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Clinical Spotlight in mCRC: Assessing Options in the
Third Line and Beyond Reference Slide Deck
Abstract #O-011 Abstract #LBA-05 Abstract #O-010
2015 World Congress on Gastrointestinal Cancer
Characteristics and Outcomes of Patients Enrolled in the CORRECT
and CONCUR Phase 3 Trials of Regorafenib for Metastatic Colorectal
Cancer (mCRC)
Grothey A, Van Cutsem E, Wagner A, Kalmus J, Qin S, Xu R, Kim TW, Li J
Abstract #O-011
• Regorafenib is an oral multikinase inhibitor that blocks the activity of multiple protein kinases involved in the regulation of oncogenesis, angiogenesis, and the tumor microenvironment1
• The international phase 3 CORRECT trial (NCT01103323) showed that regorafenib improves overall survival (OS) vs placebo in patients with previously treated mCRC2
• The phase 3 CONCUR trial (NCT01584830) confirmed the OS benefit for regorafenib in Asian patients3
• We examined the characteristics of patients and the efficacy and safety outcomes in the two trials
Background
1. Wilhelm SM, et al. Int J Cancer. 2011;129:245-255. 2. Grothey A, et al. Lancet . 2013;381:303-312. 3. Li J, et al. Lancet Oncol. 2015;16:619-629.
Grothey A, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-011.
Regorafenib 160 mg daily
3 weeks on/1 week off (4-week cycle)
Placebo
• All patients received best supportive care
• Treat until progression, death, unacceptable toxicity, or withdrawal
• Radiologic evaluation every 8 weeks
Patients with mCRC who
progressed after standard therapies
R 2:1
Primary endpoint OS
CORRECT CONCUR Number of patients randomized 760 204
Enrollment 16 countries in Europe, North-America, Asia-Pacific region, rest of the world
China, Hong Kong, Taiwan, South Korea, Vietnam
Prior targeted biologic therapy: bevacizumab; cetuximab/panitumumab (KRAS wild-type) Required Allowed, but not required
Primary analysis of OS (assumed 33.3% improvement; HR 0.75 favoring regorafenib)
One-sided alpha 0.025 90% power
One-sided alpha 0.20 80% power
Stratification factors for randomization Previous treatment with VEGF-targeting
drugs; time from mCRC diagnosis (>18 vs <18 months); geographic region
Number of metastatic sites (single vs multiple); time from mCRC diagnosis
(≥18 vs <18 months)
Study Design
HR, hazard ratio; OS, overall survival; R, randomization Grothey A, et al. Lancet. 2013;381:303-312. Li J, et al. Lancet Oncol. 2015;16:619-629.
Grothey A, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-011.
CORRECT CONCUR Regorafenib
(n = 505) Placebo (n = 255)
Regorafenib (n = 136)
Placebo (n = 68)
Median age, years (IQR) 61 (54–67) 61 (54–68) 58 (50–66) 56 (49–62)
Male, % 62 60 63 49
Race, % Asian
15
14
100
100
Median body mass index, kg/m2 25 26 23 23
ECOG PS 0/1, % 52/48 57/43 26/74 22/78
KRAS wild-type/mutant/unknown, % 41/54/5 37/62/2 37/34/29 43/26/31
>3 prior treatment lines for metastatic disease, % 49 47 38 40
Previous targeted biological treatment, % None Any (anti-VEGF, anti-EGFR, or both) Anti-VEGF, but not anti-EGFR Anti-EGFR, but not anti-VEGF Anti-VEGF and anti-EGFR
0
100 48 0
52
0
100 52 0
48
41 59 24 18 18
38 62 19 25 18
Baseline Characteristics
ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; IQR, interquartile range; VEGF, vascular endothelial growth factor Grothey A, et al. Lancet 2013;381:303-312. Li J, et al. Lancet Oncol 2015;16:619-629.
Grothey A, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-011.
Overall Survival (OS)
CORRECT
CONCUR
CI, confidence interval Grothey A, et al. Lancet. 2013;381:303-312. Li J, et al. Lancet Oncol. 2015;16:619-629. Grothey A, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-011.
