Ramaprasad Srinivasan, M.D., Ph.D. – NIH National Cancer Institute Results from a phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer
Context:
HLRCC is a type 2 papillary RCC (pRCC) variant-related familial cancer syndrome. HLRCC is caused by the gene for the Krebs cycle enzyme fumarate hydratase (FH) by germline mutations. FH inactivation results in VHL-independent hypoxia-inducible factor upregulation, dependency on aerobic glycolysis, and activation of the NRF2 pathway, characteristics that some sporadic pRCC tumors also share. We hypothesized that the metabolic alterations that underlie these tumors will be susceptible to targeted therapy with bevacizumab and erlotinib combined.
Approaches:
Advanced pRCC patients were eligible to participate in this phase II trial. Those with 1) HLRCC and 2) intermittent pRCC were enrolled in parallel, separate cohorts to enrich for patients with FH deficiency. All patients received 10 mg / kg IV of bevacizumab every 2 weeks, and 150 mg of erlotinib orally every day. It included patients who had received no more than two VEGFR pathway targeting agents. Patients continued on medication until toxicity or development became intolerable. The overall response rate (ORR) was the primary endpoint; the secondary endpoints were progression-free survival (PFS) and length of response.
Reviews:
A total of 83 patients with pRCC were enrolled on the study, including 42 in the HLRCC cohort and 41 in the sporadic cohort. Most patients had intermediate IMDC danger (53/83, 64 percent) and 27 (33 percent) had at least one previous therapy. In all patients, the ORR was 51 percent (42/83; 95 percent CI, 40-61), in the HLRCC cohort, 64 percent (27/42; 95 percent CI, 49-77), and in the sporadic cohort, 37 percent (15/41; 95 percent CI, 24-52). The median PFS was 14.2 months (95 % CI, 11.4 "“ 18.6) for all patients, 21.1 months (95 % CI, 15.6 "“ 26.6) for the HLRCC cohort, and 8.7 months (95 % CI, 6.4 "“ 12.6) for the sporadic cohort. Most Treatment-related adverse events (TRAEs) were grade 1 or 2 with the most common being acneiform rash (92%), diarrhea (77%), proteinuria (71%), and dry skin (61%). Grade 3 TRAEs occurred in 47 percent of patients, including hypertension (34 percent) and proteinuria (13 percent), with bevacizumab-related grade 5 GI bleeding in one patient (1.2 percent).
Conclusions Therein:
The combination of bevacizumab and erlotinib is well tolerated in advanced pRCC, especially in patients with FH deficient tumors, and is associated with encouraging activity. This is HLRCC’s first and largest prospective review, and provides the basis for considering bevacizumab and erlotinib as a preferred alternative in a patient population without a generally established standard. Data on clinical trials: NCT01130519.