Investigator Perspectives on the Current Utility of Validated and Emerging Biomarkers to Guide Treatment Decision-Making for Patients with Metastatic Colorectal Cancer: Personalized Selection of Systemic Therapy N = 26 Completed Surveys

Co-Chairs Survey Participants Tanios Bekaii-Saab, MD Alan P Venook, MD Professor Dirk Arnold, MD, PhD Heinz-Josef Lenz, MD Johanna Bendell, MD Christopher Lieu, MD Al B Benson III, MD John L Marshall, MD Jordan D Berlin, MD Wells A Messersmith, MD Kristen Ciombor, MD, MSCI Jeffrey A Meyerhardt, MD, MPH Steven J Cohen, MD Michael A Morse, MD, MHS Aimery de Gramont, MD Bert H O'Neil, MD Cathy Eng, MD Michael J Overman, MD Richard M Goldberg, MD Philip A Philip, MD, PhD J Randolph Hecht, MD Eric Van Cutsem, MD, PhD Howard S Hochster, MD Zev Wainberg, MD, MSc Scott Kopetz, MD, PhD Christina Wu, MD N = 26 investigators

Indications for and Practical Implementation of Biomarker Analysis for Patients with Metastatic Colorectal Cancer (mCRC)

In general, what type of tumor assays, if any, do you order for your patients with mCRC? 25 Pan-RAS (KRAS/NRAS) 25 BRAF 25 MSI status 24 HER2 PIK3CA 8 NGS panel 5 KRAS 2 NRAS 2 NTRK 1 N = 26 clinical investigators

What type of tumor assays, if any, do you believe oncologists in community practice should be ordering for these individuals? 26 Pan-RAS (KRAS/NRAS) 26 MSI status 25 BRAF 17 HER2 KRAS 2 NRAS 2 PIK3CA 2 NTRK 2 BRCA 1 N = 26 clinical investigators

Do you believe there is any current role for rebiopsy/repeat biomarker assessment in patients with progressive mCRC? Yes 16 No 10 N = 26 clinical investigators

Biology of mCRC and Role of Tumor Sidedness in First- and Later-Line Decision-Making

