5004 Background: HLRCC is a familial cancer syndrome associated with a type 2 papillary RCC (pRCC) variant. HLRCC is caused by germline mutations in the gene for the Krebs cycle enzyme fumarate hydratase (FH). FH inactivation results in VHL-independent upregulation of hypoxia inducible factor, a reliance on aerobic glycolysis, and activation of the NRF2 pathway, features also shared by some sporadic pRCC tumors. We hypothesized that the metabolic alterations underlying these tumors would be susceptible to targeted therapy with a combination of bevacizumab and erlotinib. Methods: Patients with advanced pRCC were eligible to enroll on this phase II study. To enrich for patients with FH deficiency, those with 1) HLRCC and 2) sporadic pRCC were enrolled into parallel, independent cohorts. All patients received bevacizumab 10 mg/kg IV every 2 weeks and erlotinib 150 mg orally daily. Patients who had received no more than two agents targeting the VEGFR pathway were included. Patients remained on treatment until unacceptable toxicity or progression. The primary endpoint was overall response rate (ORR); secondary endpoints were progression free survival (PFS) and duration of response. Results: A total of 83 patients with pRCC, including 42 in the HLRCC cohort and 41 in the sporadic cohort were enrolled on study. The majority of patients were IMDC intermediate risk (53/83, 64%) and 27 (33%) had at least one prior treatment. The ORR was 51% (42/83; 95% CI, 40 – 61) in all patients, 64% (27/42; 95% CI, 49 – 77) in the HLRCC cohort, and 37% (15/41; 95% CI, 24 – 52) in the sporadic cohort. The median PFS was 14.2 months (95% CI, 11.4 – 18.6) in all patients, 21.1 months (95% CI, 15.6 – 26.6) in the HLRCC cohort, and 8.7 months (95% CI, 6.4 – 12.6) in the sporadic cohort. The majority of 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% of patients, including hypertension (34%) and proteinuria (13%), with one patient (1.2%) with a grade 5 GI hemorrhage possibly related to bevacizumab. Conclusions: The combination of bevacizumab and erlotinib is well tolerated and is associated with encouraging activity in advanced pRCC, particularly in patients with FH deficient tumors. This is the first and largest prospective study in HLRCC and provides the basis for considering bevacizumab and erlotinib as a preferred option in a patient population that has no widely accepted standard. Clinical trial information: NCT01130519 .

Objective To evaluate the safety and efficacy of cabozantinib combined with docetaxel. Patients and Methods This was a phase 1/2 multicentre study in patients with metastatic castration‐resistant prostate cancer (mCRPC). Docetaxel (75 mg/m2 every 3 weeks with daily prednisone 10 mg) was combined with escalating doses of daily cabozantinib (20, 40 and 60 mg). Based on the results of the phase 1 study, the investigation was expanded into a randomized study of docetaxel with prednisone (hereafter 'docetaxel/prednisone') plus the maximum tolerated dose (MTD) of cabozantinib compared with docetaxel/prednisone alone. Results A total of 44 men with mCRPC were enrolled in this phase 1/2 trial. An MTD of 40 mg cabozantinib plus docetaxel/prednisone was determined. Dose‐limiting toxicities were neutropenic fever and palmar‐plantar erythrodysesthesia, and there was one death attributable to a thromboembolic event. In addition, grade 3 or 4 myelosuppression, hypophosphataemia and neuropathy were seen in three or more patients. In the phase 1 study, the median time to progression (TTP) and overall survival (OS) time were 13.6 and 16.3 months, respectively. In the phase 2 study, which was terminated early because of poor accrual, the median TTP and OS favoured the combination (n = 13) compared to docetaxel/prednisone alone (n = 12; 21.0 vs 6.6 months; P = 0.035 and 23.8 vs 15.6 months; P = 0.072, respectively). Conclusion Despite the limited number of patients in this study, preliminary data suggest that cabozantinib can be safely added to docetaxel/prednisone with possible enhanced efficacy.

No abstract