A Phase II, Single-arm Trial of Sunitinib and Erlotinib in Advanced Renal Cell Carcinoma



      Overexpression of the epidermal growth factor receptor (EGFR) and its ligands occur frequently in renal cell carcinoma (RCC). Combined vascular endothelial growth factor receptor (VEGF-R) and EGFR inhibition may overcome resistance to VEGF-R inhibitor monotherapy. We performed a dose-escalation phase II study of sunitinib plus erlotinib in advanced renal cell carcinoma.

      Patients and Methods

      Patients with metastatic clear cell or papillary RCC were eligible. Prior therapy was allowed except sunitinib or erlotinib. Three dose levels of erlotinib (50, 100, 150 mg daily) were evaluated in combination with sunitinib 50 mg. Thirty-seven patients were treated at maximum tolerated dose to determine efficacy. The primary endpoint was 8-month progression-free survival (PFS) rate. The trial was powered to assess for a difference between a median PFS of less than 50% with a targeted 70% PFS for the combination.


      The 8-month PFS rate was 40% (95% CI: 23-56). Median PFS was 5.8 months (95% CI: 4.1-9.7) and median overall survival (OS) was 26.3 months (95% CI: 16.1-34.0). The objective response rate was 22% and an additional 59% of patients had stable disease for at least 6 weeks. The most common adverse events for all grades were diarrhea, rash, fatigue, and dysgeusia. Dose reduction in 1 or both of the drugs was undertaken in 17 (46%) patients, while 5 (14%) discontinued study therapy due to toxicity.


      While sunitinib and erlotinib are combinable,the 8-month PFS rate did not suggest efficacy improvement over sunitinib monotherapy (NCT00425386).


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Genitourinary Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kaelin Jr., WG
        The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma.
        Clin Cancer Res. 2007; 13 (2 Pt): 680s-684s
        • Na X
        • Wu G
        • Ryan CK
        • Schoen SR
        • di'Santagnese PA
        • Messing EM.
        Overproduction of vascular endothelial growth factor related to von Hippel-Lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 alpha expression in renal cell carcinomas.
        J Urol. 2003; 170 (Pt 1): 588-592
        • Motzer RJ
        • Tannir NM
        • McDermott DF
        • et al.
        Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma.
        N Engl J Med. 2018; 378: 1277-1290
        • Rini BI
        • Plimack ER
        • Stus V
        • et al.
        Pembrolizumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma.
        N Engl J Med. 2019; 380: 1116-1127
        • Moch H
        • Sauter G
        • Buchholz N
        • et al.
        Epidermal growth factor receptor expression is associated with rapid tumor cell proliferation in renal cell carcinoma.
        Hum Pathol. 1997; 28: 1255-1259
        • Smith K
        • Gunaratnam L
        • Morley M
        • Franovic A
        • Mekhail K
        • Lee S.
        Silencing of epidermal growth factor receptor suppresses hypoxia-inducible factor-2-driven VHL-/- renal cancer.
        Cancer Res. 2005; 65: 5221-5230
        • Hainsworth JD
        • Sosman JA
        • Spigel DR
        • Edwards DL
        • Baughman C
        • Greco A.
        Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib.
        J Clin Oncol. 2005; 23: 7889-7896
        • Bukowski RM
        • Kabbinavar FF
        • Figlin RA
        • et al.
        Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer.
        J Clin Oncol. 2007; 25: 4536-4541
        • Eisenhauer EA
        • Therasse P
        • Bogaerts J
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009; 45: 228-247
        • Motzer RJ
        • Michaelson MD
        • Redman BG
        • et al.
        Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma.
        J Clin Oncol. 2006; 24: 16-24
        • Motzer RJ
        • Mazumdar M
        • Bacik J
        • Berg W
        • Amsterdam A
        • Ferrara J.
        Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma.
        J Clin Oncol. Aug 1999; 17: 2530-2540
        • Shepherd FA
        • Rodrigues Pereira J
        • Ciuleanu T
        • et al.
        Erlotinib in previously treated non-small-cell lung cancer.
        N Engl J Med. 2005; 353: 123-132
        • Motzer RJ
        • Hutson TE
        • Tomczak P
        • et al.
        Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
        N Engl J Med. 2007; 356: 115-124
        • Motzer RJ
        • Hutson TE
        • Cella D
        • et al.
        Pazopanib versus sunitinib in metastatic renal-cell carcinoma.
        N Engl J Med. 2013; 369: 722-731
        • Gordon MS
        • Hussey M
        • Nagle RB
        • et al.
        Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317.
        J Clin Oncol. 2009; 27: 5788-5793
        • Choi Y
        • Keam B
        • Kim M
        • et al.
        Bevacizumab plus Erlotinib Combination therapy for advanced hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma: a multicenter retrospective analysis in Korean patients.
        Cancer Res Treat. 2019; 51: 1549-1556
        • Ramaprasad Srinivasan SG
        • Harthy Munjid Al
        • Singer Eric A.
        • et al.
        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.
        J Clin Oncol. 2020; 38 (15_suppl Available from:) (Accessed at: May 3, 2021): 5004
      1. Available at (Accessed on 3/5/2021).

