(Important Disclosure Update: Dr. Farhat previously worked at Memorial Hospital in South Bend, Indiana, but does not work there currently. While there, he worked as an oncologist, but did not have an administrative role and was not aware of any NeuVax trials during his tenure at the hospital.)
This first of two articles is intended to give the public an oncologist's perspective on interpreting data from clinical trials and understanding the mechanism of action of medication. I will provide an inside look at what we in the oncology community take into consideration when treating our patients. It is important to be able to accurately and scientifically assess the impact of clinical trial data and to be aware of possible misrepresentations or pitfalls in the popular media.
I am a board-certified medical oncologist and hematologist in one of the largest oncology groups in the Midwest. As part of my practice, I also serve as the hospital's chairman of cancer services and the director of the cancer center. Our practice has over 100 clinical trials in all areas of cancer medicine, and I serve as the principal investigator on several of those clinical trials.
I am not a financial analyst nor am I an accountant and will not pretend to be, so this discussion will be solely focused on the medical aspect of Galena Biopharma (NASDAQ:GALE). I would like to address two areas that have been the subject of recent blog posts on financial and biotech websites.
1. NeuVax (nelipepimut-S) and why it is key to improving survival in our patients.
For many years, chemotherapy and hormonal therapy were the main treatments for our breast cancer patients, depending on their hormonal status. In recent years, treatment options have evolved dramatically. Scientists have been able to not only identify molecular markers involved in cancer growth, but more importantly have developed the ability to target those receptors and improve our patients' survival.
The next step in the evolution in cancer therapy was to not only target those molecular markers, but also stimulate patients' own immune systems to help fight the battle against cancer.
In 2011, the Nobel Prize for medicine was awarded to Bruce A. Butler, Jules A. Hoffmann and Ralph M. Steinman for their discoveries of the role of dendritic cells in adaptive immunity and the activation of innate immunity. These groundbreaking discoveries paved the way for the development of a multitude of vaccines to stimulate immunity and increase survival in our cancer patients. A first example is the advent of Provenge (sipuleucel-T, Dendreon (NASDAQ:DNDN)). This is a therapeutic cancer vaccine for prostate cancer, meaning that it stimulates an immune response against cancer cells carrying a specific antigen. Studies have shown that the use of this vaccine has increased the 3 year survival over control groups by 37.8%. In lay terms, this means that 37.8% more patients are alive at 3 years if they received the vaccine than if they didn't. Please see the graph below, taken from the Provenge website.
Further evidence of the efficacy of vaccines in cancer treatment is Yervoy, (ipilimumab, Bristol-Myers Squibb (NYSE:BMY)), which is a vaccine therapy approved by the FDA for use in metastatic melanoma. As indicated by the graph below, taken from the Yervoy website, this has almost doubled the overall survival of treated patients.
To me as a medical oncologist, these results are truly remarkable -- particularly when we are using therapy that doesn't have nearly the same cytotoxic effect as chemotherapy.
At this time, I would like to reference Matt Gravitt's article that was published on January 31st where he mentioned, "Why the NeuVax PRESENT Phase III trial is poised for failure. Simply put, science and logic will prevail." Science has already clearly demonstrated the benefit of immunotherapy (vaccine therapy) for cancer treatment. Given the efficacy that we in the medical community have already experienced with the above mentioned treatments, it is certain that NeuVax has science on its side. It is unclear to me why, in the face of this overwhelming evidence, Mr. Gravitt believes that science will not support the potential of NeuVax in preventing or delaying recurrence of breast cancer in patients who have achieved remission with standard of care treatment. I respectfully disagree as medical professional.
Let's dig further.
We can review the ASCO 2010 presentation of the phase 1/2 trial. Breast cancer patients who were node positive with a diversity of Her-2 (1, 2 and 3+) positivity were randomized to standard of care vs. standard of care in combination with NeuVax. The graph below is from Galena's website, which delineates the disease-free survival of the 97 patients that were evaluated.
