Bevacizumab (Avastin) plus erlotinib (Tarceva) demonstrated antitumor activity in patients with advanced papillary renal cell carcinoma, including those with hereditary leiomyomatosis and renal cell cancer (HLRCC)–associated and sporadic disease, according to data from the open-label, phase 2 trial (NCT01130519) published in the New England Journal of Medicine.

Findings demonstrated that evaluable patients (n = 43) achieved an overall response rate (ORR) of 72% (95% CI, 57%-83%) with HLRCC-associated papillary renal cell carcinoma, with a median progression-free survival (PFS) of 21.1 months (95% CI, 15.6-26.6) and a median overall survival (OS) of 44.6 months (95% CI, 32.7-not estimable). In patients with sporadic papillary renal cell carcinoma (n = 40), the confirmed ORR was 35% (95% CI, 22%-51%), with a median PFS of 8.9 months (95% CI, 5.5-18.3) and a median OS of 18.2 months (95% CI, 12.6–29.3).

“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,” lead study author Ramaprasad Srinivasan, MD, PhD, and colleagues noted in a discussion of these results. Srinivasan is a senior investigator in the Urologic Oncology Branch of the National Cancer Institute in Bethesda, Maryland.

What is the design of the study?

In this open-label, phase 2 study, investigators evaluated the efficacy of combination therapy with bevacizumab and erlotinib in patients with advanced papillary RCC, including those with HLRCC-associated disease and those with sporadic tumors. Patients received bevacizumab at a dose of 10 mg/kg administered intravenously every 2 weeks in combination with oral erlotinib at 150 mg once daily.2

The primary end point of the trial was ORR, as assessed by standard response criteria. Secondary end points included PFS and OS.

“Although a single-group study, this report describes a large and comprehensive evaluation of a systemic therapy approach in patients with advanced HLRCC-associated papillary RCC. The ability to conduct randomized, controlled studies in this patient population is limited by both the rarity of this entity and the lack of a suitable comparator,” Srinivasan and colleagues noted in their description of the study design.1

What were the baseline characteristics of the patients enrolled?

From May 2010 through May 2019, a total of 83 patients were enrolled, including 43 patients with HLRCC-associated papillary RCC and 40 patients with sporadic disease.

Among the HLRCC-associated cohort, there were 30 men and 13 women, with a median age of 43 years (range, 19-74). In the sporadic papillary RCC group, there were 26 men and 14 women, with a median age of 55.5 years (range, 24-74). All patients had metastatic disease (M1) at baseline and received at least 1 dose of bevacizumab or erlotinib, making them evaluable for both efficacy and safety analyses.

By International Metastatic RCC Database Consortium (IMDC) risk stratification, 26% (n = 11) of patients in the HLRCC-associated cohort were categorized as favorable risk, 56% (n = 24) as intermediate risk, and 19% (n = 8) as poor risk. In the sporadic cohort, 8% (n = 3) were categorized as favorable risk, 72% (n = 29) as intermediate risk, and 20% (n = 8) as poor risk.

Prior systemic therapy was reported in 21% (n = 9) of patients with HLRCC-associated papillary RCC, including 19% (n = 8) who had previously received at least one VEGFR TKI. The median number of prior systemic therapies in this cohort was 0 (range, 0-4). Among patients with sporadic papillary RCC, 45% (n = 18) had received previous systemic therapy, with 35% (n = 14) having received at least 1 prior VEGFR TKI. The median number of prior therapies in this group was 0 (range, 0-3).

What was the safety profile observed with the combination?

All patients experienced at least one treatment-related adverse effect (TRAE) of any grade, and 52% developed grade 3 or higher AEs. TRAEs were consistent with the known safety profile the respective agents used in this regimen. The most common all-grade AEs included acneiform rash (93%), diarrhea (89%), and proteinuria (78%).

Hypertension was the most common grade 3 or higher AE, occurring in 34% of patients, followed by proteinuria (17%), diarrhea (5%), and acneiform rash (5%). Dose modifications were largely limited to erlotinib, with reductions required in 29% of patients and permanent discontinuation in 1% due to grade 3 cutaneous toxicity. Bevacizumab discontinuation was uncommon but occurred in 4% of patients, including two cases of acute coronary syndrome and one case of bronchopulmonary hemorrhage. Bevacizumab dose reductions were not permitted per study protocol.

ReferencesSrinivasan R, Sandeep G, 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/nejmoa2200900A phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer. Clinicaltrials.gov. Updated February 21, 2025. Accessed October 2, 2025. https://clinicaltrials.gov/study/NCT01130519