Controversias actuales en el manejo de cáncer colorrectal metastàsico

Controversias actuales en el manejo de cáncer colorrectal metastásico – sesión interactiva con los fellows

Mauricio Lema Medina MDClínica de Oncología Astorga / Clínica SOMA, Medellín, Colombia

Instituto Nacional de CancerologíaBogotá, 16.02.2017

Disclaimer

“Esta presentación ha sido creada por el autor de la charla y es de su propiedad. La información, conceptos y opiniones aquí expresados son responsabilidad del autor y no comprometen a Productos Roche S.A., sus colaboradores o compañías vinculadas.”

@onconerd

Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(suppl 3):iii1-iii9. doi:10.1093/annonc/mdu260.

SynchronicMetachronic

Left-sidedRight-sided

Metastatic patterns in mCRC

Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(suppl 3):iii1-iii9. doi:10.1093/annonc/mdu260.

Group 0: Technically R0-resectable

Group 1: Potentially resectable

Group 2: Disseminated disease / intermediate intensive treatment

Group 3: Disseminated disease / non- intensive, sequential treatment

Initially resectable

Metastasic

“Con

verti

ble”

Systemic therapy in metastatic colorectal cancerIn the XXI century

Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet (London, England). 2000;355(9209):1041-1047. http://www.ncbi.nlm.nih.gov/pubmed/10744089. Accessed February 7, 2017.

Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial.

OS (mo)

TTP (mo)

ORR (%)

Irinotecan + FL (n=199)FL (n=188)

35*

17.4*

6.7*

4.4*

14.1*

22*

Grade ¾ toxicity

* Statistically significant

de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18(16):2938-2947. doi:10.1200/jco.2000.18.16.2938.

Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer.

OS (mo)

PFS (mo)

ORR (%)

FOLFOXDeGramont

50*

16.2

9.0*

6.2*

14.7

22*

Grade ¾ neuropathy (%)

n=420* Statistically significant

18* 0*

Tournigand C, André T, Achille E, et al. FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study. J Clin Oncol. 2003;22(2):229-237. doi:10.1200/JCO.2004.05.113.

FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.

OS (mo)

1st-PFS (mo)

ORR (%)

FOLFIRI then FOLFOX (n=109)FOLFOX then FOLFIRI (n=111)

56

21

8.5

8.0

20.6

54

2nd-PFS (mo)


10.914.2

Falcone A Ricci S Brunetti I Pfanner E Allegrini G et. al. Journal of Clinical Oncology. 2007 vol: 25 (13) pp: 1670-1676

Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastaticcolorectal cancer: the Gruppo

Oncologico Nord Ovest.

OS (mo)

PFS (mo)

ORR (%)

FOLFOXIRIFOLFIRI

60*

22.0*

9.8*

6.9*

16.7*

34*

R0 resection (%)


6*15*

Souglakos J Androulakis N Syrigos K Polyzos A Ziras N et. al. British Journal of Cancer. 2006 vol: 94 (6) pp: 798-805

FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in

metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG).

OS (mo)

PFS (mo)

ORR (%)

FOLFOXIRIFOLFIRI

43.0

21.5

8.4

6.9

19.5

33.6


Falcone A Ricci S Brunetti I Pfanner E Allegrini G et. al. Journal of Clinical Oncology. 2007 vol: 25 (13) pp: 1670-1676Souglakos J Androulakis N Syrigos K Polyzos A Ziras N et. al. British Journal of Cancer. 2006 vol: 94 (6) pp: 798-805

FOLFOXIRI vs FOLFIRI.

OS (mo)

PFS (mo)

ORR (%)

FOLFOXIRIFOLFIRI

43.0

21.5

8.4

6.9

19.5

33.6


OS (mo)

PFS (mo)

ORR (%)

FOLFOXIRIFOLFIRI

60*

22.0*

9.8*

6.9*

16.7*

34*

R0 resection (%)

6*15*


Access to Chemotherapy Improves Survival

Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.

