GLG News by Eric Whitman, MD

Implications: Oncophage is an autologous (or derived directly from a patient's own tumor cells) vaccine that may promote the generation of an effective anti-tumor immune response when re-injected into patients. Trials in melanoma and renal cell cancer failed to meet their primary endpoints and approval has not been forthcoming from the FDA.

Analysis: This is a fascinating development. Can new drug approval be obtained from alternative governmental agencies than the FDA or EMEA and through that approval gain access to patients (and vice-versa)? Will the revenue from this approval be significant for Antigenics? Will it lead to other non-standard country approvals for this drug? Will other companies follow suit? Will USA or EU patients, convinced of the drug's efficacy or desperate for any intervention, travel to a country where the treatment is approved, and pay cash to have the therapy?

Implications: The Data Safety Monitoring Board halted the Phase III randomized open label trial comparing the Pfizer anti-CTLA4 antibody, tremelimumab, to "standard" (and generally ineffective) chemotherapy for metastatic melanoma. The Board has reported that there is no statistical difference between the primary endpoint, overall survival, between the two study arms. Further, statistical analysis reportedly shows that further examination is "futile" or basically unlikely to ever show a statistical difference. This is a major setback for the hopes of many investigators and patients who felt that the anti-CTLA4 antibodies represent an encouraging potential new therapy for metastatic melanoma, a disease for which there is no universally accepted or generally effective therapy.

Analysis: Two questions that come from these results:

Will this completely halt all efforts by Pfizer to develop this drug in melanoma?

Will these results effect the parallel efforts of BMS and Medarex to develop a similar (but not identical) drug for the same indications?

Implications: This drug, which has just entered Phase I testing, is very interesting because it combines IL-12, which has shown both activity and significant toxicity, with a targeting antibody. Hopefully, this targeting antibody will minimize the toxicity of IL-12 on or in normal tissues.

Analysis: Like any Phase I agent, we don't know at this time if the drug will even be tolerable in clinically or pharmacologically active doses or regimens. We also don't know if the well-conceived targeting mechanism will result in reduced toxicities from the active agent. Finally, will there be any responses in the Phase I trial? (this is how Sorafenib became interesting as a potential melanoma drug)

Implications: The failure of this study has wide ranging implications for Pfizer and other melanoma trials. This drug, which only a few years ago caused much excitement in the melanoma oncology community, failed to show any survival benefit in this Phase III trial, when compared to standard, but generally ineffective, chemotherapy. Its failure casts a shadow over its sister drug's development by Medarex and BMS, which has already itself disappointed in a different population, second line patients. This was Pfizer's first recent effort in melanoma therapy, and I wonder if it will step back from that field for some time. Also, it raises the question if big pharma companies will continue to try Phase III trials in "tougher" cancers or if they will only invest in biotechs pending the results of the trials before committing to full licensure.

Analysis: The only data that has been released on this trial are overall survival. The full analysis including response rates and progression free survival (ie secondary endpoints) has not yet been published or presented publicly. Presumably this will be at ASCO in May/June.

Implications: FDA approval of Avastin in the treatment of advanced breast cancer will have an effect on the sales of the drug, but it is not clear to me how significant that effect will be, since it is already approved in Europe and has been widely used off-label for USA breast cancer patients already. I am glad that the FDA approved, or at least gave provisional approval to, an oncology therapeutic drug based on PFS (progression free survival) advantage, without a corresponding OS (overall survival) benefit. This will likely open the door to many drugs that have a clear efficacy "signal" in otherwise difficult clinical scenarios. It confirms that PFS is an acceptable endpoint for the FDA, something that had been sensed for some time.

Analysis: Until we discover therapies in diseases like breast cancer that clearly defeat the disease and induce remissions in a large percentage of those treated, it will be very difficult to show an OS benefit, since so few patients respond and those who don't rapidly move onto other drugs that may also have some benefit. In other words, you don't fail one therapy then wait around to die; you find the next line therapy, experimental or off-label, and try that. This makes OS virtually impossible to show in many cancers.

Most patients, when given an option for an extended PFS, will readily accept that therapy, provided it is not associated with unacceptable toxicities. In that regard, the FDA insistence on continued safety and efficacy studies for Avastin in breast cancer is appropriate.

