GLG News by Donald Fleming, MD

Implications: Many studies support EGFR response correlates with rash Many attempts to actually increase the incidence of rash Most patients will use the EGFR treatments despite the rash

Analysis:  I agree patients with advanced cancer will look forward to the rash. I have personally experienced patients that are actually dissapointed if they don't show up with a rash at their next visit. I guess I could keep the rash/ efficacy issue out of the initial conversation , when discussing toxicity, but I don't think it is ethical to avoid the association. I also have even seen studies in colorectal cancers showing increased efficacy when cetuximab is dosed upward until the rash occurs. The one area where rash may discourage use is in the adjuvant setting. In this setting, patients seem less willing to wear a badge of courage to display their fight against cancer. I don't think anyone is sure why rash correlates with response, but I feel it implies the EGFR receptors in the patients normal cells are affected by the treatement and this implies those of the cancer, which are also self derived, are more likely to be affected. Levels of sensitivity is likely to vary among individuals. I feel this explanation is more likely than some sort of immunologic health correlating with a healthier patient and therefore a greater chance of response. Also, this would explain why if one doses up the EGFR agent, there is also a greater chance to see a response.

Implications: Saturn trial attempted to focus on EGFR reative patients Saturn was positive as a maintenance therapy, while concurrent was not

Analysis: As with the FLEX trial and Erbitux, the Saturn trial attempted to use some form of selection that worked in their favor and I believe it also makes more sense to use the Tarceva as a post therapy maintenance than as opposed to using it concurrently with chemotherapy. I am not sure what to say about the FLEX trial in that regard, but it may be that the benefit of the maintenance portion is what made the difference and/ or MOAb have a unique benefit over TKIs in regard to helping concurrently with chemo.

Implications: TKI's have been establihed in a small number of refractory solid cancers With slow migration to other venues, we are seeing new applications

Analysis: Many TKI's have very "dirty" molecule backgrounds and therefore multiple targets that in turn allow for multiple applications. One does need to be careful as we recently saw in Avastin/ Suntinib combination did have adverse complications. I Have had a personal experience where Sutent was effective in treating metastatic medullary thyroid carcinoma and subsequently with Nexavar. Luckily I was given free samples by the pharma companies involved. This cancer in partcular has no established chemotherapy regimen that is significantly effective.

Implications: Recent Cell Genesys vaccine trial for prostate cancer fails The trial not only shows lack of efficacy, but possible harm from the vaccine arm of the trial

Analysis: As I have said again and again, vaccines are uniformily not effective in treating cancer. This does not mean that vaccines against viruses that cause cancer will not work, as we all know they do. The obstacle of rejecting self originating tumor cells has yet to be solved effectively. The trial in prostate cancer could focus on the lack of prednisone in the study group, as it would have been helpful to have a third arm that included all three drugs. The lack of prednisone may have impacted on helping the controlarm, as it seems to halp with chemo in previous prostate cancer trials, especially in pain control and therefore encouraged continuation of the treatment.

Implications: We are facing an ever increasing expense of treating cancver The so called targeted drugs are the big price items The recent discovery of theses drugs have sometimes been out of order with understanding their activity

Analysis: I can see how big pharma may get upset when one demands tailoring their drugs too the cancer. While this may limit the use , it may also eventually encourage the use , as seen with drugs like Herceptin. Until herceptin's target was known it was a drug headed for non acceptance. Now it is so accepted, it is used in the adjuvant setting. So, while at first it may seem unfavorable to demand that the targeted drug actually has a target, in the long run it can actually make a drug more successful, especially in the future where minimally effective, yet extremely expensive drugs may be rejected by healthcare providers

Implications: Be cautious of vaccine approaches to cancer No cancer has had success with the use of vaccine therapy We are far from figuring out the reason for failure of vaccines to treat cancer

Analysis: Despite the recent overnight success of the papilloma virus vaccine in preventing cervical cancer and the prior success of hepatitis B vaccine in preventing liver cancer, there has been no success in treating cancer with vaccine therapy. I have always said that the most brillant immunologist known to man is the cancer cell. The attempt to reject self originating cells is as difficult as it would seem. If one looks at the use of biologics in the treatment of an immunologicly rejectable tumor like melanoma, it appears those that have severe autoimmune side effects of treatment seem to benefit the most. The same is likely to be true for a vaccine to reject cancer, once established in the body. In conclusion, beware of tolerable vaccine studies, as the efficacy is likely not to be there

