the wider use of Erbitux.

It will also present results of a study on whether a mutation in tumour cells of KRAS -- a gene that can stimulate cancer if mutated -- could be used to predict how patients with colon cancer respond to Erbitux.

DRUG HOPES

"ASCO has announced that from nearly 5,000 abstracts accepted for the meeting, two related to Erbitux have been selected for the presentation at its main plenary session," the company said.

Over the past month, Merck shares have risen more than 10 percent as investors bet on Erbitux's rising significance.

The drug is approved to treat colorectal cancer in patients who have failed other standard therapies. It is also approved in combination with radiotherapy for the treatment of locally advanced head and neck cancer.

Merck has already applied to EMEA to extend the use of Erbitux to include the first-line treatment of colon cancer in September, wih an opinion expected in the second quarter.

The application is being reviewed by the Committee for Medicinal Products for Human Use (CHMP). The submission was supported in part by data from Merck's Crystal study that showed the efficacy of Erbitux as a first-line treatment in the treatment of metastatic colorectal cancer (mCRC).

"We anticipate the CHMP decision for Erbitux in colorectal cancer either this week or in subsequent months. A positive decision would significantly clarify the longer-term investment perspective for us," Morgan Stanley analysts said in a note.

In the first quarter, Erbitux sales rose 33 percent to 145 million euros ($232 million), helping boost Merck's revenue. The cancer drug had global sales of more than $1.3 billion last year.

Merck licensed the drug from ImClone Systems (IMCL.O: Quote, Profile, Research) and has rights for key regions including Europe. Erbitux is ImClone's only marketed drug, which it distributes in the United States along with Bristol-Myers Squibb.

© Thomson Reuters 2008.

[Barb73]

Carole,

I am glad you posted the earlier report. Thank you. It helps to see these reports in context with what is occurring in the resulting studies.

This week's ASCO meeting is supposed to have many newer drugs promised for the pipeline. My hopes are most likely overly optimistic.

When I think of what was "out there" back only a couple of years ago, it's not a stretch to think that something new might be on the horizon.

My sense is that, as knowledge is "collected," it gains exponentially. Getting all of the knowledge together in one place is going to be the problem.

We don't want time wasted with "repeats."

Maybe I'm not making any sense here. I'm suffering from 8 hours in the infusion room yesterday.

Bill is outside mowing. The grass got away from us and is on its way to seed.

You are so good to keep up on the newer stuff, Carole. I love knowing you are there "blood-hounding."

May that meeting provide some innovative therapies (for all types). We can hope. Can't we?

Barbara

[CaroleHammett]

Hi, Barb, and thanks, but I can't even come close to a claim to being a bloodhound!

In fact, the whole scientific/technological end of it keeps my head spinning most of the time. Actually, I now have empathy for the first time for the kids back in grammar school who were in "special class" (difficulty learning/mentally challenged).

Greg's the one who seems to be on top of the new therapies (and good at explaining them to folks like me, too!).

All I'm doing is running around like a squirrel collecting nuts (substitute researcher for squirrel and extraneous bits and pieces of news for nuts! )

Come to think of it: Without your postings, I'd have no nuts!

Carole

[RandyW]

I am a bloodhound WHat do you want to know!!!

[CaroleHammett]

Hi, Bloodhound!

I want to know EVERYTHING!!!

Carole

[gpawelski]

The Healthcare Channel is reporting, as suspected, there was no benefit in progression free survival for Erbitux in lung caner in the FLEX study. Therefore, the miniscule survival benefit they tout is very suspect.

Moreover, Imclone is manipulating the press by releasing old news, or well known news, about the survival data on Saturday yet failing to release any press release on the full data that was just released on Sunday: the data that has the disappointing lack of PFS benefit. http://thehcc.tv/

The outcome of progression-free survival (PFS) may result in biased trial results. Measurement PFS, a widely used endpoint in cancer clinical trials, has methodological flaws that can lead to biased estimates.