Implications: This data attempts, yet again, to suggest that Provenge is more effective when the cell counts are higher, and more of the cells have CD54 "helper" antigens on their surface. These data are similar to other misleading news releases about Provenge from Dendreon. This is a subset of patients from two trials, comprising about two-thirds of the total # of patients in the two Phase III trials, as far as I can tell. It suggests that "potency" leads to improved survival. But is that survival better than expected without Provenge therapy? Why would we expect a tumor vaccine of active specific immunotherapy to be effective if the cells were dead, ie without nuclei (this is one of their potency assays)? It seems to me to be a fairly self-fulfilling prophecy to say that an active specific immunotherapy seems to work better if the cells are alive and if they are expressing helper antigens which immunotherapies probably all need. Dendreon continues to clutch at experimental straws.

Analysis:  Provenge is an active specific immunotherapy targeting hormone refractory prostate cancer. Two parallel nearly identical prospective randomized trials failed to hit all of their endpoints. The studies were not designed to measure survival but a potential survival benefit was suggested in one but not both of the two trials. A non-oncology FDA advisory panel voted in favor of the drug but the FDA declined to approve it based on this level of data.

This is bad data but has captured the public's fancy. It should not be approved based on current information. Period.

Implications: Intron-A is currently the only FDA approved medicine to treat melanoma patients without active disease but at high risk for future recurrence. On March 12, 2008, the Oncology Drug Advisory Committee (ODAC) will discuss newly available data on the effectiveness and safety profile of PEG Intron, a longer acting pegylated version of Intron A for the treatment of these patients at risk. I believe PEG Intron has a good chance of gaining FDA approval. If so, it would dramatically alter how patients with high risk melanoma are treated following surgical resection.

Analysis:  PEG Intron, already approved in the US for hepatitis, was the subject of a recently analyzed European trial in melanoma patients. This data was presented in 2007 at ASCO. In this trial, patients at risk for recurrent melanoma were treated with adjuvant PEG Intron for up to five years versus observation alone. The data suggests that is certain pre-stratified subgroups, PEG Intron therapy is associated with statistically significant efficacy.

Schering Plough owns both Intron A and PEG Intron. To some extent, PEG Intron would cannabilize Intron A use. However, the therapy goes on for a longer time so depending on pricing this could be beneficial to SGP. Also, PEG Intron is probably better tolerated than Intron A, and therefore may be better accepted by some physicians reluctant to subject their patients to the toxicity of Intron A for what they consider to be marginal clinical benefit.

Implications: The Supreme Court, in refusing to hear arguments in a case brought that would make it easier for patients to gain access to non-approved drugs, brought a legal end to the request of the Abigail Alliance. This suit would have circumvented the drug approval process while leading to patients receiving therapy on the basis of hope and hype, not results. We may not like all the FDA rulings but we must make sure that patients receive safe drugs with proven benefits. As frustrating as it is for patients and their families, the possible complications of loosening the restrictions on these experimental therapies far outweigh the potential benefits.

Analysis: As a physician, I am often asked why a patient can't receive the next great drug they have read about in the Wall Street Journal, or Family Circle, or even Newsweek. The answer is, and has to be, that experimental drugs are only available under agreed upon, regulated, and approved clinical trials, so that any potential benefit is most readily identified, while minimizing the risk to patients.

Implications: The medical and scientific worlds lost a great man when Dr. Judah Folkman recently passed away. His work in anti-angiogenesis was very inspiring and created a whole new area of scientific research to fight cancer, which eventually led to new drugs and treatments, principally Avastin. Dr. Folkman was able to combine surgical expertise with research innovation. He adapted to the changing scientific landscape by moving from animal based studies (which were the "bread and butter" of most surgical researchers of his generation) into more complicated molecular techniques, culminating in his discovery of anti-angiogenesis agents.

Analysis:  I was fortunate enough to meet Dr. Folkman, briefly, at the very beginning of my medical career. He gave a talk to honor a recently deceased mentor of mine. The story of his angiogenesis research, culminating in a surrendipitous discovery by a surgical trainee in his lab who neglected to throw out a petri dish from an unsuccessful experiment, was one of the most inspirational talks I have heard.