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 60 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: RAS wild type 9 FOLFOX/CAPOX + bevacizumab 5 FOLFOX/CAPOX + cetuximab 4 FOLFIRI/CAPIRI + bevacizumab FOLFOX/CAPOX + panitumumab 3 FOLFIRI/CAPIRI + cetuximab 2 FOLFIRI/CAPIRI + panitumumab 1 1 FOLFIRI/CAPIRI Capecitabine + bevacizumab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 60 Symptom burden: Requires response Tumor location: Left side Biomarker status: RAS wild type 5 FOLFOX/CAPOX + panitumumab 5 FOLFOXIRI + bevacizumab 4 FOLFOX/CAPOX + cetuximab 3 FOLFOX/CAPOX + bevacizumab 2 FOLFIRI/CAPIRI + panitumumab 2 FOLFIRI/CAPIRI + cetuximab 2 FOLFOXIRI + panitumumab 1 FOLFOXIRI + cetuximab  1 FOLFIRINOX + cetuximab 1 FOLFOXIRI N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 60 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: RAS wild type 18 FOLFOX/CAPOX + bevacizumab 5 FOLFIRI/CAPIRI + bevacizumab FOLFIRI/CAPIRI 1 Capecitabine + bevacizumab 1 N = 25 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 60 Symptom burden: Requires response Tumor location: Right side Biomarker status: RAS wild type FOLFOXIRI + bevacizumab 13 6 FOLFOX/CAPOX + bevacizumab FOLFIRI/CAPIRI + bevacizumab 3 FOLFOXIRI 1 FOLFIRINOX + bevacizumab 1 N = 24 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 80 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: RAS wild type 10 FOLFOX/CAPOX + bevacizumab 5 Capecitabine + bevacizumab 3 FOLFOX/CAPOX + cetuximab FOLFOX/CAPOX 2 2 5-FU/LV + cetuximab 1 FOLFIRI/CAPIRI 1 FOLFIRI/CAPIRI + bevacizumab 1 FOLFIRI/CAPIRI + panitumumab 1 5-FU/LV + bevacizumab N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 80 Symptom burden: Requires response Tumor location: Left side Biomarker status: RAS wild type 9 FOLFOX/CAPOX + bevacizumab 5 FOLFOX/CAPOX + cetuximab 4 FOLFOX/CAPOX + panitumumab FOLFIRI/CAPIRI + bevacizumab 3 FOLFOX/CAPOX 2 FOLFIRI/CAPIRI + panitumumab 1 1 FOLFOXIRI FOLFIRI/CAPIRI + cetuximab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 80 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: RAS wild type FOLFOX/CAPOX + bevacizumab 14 5 Capecitabine + bevacizumab 5-FU/LV + bevacizumab 3 FOLFIRI/CAPIRI + bevacizumab 2 FOLFOX/CAPOX 1 FOLFIRI/CAPIRI 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 80 Symptom burden: Requires response Tumor location: Right side Biomarker status: RAS wild type 19 FOLFOX/CAPOX + bevacizumab FOLFIRI/CAPIRI + bevacizumab 4 FOLFOXIRI + bevacizumab 2 FOLFOX/CAPOX 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 60 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: RAS wild type 11 FOLFIRI/CAPIRI + bevacizumab 5 FOLFOX/CAPOX + bevacizumab 3 Irinotecan + panitumumab FOLFOX/CAPOX + panitumumab 2 Irinotecan + cetuximab 2 1 FOLFIRI/CAPIRI + panitumumab 1 FOLFOX/CAPOX 1 FOLFIRI/CAPIRI + cetuximab  N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 60 Symptom burden: Requires response Tumor location: Left side Biomarker status: RAS wild type 6 FOLFIRI/CAPIRI + panitumumab 5 FOLFIRI/CAPIRI + bevacizumab 4 Irinotecan + panitumumab 4 FOLFOX/CAPOX + bevacizumab 2 Irinotecan + cetuximab 2 FOLFIRI/CAPIRI + cetuximab 1 FOLFOX/CAPOX 1 FOLFOX/CAPOX + panitumumab 1 FOLFOXIRI + panitumumab N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 60 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: RAS wild type 15 FOLFIRI/CAPIRI + bevacizumab 5 FOLFOX/CAPOX + bevacizumab 2 FOLFIRI/CAPIRI + EGFR antibody 5-FU/LV + bevacizumab 1 FOLFOX/CAPOX 1 Irinotecan + cetuximab 1 1 Irinotecan + bevacizumab N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 60 Symptom burden: Requires response Tumor location: Right side Biomarker status: RAS wild type 13 FOLFIRI/CAPIRI + bevacizumab 3 Irinotecan + panitumumab 2 FOLFIRI/CAPIRI + panitumumab 2 FOLFOX/CAPOX + bevacizumab 2 FOLFIRI/CAPIRI + cetuximab 1 5-FU/LV + bevacizumab 1 FOLFOXIRI + bevacizumab 1 Irinotecan + cetuximab 1 Panitumumab 1 FOLFIRI + aflibercept N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 80 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: RAS wild type 9 FOLFIRI/CAPIRI + bevacizumab 4 Irinotecan + cetuximab 3 FOLFOX/CAPOX + bevacizumab 3 Irinotecan + panitumumab 2 Irinotecan + bevacizumab FOLFIRI/CAPIRI + panitumumab 1 1 FOLFOX/CAPOX 1 FOLFOX/CAPOX + panitumumab 1 Panitumumab 1 FOLFIRI/CAPIRI + cetuximab N = 26 clinical investigators