Implications: Targeted therapy for cancer is the new trend Targeted therapy will allow the use of more expensive drugs to be more practical We need to focus on hitting a target more than ever

Analysis: I agree that we are now trying to justify the use of very expensive, so called targeted, cancer therapies even more than in the past. As successful as Herceptin has been, it was almost overlooked until the proper patients were selected. I hope the trend for nationalized health care system does not succeed. One has to only look at the UK and it's recent rejection of the new TKI's for treating advanced renal cancer as the result of such organizations as NICE which is the government run health care overseerer. I can personally attest to individuals that have had dramatic response to such drugs in an otherwise terminal situation. The cancer survival rates in the UK as a result are among the lowest in the civilized world. If we truely wantg to make progress in cancer therapy, we will necessarily continue down the targeted therapy approach. Also, even chemotherapy of the past can be targeted therapy, as microarrays will in the near future tell oncologist which cancers will respond to which chemodrug as well as biologic

Implications: There has been distubing trends in nationalized health care in regrds to cancer care Recently the UK made an absolutely shocking decision on renal cancer therapy, as it has in other cancers in the past Hopefully through advances in predicting cancer therapy outcomes via microarray etc. we can keep progressing as we have over the past decade with targeted therapy

Analysis:   I agree that we are now trying to justify the use of very expensive, so called targeted, cancer therapies even more than in the past. As successful as Herceptin has been, it was almost overlooked until the proper patients were selected. I hope the trend for nationalized health care system does not succeed. One has to only look at the UK and it's recent rejection of the new TKI's for treating advanced renal cancer as the result of such organizations as NICE which is the government run health care overseerer. I can personally attest to individuals that have had dramatic response to such drugs in an otherwise terminal situation. The cancer survival rates in the UK as a result are among the lowest in the civilized world. If we truely wantg to make progress in cancer therapy, we will necessarily continue down the targeted therapy approach. Also, even chemotherapy of the past can be targeted therapy, as microarrays will in the near future tell oncologist which cancers will respond to which chemodrug as well as biologic

Implications: Beta trial implies that Avastin adds to the effectiveness of the other Genentech drug, Tarceva There is an attempt to change treatment gudelines in second line non small treatment

Analysis:  I agree. I personally felt the trial would be positive. I guess I hung on the encouraging phase II Vanderbilt and MD Anderson data. I do wander how the trial could be truely blinded however, as blinding Avastin vs a placebo seems impossible. The dependable HTN and even more revealing proteinuria is known to the individual investigators throughout the treatment period and therefore is it really meeting the goals the trial desires in order to be unbias?

Implications: In this election year some have encouraged adoption of socialized medical services UK healthcare is an example of what some in this country have said we need to model our future healthcare system The recent use of biologics such as the TKIs have resulted in options for thousands of advanced kidney cancer patients that would otherwise die of the illness UK says no to expensive tretments for advanced kidney cancer

Analysis:  This is yet another example of why jumping on the socialized medicine bandwagon can have dismal results. I can site several examples in my own practice where patients with metastaic renal cell cancer have had amazing responses to the recently made available TKIs. I agree they are expensive, but nothing in this world starts cheap. With time many drug prices moderate. Think wice before agreeing to have the Feds take over healthcare!

Implications: Recent BMS subanalysis indicate despite negative trial, EGFR indicates favorable outcome with platinum therapy EGFR will become target for frontline NSCLCa

Analysis: Earlier BMS study with the US regimen carbo/taxol was negative in regards to PFS, but the recent FLEX, which primarily included EGFR expressing patients, demonstrated a OS advantage that is in line with Avastin. The sub population in BMS implies the focus on EGFR expression is the key to success and I feel in the future we will need to have a predictive test to justify using these expensive additions to chemo. Just look at Herceptin and breast cancer. Until her-2 overexpression was required, it was felt to be a relatively ineffective Rx in breast cancer. With a significant number of NSCLCa patients inelligible for Avastin, I feel there is a niche for Cetuximab in NSCLCa.