Although our paths would never again intersect, I vividly remember the encounter and how it affected me. I consider it one of the most influential moments of my career, and will always be grateful to him.

Implications: The announcement by Wellpoint that it will offer online evaluations of doctors and their offices is very interesting. Using a tool developed by Zagat's, patients in targest markets will be able to rate their physician "experience" on several unspecified factors, presumably dealing with things like doctor/office communication, amenities, timeliness and other customer-care focused categories.

Analysis: I think this is a great idea that will benefit both doctors and patients. Too often, physicians globally are underconcerned with things that any other service provider pays particular attention to: appearance of the office, wait times, ease of making an appointment, office amenities (ie coffee or wireless internet), clarity of instructions, and in general, the overall office experience. While I stress these issues to my office staff, I am sure that we can improve and will improve. Making these evaluation tools available to patients will enable us to identify and fix our shortcomings, without threatening our licensure, quality ratings, or physician-physician reputation.
This should be viewed as a positive (although I know many will complain) and I look forward to it coming to my area.

Implications: Interleukin-21, or IL-21, is a protein that regulates immunomodulatory cell function. It appears to stimulate the activity of NK cells and cytotoxic T cells, which may be particularly relevant in targeting cancers that more responsive to the immune system, such as melanoma and renal cell carcinoma. This current trial is built upon Phase I results in melanoma and renal cell carcinoma presented over a year ago, at ASCO 2006. In that study, there was one melanoma patient with a complete response and several (not sure from abstract) with stable disease, out of a treatment cohort of 18. The current trial is a Phase 2 trial investigating single agent IL-21 in metastatic melanoma patients. The endpoints are response rate and lack of disease progression.

Analysis: It is interesting that this trial was just announced as initiating because other documents on the Zymogenetics website give the start date as July 2006, which would be more consistent with a June 2006 ASCO presentation. In the interim, they appear to have more aggressively pursued combination therapy with IL-21 and Nexavar in renal cell carcinoma, with some apparently impressive results.

Implications: Uveal melanoma, although similar histologically to the more common cutaneous melanoma, is virtually a completely different disease. Once metastatic, it has failed to respond to any form of systemic therapy, even those with some (albeit limited) efficacy in "standard" melanoma. Its relative rarity and its clear difference from cutaneous melanoma has also limited the number of treatment options available through clinical trials, as most trials for cutaneous melanoma specifically exclude uveal melanoma patients. Thus, this trial is very important because it has some possible efficacy for a disease that has no other treatment. ANY "signal" in uveal melanoma should be greeted favorably by the FDA.

Analysis: This cancer has proven incredibly difficult to treat once metastatic. Most oncologists have no ready-made answers, even off-label, for metastatic disease. I hope that the early results are confirmed in this trial. I wonder how the FDA will treat Phase II results for a disease with absolutely no accepted, effective or approved drugs. Will a Phase III trial be required (or even possible given the low numbers of these patients)?

Implications: This press release discusses Phase IIa results from a novel melanoma vaccine in a small group of patients with various levels of melanoma. Only 22 patients were treated in this study that began about two years ago. Fourteen patients developed specific activation of cytotoxic T cells that recognize the antigen, MART-1, that is expressed by the vaccine. This is an interesting if not overwhelming immunologic response profile. The real issue with all tumor vaccine trials ultimately is not whether there is a tumor specific T cell response but whether or not that immunologic response translates into a clinical response. Unfortunately that has not been the case with any tumor vaccine trial to date.

Analysis:  For this drug, its best chance will be in the adjuvant setting, where patients have no evidence of disease. They would be treated with vaccine and monitored for recurrence. These trials take years, because melanoma can recur five or more years later. Also, a large number of patients would be required to show statistical significance, since the overall recurrence rate, depending on the initial stage, is fairly low.

In summary, this trial is another example of a scientifically interesting tumor vaccine that has a long way (and many $) to go before approval.

Implications: This study is interesting because it uses gene expression profile data to choose the tumor target. Specifically, preclinical work looking at PARP expression in various tumor types identified that breast cancers negative for estrogen, progesterone, and HER2 expression were much more likely to overexpress PARP. PARP is a protein involved in DNA repair, theoretically contributing to chemotherapy resistance and over-proliferation of tumor cells. There is no mention of the exact trial design other than it will be a randomized Phase II trial comparing chemotherapy to chemotherapy plus experimental agent. This target selection process should become more prevalent in coming months and years because of the proliferation of gene expression profiling data.