22

20

18

16

14

12

Med

ian

OS

(Mos

)

0 20 40 60 80Patients With 3 Drugs (%)

LV5FU2Bolus 5-FU/LV

Infusional 5-FU/LV+ irinotecanInfusional 5-FU/LV+ oxaliplatinBolus 5-FU/LV+ irinotecanIrinotecan+ oxaliplatin

First-line therapy

OS in mCRC

24 mo

CT-only

Biologics: Bevacizumab

Macedo LT, da Costa Lima AB, Sasse AD. Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups. BMC Cancer. 2012;12(1):89. doi:10.1186/1471-2407-12-89.

Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups.

OS (HR)

CT + Bevacizumab vs CT

0.84*

PFS (HR)

ORR (HR)

1.0

1.0

1.0

0.84*

1.12n=3060* Statistically significant

Schmiegel, W., Reinacher-Schick, A., Arnold, D., Kubicka, S., Freier, W., Dietrich, G., … Graeven, U. (2013). Capecitabine/irinotecan or capecitabine/oxaliplatin in combination with bevacizumab is effective and safe as first-line therapy for metastatic colorectal cancer: a randomized phase II study of the AIO colorectal study group. Annals of Oncology, 24(6), 1580–1587. https://doi.org/10.1093/annonc/mdt028

Capecitabine/irinotecan or capecitabine/oxaliplatin in combination with bevacizumab is effective and safe as first-line therapy for metastatic colorectal

cancer: a randomized phase II study of the AIO colorectal study group.

OS (mo)

PFS (mo)

ORR (%)

CapOx - BevacizumabCapIri - Bevacizumab

53

24

12.1

25

56

Grade ¾ diarrhea (%)

1622


10.4Bevacizumab 7.5 mg/kg with

Oxaliplatin 130 mg/m(2)/day 1 plus capecitabine 1000 mg/m(2) bid/days 1-14

Irinotecan 200 mg/m(2)/day 1 plus capecitabine 800 mg/m(2) bid/days 1-14 both every 21 days

Title

OS (mo)

ORR (%)

Grade ¾ toxicity (%)


PFS (mo)

3020103366100

33

66

100

12

8

4

Reference

Yamazaki, K., Nagase, M., Tamagawa, H., Ueda, S., Tamura, T., Murata, K., … Hyodo, I. (2016). Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Annals of Oncology, 27(8), 1539–1546. https://doi.org/10.1093/annonc/mdw206

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer

(WJOG4407G).

OS (mo)

PFS (mo)

ORR (%)

FOLFIRI - BevacizumabFOLFOX - Bevacizumab

64

31

10.7

30.1

62

Grade ¾ neuropathy (%)

22*


12.1

0*

Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015;16(13):1306-1315. doi:10.1016/S1470-2045(15)00122-9.

FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival

and molecular subgroup analyses of the open-label, phase 3 TRIBE study

OS (mo)

PFS (mo)

ORR (%)

FOLFOXIRI + BevacizumabFOLFIRI + Bevacizumab

65

29.8*

12.2*

9.7*

25.8*

53

N=508* Statistically significant

Biologics: Anti-EGFR MoAs

CRC: Biologic Subsets That Respond Differently to EGFR-Targeted Agents

BRAF

KRAS

EREG or AREG

PI3K PTEN

EGFR

PIP1

PIP3

Signaling to the nucleus

Low expression of EGFR ligands → decreased response

to EGFR-targeted agents

PTEN loss of expression → decreased response to EGFR-targeted agents

Siena S, et al. J Natl Cancer Inst. 2009;101:1308-1324. Rizzo S, et al. Cancer Treat Rev. 2010;36 Suppl 3:S56-61.


