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Exelixis, Inc. Message Board

  • valleyofloire valleyofloire Dec 2, 2011 12:11 PM Flag

    Without R&D day would we be higher?

    Once again they harped on Pain relief and scans. There was definite skepticism expressed by at least 1 analyst surrounding those points. Followed today by a down grade. What's really wanted is proof of PFS. At this time Cabo is all about treating an extremely small population on their last legs. And the extension of life is a mere 11.5 months. The gd. part is they have pain relief, evidently. All the other hoped for treatments Cabo maybe gd. for are a long way off. Until then the income from MTC can only be trivial. There maybe a partner but for MTC it won't mean much to PPS.And if they don't hurry up someone else may come along with a better solution. Leaving Exel out in the cold.

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    • Yes it is fortunate when a practitioner participates and while I might not agree with Dr Kaplan's view of Provenge, no disrespect is intended.

      It is indeed ironic that Cabo shows marker and radiological improvements ( resolution of bone mets is unheard of )I hope too like Provenge it will prove to give a survival benefit. I expect it shall though and it's why I believe in it's science just as I believe in the science of Provenge and have for a very long time, way before their first FDA review with subsequent issuance of an "approvable letter"

    • <<I appreciate it.>>

      Your welcome and I enjoy the back and forth. We are fortunate here to occasionally get the perspective actual practitioners.

      It's a bit ironic that Cabo is in the opposite position of Provenge. It has all this great data on various marker and radiographic improvement, but nothing showing a survival benefit yet.

    • ernie: Excellent responses some great data and info, I appreciate it.

      When you say the "Scher recommendation" I assume you mean his less than positive remarks LOL but he seems conflicted and biased to Abiraterone. Yes he has been very harmful to Provenge's acceptance.

      "I think Provenge is a good drug and and you are right, it has the best therapeutic index of the alternatives, but until there is more data, it is IMO unreasonable to expect practitioners to represent the drug as having more efficacy than the label specifies." I'm fine with that but clearly in hormone refractory non metastatic patients it should be the clear choice given other treatment options would sync in well post Provenge.

      I think everyone's concerns about the size of the trials is valid except the final phase three trial emphatically demonstrated efficacy and the lead investigator was one of the finest clinicians in the country. Time will certainly give all the medical community more data points, for the sake of patients I hope that is even more positive.

      Rationed health care is a real concern but I strongly doubt given the demographics in this country that it's going to be a leg any politician can stand on anytime soon. Regardless is it just coincidence that there was a CMS review for a small Bio Tech company like DNDN over their very expensive oncology product when a few other BP companies have comparably expensive products out there that did not receive the same review? I hardly think PFE's product would or did and I think has a $112,000 price tag. Politics and patients well being are not good bedfellows.

      Thanks for you responses. I was not personally attacking Dr Kaplan but was trying to understand his rational of thinking on the matter.

    • <<Regardless can you explain just "Why" an oncologist would NOT choose to use Provenge in a patient who fits the criteria?>>

      You could rephrase your question to remove the hypothetical and ask why oncologists are not using Provenge in greater numbers. I am not an oncologist, so I can only speculate, but Yahoo is an appropriate forum for rank speculation, so here goes. Here are the current four drugs that have shown a survival advantage.

      Cabazetaxel HR = 0.70 (0.59-0.83), Docetaxel HR =0.761(0.619–0.936), Abiraterone HR = 0.646 (0.543, 0.768) and Provenge HR = 0.775 (0.614, 0.979)

      The first number is the hazard ratio and the numbers in parenthesis are the upper and lower confidence interval boundaries. Provenge has the widest confidence interval because it was the smallest trial. Normally, that wouldn't make that much difference, but with Provenge it does because the primary evidence of efficacy is the survival analysis. Other drugs can fall back on RECIST response rate and PSA response to complete a picture of efficacy. Provenge can't do that.