        • Srinivasan R
        • Su D
        • Stamatakis L
        • et al.
        5 Mechanism based targeted therapy for hereditary leiomyomatosis and renal cell cancer (HLRCC) and sporadic papillary renal cell carcinoma: interim results from a phase 2 study of bevacizumab and erlotinib.
        Eur J Cancer. 2014; 50: 8
        • Rowinsky EK
        • Schwartz GH
        • Gollob JA
        • et al.
        Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer.
        J Clin Oncol. 2004; 22: 3003-3015
        • Drucker B
        • Bacik J
        • Ginsberg M
        • et al.
        Phase II trial of ZD1839 (IRESSA) in patients with advanced renal cell carcinoma.
        Invest New Drugs. 2003; 21: 341-345
        • Dawson NA
        • Guo C
        • Zak R
        • et al.
        A phase II trial of gefitinib (Iressa, ZD1839) in stage IV and recurrent renal cell carcinoma.
        Clin Cancer Res. 2004; 10: 7812-7819
        • Jermann M
        • Stahel RA
        • Salzberg M
        • et al.
        A phase II, open-label study of gefitinib (IRESSA) in patients with locally advanced, metastatic, or relapsed renal-cell carcinoma.
        Cancer Chemother Pharmacol. 2006; 57: 533-539
        • Ravaud A
        • Hawkins R
        • Gardner JP
        • et al.
        Lapatinib versus hormone therapy in patients with advanced renal cell carcinoma: a randomized phase III clinical trial.
        J Clin Oncol. 2008; 26: 2285-2291
        • Zou B
        • Lee VHF
        • Yan H.
        Prediction of sensitivity to gefitinib/erlotinib for EGFR mutations in NSCLC based on structural interaction fingerprints and multilinear principal component analysis.
        BMC Bioinformatics. 2018; 19: 88
        • Sakaeda T
        • Okamura N
        • Gotoh A
        • et al.
        EGFR mRNA is upregulated, but somatic mutations of the gene are hardly found in renal cell carcinoma in Japanese patients.
        Pharm Res. 2005; 22: 1757-1761
        • Grépin R
        • Guyot M
        • Dumond A
        • et al.
        The combination of bevacizumab/Avastin and erlotinib/Tarceva is relevant for the treatment of metastatic renal cell carcinoma: the role of a synonymous mutation of the EGFR receptor.
        Theranostics. 2020; 10: 1107-1121
        • Wheler JJ
        • Falchook GS
        • Tsimberidou AM
        • et al.
        Aberrations in the epidermal growth factor receptor gene in 958 patients with diverse advanced tumors: implications for therapy.
        Ann Oncol. 2013; 24: 838-842
        • Do SI
        • Jung WW
        • Kim HS
        • Park YK.
        The expression of epidermal growth factor receptor and its downstream signaling molecules in osteosarcoma.
        Int J Oncol. 2009; 34: 797-803
        • Tan DSW
        • Chong FT
        • Leong HS
        • et al.
        Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma.
        Nat Med. 2017; 23: 1167-1175