Symptom burden: Requires response Tumor location: Left side Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on your first-line treatment of the choice? Age: 80 Symptom burden: Requires response Tumor location: Left side Biomarker status: RAS wild type 8 FOLFIRI/CAPIRI + bevacizumab 4 Irinotecan + cetuximab 3 Irinotecan + panitumumab 2 FOLFOX/CAPOX 2 FOLFOX/CAPOX + bevacizumab 2 FOLFIRI/CAPIRI + panitumumab 1 FOLFOX/CAPOX + panitumumab 1 FOLFIRI/CAPIRI + cetuximab 1 FOLFOXIRI + panitumumab 1 Panitumumab 1 FOLFIRI N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 80 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: RAS wild type 12 FOLFIRI/CAPIRI + bevacizumab 5 FOLFOX/CAPOX + bevacizumab 3 Irinotecan + bevacizumab Irinotecan + cetuximab 2 Irinotecan 2 FOLFOX/CAPOX 1 1 FOLFIRI/CAPIRI + panitumumab N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 80 Symptom burden: Requires response Tumor location: Right side Biomarker status: RAS wild type 15 FOLFIRI/CAPIRI + bevacizumab 4 FOLFOX/CAPOX + bevacizumab Irinotecan + cetuximab 2 FOLFOX/CAPOX 1 FOLFIRI/CAPIRI + panitumumab 1 FOLFIRI/CAPIRI + cetuximab 1 1 Irinotecan + panitumumab FOLFIRI 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 60 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: RAS wild type 8 Regorafenib 7 TAS-102 5 Irinotecan + panitumumab Irinotecan + cetuximab 3 FOLFOX/CAPOX + bevacizumab 1 Panitumumab 1 1 Cetuximab N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 60 Symptom burden: Requires response Tumor location: Left side Biomarker status: RAS wild type 8 TAS-102 5 Irinotecan + panitumumab 5 Regorafenib FOLFOX/CAPOX + bevacizumab 2 Irinotecan + cetuximab 2 1 FOLFIRI/CAPIRI + panitumumab 1 Cetuximab N = 24 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 60 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: RAS wild type 8 TAS-102 7 Regorafenib 5 Irinotecan + panitumumab Irinotecan + cetuximab 3 FOLFOX/CAPOX + bevacizumab 1 Panitumumab 1 N = 25 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 60 Symptom burden: Requires response Tumor location: Right side Biomarker status: RAS wild type 9 TAS-102 4 Irinotecan + panitumumab 4 Regorafenib Irinotecan + cetuximab 3 2 FOLFOX/CAPOX + bevacizumab 1 FOLFIRI/CAPIRI + panitumumab 1 Cetuximab N = 24 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 80 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: RAS wild type 11 TAS-102 6 Regorafenib 4 Irinotecan + panitumumab Irinotecan + cetuximab 2 2 Panitumumab 1 FOLFOX/CAPOX + bevacizumab N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 80 Symptom burden: Requires response Tumor location: Left side Biomarker status: RAS wild type 9 TAS-102 5 Irinotecan + panitumumab 5 Regorafenib FOLFOX/CAPOX + bevacizumab 2 Irinotecan + cetuximab 2 FOLFIRI/CAPIRI + panitumumab 1 1 Panitumumab Cetuximab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 80 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: RAS wild type 11 TAS-102 5 Regorafenib 4 Irinotecan + panitumumab Irinotecan + cetuximab 3 2 Panitumumab 1 FOLFOX/CAPOX + bevacizumab N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 80 Symptom burden: Requires response Tumor location: Right side