Originally published as JCO Early Release 10.1200/JCO.2007.11.5154 on September 17 2007

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Randomized Phase II Study of Erlotinib Combined With Bevacizumab Compared With Bevacizumab Alone in Metastatic Renal Cell Cancer

Ronald M. Bukowski, Fairooz F. Kabbinavar, Robert A. Figlin, Keith Flaherty, Sandy Srinivas, Ulka Vaishampayan, Harry A. Drabkin, Janice Dutcher, Sarah Ryba, Qi Xia, Frank A. Scappaticci, David McDermott

From the Cleveland Clinic Foundation, Cleveland, OH; University of California at Los Angeles School of Medicine, Los Angeles; Stanford University Medical Center, Stanford; Genentech Inc, South San Francisco, CA; University of Pennsylvania, Philadelphia, PA; Wayne State University, Detroit, MI; University of Colorado Health Science Center, Aurora, CO; Our Lady of Mercy Medical Center, Bronx, NY; and Beth Israel Deaconess Medical Center, Boston, MA

Address reprint requests to Ronald M. Bukowski, MD, Cleveland Clinic Foundation, 9500 Euclid Ave, R35, Cleveland, OH 44195; e-mail: bukowsr{at}ccf.org

	ABSTRACT

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Purpose Bevacizumab (Bev) has clinical activity in advanced renal cell carcinoma (RCC), and, when combined with erlotinib (Erl), has shown encouraging objective response rate (ORR) and progression-free survival (PFS). We performed a phase II, randomized, double-blind, multicenter, placebo-controlled trial to assess whether Erl provides additional clinical benefit with regard to PFS and ORR when combined with Bev in first-line treatment of metastatic RCC.

Patients and Methods One hundred four patients received intravenous Bev (10 mg/kg) every 2 weeks in combination with oral Erl (150 mg) or placebo daily. Patients were treated until progression or toxicity.

Results A landmark analysis was performed 9 months after enrollment was completed (median follow-up, 9.8 months). Sixty-five patients had discontinued therapy; time to study discontinuation did not differ between the two treatment groups. The median PFS was 9.9 months (Bev + Erl [B+E]) versus 8.5 months (Bev; hazard ratio = 0.86; 95% CI, 0.5 to 1.49; P = .58). ORR (complete plus partial) was 14% (B+E) versus 13% (Bev). One complete response occurred in the B+E group. Median survival was 20 months for B+E but not reached for Bev. The most common grade 3/4 adverse events (> 5% of patients) were hypertension, rash, proteinuria, diarrhea, and hemorrhage. One treatment-related death occurred on study (GI perforation, B+E group).

Conclusion The addition of Erl to Bev was well tolerated, but did not provide additional clinical benefit compared with Bev alone. Bev has encouraging clinical activity for previously untreated metastatic RCC patients.

	INTRODUCTION

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The landscape for treatment of metastatic renal cell cancer (mRCC) has changed with the advent of new targeted therapies, and agents that target the vascular endothelial growth factor (VEGF) pathway are now playing a significant role in the treatment of mRCC. The anti-VEGF antibody bevacizumab (Bev) has shown efficacy in phase II trials in mRCC in both the first- and second-line settings. A randomized, three-arm, placebo-controlled, phase II trial of Bev in cytokine-refractory patients with mRCC evaluated the efficacy and safety of two dose levels (3 and 10 mg/kg every 2 weeks).¹ The trial was stopped early after an interim analysis showed that the 10 mg/kg arm improved time to disease progression compared with control (4.8 v 2.5 months; P < .001). This higher dose was well tolerated, with hypertension (8%) and proteinuria (3%) the most common grade 3 toxicities.

The epidermal growth factor receptor (EGFR) pathway may also be important in RCC, and it is known that one of the ligands for this receptor, transforming growth factor (TGF)-, is often elevated in this disease.² It has also been suggested that inhibition of the EGFR pathway could lead to downregulation of VEGF expression.^3,4 On the basis of preclinical data (data on file, Genentech Inc, South San Francisco, CA), there appeared to be additive activity when erlotinib (Erl) was added to Bev with regard to inhibition of tumor growth using human RCC tumor xenografts. Additionally, because there was clinical activity of Bev in the second-line setting of mRCC, a single-arm phase II trial of Bev in combination with Erl (B+E) in the first- and second-line settings of mRCC was conducted.² A median progression-free survival (PFS) of 11 months was achieved, with median overall survival not reached. The overall survival rate at 18 months was 60%. The treatment was well tolerated.