BRAF

KRAS

EREG or AREG

PI3K PTEN

EGFR

PIP1

PIP3


Low expression of EGFR ligands → decreased response

to EGFR-targeted agents

Mutant BRAF → decreased response to EGFR-targeted agents


Mutant KRAS → decreased response to EGFR-targeted

agents


Van Cutsem E, Kohne C-H, Lang I, et al. Cetuximab Plus Irinotecan, Fluorouracil, and Leucovorin As First-Line Treatment for Metastatic Colorectal Cancer: Updated Analysis of Overall Survival According to Tumor KRAS and BRAF Mutation Status. J Clin Oncol. 2011;29(15):2011-2019. doi:10.1200/JCO.2010.33.5091.

Cetuximab Plus Irinotecan, Fluorouracil, and Leucovorin As First-Line Treatment for Metastatic Colorectal Cancer: Updated Analysis of Overall Survival According to

Tumor KRAS and BRAF Mutation Status

OS (mo)

PFS (mo)

ORR (%)

FOLFIRI - CetuximabFOLFIRI

57.3*

23.5*

8.4*

20*

39.7*

n=1198 – 89% RAS status ascertained* Statistically significant

9.9*wtKRAS

Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, Leucovorin, and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer. J Clin Oncol. 2009;27(5):663-671. doi:10.1200/JCO.2008.20.8397.

Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer.

PFS (HR)

ORR (%)

FOLFOX - CetuximabFOLFOX

0.57*

37*

n=233 KRAS status ascertained* Statistically significant

61*

wtKRAS

Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer (WT KRAS analysis)

OS (mo)

ORR (%)

Complete resection rate(%)


PFS (mo) – Primary endpoint

3020103366100

33

66

100

12

8

4

FOLFOX – PanitumumabFOLFOX

23.9

10*

10

57*

19.7

8.6*

8

48*

Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014;25(7):1346-

1355. doi:10.1093/annonc/mdu141.

Douillard J-Y, Oliner KS, Siena S, et al. Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer. N Engl J Med. 2013;369(11):1023-1034. doi:10.1056/NEJMoa1305275.

Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer

OS (mo)

PFS (mo)

FOLFOX - CetuximabFOLFOX

26*

7.9*

20*

n=512 wtKRAS* Statistically significant

10.1*

wtKRAS

Molecular Biomarkers for the Evaluation of Colorectal Cancer Guideline From the American Society for Clinical Pathology, College of

American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology

Patients with CRC being considered for anti-EGFR therapy must receive RAS mutational

testing. Mutational analysis should include KRAS and NRAS codons 12 and 13 of exon 2, 59 and

61 of exon 3, and 117 and 146 of exon 4 (‘‘expanded’’ or ‘‘extended’’ RAS)

Sepulveda AR, Hamilton SR, Allegra CJ, et al. EARLY ONLINE RELEASE. Arch Pathol Lab Med.:2016-2554.

MAPK pathway mutations in mCRCAprox. 65% mCRC

Codon 61/146 mKRAS5%

V600E BRAF

8%Codon 12/13 mKRAS 48%

mNRAS6%

Schirripa M, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3613.



Clinicians should order mismatch repair status testing in patients with colorectal cancers for the identification of patients at high risk for

Lynch syndrome and/or prognostic stratification.




BRAF p.V600 mutational analysis should be performed in dMMR tumors with loss of MLH1

to evaluate for Lynch syndrome risk. Presence of a BRAF mutation strongly favors a sporadic

pathogenesis. The absence of BRAF mutation does not exclude risk of Lynch syndrome.


Sporadic dMMR

CpG Methyl-MLH1

BRAF mutation (75%)

dMMR

Lynch syndrome

No BRAF mutation

15-20% mCRC

¾ dMMR ¼ dMMR


MLH1, MSH2, MSH6, PMS2

Bevacizumab vs Anti-EGFRs in WT KRAS mCRC

Stintzing S, Modest DP, Rossius L, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016;17(10):1426-1434. doi:10.1016/S1470-2045(16)30269-8.

FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final

RAS wild-type subgroup of this randomised open-label phase 3 trial.