Although it was not statistically significant with a p-value of 0.1194 (statistical significance requires a p-value of 0.05 or less) there is a very clear cut separation between the 2 curves. NeuVax is favored with an approximate 50% relative risk reduction in recurrence at 3 years (in another words, it cut the risk of recurrence by half). Observing this trend in itself is very impressive to the oncology community, due to the fact that there is a clear hint that the vaccine is effective in some ways. Now it is a matter of figuring out which subset of population gains the greatest benefit.
Looking further into the trial, the investigators at this point knew that there was something there that could truly benefit our patients. For such reasons, a subset analysis was performed looking at all patients that had Her-2, 1+ and 2+ excluding the patient who where Her-2 , 3+ (and thus received herceptin). Out the 97 patients that were evaluated, 45 patients met those criteria.
The graph below is from the Galena website, which once again delineates the outcome data. This is what created great enthusiasm in the oncology community. When this data was presented at our oncology meeting, my colleagues and I were very excited about the possibilities of this vaccine.
Looking at this subset analysis, we see a 100% relative risk reduction in disease-free survival. Let me say that again because it is that important. At the 3-year evaluation, there was a 100% improvement in the risk of relapse compared to the control group. Put another way, no patient relapsed in the vaccine group compared to 22.2% in the control group with a p-value of 0.035, which is statistically significant. In the oncology community, this data is some of the most impressive we have seen in any cancer trial.
At this time, I would like once more to reference Matt Gravitt's editorial when he says:
"The problem that I have with this data is that the sub-groups were too small to justify a successful study. In my opinion, the disease-free survival benefit in this sub-group is random chance. Basically, I believe it was pure luck that the control group had a few more patients with recurrence of breast cancer."
As a reminder, a P-value of less than or equal to 0.05 indicates statistical significance. A P-value ≤ 0.05 then means that the sample size was adequate and that these results were not due to "chance" or "pure luck" but instead represent a scientifically valid, significant, and reproducible finding. Let me remind you that in this subset analysis the p-value was 0.035.
I do agree with one point made by Mr. Gravitt, namely that this is a subset analysis and a more definite Phase III trial is needed to fully elucidate the possibilities raised by this data. In fact, this data was deemed compelling enough that the FDA gave a special protocol assessment (SPA) to do the Phase III PRESENT trial, which is currently ongoing. In my opinion, science suggests that this will be a very successful study. I will explain my reasoning below.
- On its own, the current data is very impressive. It reminds me of the lung cancer study that was done by Dr. Hanna et. al. and published in 2004 in the Journal of Clinical Oncology (JCO May 1, 2004 vol. 22 no. 9 1589-1597). This was a non-inferiority study looking at stage IV non-small cell lung cancer patients and comparing the use of Alimta (pemetrexed, Eli Lilly (NYSE:LLY)) to the standard of care at that time. The study met its end point and thus was a positive study. What was most impressive in that trial was the subset analysis that showed an increased benefit in patients with non-squamous histology favoring Alimta. This lead to multiple phase III trials in the front line setting and in maintenance therapy, which would eventually lead to a change in the paradigm of lung cancer treatment. Alimta became the gold standard in the therapy of non-squamous cell lung cancer patients.
Obviously we cannot compare these two studies, but Dr. Hanna's study can be seen as a preview of how clinical trials can progress through the oncology community. A subset analysis showing a statistically significant benefit can translate into a very successful Phase III trial. This is why we in the oncology community are all hopeful that the PRESENT study will be a positive trial.
Let's go back to Matt Gravitt's editorial.
"If NeuVax truly worked, why is the study aimed to treat patients who are already disease free? I predict that NeuVax will not meet the primary outcome of the PRESENT Phase III trial. In fact, I also predict the PRESENT trial won't even continue past the interim analysis."
At this point, I would like to give an overview of the natural progression of breast cancer. High-risk patients, including the node-positive patients enrolled in the PRESENT study, are treated with surgery, followed by chemotherapy and radiation as needed. After surgery, the patients could be considered "cancer free." But chemotherapy is given to reduce the risk of relapse. If the Phase III trial is successful, the risk of relapse could then be further reduced with NeuVax. By Mr. Gravitt's logic, there is no reason to give chemotherapy to these breast cancer patients, since they are already "disease-free." But this is only a matter of semantics, since preventing relapse is as important as treating the initial cancer. Our goal as oncologists is to use all means at our disposal to reduce that risk to our patients.
