1ª línea continuum of care -...

1ª línea continuum of care:

maximizando la SG en CCRm RAS wt (Cetuximab)

Ramon Salazar

Institut Català d´Oncologia

Sequence of treatment • Chemotherapy sequence (folfiri/folfox) 1

• Detrimental effect when

Panitumumab (PACCE) 2 or Cetuximab (CAIRO-2) 3

were added to CT+Bevacizumab

• Biological sequence (EGFR versus VEGF targeted) – Before Sideness – Left versus Right sideness – New Molecular Subtypes – New treatment avenues

• Molecular Dx & Liquid Biopsies

– EGFR emergent resistant clones 1.- Tournigand ,et al. JCO 2004

2.- Hecht, et al. JCO 2009

3.- Tol et al, NEJM 2009

Meta-analysis PEAK / FIRE-3 / CALGB (before sideness)

Heinemann V, Rivera F et al. EJC, 2016

1.096 pts RAS wt: 170 p + 400 p + 526 p Study level data 1º end point: OS


Heinemann V, Rivera F, et al. EJC, 2016

1.096 pts RAS wt: 170 p + 400 p + 526 p Study level data PFS


Heinemann V, Rivera F, et al. EJC, 2016

1.096 pts RAS wt: 170 p + 400 p + 526 p Study level data

RR

Biological sequencing Considerations for sequencing anti-EGFR and anti-VEGF therapy in mCRC

Tumour shrinkage Anti-EGFR mAbs may be more effective at rapidly debulking tumours than anti-VEGF mAbs

Sensitivity to second-line therapy Anti-EGFR-resistant cells may remain sensitive to anti-VEGF mAb therapy whereas anti-VEGF-resistant cells may become simultaneously resistant to anti-EGFR therapy*

Tumour and stromal cell genetics/epigenetics Tumour cells are less (epi)genetically stable than stromal cells so it may be preferable to use tumour cell-targeted drugs (e.g. an anti-EGFR mAb) early

Invasion and metastasis In preclinical models, VEGF inhibition has been reported to promote invasion and metastasis; therefore, it may be preferable to reserve VEGF mAb therapy for later lines†

• Wainberg ZA, Drakaki A. Expert Opin Biol Ther 2015;15:1205–20.

• *Via hypoxia-dependent resistance mechanisms; †controversial model; contrary data exist.

Outline • Selection of treatment

– EGFR versus VEGF targeted sequence – Detrimental effect when Panitumumab (PACCE) 1 or Cetuximab (CAIRO-2) 2

were added to CT+Bevacizumab

• Left versus Right sideness

• New Molecular Subtypes – New treatment avenues

• Molecular Dx & Liquid Biopsies

– EGFR emergent resistant clones

1.- Hecht, et al. JCO 2009 2.- Tol et al, NEJM 2009

9

There are multiple differences between the right and left colon and

their associated tumors Embryologic origin1

Midgut Hindgut

Function2

Almost inactive metabolically

Waste reservoir

Metabolism Fermentation Proteolysis

Degradation Processing

Microbiome3

Biofilm negative

Biofilm positive

Epigenetic2,4,5 Genetic4,6

Methylation MSI-High BRAF mt

See slide notes for references.

Right colon

• +++ MSI-high1,2

• +++ CIMP-high1,2

• +++ CMS13

• +++ Serrated pathway2†

CIMP-high, MSI-high and CMS

distribution varies between colorectal locations

1. Yamauchi M, et al. Gut 2012;61:847–54;

2. Missiaglia E, et al. Ann Oncol 2014;25:1995‒2001;

3. Guinney J, et al. Nat Med 2015;21:1350‒6 (and Supplementary Figure 10).

+++ denotes that a molecular or morphological subtype is

more prevalent compared with other colorectal segments.

†CIN expression and serrated pathway data are not available for rectal tumours.