OS (mo)Secondary Endpoint

Depth of response (-%)

ORR (%) – Primary Endpoint

FOLFIRI - CetuximabFOLFIRI - Bevacizumab

72

33*

-32*

56


-48*

wtKRAS

25*

PEAK: A Randomized, Multicenter Phase II Study of Panitumumab Plus Modified Fluorouracil, Leucovorin, and Oxaliplatin (mFOLFOX6) or Bevacizumab Plus mFOLFOX6 in Patients With Previously Untreated, Unresectable, Wild-Type KRAS Exon 2 Metastatic Colorectal Cancer

OS (mo)

ORR (%)

Serious Adverse Event(%)



3020103366100

33

66

100

12

8

4

Schwartzberg LS, J Clin Oncol. 2014 Jul 20;32(21):2240-7

FOLFOX – PanitumumabFOLFOX – Bevacizumab

34.2*

10.9

44

57.8

24.3*

10.1

38

53.5

Phase III 80405 Trial: First-line CT + Either Cetux or Bev in KRAS-WT mCRC

Primary endpoint: OS

Secondary endpoints: ORR, PFS, TTF, duration of response

Patients with mCRC

and KRAS WT (codons 12, 13),

ECOG PS 0/1(N = 1137)

FOLFOX or FOLFIRI + Bevacizumab q2w

(n = 559)

ClinicalTrials.gov. NCT00265850. Venook AP, et al. ASCO 2014. LBA3..

FOLFOX or FOLFIRI + Cetuximab q1w

(N = 578)

A third arm with CT + bevacizumab + cetuximab was closed to accrual in September 2009

CALGB/SWOG 80405: OS in the ITT Population

mOS (95% CI), mosCT + Cetux 29.9 (27.0-32.9)CT + Bev 29.0 (25.7-31.2)

HR 0.925 (0.78-1.09)P = 0.34

Venook AP, et al. ASCO 2014. Abstract LBA3.

012 24 36 48 60 72

Mos

80

100

60

40

0

OS

(%)

20

84

Venook AP, et al. ASCO 2014, Abstract LBA3.

Phase III 80405 Trial: First-Line CT + Either Cetuximab or Bevacizumab in KRAS-WT mCRC

OS (mo)

PFS (mo)

CT – Cetuximab (n=559)CT – Bevacizumab (n=578)

29.9

10.8

29.0


wtKRAS10.4

OS in mCRC

24 mo

CT-only

CT + Biologic

ESMO Consensus Guidelines for the Management of Patients with Metastatic Colorectal Cancer

Group 0

Group 1

Group 2

Group 3

Resectable R0

Convertible

Unlikely resectable/High tumor burden

Never resectable

Surgery/ +/- Adj CT

Conversion CT/Surgery

Active CT + Biologic

Less-toxic CT+Biologic

Cure

Cure

Long OS

QoL

Criticism: solely based on DISEASE characteristicsVan Cutsem E, Cervantes A, Nordlinger B, Arnold D, ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann

Oncol. 2014;25(suppl 3):iii1-iii9. doi:10.1093/annonc/mdu260.

A• Nacida en 04/1944 con masa de 9 cm a 4 cm del reborde anal altamente

sugestiva de carcinoma y síntomas obstructivos. • Fibrilación auricular.• Se le practica biopsia que muestra un adenocarcinoma infiltrante

moderadamente diferenciado (07/2015).• Se encuentran además 2 lesiones en hígado, segmento V y segmento VIII de 46

mm y 22 mm.• KRAS wt • Se clasifica como un cT4a cN0 cM1a • Se inició quimiorradiación con Fluoruracilo + Folinato 07/09/2015-15/10/2015.• Sin cambio en las lesiones hepáticas.

• Qué sigue?

Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386-1422. doi:10.1093/annonc/mdw235.

