<<b) Suppose that XL184 blocks a significant part of the osteoblastic pathway - but only slows down bone mets same as it slowed down soft tissue mets (which appears roughly comparible to docetaxel efficacy). Eventually the tumor will continue growing and the bone's ability to accomodate the tumor will be compromised - that might well be very unpleasant (e.g. increased pain, increased bone breakage).>>
Alright let’s address this. First, I will point out that Cabo patients with arthritic joints showed normal tracer uptake in their knees and ankles while simultaneously showing bone scan resolution of their mets. Dr. Smith (their lead investigator at Mass Gen) took it a step further and did CT scans on resolved bone mets and saw what he described as sclerotic activity consistent with remineralization of osteolytic lesions (healing). I’ll next note that they have been watching the first 20 bone scan patients for several months now and out of the total group of 62 Cabo bone scan patients, only one has progressed by bone scan. Couple these observations with the durable marker improvements comparable to those seen with bone drugs Zometa and Denosumab and the symptomatic improvement in pain and anemia and my impression is that observed facts fit a picture that says the bone scan improvements are what they appear to be, a lessening and in some cases resolution of the bone mets themselves.
The RDT did not incorporate a rigorous tool to measure pain. I recall mention of a post hoc questionaire. Cross trial comparisons are pretty much meaningless. The significance of the observation is just that it is consistent with all the other empirical observations supporting the notion that the bone scans represent a direct patient benefit.
I’ll go back to what I previously said. If a patient on AA or Taxotere or Denosumab showed a bone scan resolution similar to those seen on Cabo, the presumption would be that the mets had resolved and that the drug was benefitting the patient. The problem here is the breadth of the effect with some complete resolutions and 85% of patients showing some improvement. All of the secondary evidence presented is supportive of the thesis that the bone scans are real. I don’t like to take things on faith, but I also have to believe that the array of clinicians they have lined up, including lead investigators on other major drugs and ODAC members, all seem to indicate that there is more here than a temporary masking effect. Here are some quotes from the R&D day: Smith “These dramatic results were unexpected and unprecedented.” “No other agent has been associated with such dramatic changes in bone.” “In my opinion this is new and exciting and really is something we have been awaiting in prostate cancer for some time.” Kantoff “I remember when Ron emailed me that first bone scan response and the first response to me was that Ron must not know prostate cancer. Obviously this can’t happen. That’s how spectacular that initial response was and the way we all reacted to it. We’re very fortunate to have accrued a large number of patients since that time to sort of get a feel for whether this is really true …and I can say that it is true.” “There are many many patients who have had these bone scan responses. What’s remarkable …is the rapidity of this response in the bone and that it does correlate with clinical benefit with pain and bone markers changing.” “We’re very excited about this drug. I think it is going to be a very important drug in the next few years.”