PFS is measured as the time from start of treatment to the first measurement of cancer growth. Disease progression is typically measured by radiologic tests, such as x-rays, at scheduled intervals. X-rays have been the principal means for researchers to judge whether a cancer drug works. If tumors appear to shrink or stop growing after therapy, the drug is thought to be working.

There is growing evidence that x-rays may not accurately assess a patient's disease. Most often, researchers do not know when progression actually occurs, so they can only estimate that it happened sometime between the test that showed progression and the previous one.

Methodological problems can arise when researchers define the date of progression as the date on which it was first detected, even though progression most likely occurred prior to that day. The outcome of a trial can be heavily influenced by the surveillance interval and that comparing the PFS times of two different studies with different evaluation schedules can lead to erroneous conclusions.

The decision to use PFS as a primary endpoint should be considered carefully in the design phase of a trial. Estimates of PFS are highly dependent on when and how they look for progression.

Source: Journal of the National Cancer Institute, March 21, 2007

[CaroleHammett]

The following may have already been posted (I am scrambling to catch up after having had a friend in from LA for great four-day visit last week, followed by bout of pneumonia, followed by another overnight visitor )

I do understand that a 5 week increase in survival rate--no matter how calculated--is not exactly earth-shattering, but for those of us who are dx'd with Squamous cell, ANY forward movement that includes our sub-type is greeted with open arms!

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http://www.thestreet.com/_rms/s/flex-er ... 19231.html

FLEX: Erbitux Boosts Survival Five Weeks

Adam Feuerstein

05/31/08 - 12:54 PM EDT

CHICAGO -- The combination of ImClone Sytems' IMCL cancer drug Erbitux plus chemotherapy boosts patient survival by five weeks compared to chemotherapy alone, according to results from a closely watched lung cancer study that were released a day early at the American Society of Clinical Oncology (ASCO) annual meeting Saturday.

A five-week survival benefit for Erbitux from the so-called FLEX study straddles most investor expectations, which were generally in the four-to-six week range.

The Erbitux survival boost, however, came close to missing the threshold for statistical significance -- an indication that while positive overall, suggests some data from the FLEX study are not as strong as they could be.

Whether or not ImClone shares get an immediate lift from the new Erbitux lung cancer data remains to be seen, and will likely depend, first, on how doctors and other cancer experts gathered here at the ASCO meeting react to the presentation of the full FLEX data later this afternoon.

Regardless, ImClone executives feel strongly that FLEX is Erbitux's ticket into the lucrative front-line lung cancer treatment market.

"This is the first study in which an EGFR [epidermal growth factor receptor] inhibitor has produced a survival benefit that is both statistically significant and clinically relevant," said ImClone's chief medical officer, Eric Rowinsky, in an interview Friday afternoon. "We succeeded where many others have failed," he added.

ImClone shares closed Friday at $43.50, down from a 52-week high of $49.18 reached just at the end of April.

The FLEX Study: Results, Statistics

The FLEX study was conducted by Germany-based Merck KGaA, which sells Erbitux in Europe. Patients with newly diagnosed non-small cell lung cancer were randomized to receive chemotherapy (cisplatin and vinorelbine) plus Erbitux or chemotherapy alone.

Overall survival in the Erbitux-chemo patients was 11.3 months compared to 10.1 months for the chemotherapy-only patients, a difference of five weeks. The result was statistically significant with a p value of 0.044, which means there was a 4.4% chance the result of the study were random chance.

The generally accepted threshold for statistical significance in a clinical trial is a p value of 0.05, or 5%, so the overall survival benefit for Erbitux isn't very robust from a statistical standpoint.

Measured another way, the FLEX study's hazard ratio was 0.87, which means that patients treated with Erbitux had a 13% reduction in the relative risk of death compared to patients treated with chemo alone. That's a relatively modest benefit.

A simple way to think about this would be to compare the FLEX survival benefit statistics to a grade of C-minus or D -- still passing but just barely.