CORRECT n HR (95% CI)
Number of prior treatment lines on or after metastatic disease diagnosis
≤3 >3
395 365
0.79 (0.60–1.04) 0.75 (0.56–0.99)
No prior targeted treatment NA NA
Prior anti-VEGF but no prior anti-EGFR 375 0.83 (0.63–1.09)
Prior anti-EGFR but no prior anti-VEGF NA NA
Prior anti-VEGF and prior anti-EGFR 385 0.71 (0.54–0.94)
Any prior targeted treatment* 760 0.77 (0.63–0.93)
CONCUR
Number of prior treatment lines on or after metastatic disease diagnosis
≤3 >3
125 79
0.65 (0.43–0.99) 0.46 (0.27–0.77)
No prior targeted treatment 82 0.31 (0.19–0.53)
Prior anti-VEGF but no prior anti-EGFR 45 0.99 (0.48–2.03)
Prior anti-EGFR but no prior anti-VEGF 41 0.80 (0.38–1.68)
Prior anti-VEGF and prior anti-EGFR 36 0.48 (0.22–1.08)
Any prior targeted treatment* 122 0.78 (0.51–1.19)
Grothey A, et al. Lancet. 2013;381:303-312. Li J, et al. Lancet Oncol. 2015;16:619-629. *Anti-VEGF, anti-EGFR or both. †Unstratified Cox regression model.
Exploratory Subgroup Analysis of OS by Previous Treatment
0 0.5 1 1.5 2 2.5 Hazard ratio (95% CI)†
Favors placebo Favors regorafenib
Grothey A, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-011.
Progression-Free Survival (PFS)
CORRECT
CONCUR
Grothey A, et al. Lancet. 2013;381:303-312. Li J, et al. Lancet Oncol. 2015;16:619-629. Grothey A, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-011.
Tumor Response n (%)
CORRECT CONCUR
Regorafenib (n = 505)
Placebo (n = 255)
Regorafenib (n = 136)
Placebo (n = 68)
Complete response (CR) 0 0 0 0
Partial response (PR) 5 (1) 1 (<1) 6 (4) 0
Stable disease (SD) 216 (43) 37 (15) 62 (46) 5 (7)
Non-CR/Non-PD* 4 (1) 1 (<1) 2 (1) 0
Disease control rate† 207 (41) 38 (15) 70 (51) 5 (7)
One-sided P value P<.0001 P<.0001
*Non-CR/Non-PD included in disease control rate and followed the same criteria as SD. †CORRECT: CR or PR or SD (subjects with SD as response performed earlier than 6 weeks after randomization, were not taken into account); CONCUR: CR or PR or SD (≥6 weeks after randomization). Both according to RECIST v1.1.
Grothey A, et al. Lancet. 2013;381:303-312. Li J, et al. Lancet Oncol. 2015;16:619-629.
Grothey A, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-011.
CORRECT CONCUR
Regorafenib (n = 500)*
Placebo (n = 253)*
Regorafenib (n = 136)
Placebo (n = 68)
Median duration of treatment, months† 1.7 1.6 2.4 1.6
Mean daily dose, mg (SD) 147.1 (18.6) 159.2 (4.9) 145.4 (18.1) 160.0 (0)
Median daily dose, mg 160.0 160.0 153.5 160.0
Any treatment modification, n (%) 378 (76) 97 (38) 102 (75) 15 (22)
Treatment interruptions/delays, n (%) 352 (70) 95 (38) 90 (66) 15 (22)
Study Drug Administration
*Safety analyses are based on 753 patients who initiated treatment. †Includes time off drug/interruptions. SD, standard deviation
Grothey A, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-011.
Grothey A, et al. Lancet. 2013;381:303-312. Li J, et al. Lancet Oncol. 2015;16:619-629.
Proportion of patients (%) CORRECT† CONCUR†
Regorafenib (n = 500)‡
Placebo (n = 253)‡
Regorafenib (n = 136)
Placebo (n = 68)
Any grade, regardless of relationship to study drug 100 97 100 88
Grade ≥3 78 49 71 44
Serious 44 40 32 26
Grade 5 13 15 9 10
Leading to treatment discontinuation 18 13 14 6
Leading to dose reduction 38 3 40 0
Leading to treatment interruption 61 22 63 16
Any grade, drug-related 93 61 97 46
Grade ≥3 55 14 54 15
Treatment-Emergent Adverse Events*
*During treatment or up to 30 days post treatment. †Adverse events were graded using the NCI-CTC for Adverse Events version 3.0 (CORRECT) and version 4.0 (CONCUR). ‡Safety analyses are based on 753 patients who initiated treatment.
Grothey A, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-011.
Grothey A, et al. Lancet. 2013;381:303-312. Li J, et al. Lancet Oncol. 2015;16:619-629.