      DNDN/Provenge also has had a rocky path that rightly or wrongly has tarnished Provenge's image. The Scher recommendation, the first NDA approvable letter, the CMS evaluation, lots of press about the $93,000 treatment, the reimbursement issue all have contributed to a negative image. Frankly the Gomella poster hurts more than helps. It's another exploratory analysis trying to retroactively prove efficacy.

      I think Provenge is a good drug and and you are right, it has the best therapeutic index of the alternatives, but until there is more data, it is IMO unreasonable to expect practitioners to represent the drug as having more efficacy than the label specifies.

      I'll answer a slightly different question. What treatment would I want? I think I would be looking at early treatment with MDV 3100 or Abiraterone with concommittant Dmab. That or Provenge followed by MDV. It's a hard choice and it is complicated by reimbursement criteria which probably don't match my treatment preference. The CRPC landscape is a muddled mess right now and I think Provenge will get a bigger piece of the pie, but not as large as early projections. I sold my DNDN a year ago for that reason.

      <<Maybe the medical community needs to look at "Survival" as a point of just as much importance? I'm sure the patients do. Not everything in Medicine is fully understood but should we turn our back on the bigger picture just becuase one doesn't understand all the reasons behind the outcome? I know this must be hard on physicians.>>

      I personally would have more comfort with the notion of survival as an end onto itself if the trial were larger and the confidence interval for the benefit correspondingly tighter. I think that MD's and patients value survival, its just more of an issue of having confidence that the survival is real and not a statistical anomaly. Seeing PSA drop or a bone scan improvement provides that confidence. The absense of those confirmatory data points requires more faith.

      <<It was wrong of the CMS to review the FDA's decision plain and simple and it smacks of a panel reviewing what a Medicare or Medicaid patients life is worth, it's was wrong and unethical IMO.>>

      With government sponsored health care for all citizens over 65, the demograpics of my generation, and deficits in the trillions, it is my opinion that rationed health care is inevitable.

    • Thanks Ernie; That is exactly what I have been looking for; a really intelligent discussion of the problems with the Affirm study. Real median survival could be anything between 4.1 and 12.7 and nobody really knows. It is an important point in that one way immune therapy is just another modality and the other way it major advance in cancer treatment that was worth a Nobel prize. Greatly appreciate your comments. Anyway, everybody loves Cabo.

    • ernie: Your responses are well laid out and I appreciate your input for discussion. It's the fact that Dr Kaplan didn't want to discuss Provenge on the merits pro's and cons of the drug and the seemingly conflicting or ambiguous reasons he had for not promoting Provenge in his practice that I am still unsure of.

      Future trials in earlier stage patients of Provenge will eliminate the "frozen" issue and we will have to see what that data is. Regardless can you explain just "Why" an oncologist would NOT choose to use Provenge in a patient who fits the criteria? It's not like by using Provenge they shut the door to future options, it's not liken with Zytiga that is given together with Predisone, which as I'm sure your aware steroids can not be given concurrently with Provenge. Also and what I think is most appealing or should be to both the practitioner and especially the patient are the low to almost non existent side effects of Provenge. When the patient fails Provenge treatment there are other options, Zytiga, Taxotere and hopefully Cabo but why have the patient have to have these more side effect intensive therapies before the disease has spread to those levels? ( IE bone mets)?

      I guess I am in the school of "the means of action is not reflected in any of the accepted measures of disease progress" Yes I do understand the frustration anyone must have with this especially a clinician who has many years of experience where these "standard markers of disease progression" is such a focus point. Maybe the medical community needs to look at "Survival" as a point of just as much importance? I'm sure the patients do. Not everything in Medicine is fully understood but should we turn our back on the bigger picture just becuase one doesn't understand all the reasons behind the outcome? I know this must be hard on physicians.