ImClone and partner Bristol-Myers Squibb BMY previously announced plans to seek approval later this year from the U.S. Food and Drug Administration for Erbitux in lung cancer. The weak statistical power of the FLEX study does raise the risk that the FDA requests more data, perhaps even another clinical trial, before approving Erbitux.

ImClone's Rowinsky insists that Erbitux, right now, is an approvable lung cancer drug. "That p value will get us approved. The study was well designed and inclusive and we hit our primary endpoint."

Data on key secondary efficacy endpoints in the Erbitux FLEX study were also mixed. The response rate, or the percentage of patients whose tumors shrank significantly, was higher in the Erbitux-chemo patients (36.3%) compared to the chemo-only patients (29.2%). This was a statistically significant result.

There was no benefit recorded for Erbitux with median progression free survival, however, with both arms of the study reaching 4.8 months.

New, Larger Markets

U.S. sales of Erbitux rose 6% to $692 million in 2007, primarily coming from approved uses in colon cancer and head and neck cancer. As an approved drug, doctors are free to prescribe Erbitux to their lung cancer patients today. ImClone and Bristol-Myers hope that the FLEX data, presented with much fanfare at the ASCO meeting, convinces doctors to do just that.

Estimates vary, but lung cancer could be a $500 million-plus revenue opportunity in the U.S. for ImClone and Bristol-Myers Squibb.

Genentech's DNA cancer drug Avastin is already a major player in the non-small cell lung cancer treatment market. The drug received FDA approval based on a study in which patients taking Avastin plus chemo reported overall survival of 12.3 months compared to survival of 10.3 months in patients given chemo alone.

As discussed previously, Avastin and Erbitux won't necessarily compete for lung cancer patients because Avastin cannot be used in about 50% of patients due to safety concerns.

ImClone CEO John Johnson, in an interview Friday, says that once Erbitux is approved in lung cancer, the company's sales force will focus on these "Avastin ineligible" lung cancer patients, as well as other patient groups within the FLEX study that derived the most benefit from the drug.

One of the largest and most difficult to treat subtypes of lung cancer is squamous cell carcinoma. Avastin isn't used in these patients, but Erbitux likely will based on data from the FLEX study.

Caucasian squamous cell patients treated with Erbitux reported a median overall survival of 10.2 months compared to a median survival of 8.9 months for similar patients treated with chemotherapy alone. That's a survival benefit of five and half weeks in favor of Erbitux.

For Caucasian patients with adenocarcinoma, another large lung cancer subtype, Erbitux survival was 12 months compared to 10.2 months for those patients not treated with the drug.

These patients are most like the patients treated in Avastin's pivotal lung cancer trial, Ronwinsky said, in fact, many had more advanced disease, which tells him that Erbitux can be competitive against Avastin.

Researchers from the FLEX study also found what they describe as a "remarkable difference" in overall survival between Asian and Caucasian patients.

While faring better than the entire study population, Asian lung cancer patients treated with Erbitux reported median overall survival of 17.6 months compared to 20.4 months for those Asian patients treated with chemotherapy alone.

This result is confounding because it was generally believed that drugs targeting the epidermal growth factor receptor of cancer cells, which Erbitux does, work better in Asian patients. For instance, Tarceva, another EFGR inhibiting drug marketed by OSI Pharmaceuticals OSIP, is more effective in some Asians than Caucasians.

For Caucasians in the FLEX study, Erbitux patients reported a median overall survival of 10.5 months compared to a median overall survival of 9.1 months for patients treated with chemo alone.

-----------

Posted by Carole

[CaroleHammett]

Dr. West (formerly at onctalk.org, now cancergrace.org) has just posted on Erbitux and FLEX trials. The full posting, including charts, is at: http://cancergrace.org/lung/2008/06/04/ ... o-benefit/

Note that I am posting excerpts as follows even tho this isn't a "news" item, as I'm trying to keep the topic of Erbitux (particularly re Squamous cell) in one thread.