Proportion of patients (%) CORRECT CONCUR
Regorafenib (n = 500)†
Placebo (n = 253)†
Regorafenib (n = 136)
Placebo (n = 68)
Hand–foot skin reaction 17 <1 16 0
Fatigue 10 5 3 1
Hypertension 7 1 11 3
Diarrhea 7 1 1 1
Hypophosphatemia 4 <1 7 0
Lipase increase 3 <1 4 1
Rash 6 0 4 0
Selected Drug-Related Grade ≥3 Adverse Events*
*Adverse events were graded using the NCI-CTC for Adverse Events version 3.0 (CORRECT) and version 4.0 (CONCUR). †Safety analyses are based on 753 patients who initiated treatment.
Grothey A, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-011.
Grothey A, et al. Lancet. 2013;381:303-312. Li J, et al. Lancet Oncol. 2015;16:619-629.
Proportion of patients (%) CORRECT CONCUR
Regorafenib Placebo Regorafenib Placebo ALT increased
Grade 3 Grade 4
5
<1
3
<1
9 0
1 0
AST increased Grade 3 Grade 4
5
<1
4
<1
10 <1
3 0
Blood bilirubin increased Grade 3 Grade 4
10 3
5 3
7 4
4 0
Anemia Grade 3 Grade 4
5
<1
3 0
8 0
1 0
Neutropenia Grade 3 Grade 4
<1 0
0 0
3 1
0 0
Thrombocytopenia Grade 3 Grade 4
2
<1
<1 0
3
<1
0 0
Treatment-Emergent Hepatic and Hematologic Laboratory Values of Interest, Regardless of Relation to Study Drug
ALT, alanine aminotransferase; AST, aspartate aminotransferase
Grothey A, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-011.
Conclusions • The international phase 3 CORRECT trial demonstrated the clinical
benefit of regorafenib in patients with previously treated mCRC, and the results were confirmed by the phase 3 CONCUR trial – Statistically significant improvements in OS compared with
placebo were reported in both Asian and non-Asian populations – Regorafenib was also superior to placebo in analyses of PFS and
disease control rate in both trials • A subgroup analysis of OS in CONCUR showed that the benefit in
patients who had received previous targeted treatment (HR 0.78 [95% CI 0.51-1.19]) was similar to that seen in CORRECT (HR 0.77 [95% CI 0.64-0.94]), in which all patients received at least one prior targeted therapy
• Adverse events were generally similar in the two trials and were consistent with the known safety profile of regorafenib
• These results confirm the role of regorafenib as an important treatment option for patients whose mCRC has progressed after standard treatments
Grothey A, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-011.
Results From the Large, Open-Label Phase 3b CONSIGN Study of Regorafenib in Patients With Previously Treated Metastatic
Colorectal Cancer
Van Cutsem E, Ciardiello F, Seitz J-F, Hofheinz RD, Verma U, Garcia-Carbonero R, Grothey A, Miriyala A, Kalmus J, Shapiro J, Falcone A,
Zaniboni A, on behalf of the CONSIGN Investigators
Abstract #LBA-05
• Regorafenib is an oral multikinase inhibitor that blocks the activity of multiple protein kinases involved in oncogenesis, tumor angiogenesis, and the tumor microenvironment1
• Regorafenib was approved for patients with previously treated metastatic colorectal cancer (mCRC) based on the results of the phase 3 CORRECT trial (NCT01103323; N = 760):2
– Median overall survival significantly improved with regorafenib (6.4 months) compared with placebo (5.0 months; HR 0.77; P = .0052)
– Treatment-emergent drug-related adverse events occurred in 93% of regorafenib recipients compared with 61% of placebo recipients
– The most common grade ≥3 treatment-emergent regorafenib-related adverse events were hand-foot skin reaction, fatigue, diarrhea, hypertension, and rash or desquamation
• The phase 3b CONSIGN study (NCT01538680) was initiated to further assess the safety of regorafenib and to allow patients with mCRC access to regorafenib prior to market authorization
