ASCO 2017 updates in Colorectal and Gastric Cancers · 2017-09-20 · ASCO 2017 updates in Colorectal and Gastric Cancers May Cho, M.D. Relevant financial relationships in the past

ASCO 2017 updates in Colorectal and Gastric Cancers

May Cho, M.D.

Relevant financial relationships in the past twelve months by presenter or spouse/partner:

None

The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational.

Outline

Colorectal Cancer– IDEA trial (adjuvant therapy)

– CALGB/SWOG 80405 Prognostic Factors

– SWOG S1406 (VIC vs IC in BRAF mCRC) Gastric Cancer

– FLOT

– KEYNOTE-059

IDEA: Pooled Analysis of Adjuvant Oxaliplatinfor 3 vs 6 Months in Stage III Colon Cancer

IDEA: Trials, Treatment

Prospectively pooled analysis of data from 6 concurrent randomized phase III trials in pts with stage III CC (mITT population: N ≥ 12,834)

– Pts randomized 1:1 to 3 vs 6 mos tx with oxaliplatin-based tx (investigator’s choice of FOLFOX or CAPOX)

Slide credit: clinicaloptions.comShi Q, et al. ASCO 2017. Abstract LBA1.

Trial Stage III CC Pts, N Treatment Country Median F/u,

MosPts on

CAPOX, %TOSCA 2402 CAPOX or FOLFOX4 Italy 62 35

SCOT 3983 CAPOX or mFOLFOX6 Australia, Denmark, New Zealand, Spain, Sweden, UK 37 67

IDEA France 2010 CAPOX or mFOLFOX6 France 51 10

C80702 2440 mFOLFOX6 Canada, US 35 0

HORG 708 CAPOX or FOLFOX4 Greece 48 58

ACHIEVE 1291 CAPOX or mFOLFOX6 Japan 37 75

http://www.clinicaloptions.com/

IDEA: Statistical Plan

Primary endpoint: DFS in mITT population*– DFS: time from randomization to earliest date of relapse, secondary colorectal

primary tumor, or death

– Preplanned subgroup analyses by regimen, risk groups

Statistical analyses– DFS HR for 3 vs 6 mos (2-sided 95% CI) estimated with Cox model stratified by trial

– Predefined noninferiority margin for HR < 1.12 (12% increase in relative risk)

– Requires 3390 DFS events for 90% power with 1-sided α = 0.025

– Predefined noninferiority margin for 3-yr DFS rate difference (3 vs 6 mos): -2.7%

Additional endpoints: treatment compliance, safety

Shi Q, et al. ASCO 2017. Abstract LBA1. Slide credit: clinicaloptions.com

*Received ≥ 1 dose of study drug.


IDEA: Pt Characteristics by Tx Duration, Regimen


CharacteristicFOLFOX CAPOX

3 Mos(n = 3870)

6 Mos(n = 3893)

3 Mos(n = 2554)

6 Mos(n = 2517)

Median age, yrs 64 64 65 65ECOG PS 0/1,* % 77/22 77/22 82/18 81/19T stage, % T1-2 T3 T4

136819

146719

136324

126325

N stage, % N1 N2

7228

7327

7129

7129

Reached final planned cycle, % 90 71 86 65*1% of FOLFOX-treated pts had ECOG PS 2.


Shi Q, et al. ASCO 2017. Abstract LBA1. Reproduced with permission.

IDEA: DFS in mITT Population, Risk Subgroups

Slide credit: clinicaloptions.com

Noninferiority of oxaliplatin-based tx for 3 vs 6 mos not proven

– DFS HR: 1.07 (95% CI: 1.00-1.15)

– Difference in 3-yr DFS rates: -0.9% (95% CI: -2.4% to 0.6%)

3-yr DFS rate difference of 20% between low risk (T1-3, N1) vs high risk (T4 or N2) subgroups

T1-3, N1T4 or N2

HR

Interaction P Value

Favors 3 mos Favors 6 mosRisk Group

1.011.12

0.5 1 1.12 1.5

.11

HR


Shi Q, et al. ASCO 2017. Abstract LBA1. Reproduced with permission.