CIMP, CpG island methylator phenotype; CIN, chromosomal instability;

CMS, Consensus Molecular Subtypes; MSI, microsatellite instability.

Left colorectum

Colon

• +++ CIN+2†

• +++ CMS23

• +++ EREG expression2‡

• MT KRAS1

• EGFR expression1

• HER2 amplification

• Molecular heterogeneity may be captured by the anatomical location of the tumour

Right colon

• +++ MT BRAF1,2

• MT KRAS1

• EGFR expression1

11

CRYSTAL (FOLFIRI vs FOLFIRI + Cetuximab)

Tumor location analysis – RAS WT

RAS wt

Left-sided Right-sided

Erb + CT (n=142)

CT alone (n=138)

Erb + CT (n=33)

CT alone (n=51)

ORR

% 72.5 40.6 42.4 33.3

OR (95% CI) 3.99 (2.40–6.62) 1.45 (0.58–3.64)

p-value <0.001 0.43

PFS

Median, months 12.0 8.9 8.1 7.1

HR (95% CI) 0.50 (0.34–0.72) 0.87 (0.47–1.62)

p-value <0.001 0.66

OS

Median, months 28.7 21.7 18.5 15.0

HR (95% CI) 0.65 (0.50–0.86) 1.08 (0.65–1.81)

p-value 0.002 0.76

CT = FOLFIRI; Erb, cetuximab

Clear poor prognostic effect of right-sided tumor location in both arms

PFS & OS benefit in left-sided mCRC with cetuximab + CT vs CT alone

Tejpar S, et al. JAMA Oncol 2016; epub 10 Oct 2016; Van Cutsem E, et al. Oral presentation at ESMO 2016

No difference in outcomes between arms in right-sided tumors, but conclusions are limited by small

sample size

12

RR in CRYSTAL in Left and Right Tumors

RAS wt


CET + CT (n=142)

CT alone (n=138)

CET + CT (n=33)

CT alone (n=51)

ORR

% 72.5 40.6 42.4 33.3

OR (95% CI) 3.99 (2.40–6.62) 1.45 (0.58–3.64)

p-value <0.001 0.43

CT = FOLFIRI; CET =cetuximab

1. Tejpar S, et al. JAMA Oncol 2016; epub 10 Oct 2016; 2. Van Cutsem E, et al. Oral presentation at ESMO 2016

15

Unprecedented OS benefit with cetuximab + CT vs bevacizumab + CT in left-sided

RAS/BRAF wt mCRC1

FIRE-3 (FOLFIRI + cetuximab vs FOLFIRI + bevacizumab)

Tumor location analysis – RAS/BRAF WT

1. Heinemann V, et al. Oral presentation at ESMO 2016

RAS/BRAF wt


Erb + CT (n=143)

Bev + CT (n=139)

Erb + CT (n=28)

Bev + CT (n=37)

ORR

% 67.8 62.6 47.4 42.0

OR 1.26 1.37

p-value 0.38 0.61

PFS

Median, months 11.1 11.1 8.0 10.5

HR 0.89 1.70

p-value 0.37 0.046

OS

Median, months 38.7 28.6 18.9 23.6

HR 0.62 1.31

p-value 0.002 0.34

CT = FOLFIRI; Erb, cetuximab; bev, bevacizumab

Data consistent w RAS wt subgroup analysis

Borderline-significant increase in PFS with bevacizumab, but no significant

difference in OS or ORR. However, conclusions are limited by small

sample size

Cetuximab + QT como elección de 1ªlínea para CCRm RAS wt1 de lado izquierdo

16

FIRE-3: análisis de 2ª línea según la localización tumoral

RAS wt

Localización Tumoral Lado Izquierdo Lado Derecho

1ª línea tratamiento

Cetux + FOLFIRI

(n=170*)

Bev + FOLFIRI

(n=139*)

Cetux + FOLFIRI (n=40*)

Bev + FOLFIRI (n=62*)