Implications: The cost of medical care is increasing at an alarming rate The amount of money to support a physician's practice is going down at the same alarming rate especially in oncology

Analysis: As with anything in society, advancing technology cost more money until the patent is lost. The same applies to drugs. Whether we like it or not, while "the mother of invention is necessity; the father is profit". I can think of few medical or scientific improvements gained within a restricted, controlled society. I do feel the problem is especially true in oncology because so many of the improvements in therapy are relatively new in the area of targeted cancer therapy. It will be a long time before there are generic replacements. The big pharma companies need to get as much out of them up front in order to please the investors or no more drugs. Also, we live in a society that demands perfection. No mistakes are allowable in drug development and therefore a very expensive and time consuming process of drug testing is standard for FDA approval. The lawyers are also waiting in the wings to get as much out of a drug through personal injury claims against the manufacturer before it goes generic. Just looks at the commercilas on TV and you notice they only involve the name brands before they go generic. Basically we have established a system that will insist on excessive costs in producing drugs and if the government thinks it could take over the process, I fear for everyone's health. In regrds to oncology, tjhe only cost savings that has been seen over tha past few years has been in third party payments to oncology practices that are responsible for treating 80% of the cancer patients in the US. If people want improvements in any problem affecting society, they need to be willing to fight and pay for it . As cancer becomes the biggest killer of Americans, I would hope we are willing to trn back the recent trends of reducing payments to oncology treatment facilities by writng their representatives that control medicare reimbursements for cancer patients.

Implications: Erbitux has had a few high level trials in Non small lung cancer So far there does not appear to be a contributuion to chemotherapy Maybe we are going about it the wrong way

Analysis: Let's face it, overall there has been no major break through in the treatment of non small cell lung cancer. Despite encouraging results with Avastin and chemotherpy, still a majority of patients don't have a measurable response to chemotherapy. I think we need to recall that until we found the key to Herceptin response in breast cancer, the drug almost became "dead in the water". The same thing may be happening in lung cancer. The FLEX trial has some indications of a success and it very well may be that requiring EGFR positivity could have some how selected out for a more benefitting population. The biologic reasons for success need to be disected. Also, lets be aware of the fact if we can rethink our requirements for successful outcomes, it may only be necessary to stabilze tumors with biologics as opposed to achieving a response by RESIST criteria. With chemotherapy stabilzation was not considered a success because it was difficult to take the treatment for an indefinite time period.

Implications: New data indicates risk of invasive breast cancer in women with either BRCA mutation maybe less than previuosly thought This new information will adversely impact Myriad's business

Analysis: While the science of cancer heredity is far from complete, I feel it is a top concern to physicians as well as patients. The down grading of breast cancer risk from 40 -50% as opposed to 50-100% is not likely to give comfort to the women with the mutation, knowning thir chance of avoiding cancer is not much better than a coin toss. Also, many of the BRCA cancers are triple negative, which as particularly bad actor in regards to response to therpay. I feel companies like Myriad realize we need to pursue other hereditary factors in breast as well as other cancers which will likely lead to more $3000 test to offer.

Implications: ASA404 begins pivotal trial to explore new approach in treating lung cancer ASA404 is a drug that helps chemo treat lung cancer yet eliminate exisiting blood vessels supplying the tumors

Analysis:   As we have seen in the past, don't get too excited about phase II data. The results are often, at best, half as good when studied in a randomized fashion. I am somewhat skeptical of a drug that does not help the potential delivery of chemo to the tumor. Avastin has improved the response to chemotherapy in NSCLCa. It was later hypothesized that the Avastin increased chemo delivery before it actually decresed new vessel formation. The ASA404 does not have the potential to do this based on it's proposed mechanism of action and therefore it may not help, but actually impair chemo delivery. I feel we need to spend more time looking at preclinical models that can predict response to expensive endeavors as opposed to ignoring the proposed mechanisms and pursuing the project. While this approach of "treating first and figuring out the mechanism later" paid off for Avastin, it may be the wrong approach. I feel certain projects such as the attempt to look at the C-Met pathway to predict response in various tumors prior to embarking on clinical trial is the best way to see a lot of money go to good use, in an area where big bucks are spent, only to have negative trials .  