IDEA: DFS by Risk Subgroups and Regimen


Favors 3 mos Favors 6 mos HR (95% CI)

Noninferiority margin

Risk Group

Regimen

T1-3, N1

T4 or N2

FOLFOXCAPOX

FOLFOXCAPOX

Not provenNoninferior

InferiorNot proven

1.10 (0.96-1.26)0.85 (0.71-1.01)

1.20 (1.07-1.35)1.02 (0.89-1.17)

HR 1.0 1.12


IDEA: Safety


AE, %FOLFOX CAPOX

3 Mos 6 Mos P Value* 3 Mos 6 Mos P Value*Any event† Grade 2 Grade 3/4

3238

3257

< .0001 4124

4837

< .0001

Neurotoxicity Grade 2 Grade ¾

143

3216

< .0001 123

369

< .0001

Diarrhea Grade 2 Grade 3/4

115

137

< .0001 107

139

.0117

*For Chi-squared test for trend.†19 grade 5 events reported.


IDEA: Investigator Conclusions DFS noninferiority of adjuvant oxaliplatin-based tx for 3 vs 6 mos not established in overall

pts with stage III CC

Shorter tx associated with greater treatment compliance, much less grade ≥ 2 neuropathy

Investigators recommend risk-vs-benefit approach when selecting duration of adjuvant oxaliplatin-based tx

– Low-risk pts (T1-3, N1): 3 mos

– High-risk pts (T4, N2, or other high-risk variables): 3-6 mos depending on tolerability, ptpreferences, recurrence risk, regimen (FOLFOX vs CAPOX)



Prognostic Factors for First-line Chemotherapy + Bevacizumab or Cetuximab in Metastatic

Colorectal Cancer

CALGB/SWOG 80405: Study Design and Survival Randomized, open-label phase III trial

No difference between cetuximab and bevacizumab when combined with FOLFIRI or FOLFOX with respect to OS or PFS[1]

Pts with KRAS wild-type (Codons 12, 13) metastatic/advanced CRC and no previous therapy for advanced

disease (N = 1137)

Cetuximab + Chemotherapy*(n = 578)

Bevacizumab + Chemotherapy*(n = 559)


OS, Mos PFS, Mos

29.9 10.4

29.0 10.8

*Physician choice of FOLFIRI or FOLFOX.

1. Venook A, et al. JAMA. 2017 (in press). 2. Venook A, et al. ASCO 2017. Abstract 3503. 3. Innocenti F, et al. ASCO 2017. Abstract 3504.


Pts with right-sided tumor, n = 293 (27%); left-sided, n = 732 (68%)

– Pts with transverse colon tumors excluded from analysis (n = 66)

CALGB/SWOG 80405 Prognostic Factors: OS by Side of Tumor and Biologic Treatment

Venook A, et al. ASCO 2016. Abstract 2016. Reproduced with permission. Slide credit: clinicaloptions.com

OS by Sidedness OS by Side and Treatment

OS

(%)

Mos MosO

S (%

)

0

20

40

60

100

80

0 12 24 36 48 60 8472 10896

Side

Left

Right

mOS(95% CI)

33.3(31.4-35.7)

19.4(16.7-23.6)

N (Events)

732 (550)

293 (242)

HR(95% CI)

1.55

(1.32-1.82)

P Value

< .0001

Left

Right

0

20

40

60

100

80

0 12 24 36 48 60 8472 10896

Left/BevacizumabmOS 31.4 (95% CI: 28.3-33.6)Left/CetuximabmOS 36.0 (95% CI: 32.6-40.3)Right/BevacizumabmOS 24.2 (95% CI: 17.9-30.3)Right/CetuximabmOS 16.7 (95% CI: 13.1-19.4)


CALGB/SWOG 80405 Prognostic Factors: Current Analyses Multivariate analysis of prognostic

utility of tumor sidedness (independent of other molecular features)[1]

