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 CJ Allegra, G Yothers, MJ O’Connell, MS Roh, RW Beart, NJ Petrelli, S Lopa, S Sharif, and N Wolmark

Disclosures •

I have no relevant conflicts of interest to disclose

Goals of NSABP R-04

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Designed at the start of the millennium to address the questions: –

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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?

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Oxaliplatin was shown to have radiation sensitizing properties in preclinical models

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Oxaliplatin was shown to enhance the activity of 5-FU in the palliative and adjuvant colon settings

NSABP R-04

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July, 2004 – 2-arm study comparing 5-FU and Cape ACTIVATION

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October, 2005 – Added oxaliplatin – – 2 x 2 factorial design AMENDMENT 5-FU and Cape reduced from 7 days/wk to 5 days/wk during RT

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August, 2010 – CLOSED 1,608 accrued patients; 1595 (99.2%) Eligible

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) RANDOMIZATION Group 1 5-FU (CIV 225mg/m 2 5d/wk) + RT (46Gy over 5 wks + boost) Group 2 5-FU (CIV 225mg/m 2 5d/wk) + Oxaliplatin 50 mg/m 2 /wk X 5 + RT Group 3 Capecitabine 825 mg/m 2 PO BID + RT Group 4 Capecitabine 825 mg/m 2 PO BID + Oxaliplatin 50 mg/m 2 /wk X 5 + RT

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NSABP R-04

Primary Endpoint

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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

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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

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“Regional” – Pelvic or retroperitoneal LNs at or below L5

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NSABP R-04

Secondary Endpoints

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– – – – – – 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

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Comparison of cape and 5-FU

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Comparable if 0.86 < HazRatio < 1.17

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Roughly corresponds to 3yr L-R rate of +/- 2%

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Superiority for the addition of oxaliplatin to fluoropyrimidines

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>80% power for HazRatio = 0.59

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Roughly corresponds to 4% increase in L-R 3yr rate

Regimen # Eligible Pts Age (%) ≤ 59 ≥ 60 Gender Male Female Clinical Stage II III SS Surg

Patient Demographics

FU 461 FU+Ox 321 Cape 463 Cape+Ox 322 56 44 67 33 59 41 74 61 39 68 32 62 38 74 56 44 68 32 58 42 73 61 39 68 32 62 38 74 Non-SS Surg 26 26 27 26 Total 1567 60 40 74 26 58 42 68 32

NSABP R-04 pCR Rates (%)

P = 0.14

P = 0.42

* No significant fluoropyrimidine by oxaliplatin interaction

3 Year Overall & L-R Recurrences

P = 0.98

P = 0.70

P = 0.52

P = 0.22

* No significant fluoropyrimidine by oxaliplatin interaction

5 YEAR OUTCOMES (%)

P = 0.70

P = 0.34

P = 0.61

P = 0.38

* No significant fluoropyrimidine by oxaliplatin interaction

NSABP R-04 Primary Endpoint: Local-Regional Control

5-FU vs. Cape No Oxali vs. Oxali 5-FU 782 Pts, 95 L/R Recurrence Cape 785 Pts, 97 L/R Recurrence HR = 1.00, 95% CI (0.75-1.32) P = 0.98

No Oxali 641 Pts, 81 L/R Recurrence Oxali 643 Pts, 76 L/R Recurrence HR = 0.94, 95% CI (0.67-1.29) P = 0.70

0 1 2 3 4 Years from Randomization 5 6 0 1 2 3 4 Years from Randomization 5 6

NSABP R-04 Overall Survival

5-FU vs. Cape No Oxali vs. Oxali 5-FU 782 Pts, 141 deaths Cape 785 Pts, 138 deaths HR = 1.00, 95% CI (0.74-1.19) P = 0.61

No Oxali 641 Pts, 116 deaths Oxali 643 Pts, 103 deaths HR = 0.94, 95% CI (0.68-1.16) P = 0.38

0 1 2 3 4 Years from Randomization 5 6 0 1 2 3 4 Years from Randomization 5 6

Treatment Compliance

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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) Overall (3+) Diarrhea (3/4) Death (5) 5-FU 26.5

Capecitabine 30.1

5-FU + Oxaliplatin 39.9

Capecitabine + Oxaliplatin 42.2

7 0.3

7 1.3

16 0.3

16 1.6

NSABP R-04 Summary

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Capecitabine with preop RT achieved rates similar to CIV 5-FU for: – – – – L-R Failure – Primary Endpoint pCR DFS OS

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Oxaliplatin did not improve outcomes but added significant toxicity (diarrhea) and is therefore not indicated in combination with RT in the preop rectal setting

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Establishes capecitabine as a standard of care in the preop rectal setting

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NSABP R-04 supports pCR & neoadjuvant rectal cancer (NAR) score as surrogates for overall survival (Yothers G ASCO GI, 2014; Abst #384)

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Fully annotated tissue samples available for molecular studies