Bevacizumab (B) plus Everolimus (E) in Refractory Metastatic Colorectal Cancer

1. Bevacizumab (B) plus Everolimus (E) in Refractory Metastatic Colorectal Cancer K. E. Bullock1, H. I. Hurwitz1, H. E. Uronis1, M. A. Morse1, G. C. Blobe1, S. D. Hsu1, S.Y. Zafar1, L. A. Howard1, I. P. Altomare1, J.C. Bendell2 1Duke University Medical Center, Durham, NC, USA; 2Sarah Cannon Research Institute, Nashville, TN, USA • UPDATED ABSTRACT • Background: For patients (pts) with metastatic colorectal cancer (mCRC), no standard therapy exists after progression on 5-FU, oxaliplatin, irinotecan, bevacizumab, and cetuximab/panitumumab. Preclinical data demonstrate combined VEGF and mTOR inhibition has greater anti-angiogenic and anti-tumor activity than either monotherapy. B inhibits VEGF; E inhibits mTOR. Phase I data in patients demonstrated B + E was safe and activity was seen in several pts with refractory mCRC. • Methods: 49 pts with refractory mCRC were enrolled in an expanded cohort of B + E. Doses: B 10 mg/kg q2 wks; E 10 mg PO QD. Blood, skin, and tumor biopsies pre- and on-treatment were collected for markers of response and resistance. • Results: At this time, 49 pts (29M: 20F) are evaluable for toxicity; 43 for efficacy. Median age 56 years (range 32-78). Median number prior regimens 3. 45 of 48 pts had prior B exposure; 41 pts had progressive disease on prior B-based therapy. There was one Grade (Gr) 4 adverse event (AE) of hypokalemia.Grade 3 AE related to treatment weremucositis (n=4), hypertension (n=3), fatigue (n=2), bowel perforation/fistula (n=2), volume depletion (n=1), prolonged QT interval (n=1), thrombocytopenia (n=1), neutropenia (n=1), hyperglycemia (n=4), alk phos elevation (n=4; lab only), hypokalemia (n=3),hypophosphatemia (n=3), hyperlipidemia (n=1). Other events of interest were: Gr1-2 mucositis (n=30), Gr1 hyperlipidemia (n=14). Of 43 pts evaluable for response, 15 pts had SD as best response (median 18 wks, range 11+-54 wks); there were 5 minor responses in pts who had progressed on B (median 16 wks, range 14-27 wks).No CR or PR were seen. Biomarker data is pending. • Conclusions: B+E has activity in refractory mCRC in pts who had progressed on a B-based regimen, suggesting B+E may overcome resistance to B. • BACKGROUND • Nearly 150,000 people in the U.S. were diagnosed with colorectal cancer in 2008, with approximately 50,000 deaths.1 • For patients with mCRC, no standard therapy exists after progression on 5-FU, oxaliplatin, irinotecan, bevacizumab, and/or cetuximab/panitumumab. • Preclinical data suggest that combined vascular endothelial growth factor (VEGF) and mammalian Target of Rapamycin (mTOR) inhibition has greater anti-angiogenic and anti-tumor activity than either monotherapy.2 • Bevacizumab (B) inhibits VEGF; Everolimus (E) inhibits mTOR. • Phase I data in patients demonstrated B + E was safe and activity was seen in several pts with refractory mCRC.3 • OBJECTIVES • Primary: • To describe in an exploratory fashion the preliminary clinical efficacy (RR (CR+PR), PFS) of patients with refractory mCRC treated with B and E • Secondary: • To further describe toxicities associated with this regimen • To describe the impact of this combination therapy on dermal wound and tumor angiogenesis and inhibition of factors including, but not limited to, VEGFR2, mTOR/p70S6K and other downstream and related markers in granulation tissue and tumor biopsies • To collect blood and urine-based biomarkers to evaluate for association with clinical efficacy for these patients and association with clinical outcome in these patients • METHODS • Study Design • Open-label, non-randomized expanded cohort trial • Doses: B 10 mg/kg q2 wks; E 10 mg PO Daily in a 28 day cycle • Sample Size: 50 • 50 accrued/continuing, 43 evaluable by cut-off 24APR09 • Treatment was continued until disease progression, intercurrent illness, or unacceptable adverse