1. Circulating Tumor DNA Analysis From Pts With mCRC Who Were Treated With Panitumumab in ASPECCT
CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois
*Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals
mCRC, metastatic colorectal cancer.
This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

2. Circulating Tumor DNA Analysis in Pts With mCRC Treated With Panitumumab: Background
ASPECCT: randomized, open-label phase III study of anti-EGFR mAbs panitumumab (n = 499) vs cetuximab (n = 500) in pts with chemorefractory wild-type KRAS exon 2 mCRC[1,2]
Noninferior OS of panitumumab demonstrated
KRAS exon 2 analysis in FFPE tissue has been standard of care for pts undergoing anti-EGFR treatment
Current studies used NGS to detect ctDNA in plasma of panitumumab-treated subjects from ASPECCT[3,4]
Investigated overall mutational landscape and relationship between RAS mutations and outcomes
ct, circulating tumor; FFPE, formalin-fixed paraffin-embedded; mCRC, metastatic colorectal cancer; NGS, next-generation sequencing
1. Price TJ, et al. Lancet Oncol. 2014;15: Price T, et al. Eur J Cancer. 2016;68:51-59.
3. Boedigheimer M, et al. ASCO Abstract Price TJ, et al. ASCO Abstract 3584.
Slide credit: clinicaloptions.com

3. ASPECCT ctDNA Analysis: Methods
238/499 panitumumab-treated pts from phase III ASPECCT study had baseline and posttreatment plasma samples
24 posttreatment samples unevaluable
Plasma analyzed by NGS for mutations with 63-gene panel, 0.1% limit of detection
Mutation gain or loss assessed at amino acid level
Net change: (sum of mutations gained) – (sum of mutations lost)
Net gain and/or net loss of mutations in single gene possible for individual pts
Each RAS allele reported as (mutant reads/total reads) fraction
ct, circulating tumor; NGS, next-generation sequencing.
Slide credit: clinicaloptions.com
Boedigheimer M, et al. ASCO Abstract Price TJ, et al. ASCO Abstract 3584.

4. ASPECCT ctDNA Analysis: Population Characteristics
Plasma analysis population mirrored ITT population in BL demographics and tumor characteristics with numerically higher clinical outcome metrics
Characteristic
Plasma Analysis Population
ITT Population
Median age, yrs 61
Male sex, % 63
Race, %
White
Asian
Other 48 50 1 53 45 2
ORR, % (95% CI)
28.6 ( )
16.1 ( )
Median PFS, mos (95% CI)
4.8 ( )
3.1 ( )
Median OS, mos (95% CI)
11.5 ( )
8.4 ( )
BL, baseline; ITT, intent to treat.
Slide credit: clinicaloptions.com
Boedigheimer M, et al. ASCO Abstract Price TJ, et al. ASCO Abstract 3584.

5. ASPECCT ctDNA Analysis: Pre/Posttreatment Mutational Landscape
Pts with multiple mutations in same gene: 29% at BL, 41% posttreatment
Max number of mutations per gene in any single pt: 1-16
8 genes arising in analysis known to be commonly mutated: TP53, APC, KRAS, PIK3CA, FBXW7, NRAS, SMAD4, and CTNNB1
≥ 90% of pts had TP53 mutations at BL and posttreatment, with elevated number of mutations per pt
≥ 10% of pts acquired mutations in ≥ 1 of these genes (by frequency): APC, EGFR, ALK, HER4, TP53, AR, KRAS, BRAF, PDGFRA, STK11, ESR1, FBXWT, and KIT
≥ 40% of pts acquired mutations in APC and EGFR
BL, baseline; ct, circulating tumor; PD, progressive disease; PR, partial response; SD, stable disease
Slide credit: clinicaloptions.com
Boedigheimer M, et al. ASCO Abstract 3523.

6. ASPECCT ctDNA Analysis: Survival and Pre/Posttreatment Mutational Landscape
Significant mutational net gains across multiple gene pathways
EGFR pathway: KRAS, EGFR, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1
Non-EGFR pathways: APC, CDK6, SMARCB1, FBXW7, TERT, RB1, CTNNB1, and IDH1
28% of pts experienced overall mutational decline with panitumumab
Strong association between OS and total mutations across all genes (HR: 2.26; P < .001)
BL, baseline; ct, circulating tumor; PD, progressive disease; PR, partial response; SD, stable disease
Slide credit: clinicaloptions.com
Boedigheimer M, et al. ASCO Abstract 3523.

7. ASPECCT ctDNA Analysis: RAS Mutations
Baseline Plasma
Posttreatment Plasma
Wild type
(n = 111)
Evaluable
(n = 164)
Pts treated with panitumumab with BL/posttreatment plasma samples
(N = 238)
Wild type
(n = 188)
Emergent RAS mutant
(n = 53)
Unevaluable
(n = 24)
RAS mutant
(n = 50)
BL, baseline; ct, circulating tumor.
Slide credit: clinicaloptions.com
Price TJ, et al. ASCO Abstract 3584.

8. ASPECCT ctDNA Analysis: RAS Mutations and Clinical Response
Pts with no RAS mutations: 52%
RAS mutations not required for PD, but did not prevent SD or response
Global increase in RAS-mutant DNA fraction from BL to posttreatment
Similar increases, BL levels (P = .09) in pts with SD vs PD
Circulating Levels of Mutant RAS by
Best Response and Visit
100 64 32 16 8
Percent Mutant Reads 4 2 1
BL, baseline; ct, circulating tumor; PD, progressive disease; SD, stable disease; SFU, safety follow-up; W, week; WT, wild-type. W1
SFU W1
SFU W1
SFU W1
SFU WT
Total 28 50 27 56 94
118 64
116 60 64 38 61 3 1 PD SD PR CR
Slide credit: clinicaloptions.com
Price TJ, et al. ASCO Abstract Reproduced with permission.

9. ASPECCT ctDNA Analysis: RAS Mutations and Survival
OS, 1-yr survival probability not predicted by BL mutant RAS fraction
Circulating Levels of Mutant RAS by OS
100 64 32 16 8
Percent Mutant Reads 4 2 1
BL, baseline; ct, circulating tumor; SFU, safety follow-up; W, week; WT, wild-type. W1
SFU W1
SFU W1
SFU WT
Total 93
132 68
132 74 85 48 83 18 14 19
0-1 year
1-2 years
2-3 years
Slide credit: clinicaloptions.com
Price TJ, et al. ASCO Abstract Reproduced with permission.

10. ASPECCT ctDNA Analysis: Conclusions
In panitumumab-treated pts with mCRC, significant mutational changes under anti-EGFR selection[1]
Tumor heterogeneity increased in some, decreased in others
Poorer OS associated with elevation in total mutations
Investigators concluded that intraclonal competition, diversification, lineage truncation all potentially occurring
BL RAS mutation level did not correlate with clinical outcome[2]
Investigators concluded that RAS mutation levels cannot be used at this time to establish treatment decision threshold
BL, baseline; ct, circulating tumor; mCRC, metastatic colorectal cancer.
Slide credit: clinicaloptions.com
1. Boedigheimer M, et al. ASCO Abstract Price TJ, et al. ASCO Abstract 3584.

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