Background
HR, hazard ratio
1. Wilhelm SM, et al. Int J Cancer. 2011;129:245-255. 2. Grothey A, et al. Lancet. 2013;381:303-312.
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
• To characterize the safety of regorafenib in a large cohort of patients (primary objective)
• To allow patients with mCRC, who progressed on standard treatments, access to regorafenib prior to market authorization
• To assess progression-free survival (PFS)
Objectives
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
• Prospective, single-arm • Conducted at 188 sites across 25 countries; planned enrollment approximately 3,000 patients • Treatment with regorafenib until one of the following:
– PD by radiological assessment or clinical progression – Death – Unacceptable toxicity – Withdrawal of consent – Determination by the treating physician that discontinuation is in the best interest of the patient
Methods: CONSIGN—Open-Label, Phase 3b Study of Regorafenib in
Previously Treated mCRC
Primary endpoint: Safety Efficacy endpoint: PFS (investigator-assessed)†
Regorafenib (oral) 160 mg once daily
3 weeks on/ 1 week off
• mCRC • Progression during/
within 3 months of approved standard therapies*
• ECOG PS 0-1 • N = 2872
Treatment until PD (or longer at the discretion of the
investigator)
Safety follow-up 30 days after
last dose
*Must have included fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and cetuximab/panitumumab (if KRAS wild-type). †Per investigator using radiological and/or clinical tumor assessment according to local standards (tumor measurements performed at intervals and with methods that comply with each institution’s best standard of care). ECOG, Eastern Cooperative Oncology Group; PD, progressive disease; PS, performance status
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
• A total of 2872 patients were assigned to treatment with regorafenib between April 2012 and December 2013
• Safety analysis includes 2864 patients who received treatment
• The cut-off date for this analysis was January 2, 2015 • As of April 7, 2015, 10 patients remained on treatment at
10 sites across 6 countries
Results
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
Regorafenib (N = 2872)
Median age, years (range) 62 (19-89)
Male, % 59
Race, % White Black Asian Other/not reported
83 2 1
15
Median body mass index, kg/m2 26
Primary site of disease, % Colon Rectum Colon and rectum
64 28 8
ECOG PS, % 0/1
47/53
KRAS mutation status, % Wild-type Mutant Unknown
45 51 4
Prior treatment regimens on or after diagnosis of metastatic disease, % 0 1–2 3 ≥4
<1 26 27 46
Baseline Characteristics
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
Regorafenib (n = 2864)
Median duration of treatment*, months (range) 2.5 (0-30) Mean daily dose, mg (SD) 146 (19) Median daily dose, mg 160 Any treatment modification†, n (%) 2497 (87) Treatment interruptions/delays, n (%) 2401 (84) Dose reductions, n (%) 1394 (49)
Study Drug Administration
*Includes time off drug/interruptions. †Modifications include reductions, interruptions/delays, and re-escalations. SD, standard deviation.
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
Regorafenib (n = 2864)
n (%) Treatment-emergent drug-related
Any grade 2613 (91)
Grade ≥3 1629 (57)
Serious 251 (9)
Grade 5 13 (<1)
Treatment-Emergent Drug-Related Adverse Events*†
*During treatment or up to 30 days post treatment. †Adverse events were graded using the NCI-CTC for Adverse Events version 4.0.
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
Proportion of patients (%)
CORRECT CONSIGN
Placebo (n = 253)
Regorafenib (n = 500)
Regorafenib (n = 2864)
Any grade, regardless of relation to study drug 97 100 99
Grade ≥3 49 78 80
Serious 40 44 44
Grade 5 15 13 14
Any grade, drug-related 61 93 91
Grade ≥3 14 55 57
Grade 5 0 1 <1
Treatment-Emergent Adverse Events in CORRECT and CONSIGN*
*Adverse events were graded using the NCI-CTC for Adverse Events version 3.0 for CORRECT and version 4.0 for CONSIGN.
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
Regorafenib (n = 2864)
n (%)
Treatment-emergent regardless of
relation to study drug
Treatment-emergent
drug-related
Leading to treatment discontinuation 720 (25) 266 (9)
Leading to treatment modification‡ 2129 (74) 1732 (60)
Leading to dose reduction 1321 (46) NE
Leading to treatment interruption/delay 1934 (68) NE
Treatment-Emergent Adverse Events Leading to Treatment Modifications*†
*During treatment or up to 30 days post treatment. †Adverse events were graded using the NCI-CTC for Adverse Events version 4.0. ‡Modifications include reductions, interruptions/delays, and re-escalations. NE, not evaluated
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
n (%) Regorafenib (n = 2864)
Grade ≥3, drug-related 1629 (57) Hypertension 435 (15) Hand-foot skin reaction 396 (14) Fatigue 376 (13) Diarrhea 135 (5) Hypophosphatemia 149 (5)
Treatment-Emergent Drug-Related Grade ≥3 Adverse Events Occurring in
≥5% of Patients*
*Adverse events were graded using the NCI-CTC for Adverse Events version 4.0.
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
Regorafenib (n = 2864)
n/N % Blood bilirubin increased 374/2815 13 AST increased 193/2808 7 ALT increased 156/2809 6
Anemia 101/2786 4 Thrombocytopenia 57/2788 2 Neutropenia 23/2357 1
Treatment-Emergent Grade ≥3 Hepatic and Hematologic Laboratory Values of Interest,
Regardless of Relation to Study Drug
• One non-fatal case of severe drug-induced liver injury† was identified by ongoing monitoring
N, number of patients with measurements for the given parameter. †According to International DILI Working Group criteria in Aithal GP, et al. Clin Pharmacol Ther. 2011;89:806-815. ALT, alanine aminotransferase; AST, aspartate aminotransferase
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
Progression-Free Survival (PFS)* CORRECT
CONSIGN
*In CONSIGN, intervals for radiological assessments were not pre-determined as they were in CORRECT. PFS in CONSIGN was by investigator assessment; tumor assessments were not as rigorous as in a confirmatory study with a PFS endpoint. Grothey A, et al. Lancet. 2013;381:303-312.