– Evaluated in subset of pts with left-/ right-sided tumors (no transverse) and available molecular data (n = 728)

– Used Cox proportional hazard models*

– Evaluated potential biomarkers of sidedness/tumor burden

Analysis of mutational profile and prognostic, clinical value of DNA alterations[2]

– DNA from 504 tumor specimens

– Mutation profile determined by PCR genotyping in 12 genes, MSI-high status by microsatellite mutation analysis, mutational load in 395 genes by NGS

– Primary endpoint: OS

– Used Cox proportional hazard models* to test association with molecular alterations†

Slide credit: clinicaloptions.com1. Venook AP, et al. ASCO 2017. Abstract 3503. 2. Innocenti F, et al. ASCO 2017. Abstract 3504.

*Models stratified by adjuvant CT, prior RT. Models adjusted for age, race, sex, synchronous vs metachronous, BRAF. Sidedness analysis also adjusted for consensus molecular subtypes, MSI, NRAS, KRAS, HRAS; mutational analysis for liver metastases only, sidedness. †No adjustment for multiple comparisons.


CALGB/SWOG 80405 Prognostic Factors: Sidedness Independent of Molecular Features Multivariate analysis found that sidedness

a significant prognostic factor independent of other molecular features

– HR: 1.392 (95% CI: 1.032-1.878; P = .031*)

Clinical characteristics compared between pts with right- vs left-sided tumors to determine whether sidedness potentially a surrogate for tumor burden

– Pattern of metastases significantly differed by side (Chi-squared P = .0136)

– No significant differences with other tumor burden indicators

Slide credit: clinicaloptions.comVenook AP, et al. ASCO 2017. Abstract 3503.

Tumor Burden Indicator, %

Right-Sided Tumors(n = 167)

Left-Sided Tumors(n = 330)

Median LDH, IU/L 195.5 196.5Metastatic sites, n 1 2 ≥ 3

53.933.911.5

55.930.113.1

Prior adjuvant tx 12.0 18.81⁰ in place at tx initiation 4.8 1.8Intent, palliative/curative 86.4/13.6 83.1/16.9Pattern of metastases Liver only Liver + extrahepatic Extrahepatic only

30.362.437.0

38.373.325.8

*Per stratified, adjusted Cox proportional hazard model.


CALGB/SWOG 80405 Prognostic Factors: OS by BRAF Genotype

Patient Genotype Group Median OS, Mos (95% CI) HRadj (95% CI) P for Interaction,

BRAF/biologics

BRAF genotype Wild type (n = 432) Mutant (n = 72)

34.2 (31.0-36.4)12.9 (11.1-19.0)

1.82 (1.37-2.44) P = .0001*

BRAF wild type Treated with cetuximab (n = 225) Treated with bevacizumab (n = 207)

33.4 (29.1-39.2)34.4 (30.3-37.6)

0.97 (0.77-1.23) P = .75

.13BRAF mutant Treated with cetuximab (n = 31) Treated with bevacizumab (n = 41)

11.7 (8.6-19.7)15.0 (11.8-23.7)

0.61 (0.35-1.06) P = .51

Innocenti F, et al. ASCO 2017. Abstract 3504.

*If further adjusted for sidedness of tumor, HR: 1.67 (95% CI: 1.20-2.33; P = .0035).



CALGB/SWOG 80405 Prognostic Factors: OS by MSI Status

Patient Subgroup Median OS, Mos (95% CI) HRadj (95% CI)P for

Interaction, MSI/biologics

Microsatellite instability High level of instability (n = 29; 52%

BRAF mutant) Stable (n = 389; 11% BRAF mutant)

30.3 (22.6-NE)31.8 (29.0-35.2)

0.84 (0.51-1.39) P = .50

Microsatellite stable Treated with cetuximab (n = 224) Treated with bevacizumab (n = 220)

33.4 (29.1-39.3)32.8 (29.0-36.0)

1.03 (0.82-1.30) P = .48

.0002Microsatellite instability-high Treated with cetuximab (n = 13, 46%

BRAF mutant) Treated with bevacizumab (n = 18,

61% BRAF mutant)

