I thought hemoglobin changes were exclusive to Cabozantinib.
Summary from the article
"In summary, we describe a zig-zag pattern in hemoglobin levels
and erythrocyte numbers during sunitinib treatment in metastatic
renal cell cancer patients. On the basis of previous studies and our
findings, we hypothesize that the cyclic kinetics of hemoglobin and
erythrocytes is the result of a temporary loss of intravascular fluid
caused by inhibition of VEGFR-2 and subsequent reduction of NO,
rather than an increase in erythropoiesis."
Best response combination of 6 and 12 week scans from both 40 mg cohorts were miscalculated from my last post.
Should read this way
16/24 PR's= 66.7%
3/24 CR's= 12.5%
Total best bone scan response of 24 evaluable 19/24= 79.2%
If you take pure 12 week scans by evaluable it would look like this combining both 40 mg cohorts
combination of 2- 40 mg cohorts
12/20 PR's= 60%
3/20 CR's= 15%
Total bone scan response of 20 evaluable patients at 12 weeks= 75%
From this abstract
Abstract 4566: Investigator-Sponsored Trial of Efficacy and Tolerability of Cabozantinib at Lower Dose: A Dose- Finding Study in Men with Castration-Resistant Prostate Cancer (CRPC) and Bone Metastases
You have to read the abstract carefully. There was one cohort of 12 patients reported on for both the 6 and 12 week observation. If you take the best response, there were 10/12 BSR's, 3 of which were CR's. But you should also roll in the 40mg results that DeBono reported in September at ESMO on a sample size of 51 with a 49% BSR (25/51). So if you pool the 40mg data we have 35/63 for a 56% BSR.
Just that I overestimated the significance of cabo treated rise in hemoglobin. It appears that other vegfr therapies may demonstrate this same effect. The significance of this hemoglobin effect has dwindled in my mind over time. I originally thought the effect may be due to improved healthier bone marrow environment after cabo treatment. (In other words, crowding effect of tumor in bone marrow resulting in diminished red cells returning to a state of homeostasis or a more natural cancer free environment after cabo treatment) I am still very bullish on cabo prospects, but have tempered my enthusiasm over time. I am optimistic from small data sets in renal,hcc, and what we have seen thus far in prostate single arm trials, but I am also anxious to start seeing randomized comparator data.
Ever since seeing those bone responses with sunitinib, I am looking that much harder from a skeptical point of view. No surprise that an agent other than Cabo would eventually show some type of drastic bone scan response, but took me by surprise that it was an agent that had been tested in a failed pivotal CRPC trial for survival. The phase 2 sunitinib vs cabo in first line renal has me very intrigued at the moment. My thoughts currently are that Cabo is more active in a variety of tumor indications than sunitinib, but I would also like to see real undeniable proof.
"Does that mean COMET-2 was a unnecessary waste of money?"
Absolutely not. IMO Comet 2 will read out before Comet 1, perhaps up to a full year sooner. I firmly believe that the Comet 2 positive outcome on its primary endpoint is virtually a lock. We talked about the de Bono data. That 51 patient cohort was a trial run for Comet 2. It used the same patient reporting outcome tool used in Comet 2 with the phone response system. All patients were required to be docetaxel refractory and 2/3 were Abi/MDV refractory. It did not have the 2 week narcotic normalization period leading in to the treatment phase. Comet 2 will use a 60mg dose vs de Bono's 40mg. Here are the reported pain results: "A clinically significant reduction of pain, defined as a ≥30% decrease in BPI pain score, was observed in 18 patients (69%). Fifty-four percent of patients decreased their use of narcotics, including one patient who discontinued narcotics. The majority of patients in whom these improvements were observed had received both prior docetaxel and prior abiraterone or enzalutamide." Comet 2 will require patients to have successive periods of pain response to be considered " durable responders." Past history is that this requirement will knock that 69% rate down to the mid 50's. The primary endpoint for Comet 2 is a comparison of the number of durable responders on Cabo vs the number of durable responders on Mito. Mito's history suggests an approx 8% response rate. Compare that to Cabo's anticipated 55% rate. That is why I describe this trial as shooting fish in a barrel. In the SPA fiasco FDA did not reject a pain endpoint. FDA rejected an overly permissive protocol that would have anticipated an approval with a very low level of efficacy. EMA approval off Comet 2 is very likely and IMO FDA approval is probable.