Assessment of clinical condition of the patient

Fit Unfit (but may be suitable) Unfit

BSCFP-bevacizumab; reduced doublet, anti-EGFRGoal


OS after resection in liver metastasis

Adam R, Oncologist, 2012

B• Nacida en 30/03/1942 *Trastorno lifoproliferativo crónico / malformación

arteriovenosa cerebral* - AdenoCa Colon (ciego) - mal diferenciado - pT3 pN1c (múltiples implantes tumorales perilesionales, no compromiso ganglionar en 2 GL resecados) cM0 - IIIB - 14/11/2015: Hemicolectomía derecha (17/11/2015)--R0. Inició FOLFOX en 17/12/2015. Se atenúa la dosis por toxicidad importante en 31/03/2016 (luego de la infusión número 1 del ciclo 4). Terminó quimioterapia en 31/05/2015.

• TAC muestra anormalidad.• En 11/08/2016 PET-CT: Lesión de 2 cm en la pared abdominal adherida a

la fascia, por delante del colon transverso con SUV de 5. El mesenterio con SUV de 2.7 con adenopatía de 1.4 cm, con CEA de 6.5. Resección R0 de metástasis de tejidos blandos en pared abdominal por carcinoma pobremente diferenciado.

B• Nacida en 30/03/1942 *Trastorno lifoproliferativo crónico / malformación

arteriovenosa cerebral* - AdenoCa Colon (ciego) - mal diferenciado - pT3 pN1c (múltiples implantes tumorales perilesionales, no compromiso ganglionar en 2 GL resecados) cM0 - IIIB - 14/11/2015: Hemicolectomía derecha (17/11/2015)--R0. Inició FOLFOX en 17/12/2015. Se atenúa la dosis por toxicidad importante en 31/03/2016 (luego de la infusión número 1 del ciclo 4). Terminó quimioterapia en 31/05/2015.

• TAC muestra anormalidad.• En 11/08/2016 PET-CT: Lesión de 2 cm en la pared abdominal adherida a la

fascia, por delante del colon transverso con SUV de 5. El mesenterio con SUV de 2.7 con adenopatía de 1.4 cm, con CEA de 6.5. Resección R0 de metástasis de tejidos blandos en pared abdominal por carcinoma pobremente diferenciado.

• Inició en quimioterapia con Quásar. Inicia en fecha: 29/08/2016. En 31/01/2017 TAC de tórax y abdomen: quistes hepáticos. Dos lesiones subpleurales de 3 mm, de significancia incierta. Adenopatías axilares de hasta 11 mm.

C• Nacido en 12/1969. • Adenocarcinoma moderadamente diferenciado de colon

derecho, con metástasis hepáticas no resecables, pero convertibles, diagnosticado en 06/02/2015. cT4a cN2 cM1a.

• Mutación del KRAS en codón 2. • Inició FOLFOX + Bevacizumab en 12/03/2015, seguido por

Bevacizumab. • En 07/07/2015 TAC de abdomen contrastado: respuesta

parcial por RECIST de las lesiones en el segmento VI, VII y II de 15, 14 y 11 mm respectivamente. No aparición de nuevas lesiones. Respuesta parcial por RECIST (luego de ciclo 4).

Conversion chemotherapy approach in patients with liver-limited disease

Vie-LM-BevCELIMGONOPOCHERBOXEROLIVIA

Ye et al.

ORR73%70%80%79%78%81%62%57%29%

FOLFOXIRIBevacizumabCetuximabNo biologic agent


C• Nacido en 12/1969. • Adenocarcinoma moderadamente diferenciado de colon derecho, con

metástasis hepáticas no resecables, pero convertibles, diagnosticado en 06/02/2015. cT4a cN2 cM1a.

• Mutación del KRAS en codón 2. • Inició FOLFOX + Bevacizumab en 12/03/2015, seguido por Bevacizumab. • En 07/07/2015 TAC de abdomen contrastado: respuesta parcial por RECIST

de las lesiones en el segmento VI, VII y II de 15, 14 y 11 mm respectivamente. No aparición de nuevas lesiones. Respuesta parcial por RECIST (luego de ciclo 4).