Biomarker status: RAS wild type 11 TAS-102 4 Regorafenib 4 Irinotecan + panitumumab Irinotecan + cetuximab 3 FOLFOX/CAPOX + bevacizumab 2 FOLFIRI/CAPIRI + panitumumab 1 1 Panitumumab N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 60 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: RAS mutation 19 FOLFOX/CAPOX + bevacizumab FOLFIRI/CAPIRI + bevacizumab 5 FOLFIRI/CAPIRI 1 Capecitabine + bevacizumab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 60 Symptom burden: Requires response Tumor location: Left side Biomarker status: RAS mutation 12 FOLFOXIRI + bevacizumab 9 FOLFOX/CAPOX + bevacizumab 2 FOLFOXIRI 2 FOLFIRI/CAPIRI + bevacizumab FOLFIRINOX + bevacizumab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 60 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: RAS mutation 19 FOLFOX/CAPOX + bevacizumab FOLFIRI/CAPIRI + bevacizumab 5 FOLFIRI/CAPIRI 1 Capecitabine + bevacizumab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 60 Symptom burden: Requires response Tumor location: Right Biomarker status: RAS mutation 13 FOLFOXIRI + bevacizumab 8 FOLFOX/CAPOX + bevacizumab 3 FOLFIRI/CAPIRI + bevacizumab FOLFOXIRI 1 1 FOLFIRINOX + bevacizumab N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 80 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: RAS mutation 12 FOLFOX/CAPOX + bevacizumab 5 Capecitabine + bevacizumab 3 FOLFIRI/CAPIRI + bevacizumab 5-FU/LV + bevacizumab 3 FOLFOX/CAPOX 1 FOLFOX/CAPOX + cetuximab 1 1 FOLFIRI/CAPIRI N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 80 Symptom burden: Requires response Tumor location: Left side Biomarker status: RAS mutation FOLFOX/CAPOX + bevacizumab 18 FOLFIRI/CAPIRI + bevacizumab 3 FOLFOX/CAPOX 1 FOLFOX/CAPOX + cetuximab 1 1 FOLFOXIRI FOLFOXIRI + bevacizumab 1 5-FU/LV + bevacizumab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 80 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: RAS mutation 13 FOLFOX/CAPOX + bevacizumab 5 Capecitabine + bevacizumab 3 5-FU/LV + bevacizumab FOLFIRI/CAPIRI + bevacizumab 2 FOLFOX/CAPOX 1 FOLFOX/CAPOX + cetuximab 1 1 FOLFIRI/CAPIRI N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 80 Symptom burden: Requires response Tumor location: Right Biomarker status: RAS mutation FOLFOX/CAPOX + bevacizumab 18 4 FOLFIRI/CAPIRI + bevacizumab FOLFOXIRI + bevacizumab 2 FOLFOX/CAPOX 1 FOLFOX/CAPOX + cetuximab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 60 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: RAS mutation FOLFIRI/CAPIRI + bevacizumab 17 4 FOLFOX/CAPOX + bevacizumab FOLFOX/CAPOX 2 Irinotecan + cetuximab 2 FOLFIRI + aflibercept 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 60 Symptom burden: Requires response Tumor location: Left side Biomarker status: RAS mutation 15 FOLFIRI/CAPIRI + bevacizumab 3 FOLFOX/CAPOX + bevacizumab 3 TAS-102 2 FOLFIRI + aflibercept 1 FOLFOX/CAPOX 1 FOLFOXIRI + bevacizumab 1 Irinotecan + cetuximab N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 60 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: RAS mutation 17 FOLFIRI/CAPIRI + bevacizumab FOLFOX/CAPOX + bevacizumab 4 1 5-FU/LV + bevacizumab FOLFOX/CAPOX 1 Irinotecan + cetuximab 1 Irinotecan + bevacizumab 1 1 FOLFIRI + aflibercept N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 60 Symptom burden: Requires response Tumor location: Right side Biomarker status: RAS mutation 17 FOLFIRI/CAPIRI + bevacizumab 3 TAS-102 2 FOLFOX/CAPOX + bevacizumab 5-FU/LV + bevacizumab 1 FOLFOXIRI + bevacizumab 1 Irinotecan + cetuximab 1 1 FOLFIRI + aflibercept N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 80 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: RAS mutation 15 FOLFIRI/CAPIRI + bevacizumab FOLFOX/CAPOX + bevacizumab 4 2 FOLFOX/CAPOX Irinotecan 2 Irinotecan + bevacizumab 2 Irinotecan + cetuximab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 80 Symptom burden: Requires response Tumor location: Left side Biomarker status: RAS mutation FOLFIRI/CAPIRI + bevacizumab 17 3 FOLFOX/CAPOX + bevacizumab FOLFOX/CAPOX 2 Irinotecan + cetuximab 1 Irinotecan 1 FOLFIRI   1 1 FOLFIRI + aflibercept  N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 80 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: RAS mutation 14 FOLFIRI/CAPIRI + bevacizumab 6 FOLFOX/CAPOX + bevacizumab 3 Irinotecan + bevacizumab Irinotecan + cetuximab 1 Irinotecan 1 FOLFOX/CAPOX 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 80 Symptom burden: Requires response Tumor location: Right side Biomarker status: RAS mutation 17 FOLFIRI/CAPIRI + bevacizumab FOLFOX/CAPOX + bevacizumab 4 1 FOLFOX/CAPOX Irinotecan + cetuximab 1 Irinotecan 1 FOLFIRI 1 1 FOLFIRI + aflibercept N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 60 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: RAS mutation 15 TAS-102 Regorafenib 9 1 Irinotecan + cetuximab N = 25 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 60 Symptom burden: Requires response Tumor location: Left side Biomarker status: RAS mutation 13 TAS-102 8 Regorafenib 1 FOLFOX/CAPOX + bevacizumab Irinotecan + cetuximab 1 1 Irinotecan + panitumumab N = 24 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 60 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: RAS mutation 15 TAS-102 9 Regorafenib 1 Irinotecan + cetuximab N = 25 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 60 Symptom burden: Requires response Tumor location: Right side Biomarker status: RAS mutation 14 TAS-102 8 Regorafenib 1 FOLFOX/CAPOX + bevacizumab Irinotecan + cetuximab 1 N = 24 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 80 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: RAS mutation TAS-102 18 6 Regorafenib FOLFOX/CAPOX + bevacizumab 1 Irinotecan + cetuximab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 80 Symptom burden: Requires response Tumor location: Left side Biomarker status: RAS mutation TAS-102 17 6 Regorafenib FOLFOX/CAPOX + bevacizumab 2 Irinotecan + cetuximab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 80 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: RAS mutation TAS-102 18 6 Regorafenib FOLFOX/CAPOX + bevacizumab 1 Irinotecan + cetuximab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 80 Symptom burden: Requires response Tumor location: Right side Biomarker status: RAS mutation TAS-102 17 6 Regorafenib FOLFOX/CAPOX + bevacizumab 2 Irinotecan + cetuximab 1 N = 26 clinical investigators