Encouraging activity from the latter trial led to the present phase II study, which compared Bev alone B+E in the first-line treatment of patients with mRCC.⁵

	PATIENTS AND METHODS

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This was a randomized, double-blind, placebo-controlled trial conducted at 21 sites in the United States. Patients were enrolled from March 2004 through October 2004. Bev and Erl were provided by Genentech Inc and OSI Pharmaceuticals Inc (Melville, NY), respectively.

Eligibility
Eligible patients were required to have mRCC with predominant (> 50%) clear-cell histology, to have undergone nephrectomy, and to have measurable disease. Other requirements included no prior systemic therapy either in the adjuvant setting or for metastatic disease, no previous use of angiogenesis or EGFR inhibitors, not currently receiving dialysis, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1, serum calcium no higher than 10 mg/dL, lactate dehydrogenase no more than 1.5x the upper limit of normal per normal institutional standards, hemoglobin of at least 9 g/dL, a 24-hour urine collection with no more than 1 g of protein, no myocardial infarction or stroke within the last 6 months, no class II or higher New York Heart Association heart failure, no unstable angina or symptomatic arrhythmia, no brain or other CNS metastases, no GI perforation, and no evidence of bleeding diathesis or coagulopathy. Patients were also excluded if they underwent a major surgical procedure within 28 days of initiating study treatment. However, radiotherapy, with the exception of single-fraction radiotherapy for pain control, was allowed if not administered within 28 days of starting study treatment.

Treatment and Dose Modification
Patients were randomly assigned 1:1 using an interactive voice response service. All patients received Bev 10 mg/kg intravenously infused over 90 minutes every 2 weeks, and either oral Erl 150 mg or placebo daily. If tolerated, Bev infusion durations were reduced from 90 to 30 minutes. Patients were to be treated until progression or toxicity, or for a maximum of 104 weeks. No dose reductions were permissible for Bev; however, the Erl dose could be reduced to 100 mg daily (initially) or further to 50 mg daily if the patient developed a grade 2 rash or diarrhea. Bev was discontinued for any of the following toxicities: a second occurrence of grade 3 or 4 hemorrhage; grade 3 or 4 hypertension not controlled with medication; nephrotic syndrome; grade 4 venous thromboembolism; any grade arterial thromboembolism, GI perforation; and serious wound dehiscence requiring medical or surgical intervention.

Assessment of Efficacy and Safety
Patients were evaluated for response every 8 weeks after initiation of therapy using the Response Evaluation Criteria in Solid Tumors (RECIST).⁶ Complete or partial responses required confirmatory assessments per RECIST. Reports of disease-related symptoms were collected using the Renal Cell Cancer Symptom Index (RCCSI) instrument. Adverse events were reported using National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3. Only those that were grade 3 or 4, serious, and/or led to treatment interruption or discontinuation were reported. Patients with ongoing proteinuria (1 g protein in a 24-hour urine collection) or hypertension at treatment termination were followed up every 4 months until resolution or a maximum of 1 year.

Statistical Considerations
A landmark analysis was performed 9 months after enrollment of the last patient. The primary end points of the study were PFS and objective response rate (ORR). Median PFS and hazard ratio were estimated using the Kaplan-Meier method and stratified Cox-regression model, respectively. The stratification factors were ECOG PS (0 v 1) and time from nephrectomy to metastatic disease ( 12 v > 12 months). An estimate of ORR with 95% CI was calculated using the Fleiss method.⁷ Duration of overall survival was analyzed using methods similar to those for PFS. Safety was assessed through summaries of the incidences of adverse events. One patient without a postbaseline tumor assessment was excluded from the efficacy analysis. All statistical analyses were performed with SAS version 9.1 (SAS Institute, Cary, NC).

