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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.


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.


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


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


Placebo (n = 255)


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.


CORRECT CONCUR

Regorafenib (n = 500)*

Placebo (n = 253)*


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



Proportion of patients (%) CORRECT† CONCUR†

Regorafenib (n = 500)‡

Placebo (n = 253)‡


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.



Proportion of patients (%) CORRECT CONCUR

Regorafenib (n = 500)†

Placebo (n = 253)†


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.



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


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


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


• 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


• 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


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



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.



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.


Proportion of patients (%)

CORRECT CONSIGN

Placebo (n = 253)



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.



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


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.



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


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.


CONSIGN: PFS by KRAS Mutation Status


• 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.


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


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


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


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)


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)


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


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


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


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


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


% S

urvi

val

Ove

rall

Surv

ival

0 15 6 9 12 3 18 I I I I I I I


100 90

80 70

60 50

40 30

20 10

0


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


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


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


100

% S

urvi

val

Ove

rall

Surv

ival


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


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


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)


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


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)


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


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


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

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