11.5 (10.3-NE)30.3 (23.6-NE)

0.17 (0.07-0.41)P = .002

Innocenti F, et al. ASCO 2017. Abstract 3504. Slide credit: clinicaloptions.com


CALGB/SWOG 80405 Prognostic Factors: OS by Mutational Load

Patient Subgroup Median OS, Mos (95% CI) HRadj (95% CI)

P for Interaction, Mutational

Load/BiologicsMutational Load in MSS mCRC ≤ 8 (n = 228) > 8 (n = 65)

30.1 (25.6-34.3)35.7 (31.2-45.5)

0.67 (0.47-0.95) P = .02

Mutational Load ≤ 8 in MSS mCRC Treated with cetuximab (n = 103) Treated with bevacizumab (n = 125)

29.1 (24.3-38.5)30.3 (25.3-34.5)

1.00 (0.72-1.39) P = .97

.56Mutational Load > 8 in MSS mCRC Treated with cetuximab (n = 27) Treated with bevacizumab (n = 38)

35.8 (30.3-63.7)35.1 (31.2-53.6)

0.81 (0.43-1.52) P = .79

Innocenti F, et al. ASCO 2017. Abstract 3504. Slide credit: clinicaloptions.com


CALGB/SWOG 80405 Prognostic Factors: Investigator Conclusions In pts with mCRC and no previous therapy for advanced disease:

– Left-sided tumors significantly associated with improved OS, regardless of biologic tx[1]

– Sidedness a prognostic factor independent of other molecular features (HR: 1.392; P = .031)

– Investigators concluded that tumor sidedness differences not due to tumor burden; further study warranted to identify mechanisms behind sidedness as independent prognostic factor

– BRAF status strong prognostic marker, even when adjusted for tumor sidedness, but has no predictive interaction with biologic therapy[2]

– MSI status not prognostic but may be predictive for biologic therapy[2]

– Mutational load in pts with MSS CRC has prognostic potential but does not seem to be predictive for biologic therapy[2]

According to investigators, these data indicate that pt and tumor characteristics may help predict response to biologic therapy but larger numbers of pts and more markers need to be explored[1,2]

1. Venook AP, et al. ASCO 2017. Abstract 3503. 2. Innocenti F, et al. ASCO 2017. Abstract 3504. Slide credit: clinicaloptions.com


SWOG S1406: Vemurafenib in Combination With Irinotecan and Cetuximab in BRAF V600E

Metastatic CRC

SWOG S1406: Background

BRAF V600E: mutation leading to constitutive activation of BRAF kinase and MAPK pathway[1]

– BRAF mutated in ~ 8% of mCRC cases

– Associated with aggressive disease, poor prognosis, minimal benefit from standard chemotherapy[2]

Vemurafenib: kinase inhibitor selective for mutated BRAF protein[3]

– Vemurafenib monotherapy associated with limited activity in mCRC

– Phase I study suggested improved survival and response in combination with irinotecan + cetuximab in refractory mCRC with BRAF V600E[4]

Current study evaluated efficacy and safety of vemurafenib addition to irinotecan + cetuximab in pts with BRAF V600E mCRC[5]

Slide credit: clinicaloptions.comReferences in slidenotes.


SWOG S1406: Study Design

Randomized, multicenter, open-label phase II trial

Slide credit: clinicaloptions.comKopetz S, et al. ASCO 2017. Abstract 3505. ClinicalTrials.gov. NCT02164916.

Pts with mCRC, extended RAS WT and BRAF V600E, previously treated with 1-2

systemic CT lines for metastatic or advanced unresectable disease, no prior

panitumumab or cetuximab, no prior BRAF or MEK inhibitors, ECOG PS 0-1

(N = 106)*

Until PD

Until PD; crossover allowed to

vemurafenib arm after PD

Cetuximab 500 mg/m2 IV Q2W + Irinotecan 180 mg/m2 IV Q2W

(n = 50)

Vemurafenib 960 mg PO BID + Cetuximab 500 mg/m2 IV Q2W +

Irinotecan 180 mg/m2 IV Q2W(n = 49)

Primary endpoint: PFS

Secondary endpoints: OS, ORR, treatment-related AEs

Stratified by prior irinotecan treatment (yes vs no)Randomized 1:1

*Only 99 pts eligible to receive treatment after randomization.


