The combination of bevacizumab (Avastin) plus erlotinib (Tarceva) elicited encouraging anti-tumor activity in patients with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated papillary renal-cell carcinoma, according to findings from a phase 2 trial (NCT01130519)published in the New England Journal of Medicine.1
A phase 2 trial is ongoing to assess the efficacy of bevacizumab and erlotinib in combination with atezolizumab.
The combination also yielded durable responses in a subset of patients with sporadic papillary renal cell carcinoma.
“Few effective options exist for other variants of renal-cell carcinoma, which is exemplified by HLRCC-associated papillary renal-cell carcinoma,” the authors explained. “This variant is typically associated with an aggressive clinical course; most patients die from progressive disease, with a median overall survival of 16 to 21 months in most retrospective series.”
To address this unmet need, the trial enrolled 43 patients (30 male, 13 female) with HLRCC-associated papillary renal cell carcinoma and 40 patients (26 male, 14 female) with sporadic papillary renal cell carcinoma. Patients in the study received bevacizumab 10 mg per kilogram of body weight every 2 weeks plus erlotinib 150 mg once daily.
The primary end point was overall survival (OS), with progression-free survival (PFS) as a key secondary end point. Median follow-up was 71.9 months in patients with HLRCC-associated papillary renal cell carcinoma and 63.6 months in patients with sporadic papillary renal cell carcinoma.
Among patients with HLRCC-associated papillary renal cell carcinoma, 72% (n = 31; 95% CI, 57 to 83) achieved a confirmed response, including 2 patients (5%) with a complete response. The median time to response was 1.8 months (range, 1.7 to 18.3). Responses were observed across all IMDC risk scores, with a rate of 64% in patients with favorable risk disease, 75% among patients with intermediate risk disease, and 75% among patients with poor risk disease.
Notably, the median OS was 44.6 months (95% CI, 32.7 to NE), and the median PFS was 21.1 months (95% CI, 15.6 to 26.6). On multivariable analysis, previous treatment was shown to be associated with worse OS (HR, 5.2; 95% CI, 2.1 to 13.1).
Among patients with sporadic papillary renal cell carcinoma, 35% (n = 14; 95% CI, 22 to 51) achieved a confirmed response to treatment. The median time to response was 1.8 months (range, 1.7 to 7.3). Responses were observed across all IMDC risk scores, with a rate of 67% in patients with favorable risk disease, 31% among patients with intermediate risk disease, and 38% among patients with poor risk disease.
In these patients, the median OS was 18.2 months (95% CI, 12.6 to 29.3), and the median PFS was 8.9 months (95% CI, 5.5 to 18.3). The authors noted, “In a post hoc subgroup analysis, previous radical nephrectomy, previous use of a VEGF TKI, and IMDC risk category were not correlated with overall survival.”
Safety data in the study were consistent with the known profile for this combination. The most common treatment-related adverse events (TRAEs) were acneiform rash (93%), diarrhea (89%), and proteinuria (78%). The most common TRAEs of grade 3 or higher were hypertension (34%) and proteinuria (17%).
Based on these data, the authors reported, “This study showed that the combination of bevacizumab and erlotinib was highly active in advanced HLRCC-associated papillary renal-cell carcinoma and was approximately half as effective in sporadic papillary renal-cell carcinoma.”
They suggest that further research is warranted to elucidate the mechanisms fostering resistance to this regimen. Additionally, a phase 2 trial (NCT04981509) is ongoing to assess the efficacy of bevacizumab and erlotinib in combination with atezolizumab (Tecentriq).
Overall, the authors hope to build on the findings from the current analysis.
“The median survival now is almost 4 years with this combination treatment,” concluded W. Marston Linehan, MD, in a news release on the findings.2 “We’re thrilled about that. This has now become a standard treatment of this disorder worldwide.”
REFERENCES
1. Srinivasan R, Gurram S, Singer EA, et al. Bevacizumab and erlotinib in hereditary and sporadic papillary kidney cancer. N Engl J Med. 2025;392(23):2346-2356. doi:10.1056/NEJMoa2200900
2. Combining bevacizumab with erlotinib shrinks tumors in patients with rare and aggressive kidney cancer. News release. National Cancer Institute Center for Cancer Research. July 11, 2025. Accessed September 5, 2025. https://ccr.cancer.gov/news/article/combining-bevacizumab-with-erlotinib-shrinks-tumors-in-patients-with-rare-and-aggressive-kidney-cancer