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
CONSIGN: PFS by KRAS Mutation Status
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
• In this large, prospective study in patients with previously treated mCRC, the safety profile of regorafenib was consistent with the safety profile reported in the phase 3 CORRECT trial1
• PFS was in the range of that reported with regorafenib in treatment-refractory mCRC and was similar across KRAS wild-type and mutant subgroups
• The rate of dose reductions and treatment interruptions highlights the importance of optimal patient selection, management, and dose modification
Conclusions
1. Grothey A, Van Cutsem E, et al. Lancet 2013;381:303-312.
Van Cutsem E, et al. Ann Oncol. 2015;26(suppl 4): Abstract LBA-05.
KRAS and BRAF Gene Subgroup Analysis in the Phase 3 RECOURSE Trial of TAS-102 Versus Placebo in Patients with Metastatic
Colorectal Cancer
Hochster H, Hager S, Pipas JM, Tebbutt N, Laurent S, Gravalos C, Benavides M, Munoz FL, Portales F, Ciardiello F, Siena S, Yamaguchi
K, Muro K, Denda T, Tsuji Y, Ohtsu A, Van Cutsem E, Mayer RJ, on behalf of the RECOURSE Study Group
Abstract #O-010
TAS-102: An Oral Combination of FTD and TPI
+
Molar ratio 1 0.5 :
Hochster H, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-010.
FTD (trifluridine)
Antitumor activity
TPI (tipiracil hydrochloride)
Suppression of FTD degradation
FTD
Thymidine analogue
Trifluoromethyl group
Thymidine
Methyl group
TAS-102: Mechanism of Action • Distinct from that of 5-fluorouracil (5-FU), which is a uracil analogue
5-FU
FdUMP
Inhibit
TS
dTMP dUMP
dTTP
F3dTMP
FTD
F3dTDP
F3dTTP
5-FU TAS-102
Inhibit DNA replication
Incorporate to DNA
dTMP,deoxythymidine monophosphate; dTTP, deoxythymidine triphosphate; FdUMP, fluorodeoxyuridine monophosphaet; FTD, trifluridine; TS, thymidylate synthase
Hochster H, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-010.
RECOURSE Study Design
• Treatment continuation until progression, intolerant toxicity, or patient refusal • Multicenter, randomized, double-blind, placebo-controlled, phase 3
─ Stratification, KRAS, time from diagnosis of metastatic disease, region • Sites: 13 countries, 114 sites • Enrolllment: June 2012 to October 2013 • Mayer RJ, et al. N Engl J Med. 2015;372:1909-1919.
Metastatic colorectal cancer (mCRC) • 2 or more prior regimens • Refractory/intolerable
─ Fluoropyridimidine ─ Irinotecan ─ Oxaliplatin ─ Bevacizumab ─ Anti-EGFR if wild-
type KRAS • ECOG PS 0-1 • Age >18 years (randomized patients N=800)
RANDOM I ZAT I ON
TAS-102 + BSC (n = 534)
35 mg/m2 bid, po D1-5, 8-12 q4wks
Primary endpoint: OS
Secondary endpoints; PFS,
safety, tolerability, TTF, ORR, DCR,
DoR, subgroup by KRAS
(OS and PFS) Placebo + BSC (n = 266)
d1-5, 8-12 q4wks
2:1
Hochster H, et al. Ann Oncol. 2015; 26(suppl 4): Abstract O-010.
RECOURSE KRAS and BRAF Gene Subgroup Analysis
• Prespecified analyses of RECOURSE compared efficacy and safety of TAS-102 vs placebo in subgroups of patients who had tumors that were KRAS/BRAF wild type (WT) or mutant, as reported by investigators
• Patients were initially stratified by KRAS status determined through the interactive voice recording system (IVRS) (tumor samples were not collected)
• BRAF status was collected if available • Primary endpoint (OS) and key secondary efficacy endpoint
(PFS) were evaluated using univariate and multivariate analyses for stratification and prespecified factors
Hochster H, et al. Ann Oncol. 2015; 26(suppl 4): Abstract O-010.