Current and Future Treatment Options for Patients with BRAF Mutations

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 60 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: BRAF V600E mutation (RAS wild type) 14 FOLFOXIRI + bevacizumab 8 FOLFOX/CAPOX + bevacizumab 1 FOLFIRI/CAPIRI + bevacizumab FOLFOXIRI 1 Encorafenib + binimetinib + cetuximab 1 FOLFIRINOX + bevacizumab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 60 Symptom burden: Requires response Biomarker status: BRAF V600E mutation (RAS wild type) Tumor location: Left side 17 FOLFOXIRI + bevacizumab 3 FOLFOX/CAPOX + bevacizumab 2 FOLFOXIRI FOLFIRI/CAPIRI + bevacizumab 1 Encorafenib + binimetinib + cetuximab 1 FOLFIRINOX + bevacizumab 1 1 FOLFIRINOX N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 60 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: BRAF V600E mutation (RAS wild type) 14 FOLFOXIRI + bevacizumab FOLFOX/CAPOX + bevacizumab 8 FOLFIRI/CAPIRI + bevacizumab 1 FOLFOXIRI 1 Encorafenib + binimetinib + cetuximab 1 1 FOLFIRINOX + bevacizumab N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 60 Symptom burden: Requires response Tumor location: Right side Biomarker status: BRAF V600E mutation (RAS wild type) FOLFOXIRI + bevacizumab 18 2 FOLFOX/CAPOX + bevacizumab FOLFOXIRI 2 Encorafenib + binimetinib + cetuximab 2 FOLFIRINOX + bevacizumab 1 FOLFIRINOX 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 80 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: BRAF V600E mutation (RAS wild type) 14 FOLFOX/CAPOX + bevacizumab 4 Encorafenib + binimetinib + cetuximab FOLFIRI/CAPIRI + bevacizumab 2 2 FOLFOXIRI + bevacizumab FOLFOX/CAPOX 1 FOLFOXIRI 1 1 5-FU/LV + bevacizumab Capecitabine + bevacizumab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 80 Symptom burden: Requires response Tumor location: Left side Biomarker status: BRAF V600E mutation (RAS wild type) 14 FOLFOX/CAPOX + bevacizumab 4 Encorafenib + binimetinib + cetuximab FOLFOXIRI + bevacizumab 3 2 FOLFIRI/CAPIRI + bevacizumab FOLFOX/CAPOX 1 FOLFOXIRI 1 1 FOLFIRINOX N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 80 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: BRAF V600E mutation (RAS wild type) 14 FOLFOX/CAPOX + bevacizumab 4 Encorafenib + binimetinib + cetuximab FOLFIRI/CAPIRI + bevacizumab 2 2 FOLFOXIRI + bevacizumab FOLFOX/CAPOX 1 FOLFOXIRI 1 1 5-FU/LV + bevacizumab Capecitabine + bevacizumab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred first-line systemic treatment choice outside of a clinical trial for this patient with newly diagnosed mCRC? Age: 80 Symptom burden: Requires response Tumor location: Right side Biomarker status: BRAF V600E mutation (RAS wild type) 14 FOLFOX/CAPOX + bevacizumab 4 Encorafenib + binimetinib + cetuximab FOLFOXIRI + bevacizumab 3 2 FOLFIRI/CAPIRI + bevacizumab FOLFOX/CAPOX 1 FOLFOXIRI 1 1 FOLFIRINOX N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 60 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: BRAF V600E mutation (RAS wild type) 7 Encorafenib + binimetinib + cetuximab 6 FOLFIRI/CAPIRI + bevacizumab Irinotecan + cetuximab + vemurafenib 5 3 Irinotecan + panitumumab + vemurafenib FOLFOX/CAPOX + bevacizumab 1 Dabrafenib + trametinib + panitumumab 1 1 FOLFOXIRI + bevacizumab 1 Encorafenib + binimetinib + panitumumab 1 Irinotecan N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 60 Symptom burden: Requires response Tumor location: Left side Biomarker status: BRAF V600E mutation (RAS wild type) Encorafenib + binimetinib + cetuximab 9 Irinotecan + cetuximab + vemurafenib 7 3 FOLFIRI/CAPIRI + bevacizumab 3 Irinotecan + panitumumab + vemurafenib FOLFOXIRI + bevacizumab 2 Encorafenib + binimetinib + panitumumab 1 1 Dabrafenib + trametinib + panitumumab N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 60 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: BRAF V600E mutation (RAS wild type) 7 Encorafenib + binimetinib + cetuximab 6 FOLFIRI/CAPIRI + bevacizumab Irinotecan + cetuximab + vemurafenib 5 Irinotecan + panitumumab + vemurafenib 3 FOLFOX/CAPOX + bevacizumab 1 Dabrafenib + trametinib + panitumumab 1 1 FOLFOXIRI + bevacizumab 1 Encorafenib + binimetinib + panitumumab 1 Irinotecan N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 60 Symptom burden: Requires response Tumor location: Right side Biomarker status: BRAF V600E mutation (RAS wild type) 9 Encorafenib + binimetinib + cetuximab 7 Irinotecan + cetuximab + vemurafenib FOLFIRI/CAPIRI + bevacizumab 3 3 Irinotecan + panitumumab + vemurafenib FOLFOXIRI + bevacizumab 2 Dabrafenib + trametinib + panitumumab 1 Encorafenib + binimetinib + panitumumab 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 80 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: BRAF V600E mutation (RAS wild type) 6 FOLFIRI/CAPIRI + bevacizumab 4 Encorafenib + binimetinib + cetuximab 4 Irinotecan + cetuximab + vemurafenib 3 FOLFOX/CAPOX + bevacizumab Irinotecan + panitumumab + vemurafenib 3 2 Irinotecan FOLFOXIRI + bevacizumab 1 1 Dabrafenib + trametinib + panitumumab Capecitabine + bevacizumab 1 N = 25 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 80 Symptom burden: Requires response Tumor location: Left side Biomarker status: BRAF V600E mutation (RAS wild type) 7 Encorafenib + binimetinib + cetuximab Irinotecan + cetuximab + vemurafenib 6 3 FOLFOX/CAPOX + bevacizumab 3 FOLFIRI/CAPIRI + bevacizumab 2 Irinotecan + panitumumab + vemurafenib 1 FOLFOXIRI + bevacizumab 1 Dabrafenib + trametinib + panitumumab 1 Irinotecan + bevacizumab Capecitabine + bevacizumab 1 N = 25 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 80 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: BRAF V600E mutation (RAS wild type) FOLFIRI/CAPIRI + bevacizumab 6 Encorafenib + binimetinib + cetuximab 4 Irinotecan + cetuximab + vemurafenib 4 FOLFOX/CAPOX + bevacizumab 3 3 Irinotecan + panitumumab + vemurafenib Irinotecan 2 FOLFOXIRI + bevacizumab 1 1 Dabrafenib + trametinib + panitumumab Capecitabine + bevacizumab 1 N = 25 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred second-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first-line treatment of your choice? Age: 80 Symptom burden: Requires response Biomarker status: BRAF V600E mutation Tumor location: Right side (RAS wild type) Encorafenib + binimetinib + cetuximab 7 Irinotecan + cetuximab + vemurafenib 6 FOLFOX/CAPOX + bevacizumab 3 FOLFIRI/CAPIRI + bevacizumab 3 2 Irinotecan + panitumumab + vemurafenib FOLFOXIRI + bevacizumab 1 Dabrafenib + trametinib + panitumumab 1 1 Irinotecan + bevacizumab Capecitabine + bevacizumab 1 N = 25 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 60 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: BRAF V600E mutation (RAS wild type) 11 TAS-102 Regorafenib 5 4 Encorafenib + binimetinib + cetuximab Irinotecan + cetuximab + vemurafenib 2 Irinotecan + cetuximab 1 Irinotecan + panitumumab + vemurafenib 1 N = 24 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 60 Symptom burden: Requires response Tumor location: Left side Biomarker status: BRAF V600E mutation (RAS wild type) 11 TAS-102 Regorafenib 4 Irinotecan + cetuximab + vemurafenib 3 2 Encorafenib + binimetinib + cetuximab FOLFIRI/CAPIRI + bevacizumab 1 Irinotecan + cetuximab 1 Irinotecan + panitumumab + vemurafenib 1 Dabrafenib + trametinib + panitumumab   1 N = 24 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 60 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: BRAF V600E mutation (RAS wild type) 11 TAS-102 5 Regorafenib Encorafenib + binimetinib + cetuximab 4 Irinotecan + cetuximab + vemurafenib 2 Irinotecan + cetuximab 1 Irinotecan + panitumumab + vemurafenib 1 N = 24 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 60 Symptom burden: Requires response Tumor location: Right side Biomarker status: BRAF V600E mutation (RAS wild type) 11 TAS-102 4 Regorafenib Irinotecan + cetuximab + vemurafenib 3 2 Encorafenib + binimetinib + cetuximab FOLFIRI/CAPIRI + bevacizumab 1 Irinotecan + cetuximab 1 Irinotecan + panitumumab + vemurafenib 1 Dabrafenib + trametinib + panitumumab   1 N = 24 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 80 Symptom burden: Clinically stable Tumor location: Left side Biomarker status: BRAF V600E mutation (RAS wild type) 12 TAS-102 4 Regorafenib Encorafenib + binimetinib + cetuximab 3 3 Supportive care Irinotecan + cetuximab + vemurafenib 2 Irinotecan + cetuximab 1 1 Irinotecan + panitumumab + vemurafenib N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 80 Symptom burden: Requires response Tumor location: Left side Biomarker status: BRAF V600E mutation (RAS wild type) 13 TAS-102 3 Irinotecan + cetuximab + vemurafenib 3 Supportive care 3 Regorafenib 1 Encorafenib + binimetinib + cetuximab FOLFIRI/CAPIRI + bevacizumab 1 1 Irinotecan + cetuximab Irinotecan + panitumumab + vemurafenib 1 N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 80 Symptom burden: Clinically stable Tumor location: Right side Biomarker status: BRAF V600E mutation (RAS wild type) 12 TAS-102 4 Regorafenib Encorafenib + binimetinib + cetuximab 3 3 Supportive care Irinotecan + cetuximab + vemurafenib 2 Irinotecan + cetuximab 1 1 Irinotecan + panitumumab + vemurafenib N = 26 clinical investigators

