"Twelve patients were enrolled in the 40 mg cohort. One of the these patients discontinued the study at Week 2 due to worsening of pre-existing anorexia and fatigue, and another patient discontinued at Week 6 after experiencing a pathologic hip fracture. Eleven patients were evaluable at Week 6, of which 10 had bone scan responses. The median decrease in bone scan lesion area was 61.5%. Eight of the 10 responding patients had a confirmation of the bone scan response at week 12 and continue on treatment with a median duration of treatment of 19 weeks."
Within the limitation that this is still a small sample, there is no discernable drop off in efficacy at 40mg/day.
"Based on the bone scan findings of the 40 mg cohort, a second cohort of 11 patients was enrolled and is receiving cabozantinib at a dose of 20 mg daily. Nine of these patients were evaluable at 6 weeks, of which two had a bone scan response. Six other patients had stable disease (SD) by bone scan (<30% decrease to <30% increase in bone scan lesion area), and one patient had progressive disease by bone scan (≥30% increase in bone scan lesion area)."
There is a pronounced and obvious drop in efficacy from 40mg to 20mg. It is nice to see an experiment with unambiguous results. It is clear that 40-60mg treatment represents an optimized dose for efficacy vs side effects for bone met treatment.
Not yet fully understood is what an optimized dose would be for visceral disease. Although a small sample size, the Japanese low dose data reopens that question.
"In the phase 1 trial (N=6), two patients with non-small cell lung cancer (NSCLC) in the 40 mg arm had confirmed partial responses with target lesion shrinkage of 38% and 41%; three patients had stable disease, and one patient had disease progression. No dose-limiting toxicities, serious adverse events, or Grade 4 or 5 adverse events have been reported to date in this trial. The only Grade 3 adverse events reported were neutropenia in one patient and increased lipase in one patient, both at the 40 mg dose level."
The recently reported differentiated thyroid cancer (DTC) data showed very good efficacy, but that trial also reported another grade 5 (death) SRE. One unwanted reaction to the low dose efficacy now being seen will be a questioning by FDA/ODAC regarding the MTC data and whether further trials should explore a lower dose alternative before approval.
"The recently reported differentiated thyroid cancer (DTC) data showed very good efficacy, but that trial also reported another grade 5 (death) SRE." I don't think anyone knows absolutely that the death was a result of Cabo. How sick was the person? Were there other drugs or something else involved? Was the person due to die at that time no matter what was done?
Good job, Ernie. I noticed that the AE5 in the DTC trial had received prior mediastinal XRT. Mightn't this alone account for a higher statistical potential for mortality? Doesn't this sort of requalify or recategorize this particular AE?
<<I noticed that the AE5 in the DTC trial had received prior mediastinal XRT. Mightn't this alone account for a higher statistical potential for mortality? Doesn't this sort of requalify or recategorize this particular AE?>>
It certainly should be looked at as a mitigating factor, but the VEGF inhibitors as a class have a history of causing fistulae and Cabo has this history also. Although obviously in pretty tough shape, this AE5 was at least ECOG 1 at trial entry, so it is hard to argue that the assignment as a treatment induced mortality is not justified.