KRAS and BRAF Gene Subgroup Analysis: Mutational Status (ITT Population)
TAS-102 (n = 534)
Placebo (n = 266)
Total (n = 800)
KRAS status,a n (%) WT 260 (48.7) 134 (50.4) 394 (49.3) Mutant 274 (51.3) 132 (49.6) 406 (50.8) KRAS mutation type, n (%) Codon 12 201 (37.6) 102 (38.3) 303 (37.9) Codon 13 55 (10.3) 28 (10.5) 83 (10.4) Other 6 (1.2) 3 (1.2) 9 (1.2) Unknown 26 (4.9) 8 (3.0) 34 (4.3) BRAF status, n (%) WT 75 (14.0) 41 (15.4) 116 (14.5) Mutant 4 (0.7) 4 (1.5) 8 (1.0) Missing 455 (85.2) 221 (83.1) 676 (84.5) • There was a higher proportion of patients in the mutant KRAS gene subgroup than expected (~5%),
perhaps due to fewer available therapeutic options ITT, intention to treat Per assignment on the case report forms
Hochster H, et al. Ann Oncol. 2015; 26(suppl 4): Abstract O-010.
KRAS Subgroup Patient Demographics and Baseline Characteristics (ITT Population)
KRAS WT KRAS Mutant TAS-102 (n = 260)
Placebo (n = 134)
TAS-102 (n = 274)
Placebo (n = 132)
Gender, male, n (%) 168 (64.6) 83 (61.9) 158 (57.7) 82 (62.1) Age, y, mean (SD) 62.1 (10.33) 61.6 (9.46) 60.9 (10.09) 61.4 (11.51) Race, n (%) Caucasian 139 (53.5) 82 (61.2) 167 (60.9) 73 (55.3) Black/African-American 2 (0.8) 1 (0.7) 2 (0.7) 4 (3.0) Asian 97 (37.3) 43 (32.1) 87 (31.8) 51 (38.6) Not collected 22 (8.5) 8 (6.0) 18 (6.6) 4 (3.0) ECOG PS, n (%) 0 149 (57.3) 63 (47.0) 152 (55.5) 84 (63.6) 1 111 (42.7) 71 (53.0) 122 (44.5) 48 (36.4) Primary tumor site, n (%) Colon 155 (59.6) 80 (59.7) 183 (66.9) 81 (61.4) Rectal 105 (40.4) 54 (40.3) 91 (33.2) 51 (38.6)
Hochster H, et al. Ann Oncol. 2015; 26(suppl 4): Abstract O-010.
KRAS Subgroup Patient Demographics and Baseline Characteristics (ITT Population) (cont)
KRAS WT KRAS Mutant
TAS-102 (n = 260)
Placebo (n = 134)
TAS-102 (n = 274)
Placebo (n = 132)
Number of prior regimens, a n (%) 1 0 0 0 0 2 25 (9.6) 8 (6.0) 70 (25.5) 37 (28.0) 3 50 (19.2) 22 (16.4) 69 (25.2) 32 (24.2)
>4 185 (71.2) 104 (77.6) 135 (49.3) 63 (47.7)
All patients had prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies; all but 1 patient had received bevacizuamb, and all but 2 patients with KRAS WT tumors had received panitumumab or cetuximab.
Other prior systemic cancer therapies, a n (%) Regorafenib 40 (15.4) 31 (23.1) 51 (18.6) 22 (16.7) Other 228 (87.0) 118 (88.0) 243 (88.7) 121 (91.7)
• Subgroups were similar with respect to baseline and demographic characteristics except for time since diagnosis of metastasis ─ Consistent with the availability of additional therapeutic options for patients with KRAS WT
• Within each subgroup, the treatment groups (TAS-102 and placebo) were well balanced aIncludes all prior systemic therapies (neoadjuvant, adjuvant metastatic)
Hochster H, et al. Ann Oncol. 2015; 26(suppl 4): Abstract O-010.
100 90
80 70
60 50
40 30
20 10
0
KRAS Gene Subgroup Efficacy: Progression-Free Survival and Disease Control Rate
• DCR was similar between patients with KRAS WT or mutant genotypes who received TAS-102 (45.8% and 42.2%, respectively) ─ In the overall study, DCR in patients who received TAS-102 was 44% vs 16.3% in the placebo group
KRAS WT KRAS Mutant TAS-102 (n = 262)
Placebo (n = 131)
TAS-102 (n = 272)
Placebo (n = 135)
Median PFS, mos 2.1 1.7 1.9 1.8
HR (95% CI) 0.48 (0.39-060) 0.43 (0.39-0.61)
P<.0001 P<.0001
Overall RECOURSE Population TAS-102 (n = 534)
Placebo (n = 266)
Median PFS, mos 2.0 1.7
HR (95% CI) 0.48 (0.41-0.57)
P<.0001
0 10 4 6 8 2 12 14 16 I I I I I I I I I
100 90
80 70
60 50
40 30
20 10
0 0 10 4 6 8 2 12 14 16 I I I I I I I I I
Months From Randomization
% E
vent
Fre
e
Prog
ress
ion-
Free
Sur
viva
l
Hochster H, et al. Ann Oncol. 2015; 26(suppl 4): Abstract O-010.