	RESULTS

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Patient Characteristics
One hundred four patients were enrolled onto this study (53 Bev, 51 B+E). At the time of unblinding and study analysis, 65 patients had discontinued therapy, with a median follow-up time of 9.8 months. There was no significant difference between the two treatment groups in the time to study discontinuation (log-rank P = .4550). Pretreatment characteristics were generally well balanced between arms except age: The median age was 66 years for the B+E arm and 61 for the Bev arm. There were also more males in the Bev arm (75%) than in the B+E arm (65%), but this difference was not significant. This study also selected for patients with low- and intermediate-risk prognostic categories (defined by Memorial Sloan-Kettering Cancer Center [MSKCC; New York, NY] criteria) as opposed to patients with high risk. In this regard, the arms were well balanced for patients in each of these risk categories (Table 1).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Progression-free survival (PFS). Progression occurred in 29 bevacizumab plus placebo (B) patients and 26 bevacizumab plus elotinib (B+E) patients. Median PFS was 8.5 months in B patients and 9.9 months in B+E patients (stratified hazard ratio = 0.86; 95% CI, 0.50 to 1.49; log-rank P = .58). Patients who had not progressed or who died at the data cutoff date were excluded.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Percentage of change in sum of the longest dimensions (SLD) of tumors for individual patients. Reflects patients who have had at least one postbaseline tumor assessment. The P value for testing no difference between the two treatment groups using the Mann-Whitney-Wilcoxon test is .4667. B, bevacizumab plus placebo; B+E = bevacizumab plus erlotinib.

Overall survival data are not mature (Fig 3). Seventeen patients (32%) have died in the Bev arm, compared with 23 (45%) in the B+E arm. At a landmark interval of 12 months from random assignment, 83% of patients were alive in the Bev arm versus 70% in the B+E arm. Analysis of second-line therapies as a possible explanation for the apparent separation of the curves revealed that 32% of patients had recorded receiving a second-line therapy in the Bev arm versus 14% in the B+E arm. It is unknown whether these therapies included sorafenib or sunitinib.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Overall survival. Intent-to-treat analysis with updated information (four patients discontinued erlotinib as a result of unblinding). Seventeen bevacizumab plus placebo (B) patients and 23 bevacizumab plus erlotinib (B+E) patients died. Median survival was not reached in the B group and was 20 months in the B+E group (stratified hazard ratio = 1.57; 95% CI, 0.84 to 2.94; log-rank P = .16).

Safety
Selected adverse events are summarized in Table 3. Patients in the B+E and Bev arms received a similar number of Bev doses (median = 17 and 16, respectively). Slightly more patients in the Bev arm (45.3%) than in the B+E arm (37.3%) did not miss any dose during the treatment period.

The most common grade 3/4 adverse events (> 5% of patients) were hypertension, rash, diarrhea, proteinuria, and hemorrhage. Adverse events known to be associated with Erl, rash and diarrhea, were observed only in the B+E arm (16% and 7.8% of patients, respectively). Rates of hypertension and proteinuria, which are known toxicities associated with Bev, were similar for the two treatment arms.

	DISCUSSION

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The activity of Bev as a monotherapy was first revealed by Yang et al¹ in a placebo-controlled trial in cytokine refractory mRCC. Preclinicaldata as well as clinical data from a single-arm phase II B+E study also supported further clinical exploration of this combination.²

The clinical heterogeneity of RCC renders historical comparisons of phase II results problematic. We designed this trial to more rigorously evaluate the potential benefit of adding Erl to Bev in patients with first-line mRCC. In other clinical scenarios, data with single-agent EGFR inhibitors, including gefitinib,⁸ ABX-EGF,⁹ cetuximab,¹⁰ lapatinib,¹¹ and Erl¹² have failed to demonstrate clinical activity in this disease, suggesting that inhibition of EGFR alone is insufficient to affect the course of disease in most patients.

Although this study did not demonstrate the clinical benefit of combining Erl with Bev compared with Bev alone, it did demonstrate potential clinical activity of Bev with regard to PFS and 1-year overall survival. The Bev monotherapy arm (n = 53) had a median PFS of 8.5 months and 1-year survival of 83%. This compares favorably with historical data on PFS achieved with interferon (INF)- therapy.¹³ On the basis of MSKCC criteria, patients treated with INF- and who are considered low risk are expected to have a median PFS of 8.3 months and those with intermediate risk a PFS of 5.1 months. In the Bev monotherapy arm of this study, these values were 13.1 and 7.3 months for these subgroups, respectively. Also using MSKCC criteria, patients with low risk are expected to have a 1-year survival of 83% and intermediate risk of 58%. The Bev monotherapy subgroups showed these values to be 95% and 77%, respectively. These data show encouraging clinical activity of Bev in mRCC based on this small experience compared with historical use of INF-.