"... for patients in whom you might be particularly worried about bleeding risk but are still technically avastin-eligible, such as the patients with central cavitary tumors or a history of coughing up small amounts of blood, erbitux may be an attractive alternative. There are also some patients who develop problematic side effects on avastin, whether with nosebleeds or kidney problems or high blood pressure, who might switch from avastin to erbitux.

"But I think that the easiest transition of use of erbitux will be in patients with squamous tumors, despite the rather modest median overall survival advantage of 1.3 months. There are several real challenges, including the problematic rash, the weekly infusion schedule, and other potential side effects, including higher risk of fevers with low white blood cell counts (known as febrile neutropenia) that we usually hospitalize patients for. There is also a cost that will average tens of thousands of dollars per patient (which for many patients amounts to a very significant co-payment with each treatment), which may be considered to be too expensive to gain what many will perceive as relatively little. I think it will be worth a discussion with patients, but many doctors may recommend that it doesn’t offer enough benefit to a general population to justify adding it, that the juice may not be worth the squeeze.

"The equation could change, though, if we could better identify a target population. One factor that I think could emerge as extremely important is selection by EGFR gene amplification, detected by a lab test called fluorescence in situ hybridization, or FISH. I described this very provocative issue in a prior post, in which it appeared that within the limited subset of patients who had received carbo/taxol chemotherapy combined in some way with erbitux in whom tumor tissue was available for EGFR FISH testing, both the progression-free and overall survival were markedly greater (doubled, in fact) in patients who were EGFR FISH positive vs. EGFR FISH negative (pretty evenly divided between two categories). Those are small numbers and not enough to change practice at this point, most experts would agree, but additional tumor tissue from ongoing trials is being tested in the coming months. If that work supports the same conclusion, it would support adding this variable into future trials and arguably using this factor as a clinical decision-making tool.

Another concept that may be relevant here is the presence or absence of a K-Ras mutation (see prior post), one of the important cancer-inducing factors, in the tumor. One of the biggest stories at ASCO this year was work that clearly demonstrated that patients with colon cancer who have a K-Ras mutation in their tumor are very unlikely to benefit from erbitux. There has been work in lung cancer that has shown that patients with K-Ras mutations (about 20-30% of lung cancer patients overall, and usually correlated with smoking more) have almost no chance of responding to tarceva, and they also do very poorly with chemo – so it’s not clear what would be a useful treatment for these patients. I don’t think we’ve seen any work yet on the topic of K-Ras mutations correlating with benefit on erbitux in the setting of NSCLC, but that’s a subject we need to address.

I’ll just close by saying that this work, whether talking about differences between patients with adenocarcinomas or squamous tumors, or considering EGFR FISH and K-Ras testing, all require a reasonable amount of tumor tissue. After years of settling on the smallest amount of tumor tissue possible, often with a fine needle aspirate that collects just a few cells, we need to use larger bore needles to perform core biopsies or even remove entire lymph nodes, so that we can collect enough tissue to more reliably determine the histology (type of lung cancer) and molecular features of a cancer. Accounting for these variables, we may well be able to focus on a narrower population of patients who can gain a more clinically significant benefit from drugs like erbitux, and potentially others..."

------------------

I have not been tested for EFGR or K-Ras, in part because up to now, decision-making re various chemos has now reached a point of "If it could possibly slow progression, go for it no matter what!"

I am currently on Alimta, however, and--as a Squamous cell patient--the only two remaining alternatives for me are Erbitux and docetaxel (and the latter is questionable due to my having had one infusion of same before my chemo had to be halted early last year).

My second line chemo choices have been based on an "I'll try anything approach," with emphasis on chemos with less side effects; ergo, first we tried Tarceva, and when it failed, Alimta (which has only an 8% chance of working at any level).

Both Erbitux and docetaxel carry heavy side effect "baggage," heavy enough that I will have to be making further "quality of life" vs. "buying time" decisions, which may necessitate my knowing about my EFGR and K-Ras... which may also trigger a dispute re approval for these expensive tests (and the new biopsy which will need to precede them).