In my medical opinion, the interim analysis will be favorable and very encouraging to our patients and will lead to one more step forward in the fight against breast cancer.
2. Abstral - a sigh of relief for our patients with cancer-related pain
Although I am not discussing clinical trial data in this case, I would like to provide some insight into the management of pain in cancer patients. As an oncologist, I feel compelled to address the comments made by Adam Feuerstein in his biotech blog, entitled "Galena, free fentanyl samples and the 'zombie apocalypse." Here he is quoting John Hempton's blog post on brontecapital.blogspot.com:
"GALE's hot new product is a sublingual version of an old drug. The marketing (on their website) argues this drug is really fast. To quote: "Patients preferred Abstral for speed". However to give it that extra marketing pizazz they are giving it away. Here is the pitch - which I believe as a matter of policy should be criminalized.* [I note that tobacco companies are not allowed to give free samples of cigarettes - and it is curious that same does not apply here.] The advert has an irony of its own. It shows a new-age style woman completely blissed out (with a smiling kid) and the slogan "time better spent." We have US corporations doing hippy-alternative-lifestyle drug marketing for drugs that are especially effective in turning you into a zombie. Capitalism meets the zombie apocalypse. It is as if Tim Leary was reincarnated as a cynical capitalist going for the mega-dollars."
In light of the severe pain that my cancer patients experience on a daily basis, I find Abstral to be an important and effective therapeutic intervention.
First of all, it is ludicrous to compare a prescription drug intended to relieve pain in cancer patients to a known carcinogen like cigarettes. This is casting doubt on the safety of this medication with absolutely no scientific evidence to back up such spurious claims. And this is a medication that is very much needed. Although I treat cancer patients every day, I can't begin to imagine the experience of cancer-related pain, and I believe that neither can anyone that is not going through it. But let give you a small insight. Pain control can mean the difference to these patients between being bedridden in agony or having quality time with their children and grandchildren, or enjoying the little things such as walking in the park during the few days, weeks or months they have left on this planet.
To address the suggestion that Abstral is being given away in an attempt to create addicts, let me remind you that this is a controlled substance whose purpose is to alleviate the torture that cancer pain can inflict on our patients. Samples of this medication were provided for licensed physicians to dispense to our patients, not handed out on the street to anyone passing by. Pain control in cancer patients is not a "hippy-alternative-lifestyle," as Hempton (and by association, Fuerstein) suggests. It is a matter of life or death. Would you argue that "time better spent" would not be with one's child in a state of relative comfort and calm, but rather writhing in agony?
Let us go back to what really matters. We in the oncology community understand that pain control has always been a very important part of what we do for our patients. After all, our goal is to improve the lives of our patients even when there is no possibility for a cure. The limitation we always run into is the length of time that conventional pain medication takes to work. My colleagues and I believe that this therapy is a useful addition to our armamentarium when it comes to controlling our patients' pain and improving their quality of life. I can definitely envision this medication being used more and more in the near future. Abstral's mechanism of action and rapid onset is self-explanatory and I can project that it will be widely used in emergency departments, in hospitals for patients that don't have an IV or other venous access, and for cancer and other chronic disease patients who require rapid relief of breakthrough pain.
This is the first article I have written about a biotech company. The only reason I did so is because of the multiple infuriating and inaccurate statements that have been posted recently about the oncology community acting only for the almighty dollar. It is easy to malign others when you have no understanding of the day-to-day struggles involved in cancer care.
It is also very easy to write a negative article about a company. It is a much more difficult to approach the matter from a scientific perspective and let the data speak for itself. As a company, Galena has put in years of hard work to provide a vaccine that holds great promise for the prevention of breast cancer recurrence and a fast-acting opioid that can provide relief for our patient's worst pain. I find it difficult to fault them for that.
As you all know, all biotech companies have their challenges, and it is impossible to predict phase III trials with certainty. Investors should do their due diligence when making financial decisions. I hope this article has shed some light at the scientific aspect of GALE's latest venture. In my opinion, GALE is a long-term investment that will not only benefit its investors but also our patients.
Disclaimer: I was never contacted by Galena Biopharma and I am not receiving any compensation from the company or any of its associated parties.