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

Disclosures I have no relevant conflicts of interest to disclose

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

July, 2004 ACTIVATION – 2-arm study comparing 5-FU and Cape October, 2005AMENDMENT – 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 NSABP R-04

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

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

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

NSABP R-04 Statistical 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

Regimen # Eligible Pts FU 461 FU+Ox 321 Cape 463 Cape+Ox 322 Total 1567 Age (%) ≤ 59 ≥ Gender Male Female Clinical Stage II III SS Surg Non-SS Surg Patient Demographics

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

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

P = 0.34P = 0.70P = 0.61P = 0.38 * No significant fluoropyrimidine by oxaliplatin interaction 5 YEAR OUTCOMES (%)

NSABP R-04 Primary Endpoint: Local-Regional Control 5-FU vs. Cape Years from Randomization L/R Recurrence Free (%) FU 782 Pts, 95 L/R Recurrence Cape 785 Pts, 97 L/R Recurrence HR = 1.00, 95% CI ( ) P = 0.98 No Oxali vs. Oxali Years from Randomization L/R Recurrence Free (%) No Oxali 641 Pts, 81 L/R Recurrence Oxali 643 Pts, 76 L/R Recurrence HR = 0.94, 95% CI ( ) P = 0.70

NSABP R-04 Overall Survival Years from Randomization Alive (%) FU 782 Pts, 141 deaths Cape 785 Pts, 138 deaths HR = 1.00, 95% CI ( ) P = 0.61 Years from Randomization Alive (%) No Oxali 641 Pts, 116 deaths Oxali 643 Pts, 103 deaths HR = 0.94, 95% CI ( ) P = FU vs. CapeNo Oxali vs. Oxali

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

NSABP R-04 Mortality & Adverse Events (%) Toxicity (Grade)5-FUCapecitabine 5-FU + Oxaliplatin Capecitabine + Oxaliplatin Overall (3+) Diarrhea (3/4) 7716 Death (5)

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

Stage II/III Rectal Cancer Treated with Pre-op Fluoropyrimidines + RT +/- Oxaliplatin Study# PtsChemoRT Regimen ypCR Rate (%) ACCORD 12 (JCO 2010) 291 Cape+RT Cape + Oxali 50mg/m2 wkly+RT 19 (p=0.09) STAR-01 (JCO 2011) 379 FU CI+RT FU CI + Oxali 60mg/m2 wkly+RT 16 German AIO-04 (Lancet 2012) 623 FU CI+RT FU CI + Oxali 50mg/m2 wkly+RT 17 (p=0.038) PETAAC-6 (PASCO, 2013) 547 Cape+RT Cape + Oxali 50mg/m2 wkly+RT 13 (p=0.031) NSABP R-04 ( PASCO, 2012) 636 FU/Cape+RT FU/Cape + Oxali 50mg/m2 wkly+RT 20 (p=0.42)