Carole

Life is a Terminal Condition

[Barb73]

Carole,

You have me in the rooting section for anything that provides a benefit - most especially in that it can be given to treat squamous cell lung cancer.

(The longer we live, the longer we live.)

All I know is that survival is only appreciated by those who have a vested interest in experiencing it.

You won't find me belittling survival time. I have a loved one with the disease. I see what it can do on a daily basis. It is an integral part of my life.

Lung cancer is a bit different in that it is a disease where research has treated it as anathema. For what seems to be eons, those with it were treated with disdain, derision, or contempt.

One of these days, they will come up with longer and longer survival times and/or increased median times to progression.

The collective scientific information is bound to catch up. Also, because cancer is more than 200 diseases, the step toward better treatments, and/or an eventual "cure," will necessitate a wait.

We wait.

Barbara

[Barb73]

"CaroleHammett"]Dr. West (formerly at onctalk.org, now cancergrace.org) has just posted on Erbitux and FLEX trials. The full posting, including charts, is at: http://cancergrace.org/lung/2008/06/04/ ... o-benefit/

Note that I am posting excerpts as follows even tho this isn't a "news" item, as I'm trying to keep the topic of Erbitux (particularly re Squamous cell) in one thread.

Carole,

When I sent my previous reply, I had not seen the your posting with reference to Dr. West's commentary on Erbitux.

Thank you for posting it. It is most interesting and informative.

Knowledge is power - even when we decide against something - or are able to move forward with an informed decision.

Barbara

[CaroleHammett]

Hi, Barb.

I'm with you all the way on "Knowledge is Power." Knowledge has served me well all my life and no way am I changing trains now! As to statistical survival rates, as you know, my position is that I need to know them both to beat them (buying time) and in order to prioritize the time I've bought (quality of life).

I also just read Randy's posting of news about Cetuximab (Erbitux), which is located at: http://lungevity.org/l_community/viewtopic.php?t=37179 and to which I added a link to this thread (in my ongoing effort to keep all these Erbitux postings together ).

My apologies for reading/replying out of order, but as I noted elsewhere this a.m., I had a long-time friend come in from out of town for a few days and apparently "overdid" as we ended up spending Sunday (her last day here) at ER where I learned I had pneumonia.

The good news is that I'm still the "bounce back kid;" i.e., no admission, just a big jolt of IV antibiotics, following which she flew back to LA, and I went home and rested a couple hours, after which I exercised my "Quality of Life" option by going out to dinner with cousins, one of whom was also an out of towner who went on to stay the night! )

Further proof of the importance of Quality of Life: During dinner, my supplemental oxygen needs dropped from 3 liters to 2 liters and my temp dropped 1.6 degrees! So much for bedrest! LOL

Carole the Incorrigible!

Life is a Terminal Condition

[gpawelski]

Carole, as stated above, the problem arises when researchers define the date of progression as the date on which it was first detected, even though progression most likely occurred prior to that day. Researchers do not know "when" progression actually occurs, so they can only estimate that it happened sometime between the test that showed progression and the previous one. There may not have been a 5-week increase in survival.

In regards to West's suggestion about identifying a target population, all the gene amplification studies can tells us is whether or not the cells are potentially susceptible to a mechanism of attack. The aim is to tell if there is a theoretical predisposition to drug response. They don't tell you if one drug is better or worse than some other drug which may target this.

The drug has to get inside the cells in order to target anything. EGFR/VEGF-targeted drugs are poorly-predicted by measuring the ostansible targets, but can be well-predicted by measuring the effect of the drugs on the "function" of live cells. Cell-based testing not only examines for the presence of gene and proteins but also for their "functionality" (their interaction with other genes, proteins, and processes occurring within the cell, and for their response to targeted drugs).

When considering a targeted cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect. There are many mechanisms/pathways to altered cellular function. Functional profiling measures what happens at the end, rather than the status of the individual mechanisms/pathways.