Analysis: This is a good trial design for the intended target. Patients will either receive a standard variety of chemotherapy or the chemotherapy with the PARP inhibitor. Other trials they have done preclinically have used oxaliplatin but it is not clear to me what chemo will be used in the newly announced trial. The trial design would be ideal if it were double blind and randomized to give a truer perspective on the efficacy of the agent compared to conventional therapy.

Implications: M-Vax, an autologous tumor vaccine modified by treatment with HNP, has been proposed as a potential treatment for advanced melanoma. Prior trials that I am aware of were non-randomized and therefore could not be compared to other types of therapy. The majority of the earlier trials were in Stage III melanoma, not Stage IV as in this case. The clinical activity of M-VAX in Stage IV is unclear. The choice of low dose interleukin-2 as a part of the therapy is curious, since interleukin-2 is only approved for use in high dose regimens. There have been some prior trials using low dose interleukin-2 in melanoma but none have shown any significant benefits. See Maxim Pharmaceuticals, now a historical footnote. Overall, I am not excited about this project and this trial. There are many other competing trials and their timeline is overly ambitious.

Analysis:  There is certainly an unmet need for better treatments for advanced melanoma. However, there are several potential huge problems with this trial and I am not enthusiastic. There are limited data suggesting this vaccine's efficacy in Stage IV melanoma patients. Also, the efficacy of low dose interleukin-2 is virtually non-existent. So that "control" arm is really to document the side effects from the interleukin-2 independent of any from the M-Vax. How will the FDA react to this control arm as the comparator for a new biologic agent?

This is a rather small Phase III trial for metastatic melanoma patients. I haven't seen their statistical analysis but I would be worried about possible unrealistic expectations for the experimental arm.

Vaccine manufacturing is also a problem. This trial was announced a year ago; were they delayed because of GMP considerations? There is no way they are ready to analyze data in 2008.

Implications: This Phase II study of a novel dendritic cell melanoma vaccine shows a significant yet not overwhelming response rate of just under 10%. An additional 20% of patients had stable disease. The progression free survival is in-line with other recent melanoma studies in this population as is the 1 year survival. These data do no suggest easy or imminent approval but do justify additional studies in melanoma, a cancer that has proven very difficult to consistently treat once systemic spread has occurred.

Analysis: These are easily the best results I have heard of for dendritic cell vaccines in melanoma. Generally, studies only describe the immunologic responses because there are almost never any clinical responses. In this study there were apparently 1/33 complete responses and 2/33 partial responses, all of which are reported as ongoing. In addition there were 6/33 stable disease patients. The progression free survival of 4.8 months is good but not great, although I do not have information on the overall health and status (front line, second line, salvage, etc) of the patients. The recent PRISM trial in second line melanoma patients showed a PFS of 4 months in the control arm of taxol/carboplatin. Likewise, a 1 year survival of 67% is probably consistent with historical data without necessarily being better or worse, depending on the patient population at risk.
The data definitely will generate enough interest to lead to a larger scale trial, perhaps even a Phase III trial, depending on the opinion/actions of the big Pharma partner. The problems then will be: 1) what is the control arm  2) who is eligible (front line vs second line) and 3) the large number of competing trials currently ongoing in metastatic melanoma in the USA and around the world.

Implications: Asuragen is a contract lab with apparently high capabilities in gene expression profiling, miRNA detection, and other molecular diagnostic techniques. This news item announces a business arrangement between Merck and Asuragen, to develop a biomarker assay using pharmacogenomics for use in cancer clinical trials. It makes no mention of the exact type of test, the basis for the interest in the test, or the types of cancer clinical trials it would be used in.

Analysis:

This news announcement provides little information other than the fact that a new business arrangement exists between Merck and Asuragen. The type of test being developed is not really mentioned, nor is the indication/disease type that the test would be used for. Finally, the test is for use in cancer clinical trials, so it does not appear (at this point) that there is any intention of developing it for general clinical use.