I I
I I
I I
I I
I I
I
I I
I I
I I
I I
I I
I
Mutant, TAS-102 Mutant, Placebo
TAS-102 Placebo
Months From Randomization 534 266
18 2
121 10
66 2
30 2
238 51
5 1
4 1
2 0
Mutant, TAS-102: Mutant, Placebo:
100 90
I I
I I
I I
I I
I I
I
KRAS Gene Subgroup Efficacy: Overall Survival
KRAS WT KRAS Mutant TAS-102 (n = 262)
Placebo (n = 131)
TAS-102 (n = 272)
Placebo (n = 135)
Median OS, mos 8 5.7 6.5 4.9
HR (95% CI) 0.58 (0.45-074) 0.8 (0.63-1.02)
P<.0001 P=.0712
Overall RECOURSE Population TAS-102 (n = 534)
Placebo (n = 266)
Median OS, mos 7.1 5.3
HR (95% CI) 0.68 (0.58-0.81)
P<.0001
80 70
60 50
40 30
20 10
0
Months From Randomization
% S
urvi
val
Ove
rall
Surv
ival
0 15 6 9 12 3 18 I I I I I I I
Hochster H, et al. Ann Oncol. 2015; 26(suppl 4): Abstract O-010.
100 90
80 70
60 50
40 30
20 10
0
Months From Randomization
I I
I I
I I
I I
I I
I
0 15 6 9 12 3 18 I I I I I I I
TAS-102 Placebo Mutant, TAS-102
Mutant, Placebo
137 47
534 266
459 198
294 107
64 24
23 9
7 3
TAS-102: Placebo:
KRAS Gene Subgroup Efficacy: Overall Survival
KRAS WT KRAS Mutant TAS-102 (n = 262)
Placebo (n = 131)
TAS-102 (n = 272)
Placebo (n = 135)
Median OS, mos 8 5.7 6.5 4.9
HR (95% CI) 0.58 (0.45-074) 0.8 (0.63-1.02)
P<.0001 P=.0712
Overall RECOURSE Population TAS-102 (n = 534)
Placebo (n = 260)
Median OS, mos 7.1 5.3
HR (95% CI) 0.68 (0.58-0.81)
P<.0001
100 90
80 70
60 50
40 30
20 10
0 0 15 6 9 12 3 18 I I I I I I I
Months From Randomization
100
% S
urvi
val
Ove
rall
Surv
ival
Hochster H, et al. Ann Oncol. 2015; 26(suppl 4): Abstract O-010.
I I
I I
I I
I I
I I
I
I I
I I
I I
I I
I I
I
90 80
70 60
50 40
30 20
10 0
Months From Randomization
I I
I I
I I
I I
I I
I
0 15 6 9 12 3 18 I I I I I I I
TAS-102 Placebo Mutant, TAS-102
Mutant, Placebo Wild, TAS-102 Wild, Placebo
137 47
534 266
459 198
294 107
64 24
23 9
7 3
TAS-102: Placebo:
KRAS Status Is Not Predictive of Treatment Outcome
• A stepwise selection process identified a final subset of prognostic/predictive factors to include in a Cox proportional hazard (CPH) model
• An exploratory analysis of treatment-by-factor interactions using the CPH model was conducted and included the following factors ─ KRAS status ─ Time since diagnosis of first metastasis ─ Region ─ Primary tumor site ─ ECOG PS ─ Number of metastatic sites
• KRAS status was not predictive of treatment outcome, with an interactions P = .4213a
Hochster H, et al. Ann Oncol. 2015; 26(suppl 4): Abstract O-010.
KRAS Gene Subgroup Analysis: Safety
• There were no marked differences between patient subgroups based on KRAS status with respect to overall incidence of adverse events (AEs), grade ≥3 AEs or serious AEs in either the TAS-102 or placebo groups
As-Treated Population KRAS WT KRAS Mutant
TAS-102 (n = 260)
Placebo (n = 133)
TAS-102 (n = 273)
Placebo (n = 132)
Any AE, n (%) 258 (99.2) 124 (93.2) 266 (97.4) 123 (93.2) Grade ≥3 AEs, n (%) 177 (68.1) 69 (51.9) 193 (70.7) 68 (51.5) Serious AEs, n (%) 84 (32.3) 42 (31.6) 74 (27.1) 47 (35.6)
Hochster H, et al. Ann Oncol. 2015; 26(suppl 4): Abstract O-010.