• En 05/10/2015 Metastasectomía hepática R0 (se resecan 3 lesiones de los segmentos VI x2, III de 25, 8 y 3 mm, respectivamente) CEA (Normal <4): 1.4.

D

• Nacido en 08/1941. Carcinoma de colon - sigmoides - pT4a pN0 cM0 - Estadío IIB, alto riesgo (por invasión perineural y vascular, y por n resecados). Resecado en 27/06/2013. Recibe quimioterapia adyuvante con fluoruracilo + folinato entre 07/08/2013 y 16/01/2014. En 20/02/2014 durante el cierre de colostomía se establece recaída con carcinomatosis peritoneal y compromiso retroperitoneal.

D• Nacido en 08/1941. Carcinoma de colon - sigmoides - pT4a

pN0 cM0 - Estadío IIB, alto riesgo (por invasión perineural y vascular, y por n resecados). Resecado en 27/06/2013. Recibe quimioterapia adyuvante con fluoruracilo + folinato entre 07/08/2013 y 16/01/2014. En 20/02/2014 durante el cierre de colostomía se establece recaída con carcinomatosis peritoneal y compromiso retroperitoneal.

• Se inicia quimioterapia CAPOX-bevacizumab (capecitabina + oxaliplatino) - bevacizumab en 21/03/2014. Sin evidencia de enfermedad en tac de 12/06/2014, 17/09/2015, 27/07/2016

Assessment of clinical condition of the patient

Fit Unfit (but may be suitable) Unfit

BSCFP-bevacizumab; reduced doublet, anti-EGFRGoal

Phase 3 trial, Patients aged 70 years and older with previously untreated, unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were randomly assigned in a 1:1 to capecitabine alone or with bevacizumab

Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14(11):1077-1085. doi:10.1016/S1470-2045(13)70154-2.

Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label,

randomised phase 3 trial.

OS (mo)


ORR (%)

Capecitabine - BevacizumabCapecitabine

19*

20.7

5.1*

16.810*Grade ¾ toxicity (%)

22*40*


9.1*

E

• Nacido en 04/1955. • Síntomas obstructivos• Cáncer de colon ascendente pT4a cN1c cM1b estadío

iv (metastásico a pulmón, hígado, retropritoneo, óseo ?). Adenocarcinoma bien diferenciado.

• KRAS no mutado• Colectomía parcial en 08/05/2014 (con colostomía

temporal). • Qué sigue?

Primary tumour location

• Incidence: ~40% (increasing)• Older patients• Microsatellite instability• BRAF mutations• Worse prognosis

Right-sided tumours• Incidence: ~60%• Younger patients• Predominantly WT• Better prognosis

Left-sided tumours

R L

Iacopetta, et al. Int J Cancer 2002; Brule, et al. ASCO 2013. Abstract 3528;Missiaglia, et al. ASCO 2013. Abstract 3526

CALGB 80405: retrospective analysis of effect of primary tumour location on OS and PFS

Venook, et al. ASCO 2016. Abstract 3504

• CALGB 80405 (NCT00265850) is a phase III, randomised, open-label study• Primary endpoint: OS• Secondary endpoints: PFS, time to treatment failure, DoR

Avastin + FOLFOX/FOLFIRIPreviously untreated patients with mCRC(N=1137 KRAS WT)

252 KRAS MT patients enrolled prior to KRAS WT

protocol amendment

Cetuximab + FOLFOX/FOLFIRI

R

All KRAS WT Avastin

Cetuximab

All KRAS MT

All KRAS WT Avastin

Cetuximab

Right Left

Right Left

Right Left

Right Left

Right Left

Right Left

Right Left

OS (months)

19.4

33.3

24.2

31.4

16.7

36.0

23.1

30.3

PFS (months)

8.9 11.7

9.6 11.2

7.8 12.4

HR (95% CI)

1.55 (1.32–1.82)

1.32 (1.05–1.65)

1.87 (1.48–2.32)

1.28 (0.95–1.73)

HR (95% CI)

1.03 (1.11–1.50)

