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 (RCC).

TPS4680 Background: There are currently no treatment options of proven efficacy for patients with advanced papillary RCC. The evaluation of families with inherited forms of RCC has allowed for the identification of genetic alterations associated with papillary RCC. HLRCC is one such familial condition with a propensity for the development of a clinically aggressive variant of papillary RCC characterized by unique histopathologic features. Germline mutations in the gene for the Krebs cycle enzyme fumarate hydratase (FH) are the genetic hallmark of HLRCC. Mutational inactivation of FH leads to von Hippel-Lindau-independent upregulation of hypoxia inducible factors (HIF) and their downstream transcriptional targets such as vascular endothelial growth factor (VEGF) and transforming growth factor-alpha (TGF-α) / epidermal growth factor receptor (EGFR). Upregulation of the HIF pathway may also be important in sporadic papillary RCC, although the prevalence of FH inactivation in these patients is unknown. We propose to evaluate the activity of dual VEGF/EGFR blockade with bevacizumab/erlotinib in patients with HLRCC-associated RCC and sporadic papillary RCC. Methods: This is a single arm phase II study based on an open label Simon two-stage minmax design with a maximum accrual of 20 patients in each of two cohorts: Cohort 1- patients with HLRCC; Cohort 2- patients with sporadic papillary RCC. The primary endpoint is RECIST overall response rate, assessed independently in each cohort. Patients will receive bevacizumab (10mg/Kg IV every 2 weeks) and erlotinib (150mg PO daily). Dose reductions and drug interruptions for toxicity are allowed. Patients will be evaluated for response every 8 weeks. Major eligibility criteria include: advanced RCC associated with HLRCC or sporadic papillary RCC; age >18 years; ECOG 0-2; measurable disease by RECIST; no brain metastases; no more than 2 prior regimens containing a VEGF inhibitor; and no prior therapy with bevacizumab. The prespecified activity goal for the first stage of accrual has been met for both cohorts. NCT01130519.

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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.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.5004 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 5004-5004 ◽

Cited By ~ 5

Author(s):

Ramaprasad Srinivasan ◽

Sandeep Gurram ◽

Munjid Al Harthy ◽

Eric A. Singer ◽

Abhinav Sidana ◽

...

Keyword(s):

Phase Ii ◽

Renal Cell Cancer ◽

Renal Cell ◽

Phase Ii Study ◽

Aerobic Glycolysis ◽

Familial Cancer ◽

Cell Cancer ◽

Fumarate Hydratase ◽

Cancer Syndrome ◽

Cycle Enzyme

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 .

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