At the time of analysis, the data were not mature for overall survival (only 40 deaths in 104 enrolled patients). Only the median for the B+E arm was reached (20 months), but there was no statistically significant difference between the B+E and Bev arms in overall survival. The apparent separation of the survival curves may result from the small number of events or, alternatively, an imbalance of second-line therapies favoring the Bev arm. Assessing overall survival in mRCC may become increasingly difficult, with multiple agents approved in this setting. Analysis of clinical benefit in patients receiving all these active agents as compared with a subset of them, may be a better way of determining clinical benefit. As such, the overall potential benefit to patients who receive all active agents at some time during their treatment may be more clinically meaningful than the benefit of a particular agent in first or second line.¹⁴

Analysis of time to symptom progression also did not show any significant benefit of adding Erl to Bev compared with Bev alone. The tumor response patterns in the two treatment arms were similar, as illustrated by the figures showing individual patient data for maximum tumor shrinkage and tumor shrinkage over time.

The safety profile was very similar to what was expected for each agent alone. No new safety signals were noted from the addition of Erl to Bev in patients with mRCC relative to events identified for each agent alone. Slightly more patients in the B+E arm had grade 3 or 4 adverse events, but this may be accounted for by the toxicities of rash and diarrhea that are associated with Erl treatment. These Erl-associated toxicities were observed only in the combination arm, and are consistent with those previously reported.² The B+E arm had one treatment-related death. This death was due to GI perforation, which has been described in settings outside of metastatic colorectal cancer (data on file, Genentech Inc).

The rates of grade 3 or 4 hypertension (25% to 31%) were similar to those previously reported in second-line Bev treatment (21%).¹ In the pivotal metastatic colorectal cancer trial, by Hurwitz et al in 2004,¹⁵ the hypertension rate was approximately 8% to 13% for Bev in combination with chemotherapy (irinotecan/fluorouracil/leucovorin or fluorouracil/leucovorin). The differences may be related to reporting patterns among these various studies, as well as other disease characteristics. For example, the higher rates of hypertension seen in this study could be related to a compromised renovascular system caused by the presence of only one kidney.

Other than hypertension, the limited toxicity of Bev may facilitate combination with other targeted therapies, such as sunitinib. Unlike tyrosine kinase inhibitors such as sunitinib, Bev alone showed no grade 3/4 toxicities of fatigue, hand-foot syndrome, diarrhea, stomatitis, neutropenia, or thrombocytopenia.

Bev has demonstrated clinical activity in mRCC in this and other phase II studies.^1,2,16 phase III clinical trials comparing INF- alone with INF- plus Bev (Roche B017705 and Cancer and Leukemia Group B [CALGB] 90206) in first-line mRCC are fully recruited and these results may provide definitive evidence of clinical benefit. Ongoing exploratory clinical studies in mRCC are evaluating combinations of Bev with other targeted agents including VEGF receptor tyrosine kinases and mTOR (mammalian target of rapamycin) inhibitors. Despite the lack of additional clinical benefit of combining Erl with Bev compared with Bev alone in mRCC, rational combinations as well as sequencing of active targeted agents represent important opportunities for continued improvement of the clinical outcomes of this disease.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Sarah Ryba, Genentech; Qi Xia, Genentech; Frank A. Scappaticci, Genentech Leadership: N/A Consultant: Ronald M. Bukowski, Genentech, Pfizer, Bayer/Onyx, Wyeth, Novartis; Keith T. Flaherty, Genentech; Janice P. Dutcher, Genentech, Wyeth, Bayer/Onyx, Roche; David F. McDermott, Genentech, Bayer/Onyx Stock: Sarah Ryba, Genentech; Frank A. Scappaticci, Genentech Honoraria: Ronald M. Bukowski, Pfizer, Onyx, Bayer; Ulka Vaishampayan, Genentech; Janice P. Dutcher, Bayer, Chiron/Novartis, Pfizer; David F. McDermott, Novartis Research Funds: Ronald M. Bukowski, Bayer/Onyx, Genentech, Wyeth, Pfizer, Amgen; Robert A. Figlin, Genentech; Janice P. Dutcher, Bayer, Pfizer, Wyeth, Chiron/Novartis, Idera, Genentech; David F. McDermott, Genentech, Pfizer, Bayer/Onyx Testimony: N/A Other: Janice P. Dutcher, Bayer, Roche

	AUTHOR CONTRIBUTIONS

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Conception and design: Ronald M. Bukowski, Fairooz F. Kabbinavar, Robert A. Figlin, Sandy Srinivas, Frank A. Scappaticci