The search for rational and predictive biomarkers in cancer continues. We have very few specific biomarkers other than PSA for prostrate cancer (which itself continues to be refined as a test). The regulatory pathway for the newere genetic tests, particularly when they involve a panel of genes being measured, continues to be murky as the FDA considers how best to address their implications (eg Oncotype Dx).

Implications: This article reports on two related prospective studies of Remicade treatment for refractory ulcerative colitis. The data suggest that Remicade therapy reduces the short term (one year) need for colon surgery in these difficult to treat patients. Further follow-up is needed to better understand the long term implications of these findings, if any.

Analysis: Remicade is an innovative biologic agent that targets TNF or tumor necrosis factor, a key mediator of inflammation in multiple clinical situations. It is currently approved for a multitude of indications related to auto-immune disorders, including ulcerative colitis, Crohn's disease, psoriatic arthritis, and others.

The key point of these studies from my perspective is that they suggest that continued therapy with Remicade in refractory (resistant to other therapies) patients with ulcerative colitis may prevent or at delay the need for colectomy (surgical removal of the colon).

Like any good study, the questions raised are as good if not better than the ones partially answered:
1. how long does the effect last? If you follow the patients longer do they all need surgery anyway?
2. by extension to #1, can you prolong the effect by continuing the Remicade therapy longer? The trial allowed extended therapy but did not mandate it.
3. Can Remicade also reduce the long term incidence of colorectal cancer in these patients? This will require very long term followup.

Implications: This reports on a small scale pilot study of combination therapy with Avastin and Irinotecan in patients with an aggressive brain cancer, glioblastoma multiforme, who have already failed standard treatment with chemotherapy and radiation therapy. Although comparing only to historical controls, the results are impressive and virtually unprecedented in this patient population with a uniformly dismal outlook. For example, the 6 month PFS of 47% compares to the published PFS in this setting of 21%. Although there was significant toxicity to the regimen, it was considered acceptable given the poor prognosis of these patients generally.

Analysis: This study by itself is unlikely to result in regulatory approval by the FDA. However, it does prompt several fascinating questions:

1. Does Avastin cross the blood brain barrier and retain its effectiveness?
2. Does this combination therapy hold promise in other clinical settings?
3. Would this combination be effective also in front line therapy for GBM?
4. Are there other agents that could make this combination even more effective, especially in the front line setting? (ie Temozolomide)
5. Will these results lead to off-label use of Avastin for brain cancer?

A randomized Phase II study by the same investigators comparing the combination to single agent Avastin is underway.

Implications: Genasense is an antisense compound that is pro-apoptotic in cancer cells. A large scale Phase III trial in patients with metastatic melanoma was not considered approvable by the FDA in spring 2004. However, subsequent analysis along pre-specified stratification points (ie LDH level) show striking survival curves, suggesting that patients most likely to respond to the combination of Genasense and DTIC chemotherapy can be pre-selected by LDH level at or below upper limit of normal (ULN). As a result of this new analysis of data, a new trial, labeled AGENDA, is underway in the US and soon overseas. This news release is significant because no site in France can participate in this trial without central regulatory authorization, which is different than the rules in the USA>

Analysis: I must initiate my comments by stating that I was not an investigator on the original Genasense trial in Stage IV malignant melanoma, although I have read and heard presentations on the data multiple times over the last four years. I was asked to be an investigator on the AGENDA trial. The new data analysis is very striking in my opinion. There are no prior studies that have attempted to prospectively correlate relative LDH level with survival, nor to separate the LDH level into subgroups predictive of survival and response to therapy. The advantage the Genta team has is that their study remains the largest Phase III randomized study for advanced melanoma patients looking at survival. Their data suggests that patients with normal LDH levels are more likely to survive longer when treated with Genasense and DTIC than with DTIC alone. This effect goes away when the LDH level rises, implying the biology of melanoma changes in some way with rising LDH, with increased resistance to therapy that may be effective otherwise.

I was very skeptical of the data at first but I have been convinced. I look forward to participating in the AGENDA trial and hopefully to proving that (finally) a drug can extend survival in Stage IV melanoma patients, something that NO OTHER DRUG has ever done, including Interleukin-2, Inteferon, tumor vaccines, chemotherapy, biochemotherapy, anti-CTLA4 antibodies, BRAF inhibitors, etc.