events • Efficacy: Assessed every 2 cycles with CT using RECIST criteria • Correlative Assessments: • Plasma and urine biomarkers collected at baseline, at every restaging, and at progression • Dermal wound assays pre- and on-treatment to investigate changes in healing (granulating) dermal tissue • Tumor biopsies pre- and on-treatment (if amenable lesion) • Adverse Events: NCI Common Toxicity Criteria version 3.0 • ELIGIBILITY • Key Inclusion Criteria: • Patients must have histologically confirmed adenocarcimona of the colon or rectum that has progressed on, or patient could not tolerate fluoropyrimidine, oxaliplatin, irinotecan, and cetuximab and/or panitumumab chemotherapy (if indicated per k-ras testing). • Disease measurable by RECIST criteria • Karnofsky performance status > 70% • Life expectancy of at least 3 months • Adequate organ and marrow function • Key Exclusion CriteriaPatients who have had: • Treatment for cancer within 28 days prior to the study • Known CNS metastases, untreated, or on chronic steroids • Inadequately controlled hypertension (150/100 mmHg) • Significant poorly controlled cardiovascular or vascular disease with acute event within 6 months • History of abdominal fistula, perforation, or abscess within 6 months • Active, bleeding diathesis or on oral anti-vitamin K medication (except warfarin); no major bleeding within previous 6 months • RESULTS • Table 1. Patient Characteristics Figure 1. Waterfall Plot of Best Response Other Related Events of Interest • Gr1-2 Mucositis (65%) • Includes oropharyngeal, proctitis, vaginitis • Gr1-2 Hyperlipidemia (29%) • Everolimus Dose Reductions 18 (13 pts; 26%) • Bevacizumab Dose Holds 14 (13 pts) • One Death, Grade 5 Aspiration with Sepsis at Day 18 SD/MR PD • CONCLUSIONS • B+E has activity in refractory mCRC in patients who had progressed on a B-based regimen, suggesting B+E may overcome resistance to B in some patients. • Correlative biomarker analyses are ongoing. • ACKNOWLEDGEMENTS • We are thankful for the patients who participated in this study and our research team: Wanda Honeycutt, Sherri Haley, Jennifer Meadows, Christy Arrowood, Margot O’Neill, Kim Huck, Ivy Altomare, Anthony Amara, Laurie Rouse, Kellen Meadows, Neal Kaplan, Kathleen Coleman, Demetrice Broadnox, Pat Phinney, and Amy Franklin. • This study was supported by Genentech, Inc. and Novartis Oncology. • REFERENCES • Ries LAG, Melbert D, Krapcho M, Stinchcomb DG, Howlader N, Horner MJ, Mariotto A, Miller BA, Feuer EJ, Altekruse SF, Lewis DR, Clegg L, Eisner MP, Reichman M, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2005, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2005/, based on November 2007 SEER data submission, posted to the SEER web site, 2008. • Hudson CC, Liu M, Chiang GG. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002;22:7004-14. • 3 Bendell JC, George D, Nixon A, et al. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 3548. Figure 2. Duration of Disease Stability Median PFS 3.3 months N=43 * * * * * * * * * * * * * * * Patient remains on study *3 pts had not received prior B; 5 pts who received B had not progressed at time of study entry Safety/Tolerability Table 2. Grade 3/4 Related Adverse Events • Efficacy • 49 patients (M: F) are evaluable for toxicity; 43 for efficacy • Median Progression Free Survival 3.3 mo (range 0.3-13.5) • Of all 43 patients evaluable for response who had progressed on B: • 12 pts had Stable Disease (median 5 mo, range 2.8-13.5) • 5 pts had Minor Responses (median 4 mo, range 3.5-6.8) • 5 patients with clinicallyprogressive disease prior to first restaging did not have final radiographic imaging • 4 patients developed toxicity related to treatment prior to first restaging and did not have final radiographic imaging • 7 patients have not yet reached first restaging • No CR or PR were seen *Requiring admission, secondary to mucositis/ SBO