SWOG S1406: Baseline Characteristics

Slide credit: clinicaloptions.comKopetz S, et al. ASCO 2017. Abstract 3505.

Characteristic, n (%) VIC(n = 49)

IC(n = 50)

Median age, yrs (range) 60 (34-83) 62 (31-83)Female 21 (43) 37 (74)Race White Black Asian

43 (88)1 (2)4 (8)

49 (98)0 (0)1 (2)

Hispanic ethnicity 2 (4) 2 (4)ECOG PS 1 25 (51) 27 (54)Prior irinotecan 20 (41) 19 (38)Prior regimens for mCRC 1 2 Failed adjuvant within 6 mos

27 (55)19 (39)3 (6)

26 (52)17 (34)7 (14)


SWOG S1406: PFS (Primary Endpoint)


PFS

(%)

HR: 0.48 (95% CI: 0.31-0.75; P = .001)

Events, n mPFS (95% CI)VIC 40 4.3 (3.6-5.7)

IC 48 2.0 (1.8-2.1)

Kopetz S, et al. ASCO 2017. Abstract 3505. Reproduced with permission.

Median follow-up: 7.3 mos

Among 48% of pts who crossed over to VIC after PD on IC, mPFS was 5.8 mos

PFS significantly prolonged with vemurafenib in most subgroups

– Significant benefit in pts with tumors on right vs left/rectum, no prior irinotecan, MSS, or mutated PIK3CA

0

20

40

60

80

100

0 3 6 8 10 12 14Mos


SWOG S1406: OS, Response In crossover pts, mOS: 12.1 mos (95%

CI: 4.5-12.5)

Distribution of responses significantly different with addition of vemurafenib vs IC alone (Chi-squared P = .001)


Endpoint, % VIC(n = 44)*

IC(n = 47)*

Crossover(n = 24)†

PR‡ 16 4 17SD 50 17 55PD§ 18 66 NRDCR 67 22 72

*Measurable disease in 93 pts overall. †Excludes 6 pts (2 pts without PD before crossover, 4 pts without measurable disease). ‡Includes confirmed and unconfirmed. §Includes symptomatic deterioration.

mOS, Mos 95% CIVIC 9.6 (7.5-13.1)IC 5.9 (3.0-9.9)

HR: 0.73 (95% CI: 0.45-1.17; P = .19)

OS

(%)

0

20

40

60

80

100

0 3 6 9 12 15 18Mos

Kopetz S, et al. ASCO 2017. Abstract 3505. Reproduced with permission.


SWOG S1406: Safety

AE-related discontinuations more common with vemurafenib combination (16%) vs cetuximab + irinotecan alone (6%)

Median duration of treatment imbalanced between arms

– 88 days for VIC

– 47 days for IC

Slide credit: clinicaloptions.comKopetz S, et al. ASCO 2017. Abstract 3505.

Grade 3/4 AE, n (%) VIC(n = 46)

IC(n = 46)

Anemia 6 (13) 0 (0)Dehydration 5 (11) 3 (7)Diarrhea 11 (24) 6 (13)Febrile neutropenia 5 (11) 2 (4)Fatigue 7 (15) 7 (15)Neutropenia 15 (33) 3 (7)Rash 2 (4) 3 (7)Hypomagnesemia 0 (0) 2 (4)Nausea 9 (20) 1 (2)Arthralgia 3 (7) 0 (0)


SWOG S1406: Investigator Conclusions

Addition of vemurafenib to cetuximab + irinotecan associated with significantly prolonged PFS in mCRC pts with BRAF V600E

– mPFS: 4.3 vs 2.0 mos, respectively (HR: 0.48; P = .001)

– PFS benefit observed across most subgroups

Addition of vemurafenib associated with benefit in pts crossing over after PD on IC alone

– mPFS: 5.8 mos; mOS: 12.1 mos

mOS numerically higher with VIC (9.6 mos) vs IC alone (5.9 mos), but did not reach statistical significance (HR: 0.73; P = .19)

– Analysis limited by 48% crossover to VIC after PD on IC alone

Investigators concluded that VIC is a new treatment for BRAF V600E mCRCSlide credit: clinicaloptions.comKopetz S, et al. ASCO 2017. Abstract 3505.


Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin(FLOT)

versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or

gastroesophageal junction (GEJ) adenocarcinoma (FLOT4): A multi center,

randomized phase III trial

FLOT4 Study Design

Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting

Endpoints and Populations


Baseline 1


Surgery 1


Histopathology (ypTN)


FLOT4: Progression-Free Survival


FLOT4: Overall Survival


Chemo Related Toxicity 1


<>>><<<<

DiscussionStrengths Well designed and executed

prospective randomized phase III study

Clear benefit to FLOT over ECF – Increased rates of curative surgery, PFS

and OS

Limitations Overlap with patients treated in

CROSS trial – similar mOS (48.6m)

Does not answer the question – do patients need adjuvant therapy?

Practice Changing?• Yes, for perioperative chemotherapy approach

KEYNOTE-059 (Cohort 1): PembrolizumabMonotherapy in Previously Treated Advanced

Gastric or GEJ Adenocarcinoma

Pembrolizumab for Pretreated Advanced Gastric or GEJ Adenocarcinoma: Background PD-L1 overexpression a feature of gastric cancers[1-3]

Pembrolizumab: humanized anti–PD-1 IgG4-κ mAb; blocks PD-1 interaction with its ligands PD-L1/2[4]

– Phase Ib KEYNOTE-012: manageable toxicity, 22% ORR in pts with advanced PD-L1+ gastric cancer[5]

Current analysis reports data from phase II KEYNOTE-059 of pembrolizumab with focus on cohort 1 (pts with advanced gastric/GEJ cancer and ≥ 2 prior lines of therapy who received pembrolizumab monotherapy)[6]

1. Kim JW, et al. Gastric Cancer. 2016;19:42-52. 2. Qing Y, et al. Drug Des Devel Ther. 2015;9:901-909. 3. Dong M, et al. Hum Pathol. 2016;53:25-34. 4. Pembrolizumab [package insert]. 5. Muro K, et al. Lancet Oncol. 2016;17:717-726. 6. Fuchs CS, et al. ASCO 2017. Abstract 4003. Slide credit: clinicaloptions.com


KEYNOTE-059: Study Design

Open-label, multicohort phase II study

Primary endpoints: ORR, safety; secondary endpoints: DoR, PFS, OS

Exploratory biomarker endpoints: efficacy by MSI, GEP

Cohort 1≥ 2 prior

lines of CTPts with recurrent or metastatic gastric or

GEJ adenocarcinoma; ECOG PS 0/1;

HER2/neu negative*; no prior PD-1/PD-L1 tx, systemic steroids, autoimmune disease, ascites, or CNS mets

(N = 259)

Pembrolizumab200 mg Q3W

Pembrolizumab 200 mg Q3W +Cisplatin 80 mg/m2 Q3W +

5-FU 800 mg/m2 Q3W orCapecitabine 1000 mg/m2 BID Q3W

Tx continued for 24 mos or until PD, intolerable toxicity,

or withdrawal of consent; survival

follow-up until study end, death, or

withdrawal


Pembrolizumab200 mg Q3W

Cohort 2No prior tx

Cohort 3No prior tx,

PD-L1+

Fuchs CS, et al. ASCO 2017. Abstract 4003.

*HER2/neu positive allowed in cohort 1 if prior trastuzumab administered.


KEYNOTE-059 (Cohort 1): Baseline Characteristics

Slide credit: clinicaloptions.comFuchs CS, et al. ASCO 2017. Abstract 4003.