Provision of study materials or patients: Ronald M. Bukowski, Fairooz F. Kabbinavar, Robert A. Figlin, Keith T. Flaherty, Sandy Srinivas, Ulka Vaishampayan, Harry Drabkin, Janice P. Dutcher, David F. McDermott

Collection and assembly of data: Ronald M. Bukowski, Fairooz F. Kabbinavar, Robert A. Figlin, Keith T. Flaherty, Sandy Srinivas, Ulka Vaishampayan, Janice P. Dutcher, Sarah Ryba, Frank A. Scappaticci

Data analysis and interpretation: Ronald M. Bukowski, Robert A. Figlin, Keith T. Flaherty, Sandy Srinivas, Janice P. Dutcher, Sarah Ryba, Qi Xia, Frank A. Scappaticci

Manuscript writing: Ronald M. Bukowski, Robert A. Figlin, Keith T. Flaherty, Sandy Srinivas, Ulka Vaishampayan, Harry Drabkin, Frank A. Scappaticci, David F. McDermott

Final approval of manuscript: Ronald M. Bukowski, Fairooz F. Kabbinavar, Robert A. Figlin, Keith T. Flaherty, Sandy Srinivas, Ulka Vaishampayan, Harry Drabkin, Janice P. Dutcher, Sarah Ryba, Qi Xia, Frank A. Scappaticci, David F. McDermott

	Appendix

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View larger version (25K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Tumor shrinkage patterns (percent change in sum of the longest dimensions [SLD] of tumor) over time for individual patients. One patient was lost to follow-up before postbaseline tumor assessment. B, bevacizumab plus placebo; B + E, bevacizumab plus erlotinib.

	ACKNOWLEDGMENTS

 
We thank the study patients, the investigators, subinvestigators, nurses, and patient coordinators. At Genentech, we thank a multitude of individuals from operations, field monitoring, data management, drug safety, regulatory, corporate compliance, and clinical science. Writing assistance was provided by Genentech Inc.

	NOTES

 
published online ahead of print at www.jco.org on September 17, 2007.

Supported by Genentech Inc.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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4. Riedel F, Gotte K, Li M, et al: EGFR antisense treatment of human HNSCC cell lines down-regulates VEGF expression and endothelial cell migration. Int J Oncol 21:11-16, 2002[Medline]

5. Bukowski RM, Kabbinavar F, Figlin RA, et al: Bevacizumab with or without erlotinib in metastatic renal cell carcinoma (RCC). J Clin Oncol 24:222s, 2006 (suppl; abstr 4523)

6. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

7. Fleiss J: Statistical Methods for Rates and Proportions (ed 2). New York, NY, John Wiley & Sons, 1981

8. 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 57:533-539, 2006[CrossRef][Medline]

9. 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 22:3003-3015, 2004[Abstract/Free Full Text]

10. Motzer RJ, Amato R, Todd M, et al: Phase II trial of antiepidermal growth factor receptor antibody C225 in patients with advanced renal cell carcinoma. Invest New Drugs 21:99-101, 2003[CrossRef][Medline]

11. Ravaud A, Gardner J, Hawkins R, et al: Efficacy of lapatinib in patients with high tumor EGFR expression: Results of a phase III trial in advanced renal cell carcinoma (RCC). J Clin Oncol 24:217s, 2006 (suppl; abstr 4502)[CrossRef]

12. Beeram M, Rowinsky EK, Weiss GR, et al: Durable disease stabilization and antitumor activity with OSI-774 in renal cell carcinoma: A phase II, pharmacokinetic (PK) and biological correlative study with FDG-PET imaging. J Clin Oncol 22:207s, 2004 (suppl; abstr 3050)

13. Motzer RJ, Bacik J, Murphy BA, et al: Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289-296, 2002[Abstract/Free Full Text]

14. Grothey A, Sargent D, Goldberg RM, et al: Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209-1214, 2004[Abstract/Free Full Text]

15. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004[Abstract/Free Full Text]

16. Thompson DS, Greco FA, Spigel DR, et al: Bevacizumab, erlotinib, and imatinib in the treatment of patients with advanced renal cell carcinoma: Update of a multicenter phase II trial. J Clin Oncol 24:240s, 2006 (suppl; abstr 4594)

Submitted March 2, 2007; accepted June 13, 2007.

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