Implications: Hedgehog path new and will improve on chemo/biologic therapy available for colorectal cance Past attempts at ading to regimens have not always been successful ie PACE

Analysis:  The introduction of a new agent to cancer therapy is always interesting. It remains to be seen how the drug interacts with conventional chemotherapy. In some cases it orks and in others it doesn't and may even have disadvantages over chemotherapy without the new drug. It is difficult to predict how these things will turn out and this has been demonstrted tim and time again when one uses the basis for their project"if one drug works good, more will work better". the hedghog path is a tumor repir and growth pathway, but one can see how inhibiting this process can either be good or bad. The only outcome that will be a success is of course a significant improvemnt and with a disease like colorectal cancer PFS may not be enough , as there areso may regimens being developed to salvage patients.

Implications: Xeloda has time after time demonstrated to be as good if not better than 5FU Xeloda continues to lag behind 5FU in the US Recent trial results are not likely to change things overnight

Analysis:  I agree completely that Xeloda is likely in any situation to be at least equal to 5FU  as either singe agent and in combination. Does anyone wander why then Xeloda has not caught on in the US vs. Europe? I think the opinion about the success of a chemotherapy product in the US needs to reflect economic disadvantages in the 80% cancer treatment settings, i.e. private practice infusion centers where there is an advantage to giving iv treatment , albeit at an ever so shrinking rate. I have been in both worlds (academic and private) and I shutter to think what will happen to cancer care in this country once the incentive to be an oncologist is eliminated. The future of the field is already dismal and more cuts in revenue will be disastrous for the field that treats the leading cause of death in many parts of this nation. One just needs to look at the products that have come out with oral or subq forms of delivery only to switch to iv infusions. Emend and Vidaza are recent examples. Oncologist cannot live on profees and the government’s solutions to compensation decline have been very inadequate. I have seen services cut and patients turned away since the MMA of the CMS.  

Implications: Lilly will likely get front line approval for Alimta in non small cell lung cancer Most patients with advanced disease never see a response to therapy

Analysis:  Yes it is major for Lilly and less for the patients. Lung cancer unlike others has a reputation for needing to get the drugs approved front line as a majority of patients decline or don't qualify for subsequent lines of therapy. Remember, we still don't see a majority of patients respond to first line therapy in this disease and even though this will likely result in Lilly's Alimta getting first line approval in the US we have a long way to go in making exciting news in non small celll lung cancer.

Implications: Sutent is demonstrating some activity in Lung cancer Sutent is unique in this regard versus other TKIs ? I would focus on the FELT for obvious reasons

Analysis: NSCLca is a disease that we have yet to cause most of the patients to respond to therapy. I am amazed at the excitement dispayed at recent studies that shw very small , yet statistical benefit using chemo bio/ chemotherapy. We are all waiting on the details of the FELT trial as if they are going to be anything near that of herceptin in breast. I think there are going to continue to be so many small molecule therapies looked at in NSCLCa and unless we pick out the phenotype that will benefit, the responses are or the forseeable future be mediocre improvements at best. That's why some of the newer trials such as SATURN etc. are doing just that and focusing on groups that are likely to benefit from the very expensive biologics. I feel the FELT trial will be looked on with so much favortism due to the fact oncologist wll be paid to give it as it's iv and the fact it allows oncologist o fill the majority gap left by those patients who who like the edge offered by Avastin yet cannot tolerate it or were it's contraindicated for various reasons.

Implications: Hematde is a new ESA with potential benefit over older ESAs hematide may look especially god coming off some of the recent FDA concerns abiut ESAs

Analysis: Recently he CMS decided to gang up on ESAs in order to reduce medicare spending by making outragous comments on the dangers of ESAs based on studies that in few ways reflected the way we oncologist use the gents.Never the less the concern about cross stimulation of cancer cells with erythroid cells led to the new rules to reduce patient exposure tothe agents. The new Hematide based on it's molecular properties is not likely to cause this probelm and what's more also may not have the other T/E event concern seen with previous ESAs.