Characteristic All Pts (N = 259)

Median age, yrs (range) 62 (24-89)Male, n (%) 198 (76.4)Geographic region, n (%)United States East AsiaOther

124 (47.9)34 (13.1)

101 (39.0)ECOG PS, n (%) 0 1

107 (41.3)151 (58.3)

Primary tumor location, n (%)GastricGEJ

125 (48.3)133 (51.4)

Characteristic, n (%) All Pts (N = 259)

Prior therapies 2 3 ≥ 4

134 (51.7)75 (29.0)50 (19.3)

Prior surgery for gastric cancer 66 (25.5)

HER2 positive 63 (24.3)PD-L1 expression Positive*Negative

148 (57.1)109 (42.1)

*CPS ≥ 1% where CPS is (PD-L1 staining cells/total tumor cells) x 100.


KEYNOTE-059 (Cohort 1): Response

Median follow-up: 5.8 mos (range: 0.5-21.6 mos)


*CR + PR + SD ≥ 2 mos.

Confirmed Response, % (95% CI)

All Pts (N = 259)

ORR 11.6 (8.0-16.1)CR 2.3 (0.9-5.0)PR 9.3 (6.0-13.5)SD 16.2 (11.9-21.3)PD 56.0 (49.7-62.1)DCR* 27.0 (21.7-32.9)


KEYNOTE-059 (Cohort 1): Safety


D/c for TRAEs: abnormal hepatic function, bile duct stenosis, n = 1 each.Grade 5 TRAEs: acute kidney injury, pleural effusion, n = 1 each.

irAE Occurring in > 1% of Pts, %

All Pts (N = 259)Any Grade Grade 3/4

Any 17.8 4.6Hypothyroidism 8.9 0.4Hyperthyroidism 3.5 0Colitis 2.3 1.2Pneumonitis 1.9 0.8Thyroiditis 1.5 0.4Infusion reaction 1.5 0Severe skin reaction* 1.5 1.5

TRAE Occurring in > 5% of Pts, %

All Pts (N = 259)Any Grade Grade 3/4

Fatigue 18.9 2.3Pruritus 8.9 0Rash 8.5 0.8Hypothyroidism 7.7 0.4Decreased appetite 7.3 0Anemia 6.9 2.7Nausea 6.9 0.8Diarrhea 6.6 1.2Arthralgia 5.8 0.4 *Includes erythema multiforme, jaundice, rash, maculopapular rash.

Systemic corticosteroids for irAEs: n = 13. Treatment interruption due to irAEs: n = 10.


KEYNOTE-059 (Cohort 1): Response by PD-L1 Expression and Line of Therapy


*CR + PR + SD ≥ 2 mos.


PD-L1 Line of Therapy PD-L1 and Third Line of Therapy

Positive(n = 148)

Negative(n = 109)

Third (n = 134)

≥ Fourth(n = 125)

Positive(n = 75)

Negative(n = 58)

ORR 15.5 (10.1-22.4)

6.4 (2.6-12.8)

16.4 (10.6-23.8)

6.4 (2.8-12.2)

22.7 (13.8-33.8)

8.6 (2.9-19.0)

CR 2.0 (0.4-5.8)

2.8 (0.6-7.8)

3.0 (0.8-7.5)

1.6 (0.2-5.7)

2.7 (0.3-9.3)

3.4 (0.4-11.9)

PR 13.5 (8.5-20.1)

3.7 (1.0-9.1)

13.4 (8.2-20.4)

4.8 (1.8-10.2)

20.0 (11.6-30.8)

5.2 (1.1-14.4)

DCR* 33.1 (25.6-41.3)

19.3 (12.3-27.9)

31.3 (23.6-39.9)

22.4 (15.4-30.7)

38.7 (27.6-50.6)

22.4 (12.5-35.3)


KEYNOTE-059 (Cohort 1): Maximum Change From Baseline in Target Lesion Size

Slide credit: clinicaloptions.comFuchs CS, et al. ASCO 2017. Abstract 4003. Reproduced with permission.

