CJ Allegra, G Yothers, MJ O ’ Connell, MS Roh, RW Beart,

1. Neoadjuvant Therapy For Rectal Cancer: Mature Results From NSABP Protocol R-04A Collaborative National NCI Protocol Conducted by NSABP, NCCTG, ECOG, CALGB, and SWOG CJ Allegra, G Yothers, MJ O’Connell, MS Roh, RW Beart, NJ Petrelli, S Lopa, S Sharif, and N Wolmark

2. Disclosures • I have no relevant conflicts of interest to disclose

3. Goals of NSABP R-04 • Designed at the start of the millennium to address the questions: • Can the oral fluoropyrimidine, capecitabine be substituted for the standard of care in the curative setting of Stage II & III rectal cancer namely, CIV 5-FU, during neoadjuvant RT? • CIV 5-FU became the SoC based on a US cooperative group study (O’Connell et al; NEJM August, 1994) showing superiority over bolus administrations of 5-FU • Capecitabine was shown to be non-inferior to 5-FU in the palliative & adjuvant colon settings and does not require a central venous catheter or infusion pump • Small retrospective studies support similar outcomes with 5-FU and capecitabine in the rectal neoadjuvant setting • Can the addition of oxaliplatin enhance the activity of fluoropyrimidine sensitized RT? • Oxaliplatin was shown to have radiation sensitizing properties in preclinical models • Oxaliplatin was shown to enhance the activity of 5-FU in the palliative and adjuvant colon settings

4. NSABP R-04 • July, 2004 ACTIVATION • 2-arm study comparing 5-FU and Cape • October, 2005 AMENDMENT • Added oxaliplatin • 2 x 2 factorial design • 5-FU and Cape reduced from 7 days/wk to 5 days/wk during RT • August, 2010CLOSED • 1,608 accrued patients; 1595 (99.2%) Eligible

5. NSABP R-04 Rectal AdenoCa < 12 cm from anal verge STRATIFICATION Gender; Clinical Stage II/III; Intent for Type of Surgery (sphincter saving v. APR) Group 1 5-FU (CIV 225mg/m2 5d/wk) + RT (46Gy over 5 wks + boost) Group 2 5-FU (CIV 225mg/m2 5d/wk) + Oxaliplatin 50 mg/m2/wk X 5 + RT RANDOMIZATION Group 3 Capecitabine 825 mg/m2 PO BID + RT Group 4 Capecitabine 825 mg/m2 PO BID + Oxaliplatin 50 mg/m2/wk X 5 + RT

6. NSABP R-04– Primary Endpoint – • Local-regional control with 3 years minimum follow-up • Time from randomization to first L-R failure • Inoperable patients or those with positive margins are considered L-R failures at the time of surgery • Patients without documented clinical CR who do not undergo surgery will be considered a L-R failure at the time they should have had surgery • “Local” – Anastomotic and pelvis • “Regional” – Pelvic or retroperitoneal LNs at or below L5

7. NSABP R-04 –Secondary Endpoints – • Rate of pathologic CR • Number of pts undergoing sphincter-saving surgery • Disease free and overall survival • Quality of Life • Toxicity • Correlating genetic patterns and specific tissue biomarkers with response and prognosis

8. NSABP R-04Statistical Design • Comparison of cape and 5-FU • Comparable if 0.86 < HazRatio < 1.17 • Roughly corresponds to 3yr L-R rate of +/- 2% • Superiority for the addition of oxaliplatin to fluoropyrimidines • >80% power for HazRatio = 0.59 • Roughly corresponds to 4% increase in L-R 3yr rate

9. Patient Demographics

10. NSABP R-04 pCR Rates (%) P = 0.14 P = 0.42 * No significant fluoropyrimidine by oxaliplatin interaction

11. 3 Year Overall & L-R Recurrences P = 0.98 P = 0.70 P = 0.52 P = 0.22 * No significant fluoropyrimidine by oxaliplatin interaction

12. 5 year Outcomes (%) P = 0.70 P = 0.34 P = 0.61 P = 0.38 * No significant fluoropyrimidine by oxaliplatin interaction

13. NSABP R-04 Primary Endpoint: Local-Regional Control 5-FU vs. Cape No Oxali vs. Oxali 100 100 80 80 60 60 5-FU 782 Pts, 95 L/R Recurrence No Oxali 641 Pts, 81 L/R Recurrence L/R Recurrence Free (%) L/R Recurrence Free (%) Cape 785 Pts, 97 L/R Recurrence Oxali 643 Pts, 76 L/R Recurrence 40 40 HR = 1.00, 95% CI (0.75-1.32) HR = 0.94, 95% CI (0.67-1.29) P = 0.98 P = 0.70 20 20 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years from Randomization Years from Randomization

14. NSABP R-04 Overall Survival 5-FU vs. Cape No Oxali vs. Oxali 100 100 80 80 60 60 No Oxali 641 Pts, 116 deaths 5-FU 782 Pts, 141 deaths Alive (%) Alive (%) Cape 785 Pts, 138 deaths Oxali 643 Pts, 103 deaths 40 HR = 1.00, 95% CI (0.74-1.19) 40 HR = 0.94, 95% CI (0.68-1.16) P = 0.61 P = 0.38 20 20 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years from Randomization Years from Randomization

15. Treatment Compliance • At least 80% of treatment completed per protocol • FU – 90% alone; 84% with Oxali • Cap – 97% alone; 96% with Oxali • Oxali – 69% with FU; 62% with Cap • RT – 96-98% depending on the arm

16. NSABP R-04 Mortality & Adverse Events (%)

17. NSABP R-04 Summary • Capecitabine with preop RT achieved rates similar to CIV 5-FU for: • L-R Failure – Primary Endpoint • pCR • DFS • OS • Oxaliplatin did not improve outcomes but added significant toxicity (diarrhea) and is therefore not indicated in combination with RT in the preop rectal setting • Establishes capecitabine as a standard of care in the preop rectal setting • NSABP R-04 supports pCR & neoadjuvant rectal cancer (NAR) score as surrogates for overall survival (Yothers G ASCO GI, 2014; Abst #384) • Fully annotated tissue samples available for molecular studies