I agree with West's statement about fine needle aspirates vs larger bore needles (Tru-cut needle biopsies) to perform core biopsies to collect enough tissue to more reliably determine the biologic and molecular features of a cancer. However, gene-based testing involves the use of dead, formaldehyde preserved cells that are never exposed to targeted drugs. Gene-based tests cannot tell us anything about the uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Gene-based tests cannot discriminate among the activities of different drugs within the same class. Instead, it assumes that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Gene-based tests tell us anything about drug combinations.

Cell-based testing looks at 'fresh' living cancer cells. It assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. It can discriminate differing anti-tumor effects of different drugs within the same class. It can also identify synergies in drug combinations.

[CaroleHammett]

Thanks, Greg.

Once again you've helped increase my comprehension (and thus understanding) of the "scientific stuff" (which reeeaaallllly strains my brain ).

Am I right in concluding that ultimately these biopsy results can be of key importance important in determing the "order" of trying out the patient on the various therapies; i.e., which drugs to try in which order would be based on which are more likely to work?

Carole

Life is a Terminal Condition

[gpawelski]

Carole

It is very important to get a reasonable amount of tumor tissue to more reliably determine the biologic and molecular features of a cancer. The more you have the more you can analyse. Then it is important what you do with the specimen.

Gene-based tests use dead, formaldehyde preserved cells - while important in order to identify new therapeutic targets (does the cell express a particular target that the drug is supposed to be attacking) and thereby to develop useful drugs - they are never actually exposed to the drugs whose activity they are trying to assess.

Cell-based tests measure "cell-death" of three dimensional microclusters of live "fresh" tumor cells. This can improve the conventional situation by allowing more drugs to be considered. The key to improving drug sensitivity is related to the number and types of drugs tested. The more anti-cancer drug types there are in the selective arsenal, the more likely the system is to prove beneficial.

In a cell-based test using "functional" profiling, it looks if the cell is being killed regardless of the pathway/mechanism. It assesses the activity of combinations of drugs, upon combined effect of all the cellular processes going on, using several endpoints (metabolic and morphologic).

The morphologic endpoint information is gathered by examing the state of hundreds of individual cells, while the metabolic endpoints measure the combined metabolism of all cells present in the culture. And it can simultaneously test for direct anti-tumor activity as well as for anti-vascular activity.

In a gene-based test, it looks if the cell expresses a particular target that the drug is supposed to be attacking. And it tells you only whether or not to give "one" drug. If you are given that one drug (like Tarceva) and there are other mutations/pathways/mechanisms, the cancer may shrink but then return, or never work in the first place.

A "functional" assay can find other compounds and combinations and can recommend them from the one assay. You need to measure the net effect of all processes, not just the individual molecular targets.

You are better off using a chemotherapy drug your tumor reacts to strongly than one your tumor resists. There should be an inclusive effort to study and utilize technologies which are based on both the sub-cellular (molecular) level and at the cellular (cell function) level.

Don't stop researching. You'll gradually understand it the more you delve into it (it seems like you already have).

[CaroleHammett]

Hi, Greg.

Re progression, I hadn't even considered that, but reading your explanation brought back the confusion when my 12/07 CT scan showed increase in tumor and lymph node sizes (and location) when compared to the 09/07 scan; i.e., there was no telling when the growth had begun within the three-month period, thus no telling how fast-growing.

I confused the situation further by opting to wait a month (quality of life decision) before beginning Tarceva without a new scan, which meant that I had increased the difficulty of determing the efficacy of the Tarceva.

Unfortunately, the next scan showed so much growth that there was no question the Tarceva wasn't working, which is why I'm now on Alimta, which has worse side effects, but not as bad as the next suggested (Erbitux), whose side effects will not be as bad as docetaxel (which is last on the list so far).

In other words, rather than decisions as to which maintenance drug to choose being based on efficacy level, the decisions have been based on quality of life (agreed to by my doctor and myself).

Although it would seem to make more sense to make selections based on efficacy rather than side effects, that would require the biopsy, which I don't think(?) my provider covers (I'm going to check into it asap).

Thanks again, Greg. Very helpful.

Carole

Life is a Terminal Condition