Relative Risk of Selected Adverse Events ≥3%* for KRAS WT vs Mutant: TAS-102 Group
KRAS WT (n = 260)
KRAS mutant (n = 273)
Relative risk mutant vs WT
(95% CI) Grade ≥3 hematologic events, n (%) Clinical findings Febrile neutropenia 14 (5.4) 6 (2.2) 0.41 (0.16-1.05) Laboratory abnormalities Anemia 55 (21.2) 41 (15.2) 0.71 (0.49-1.02) Neutropenia 108 (41.7) 92 (34.2) 0.81 (0.65-1.01) Thrombocytopenia 20 (7.7) 7 (2.6) 0.33 (0.14-0.78) Grade ≥3 nonhematologic events, n (%) 75 (14.0) 41 (15.4) 116 (14.5) Asthenia 6(2.3) 12 (4.4) 1.90 (0.73-5.00) Decreased appetite 9 (3.5) 10 (3.7) 1.06 (0.45-2.56) Diarrhea 7 (2.7) 9 (3.3) 1.22 (0.46-3.24) Fatigue 10 (3.8) 11 (4.0) 1.05 (0.45-2.43) Vomiting 8 (3.1) 3 (1.1) 0.36 (0.10-1.33) Any grade nonhematologic events, n (%) Cardiac (arrhythmic) 8 (3.1) 7 (2.6) 0.83 (0.31-2.27) Thromboembolic events (arterial and venous) 12 (4.6) 9 (3.3) 0.71 (0.31-1.67)
*In either KRAS WT or mutant group
Hochster H, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-010.
BRAF Subgroup Patient Demographics and Baseline Characteristics (ITT Population)
• Subgroups were similar with respect to baseline and demographic characteristics except for time since diagnosis of metastasis
BRAF WT BRAF Mutant TAS-102 (n = 75)
Placebo (n = 41)
TAS-102 (n = 4)
Placebo (n = 4)
Gender, male, n (%) 52 (69.3) 26 (63.4) 2 (50.0) 2 (50.0) Age, y, mean (SD) 60.7 (11.45) 60.3 (10.60) 53.8 (17.31) 65.0 (8.76) Race, n (%) Caucasian 47 (62.7)) 28 (68.3) 4 (100.0) 4 (100.0) Black/African-American 2 (2.7) 0 0 0 Asian 12 (16.0) 8 (19.5) 0 0 Not collected 14 (18.7) 5 (12.2) 0 0 ECOG PS, n (%) 0 47 (62.7) 23 (56.1) 2 (50.0) 2 (50.0) 1 33 (44.0) 15 (36.6) 1 (25.0) 2 (50.0) KRAS status,a n (%) WT 42 (56.0) 26 (63.4) 3 (75.0) 2 (50.0) Mutant 33 (44.0) 15 (36.6) 1 (25.0) 2 (50.0) Time since diagnosis of first metastasis,a n (%) <18 months 21 (28.0) 8 (19.5) 1 (25.0) 2 (50.0) > 18 months 54 (72.0) 33 (80.5) 3 (75.0) 2 (50.0)
Hochster H, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-010.
BRAF Gene Subgroup Results • Efficacy
─ The small sample size (116 WT and 8 mutant tumors) limited evaluations of efficacy
• Safety ─ Adverse events were similar to those seen in
patients with KRAS WT and mutant tumors and in the overall RECOURSE trial
Hochster H, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-010.
Conclusions • In the RECOURSE study, improvements in OS
and PFS were observed in patients with KRAS WT and mutant tumors who received TAS-102 vs placebo, with a favorable safety profile
• While the effect on PFS was the same for KRAS WT and mutant groups, OS showed a more pronounced effect on wild type with an HR of 0.6 and 0.8, respectively
• Although similar improvements with TAS-102 were seen for OS and PFS with respect to BRAF status, the small patient sample size limited definitive conclusions
Hochster H, et al. Ann Oncol. 2015;26(suppl 4): Abstract O-010.
Clinical Spotlight in mCRC: Assessing Options in the
Third Line and Beyond Reference Slide Deck
Abstract #LBA-05 Abstract #O-010 Abstract #O-011
2015 World Congress on Gastrointestinal Cancer