Let me put this discussion to rest as it is getting ridiculous. As we all know there are two endpoints for which we await results. The survival endpoint requires a certain target event number (deaths). That number has not been reached yet. The company originally thought that event number would be reached at the end of 2011 based on expectations of median survival of 11 months for the control and 18 months for A7. Then the company thought it might happen by mid 2012. Then the company thought the event number might happen by the end of 2012. Now they expect the target event number will be reached by mid 2013. Why the delay? Why the confusion? The answer is simple. Patients are living longer than originally projected. This is not some conspiracy. It is simply longer survival. That is most likely good for Vical. The control is most likely living longer than a median of 11 months. But if one studies all previous trials where DTIC was the control, one realizes that while 11 months may have been a little low for patients with the enrollment characteristics of this trial, it is not way out of range. Most likely the control arm has a median OS of 15 months with a possible range being 13-17 months. Study the previous trials using DTIC, look at the patient baselines and you will come up with those numbers. Now that type of survival will extend the trial beyond the end of 2011 but cannot explain a major part of what now looks like a 2 year delay. What probably explains most of the delay is that the A7 arm has a median survival of more than 18 months. In the phase 2 trial it was 19 months, but looking at chemo naive patients that equates to this trial the median OS was 22.5 months. When one considers that over 60% of patients in phase 2 got less than 1 course of treatments and everyone in phase 3 got 2 or more courses of treatments, that 22.5 months median OS could easily be higher. So we could easily see a control median OS of 15 months and an A7 median of over 25 months. That would go a long way to explaining the delays.
The other endpoint is durable response rate. It is true that data was collected in February-May of 2012. It is now being evaluated and adjudicated by an expert panel with Vical blind to the data and decisions being made. This process could have been done in a few months if the panel worked full time. But to save money and realizing that the results would sit in a file that could not be unblinded until the survival data was available, this process has been extended. The experts only work a couple of days a month while having full-time medical practices. Vical is totally blind to the response data right now.
Sentiment: Strong Buy
Great logic and reasonable estimates on OS for both arms. Let's all remember that the primary end point is durable response, with median survival benefit for Allovectin as secondary (but crucial for FDA approval and market pricing).
The poker stakes here are high and the game has shifted a bit since the A7 trial started. Vical believes it's holding a very strong hand; after all, they helped stack the deck by designing the trial to the FDA's satisfaction. With immunotherapies, time is valuable provided the immune system is healthy.
IMO the "home run" for Vical could show over 35% durable response and over 12 months survival benefit vs. chemo arm with under 10% adverse effects.
Does it take 3 + years from final patient enrollment to "see" this hand play out? Probably yes--especially if more A7 patients have durable responses after multiple injection cycles.
Would an Allovectin 7 home run with these prime time stats on both end points make headlines? Probably yes.
Only time will tell whether Vical wins this hand and what the payoff pot is worth.
Finn, Markovic, Joseph Therapies for Metastatic Melanoma, Past Present and Future
With approximately 13,000 annual deaths and a median overall survival (OS) of 8 to 18 months, metastatic melanoma is the most aggressive form of skin cancer . Until 2011, only two FDA therapies for metastatic melanoma were approved, dacarbazine and high dose interleukin 2 (HD IL-2), both of which do not increase median OS [2-4]. Dacarbazine is limited by a low response rate (10% to 15%) and an overall survival of eight months . HD IL-2 is limited by an even lower response rate (6% to 10%) and severe toxicity with only a minority of patients achieving a long-term, durable response [3,4].
Thanks for your response. Did VJ's recent update on the patient demographics in the study, e.g. 63% stage IV in PIII vs 48% in PII, median age in PII 4 years younger than PIII, alter your thinking on the OS for the control group? He seemed to be saying, "I know what everyone is thinking (control group must have be living a lot longer), but it probably isn't true". In one of his prior updates (presumably before counsel got a hold of him) he had flat out said "I think we have a home run". It certainly seems possible with the overall slow event rate....
Knowing that 63% were stage 4 and the median age was 64 is important information as it limits the chances of a wildly high survival number for control arm. It does not mean that the control group is likely to have an 11 month median survival. There are still 37% late stage 3 patients who are very likely to live more than 11 months and some m1a patients who are likely to live a little longer. Also there are no liver mets which usually die in 6 to 10 months. So I did not change my forecast of 15 months but at least see 17 months as an upper limit for the control unless we are in black swan territory. It also means that I am not looking for any crazy high median survival numbers in the A7 arm where I am predicting 25 months median survival with a chance at high twenties. I would not look for numbers in the 30's even if A7 works great as many of these patients will be in their 70's and quite ill. Even with a good response to A7, they could die from many causes at that age. I would consider 15 months median OS in the control arm and 25 months in the A7 arm a home run. Remember DTIC and Yervoy have a grade 3,4 adverse effect rate of 25%-30% and Abraxane has shown approximately 50%. A7 had zero grade 3,4 adverse effects in phase2. While I am not expecting zero in phase 3, it would be very likely that the number is below 5%.
Sentiment: Strong Buy
Nice summary of the situation. Hopefully people read it carefully so they can learn something.
I agree with you - it seems very unlikely that survival data has been delayed this long because the chemo patients are living far longer than has been observed in previous clinical trials. It makes more sense that the Allovectin patients are living far longer than expected, which is consistent with prevous trials plus a significantly improved clinical design. I don't know about you, but I think VICL has a good shot at meeting both endpoints, though at this point I'm a bit more worried about meeting the response endpoint more than the survival one.
Today the only thing the shorts can hang their hat on is the poor performance of the stock, despite knowing patients, two-thirds of whom received Allovectin, are living far longer than expected. The weak stock performance could be due to pressure from short sellers as well as investor disappointment that the results have been delayed so many times.
If Allovectin works very well, it would not surprise me if there were further delays. In the mean time, the rest of the pipeline is moving forward nicely, which VICL gets little or no credit for. The stock can only go down a few points from here, but if Allovectin or any other pipeline candidates are successful, the potential upside is many times that.
Check out this guy. There can be more delays because the drug is working too well When a real cancer drug comes along it will not be delayed. Some gamblers are always optimistic despite the absurdity of their contentions.
2 questions :
The comparable studies you reference relative to Chemo O/S, did those studies exclude brain and liver mets?
Second, does anyone know if there is any information available that would indicate that A-7 is STILL being shipped? CC or other? I did not hear it come up during the last CC.
Nice post by both of you. I too would like to be a purest and believe in the integrity of a sound trial design. Also, a good reminder that 2/3 of the subjects are in the A-7 group with a 2 year delay in OS events. This fall in pps is a classic example of the biotech money moving around in order to capture shorter term caltalysts.