Some observations about the 4 patients with bone metastasis at baseline.
1. Only 1 patient was followed by bone scan, and that patient observed a bone response.
2. 2/2 patients with bone pain had a bone pain response. One patient had a pain score of 5/10 with complete resolution of pain for 73+ weeks. The other patient had pain response until 25 weeks.
What makes the observations very interesting is the fact that renal cancer patients that have bone metastasis are predominately osteolytic in nature. If you follow the literature typically 70% of the bone lesions are osteolytic in RCC. Now if 70% of lesions are typically osteolytic, I would imagine that patient with extreme complete pain response lasting 73+ weeks would have majority of bone lesions being of osteolytic variety. (Renal cancer can demonstrate pure lytic behavior, although not to the degree multiple myeloma does) Osteolytic lesion response by bone scan is somewhat less specific to what a bone scan is actually measuring. For example, osteolytic lesion typically needs an accompanying osteoblastic response, or fracture in weakened lytic bone to visualize by bone scan. Judging by how followup was weak by bone scan criteria in the other patients, I suspect that there wasn't another imaging modality used to measure baseline and followup osteoclastic lesion response.(after all only 1/4 patients were followed by bone scan, and that patient happened to respond by bone scan criteria) I suspect those osteolytic lesions could demonstrate sclerotic healing. I have a hard time imagining an RCC patient's dramatic durable pain response was due solely to osteoblastic therapeutic effects.
Exelixis states that cabo impacts both osteoclasts and osteoblasts, but to date we haven't really seen extent on osteolytic lesions. I am really intrigued to see what therapeutic extent on osteoclastic lesions we are seeing? Are we seeing some new normal bone growth in these lytic regions?
What's is the model of what's happening here? I seem to recall a video where one of the panelists at a prostate conference said that prostate cells in mCRPC think that they're bone cells. So I'm guessing tumor cells are proliferating migrating to the bone, mutating into errant osteoclasts and osteoblasts, further proliferating as they overexpress the c-Met and VEGF-R receptors present on normal osteoblasts and osteoclasts receiving the HGF / VEGF ligands, and wreaking havoc on physical bone structures as a result.
I'm guessing that an implication of what you're saying is that Cabo could deliver a better effect than say Xgeva due to its effect on both types of cells, presumably replacing it in other types of indications as well.
"So I'm guessing tumor cells are proliferating migrating to the bone, mutating into errant osteoclasts and osteoblasts" wildbiftek
I mentioned that it is complex, but here is a quote that may help to better understand.
"In the bone microenvironment, tumor cells secrete soluble factors that promote bone remodeling resulting in the release of additional bone matrix-bound growth factors which further activates OCs and osteoblasts (OB) and tumor growth"
My guess is that the tumor cells are regulating osteoblasts/osteoclasts rather than normal cells. Under osteoblastic model, the osteoblast is trapped by its own doing. Meaning that it weaves a collagen wall around itself, and becomes a bone cell. Now I believe this host bone cell may have tumor like properties past on from interaction with original tumor cell that secreted factors that stimulated its creation.
Think of bone much like skin or a paved road. Osteoclasts break down old bone, while osteoblasts lay down new stronger bone. There is a balance between osteoblast and osteoclast production that must be maintained to provide an equilibrium of sorts. When tumor cell mediation occurs, the equilibrium is all out of whack. Producing all sorts of uneven bone growth, or recession. Too much osteoblastic phenotype produces irregular bone formations that are rigid rather than smooth.(bone overgrowth) Too much osteoclastic phenotype produces bone loss.(holes in bone)
Lots of other factors in play here such as parathyroid regulation of calcium(bone building block) in bloodstream and bone etc.
Long way of saying I really don't know for sure, but I gave it the good ole college try.
All of the literature I have read portends that bone metastases in Multiple Myeloma are entirely osteolytc. Is it likely that we can extend the rationale of your observations in RCC and extrapolate bone scan response for the MM trial? Is there some other mechanism at play...or could this be an apples-to-apples comparison?
I guess what I'm asking is: Are all osteolytic lesions equal?
Or do they differentiate by the nature of their origination?
Thanks in advance...
"I guess what I'm asking is: Are all osteolytic lesions equal?
Or do they differentiate by the nature of their origination?"
Many growth factors at play here, and hard to ascertain how similar between cancer indications.
That said, it is certainly a positive that Cabo bone scan resolution phenonomenon is crossing over to other cancer indications, so there is some similarity between cancer indications at the least.
"All of the literature I have read portends that bone metastases in Multiple Myeloma are entirely osteolytc. Is it likely that we can extend the rationale of your observations in RCC and extrapolate bone scan response for the MM trial?"
I know my post here is teasing at extrapolation into MM, but I'm not comfortable extrapolating RCC to MM at this point. In fact, I am wondering what happened with that MM trial? I'm almost thinking early results are not very good, as at one point Exelixis had plans to present in late 2012.(even before the trial started) Either that, or the trial is having difficulty recruiting even small numbers. This MM trial started in June of last year. For comparison sake, the Lung RET trial started one month after that MM trial started. We have results on the first 3 patients from that lung RET trial. (2/3 partial responses) I feel confident that the FDG PET/CT response endpoint is sufficient to tease out a therapeutic benefit in MM with Cabo, if there is one.
MM is often described as being purely osteolytic, and bone scans only pick up active bone remodeling.(osteoblastic ) The literature that I read, tends to state that 50% of MM lesions are visualized by bone scan in comparison to 80% by x-ray bone survey. That said, I don't really know how they define purely lytic, as surely there would have to be some sort of osteoblastic activity, however remote, to be visualized by bone scan. I rarely if ever scan for multiple myeloma, so I really don't have any real experience here. A few(probably not typical) interesting MM bone scan case studies I've seen show photopenic regions over large pure lytic areas sometimes, and at other times demonstrate a faint rim activity at perimeter of bone loss areas.(Technical speak= almost simiar to what a hip prosthetic would look like)