Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor-targeted therapy.
BACKGROUND
The clinical activity of allosteric inhibitors of mammalian target of rapamycin (mTOR) inhibitors in renal cell carcinoma (RCC) may be limited by upstream activation of phosphatidylinositol 3 (PI3)-kinase/Akt resulting from mTOR1 inhibition. On the basis of this rationale, 2 independent phase 2 trials (Perifosine 228 and 231) were conducted to assess the efficacy and safety of the novel Akt inhibitor perifosine in patients with advanced RCC who had failed on previous vascular endothelial growth factor (VEGF)-targeted therapy.


METHODS
In the Perifosine 228 trial, 24 patients with advanced RCC received oral perifosine (100 mg daily). Perifosine 231 enrolled 2 groups that received daily oral perifosine (100 mg daily): Group A comprised 32 patients who had received no prior mTOR inhibitor, and Group B comprised 18 patients who had received 1 prior mTOR inhibitor.


RESULTS
In the Perifosine 228 trial, 1 patient achieved a partial response (objective response rate, 4%; 95% confidence interval, 0.7%-20%), and 11 patients (46%) had stable disease as their best response. The median progression-free survival was 14.2 weeks (95% confidence interval, 7.7-21.6 weeks). In the Perifosine 231 trial, 5 patients achieved a partial response (objective response rate, 10%; 95% confidence interval, 4.5%-22.2%) and 16 patients (32%) had stable disease as their best response. The median progression-free survival was 14 weeks (95% confidence interval, 12.9, 20.7 weeks). Overall, perifosine was well tolerated, and there were very few grade 3 and 4 events. The most common toxicities included nausea, diarrhea, musculoskeletal pain, and fatigue.


CONCLUSIONS
Although perifosine demonstrated activity in patients with advanced RCC after failure on VEGF-targeted therapy, its activity was not superior to currently available second-line agents. Nonetheless, perifosine may be worthy of further study in RCC in combination with other currently available therapies.
Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. dcho1@bidmc.harvard.edu
Daniel C
DC
Cho
Thomas E
TE
Hutson
Wolfram
W
Samlowski
Peter
P
Sportelli
Brad
B
Somer
Paul
P
Richards
Jeffrey A
JA
Sosman
Igor
I
Puzanov
M Dror
MD
Michaelson
Keith T
KT
Flaherty
Robert A
RA
Figlin
Nicholas J
NJ
Vogelzang
D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D016879:Salvage Therapy; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
D047428:Protein Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D010767:Phosphorylcholine; C105905:perifosine; D051057:Proto-Oncogene Proteins c-akt