PFS2

Mediana, meses 6.7 5.3 5.3 3.2

HR (95% CI) 0.65 (0.50–0.85) 1.02 (0.65–1.61)

p-value 0.001 0.98

OS2

Mediana, meses 17.6 14.1 11.0 12.4

HR (95% CI) 0.65 (0.49–0.85) 1.02 (0.64–1.61)

p-value 0.002 0.94

Diferencia significativa en PFS2 y OS2 tras 1ª línea Cetuximab + FOLFIRI vs 1ª línea bevacizumab + FOLFIRI en CCRm RAS wt de

lado izquierdo

No hubo diferencias en los resultados de 2ª línea en CCRm de

lado derecho; no obstante, las conclusiones son limitadas por el

pequeño tamaño muestral

Los datos confirman el impacto pronóstico de la localización

tumoral en las líneas de tratamiento

*Patients with known primary tumor location who received 2nd line therapy. FIRE-3 did not meet its primary endpoint of significantly improving ORR in patients with KRAS (exon 2) wt mCRC based on investigators’ read6; The OS benefit of cetuximab plus chemotherapy vs bevacizumab plus chemotherapy demonstrated for RAS wt mCRC patients in the FIRE-3 study7 could not be confirmed in the CALGB/SWOG 80405 study8

1. Modest DP, et al. ASCO 2017 (Abstract No. 3525);

Tumor location analysis – RAS WT

17 Venook AP, et al. Oral presentation at ESMO 2016

CT = Investigator’s choice of FOLFIRI or mFOLFOX6 *Adjusted for biologic, protocol CT, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary, liver metastases

CALGB/SWOG 80405 (CT + cetuximab vs CT + bevacizumab)

RAS wt


CET + CT (n=173)

Bev + CT (n=152)

CET + CT (n=71)

Bev + CT (n=78)

PFS

HR (95% CI) 0.84 (0.66–1.06) 1.64 (1.15–2.36)

p-value 0.15 0.006

Treatment × tumor location interaction (p-value)*

0.001

OS

Median, months 39.3 32.6 13.7 29.2

HR (95% CI) 0.77 (0.59–0.99) 1.36 (0.93–1.99)

p-value 0.04 0.10

Treatment × tumor location interaction (p-value)*

0.009

Longer PFS with bevacizumab vs cetuximab, and non sig

difference in OS between arms, in right-sided tumors;

conclusions are limited by small sample size

Significant OS benefit with cetuximab + CT vs bevacizumab + CT in left-sided RAS wt mCRC

Significant treatment × tumor location interaction for PFS and OS

Clear poor prognostic effect of right-sided tumor location on

OS in both arms

19

Meta-analyses support the preferential use of anti-EGFR + CT over bevacizumab + CT for LS tumors

1. Holch JW, et al. Eur J Cancer 2017;70:87–98; 2. Arnold D, et al. Ann Oncol 2017; epub Apr 12. doi: 10.1093/annonc/mdx175;

3. Heinemann V, et al. Lancet Oncol 2014;15:1065–1075; 4. Stintzing S, et al. Lancet Oncol 2016;17:1426–1434;

5. Venook A, et al. JAMA. 2017;317:2392-2401.

Arnold meta-analysis of OS2 Holch meta-analysis of OS1

1st line CT + anti-EGFR vs CT + bevacizumab in patients with LS tumors*

1st/2nd line CT + anti-EGFR vs CT ± bevacizumab in patients with LS tumors*

FE, fixed-effects model; RE, random-effects model *FIRE-3 did not meet its primary endpoint of significantly improving ORR in patients with KRAS (exon 2) wt mCRC based on investigators’ read;3 the OS benefit of cetuximab plus chemotherapy vs bevacizumab plus chemotherapy demonstrated for patients with RAS wt mCRC in the FIRE-3 study4 could not be confirmed in the CALGB/SWOG 80405 study5

86% of LS anti-EGFR + CT-treated patients in the head-to-head trials vs bevacizumab + CT received cetuximab + CT