      Lastly I am in full agreement DNDN's management has dropped the ball in almost every conceivable way especially from a marketing a physician eduction standpoint, I'm sure had they partnered with a large BP group those issues would not be present. Big Pharma knows how to sell and market for sure! I will say though once again that the year long CMS review and the uncertainties that it caused with providers is one of the biggest reasons for the slow product launch. It was wrong of the CMS to review the FDA's decision plain and simple and it smacks of a panel reviewing what a Medicare or Medicaid patients life is worth, it's was wrong and unethical IMO.

    • <<Critical information was presented at ASCO by Gomella in 2011 poster presentation that control group that did not get Provenge had 12.7 month median survival compared to group that got Provenge and had 25.4 month median survival.>>

      http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=82559

      As a trained pathologist I would expect that you would be aware of the shortcomings of the comparison and pay closer attention to Gomella's attempts to correct for those shortcomings. Gomella's own conclusions come with several modifiers and a level of uncertainty. It is an exploratory analysis and the sample size for nonparticipants is small. Gomella's attempt to account for prognostic sample disparity was a wag and even so moved the p value from infinitesimal to nonsignificant p=.17.

    • <<A clinician from a large leading Oncology practice would have to be living in a closet to have not been on top of the Provenge story in it's entirety we're talking two phase 3 trials and the most "emotionally" charged and controversial drug in recent history.>>

      You are working from the assumption that anyone looking more deeply into the raw data will come away with the same conclusions as yourself, that the label conferring a 4 month survival advantage understates efficacy, perhaps by multiple factors. A cursory examination would lead one to look at the control arm and compare patients who took advantage of the crossover vs those who did not. Those control patients receiving the frozen Provenge enjoyed a 12+ month survival advantage. It is flawed logic. The process itself selects for a survival advantage for those willing and able to comply with requisite office visits and undergo the transfusion process. Even for the crossover patients, waiting a 2nd time for progression further delays moving on to docetaxel, which most patients on both arms eventually did, but the Provenge patients would have done it sooner than their control counterparts.

      Let's revisit the lack of secondary efficacy measures. One would expect a drug that confers a significant survival advantage to show some secondary efficacy, soft tissue tumor response (only 1 reported in the entire trial), PSA response (2.6%). There are two possible explanations, the survival advantage is a statistical fluke or the means of action is not reflected in any of the accepted measures of disease progress. Or perhaps there is a middle ground, the statistical survival advantage is real, but the degree of the effect is treated with skepticism because of the lack of supporting secondary data. So one looks at the largest trial and the hazard ratio, to wit HR = 0.775 (95% CI: 0.614, 0.979). So if one looks at a data set with a justified degree of skepticism, one would focus on the confidence interval. Worst case here is .979 which would mean negligible patient benefit.

      I am not saying that Provenge is not an effective drug. I am saying that there is room for differing opinions as to the degree of that effectiveness and that MD's who do not share your fervor are not bereft in their responsibility as patient advocates. It is sponsor responsibility to design and conduct trials that produce definitive results. The Provenge results were convincing enough to warrant approval, but a healthy dose of skepticism remains.

    • Hey Ernie, Esdbass, Agree with Esdbass; Every physician has a non-delegable duty to be well informed. Critical information was presented at ASCO by Gomella in 2011 poster presentation that control group that did not get Provenge had 12.7 month median survival compared to group that got Provenge and had 25.4 month median survival. Dr. Kaplan is a treating Oncologist. He had a duty to be aware of this critical information. He can not fall back on DNDN screwed up and the fooled FDA about control, so I don't need to know anything else about it.
      He is responsible for having a well informed opinion of the value of Provenge. In order to know the value of Provenge he needs to be fully aware of the date presented by Gomella at ASCO 2011. He needs to know this information as it regards treatment of his patients.
      His comment about 4.1 months shows he is terrible uninformed.

    • Last time I looked this was a Exelexis board and not Dendreon. I am done with this fruitless discussion. I am not the only oncologist in town. Why don't you take the issue up with the many oncologists who haven't even used the drug once. I don't think the sales figures for Provenge indicate its wide adaptation. Maybe you can try with some of the others. As I said I have had enough.

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