*Included pts with measurable disease at BL and ≥ 1 post-BL assessment (n = 223).

Pts With Reduction, %All pts* 42.4PD-L1 positive 47.3PD-L1 negative 36.3

120

Cha

nge

From

BL

(%)

10080

6040

200

-20-40

-60-80

-100

PD-L1 positivePD-L1 negativePD-L1 expression unknown


12

KEYNOTE-059 (Cohort 1): Depth and Duration of Response

Slide credit: clinicaloptions.comFuchs CS, et al. ASCO 2017. Abstract 4003. Reproduced with permission.*Included pts with measurable disease at BL and ≥ 1 post-BL assessment (n = 30). †No PD at last disease assessment.

Outcome All Pts* PD-L1+ PD-L1-Median DoR, mos (95% CI) 8.4 (1.6+† to 17.3+) 16.3 (1.6+ to 17.3+) 6.9 (2.4 to 7.0+)

Treatment Exposure and Duration of Response Longitudinal Change From BL in Tumor Size Among Responders (n = 30)

240 2 4 6 8 10 1614 18 20 22Mos Since First Dose

Con

firm

ed R

espo

nder

s (n

= 3

0)

CRPRPDDeathOngoing pembrolizumab treatment

Treatment discontinuedTreatment ongoing

Cha

nge

From

BL

(%)

20

0

-20

-40

-60

-80

-10024

Mos Since Treatment Initiation0 2 4 6 8 10 12 14 16 18 20 22


KEYNOTE-059 (Cohort 1): Survival

Slide credit: clinicaloptions.comFuchs CS, et al. ASCO 2017. Abstract 4003. Reproduced with permission.

All Pts (N = 259)

Median OS, mos (95% CI) 5.6 (4.3-6.9)12-mo OS rate, % 23.4

All Pts (N = 259)

Median PFS, mos (95% CI) 2.0 (2.0-2.1)100

80

60

40

20

0

OS

(%)

Mos220 2 4 6 8 10 12 14 16 18 20

Pts at risk, n259 199 144 112 51 27 22 12 7 287 0

100

80

60

40

20

0

PFS

(%)

Mos220 2 4 6 8 10 12 14 16 18 20

Pts at risk, n259 136 51 34 17 4 2 2 2 022 0

OS PFS


KEYNOTE-059 (Cohort 1): Exploratory Analyses

MSI assessed in 174 pts

– MSI-high: 4.0%

18-gene T-cell–inflamed GEP score, assessed in 144 pts, associated with significantly improved response to pembrolizumab (P = .014)



MSI-High(n = 7)

Non–MSI-High(n = 167)

ORR 57.1 (18.4-90.1)

9.0 (5.1-14.4)

CR 14.3 (0.4-57.9) 2.4 (0.7-6.0)PR 42.9 (9.9-81.6) 6.6 (3.3-11.5)DCR* 71.4 (29.0-96.3) 22.2 (16.1-29.2)*CR + PR + SD ≥ 2 mos.

0.0

0.5

-0.5

18-G

ene

T-C

ell−

Infla

med

G

EP S

core

Nonresponder Responder

Fuchs CS, et al. ASCO 2017. Abstract 4003. Reproduced with permission.


KEYNOTE-059 (Cohort 1): Conclusions

In pts with advanced gastric/GEJ cancer and ≥ 2 prior therapies, pembrolizumab well tolerated with promising antitumor activity, durable responses– ORR: 11.6%; higher in PD-L1+ vs PD-L1- tumors (15.5% vs 6.4%)

and MSI-high vs non–MSI-high tumors (57.1% vs 9.0%)

Study investigators suggest pembrolizumab as potential therapeutic option for this pt population

Pembrolizumab in earlier-line therapy and in chemotherapy combinations under investigation for advanced gastric/GEJ cancer in ongoing randomized trials



Thank You

Documents

ASCO 2017 updates in Colorectal and Gastric Cancers · 2017-09-20 · ASCO 2017 updates in Colorectal and Gastric Cancers May Cho, M.D. Relevant financial relationships in the past