LEFT Meta-analysis OS

20

Meta-analyses support the preferential use of anti-EGFR + CT over bevacizumab + CT for LS tumors

Arnold meta-analysis of ORR2 Holch meta-analysis of ORR1




1st line CT + anti-EGFR vs CT + bevacizumab in patients with LS tumors*

1st/2nd line CT + anti-EGFR vs CT ± bevacizumab in patients with LS tumors*


LEFT Meta-analysis ORR

21

No PFS benefit for CT + anti-EGFR vs CT ± bevacizumab for RS tumors

Arnold meta-analysis of PFS2 Holch meta-analysis of PFS1




1st line CT + anti-EGFR vs CT + bevacizumab in patients with RS tumors*

1st/2nd line CT + anti-EGFR vs CT ± bevacizumab in patients with RS tumors*


RIGHT Meta-analysis PFS

22

No significant difference in OS for CT + anti-EGFR vs CT ± bevacizumab for RS tumors

Arnold meta-analysis of OS2 Holch meta-analysis of OS1







RIGHT Meta-analysis OS

23

RIGHT Meta-analysis ORR

Cetuximab + CT is effective in patients with RS tumors: ORR numerically favors anti-EGFR + CT over bevacizumab +

CT




Arnold meta-analysis of ORR2 Holch meta-analysis of ORR1




WCGIC 2017 The Left versus Right cancer story:

What is the truth?

WCGIC 2017, Session XIX: Colorectal cancer, Controversy debate: Updates on treatment algorithms in mCRCin 2017 The left versus right colon cancer story: What is the truth: Axel Grothey, MD

CMS1-4 in CALGB 80405 & Fire-3

Proposed taxonomy of colorectal cancer

Inmune checkpoints

blockade

TGF- inhibition + Inmune

checkpoint blockade

Prognosis

Drug response

prediction

Metabolism &

DNA damage

Oncogene drivers

Amplifications

Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

CALGB 80405

FOLFIRI cetuximab vs. FOLFIRI bevacizumab

Presented By Sebastian Stintzing at 2017 ASCO Annual Meeting

Fire-3

www.iconcologia.net

Institut Català d’Oncologia

ICO l’Hospitalet Hospital Duran i Reynals Gran Via de l’Hospitalet, 199-203 08907 l’Hospitalet de Llobregat

ICO Badalona Hospital Germans Trias i Pujol Ctra. del Canyet s/n 08916 Badalona

ICO Girona Hospital Doctor Trueta Av. França s/n 17007 Girona

[email protected]

BACK up slides….

Sensitivity to 2nd-line therapy Putative mechanisms of decreased anti-EGFR mAb

efficacy after anti-VEGF exposure

Putative effect of VEGF pathway inhibition:

• Hypoxia-induced EGFR-independent RAS signal activation1

• Hypoxia-induced EMT transition2

– sensitivity to EGFR inhibition

– Aggressive/invasive cell characteristics

• VEGF-A VEGF-A-induced resistance to anti-EGFR3 in WT KRAS/NRAS colon cancer cell lines

– VEGFR2/Stat-3-dependent

Adapted from Zaniboni A, Formica V. Cancer Chemother Pharmacol 2016 [Epub ahead of print]. 1. Zang M, et al. PLoS One 2010;5:e10966; 2. Zhou J, et al. Oncotarget 2015;6:44332‒45; 3. Derangère V, et al. Oncotarget 2016;7:9309‒21.

EMT, epithelial-mesenchymal transition;

Vogelstein et al. PNAS 1999; mod. Diehl et al Curr

Opin Oncol. 2007

Digital PCR Conventional PCR

Wild-type DNA

Mutant DNA Partitioning of DNA

into many individual

reactions

Digital signal readout Relative signal readout

Digital PCR allows high sensitivity and quantitative results

RAS mutants: MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors

1Turke A et al. Cancer Research 2012

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