Regulatory and reimbursement issues aside, what is your preferred third-line systemic treatment choice outside of a clinical trial for this patient with mCRC who has received and experienced disease progression on the first- and second-line treatments of your choice? Age: 80 Symptom burden: Requires response Tumor location: Right side Biomarker status: BRAF V600E mutation (RAS wild type) 13 TAS-102 3 Irinotecan + cetuximab + vemurafenib Supportive care 3 Regorafenib 3 Encorafenib + binimetinib + cetuximab 1 FOLFIRI/CAPIRI + bevacizumab 1 1 Irinotecan + cetuximab Irinotecan + panitumumab + vemurafenib 1 N = 26 clinical investigators

Do you typically administer BRAF-targeted therapy for your patients with mCRC with BRAF V600E mutations? 24 Yes No 2 N = 26 clinical investigators

Optimal Management of Microsatellite Instability (MSI) High or DNA Mismatch Repair Deficient (dMMR) mCRC

First line Second line Third line or beyond Reimbursement and regulatory issues aside, for a patient with MSI-high mCRC, in what line of therapy would you generally administer an anti-PD-1/ PD-L1 antibody? 7 First line 14 Second line Third line or beyond 5 N = 26 clinical investigators

Which of the following checkpoint inhibitors have you administered to a patient with MSI-high mCRC? (Select all that apply.) 23 Pembrolizumab 19 Nivolumab 16 Nivolumab/ ipilimumab Atezolizumab 5 Durvalumab 1 N = 26 clinical investigators

What is your usual first-line treatment recommendation for a 60-year-old patient with left-sided, pan-RAS wild-type, MSI-high mCRC? 12 FOLFOX/CAPOX + bevacizumab 5 FOLFOX/CAPOX + EGFR antibody Nivolumab/ipilimumab 3 2 FOLFIRI/CAPIRI + bevacizumab FOLFOXIRI 1 Pembrolizumab 1 1 FOLFIRI/CAPIRI + EGFR antibody N = 25 clinical investigators

What is your usual first-line treatment recommendation for an 80-year-old patient with left-sided, pan-RAS wild-type, MSI-high mCRC? FOLFOX/CAPOX + bevacizumab 7 6 Pembrolizumab FOLFOX/CAPOX + EGFR antibody 3 3 Nivolumab/ipilimumab 3 Nivolumab 2 FOLFIRI/CAPIRI 1 FOLFOX/CAPOX Pembrolizumab or nivolumab (“coin flip”) 1 N = 26 clinical investigators

What is your usual second-line treatment recommendation for a 60-year-old patient with left-sided, pan-RAS wild-type, MSI-high mCRC who responds to first-line FOLFOX/bevacizumab and experiences disease progression after receiving 9 months of bevacizumab maintenance? 11 Pembrolizumab 8 Nivolumab/ipilimumab FOLFIRI/CAPIRI + bevacizumab 4 2 Pembrolizumab or nivolumab (“coin flip”) Nivolumab 1 N = 26 clinical investigators

What is your usual second-line treatment recommendation for an 80-year-old patient with left-sided, pan-RAS wild-type, MSI-high mCRC who responds to first-line FOLFOX/bevacizumab and experiences disease progression after receiving 9 months of bevacizumab maintenance? 14 Pembrolizumab 4 Pembrolizumab or nivolumab (“coin flip”) Nivolumab/ipilimumab 3 3 Nivolumab FOLFIRI/CAPIRI + bevacizumab 2 N = 26 clinical investigators

What is your usual third-line treatment recommendation for a 60-year-old patient with left-sided, pan-RAS wild-type, MSI-high mCRC who receives first-line FOLFOX/bevacizumab and second-line FOLFIRI/bevacizumab and is now experiencing disease progression? 13 Nivolumab/ipilimumab 9 Pembrolizumab Nivolumab 3 Pembrolizumab or nivolumab/ipilimumab (“coin flip”) 1 N = 26 clinical investigators

What is your usual third-line treatment recommendation for an 80-year-old patient with left-sided, pan-RAS wild-type, MSI-high mCRC who receives first-line FOLFOX/bevacizumab and second-line FOLFIRI/bevacizumab and is now experiencing disease progression? 13 Pembrolizumab 4 Pembrolizumab or nivolumab (“coin flip”) Nivolumab/ipilimumab 4 4 Nivolumab FOLFIRI/CAPIRI + EGFR antibody 1 N = 26 clinical investigators

HER2 Positivity and Other Potential Biomarkers

Reimbursement and regulatory issues aside, for a patient with mCRC with HER2 mutation/amplification, in what line of therapy would you generally administer anti-HER2 therapy? 3 First line 11 Second line Third line or beyond 11 1 I would not administer anti-HER2 therapy N = 26 clinical investigators

For a patient with mCRC with HER2 mutation/amplification to whom you would administer anti-HER2 therapy, which regimen would you recommend? 11 Trastuzumab/pertuzumab 9 Trastuzumab/lapatinib Trastuzumab 5 N = 25 clinical investigators