1.06(0.86–1.31)

1.56(1.26–1.94)

p value <0.0001 0.01 <0.0001 p value 0.0006 0.55 <0.0001

CALGB 80405: OS by primary tumour location

1.0

OS e

stim

ate

0.8

0.6

0.4

0.2

00 12 24 36 48 60 108

Time (months) Time (months)

1.0

OS e

stim

ate

0.8

0.6

0.4

0.2

0

LeftRightHR=1.55 (1.32–1.82)p<0.0001

Left/AvastinRight/Avastin

72 84 96

Total population By treatment

0 12 24 36 48 60 10872 84 96

19.4

33.3

16.7

24.2 36.0

31.4

This CALGB 80405 retrospective subset analysis was hypothesis generatingand should be interpreted with caution

Primary tumour location is a prognostic factor for poorer outcome in patients with right-sided tumours irrespective of therapy

More biomarker data are needed to fully understand the predictive value of these dataIn previous studies, Avastin has consistently shown efficacy in both right- and left-sided

tumours

Cetuximab vs Avastin

HR (95% CI)p

valueLeft 0.817

(95% CI: 0.69–0.96)

0.018

Right

1.269 (95% CI: 0.98–

1.63)

0.065

Venook, et al. ASCO 2016. Abstract 3504

Left/CetuximabRight/Cetuximab

Relationship between primary tumour sidedness and prognosis in CRC

• Observational analysis from the SEER database• Primary endpoints: median OS and 3-year OS

Provides further evidence from a large population that right-sided stage III and IV tumours are associated with poor survival

Stage III and IV primary CRC PDSEER

analysis

Stage IV (N=64,770) Stage III (N=91,009)Right Left Rectal Right Left Rectal

mOS (months) 9.5 15.5 15.5 62.5 93.5 85.5Survival probability Unadjusted HR (95% CI)

1.32 (1.30–1.35)

1.0 1.01 (0.99–1.03)

1.35 (1.32–1.38)

1.0 1.03 (1.01–1.06)

Survival probabilityAdjusted HR (95% CI)

1.25 (1.22–1.27)

1.0 0.83 (0.81–0.85)

1.12 (1.09–1.15)

1.0 1.11 (1.08–1.14)

Schrag, et al. ASCO 2016. Abstract 3505

Association of tumour location and molecular features with PFS and OS after anti-EGFR therapy

• Retrospective study• Primary endpoint: PFS• Secondary endpoint: OS

Right CIMP-High BRAF MT NRAS MTPFS, HR (95% CI); p value 1.56 (1.01–2.41);

0.0402.38 (1.47–

3.85); 0.00062.14 (1.26–3.65);

0.0042.12 (1.23–3.65);

0.006OS, HR (95% CI); p value 1.45 (1.04–2.01);

0.0281.53 (1.08–2.16); 0.001

2.46 (1.61–3.74); <0.0001

NA

KRAS WT mCRC treated with anti-

EGFR therapy(N=198)

CIMP testing

BRAF, NRAS and PIK3CA sequencingMSI status

• On multivariate analysis, BRAF MT (p=0.001), and NRAS MT (p=0.060) remained significant for OS, but primary tumour location did not (p=0.121)

• Right-sided CRC and CIMP-high were associated with hypermethylation of EREG and AREG, and distinct expression patterns of consensus molecular subtypes (CMS) 1 and 3

Lee, et al. ASCO 2016. Abstract 3506

Right-sided tumours were associated with inferior OS and PFS after anti-EGFR therapy Factors influencing outcome in right-sided tumours were BRAF MT, NRAS MT, molecular

subtypes, and tumour methylation

Primary tumour location: combined analysis of JACCRO CC-05 and -06 studies

Sunakawa, et al. ASCO GI 2016. Abstract 613

Cetuximab + mFOLFOX6(n=57)

Cetuximab + S-1 + oxaliplatin

(n=67)

Patients with KRAS exon 2 WT mCRC with EGFR-expressing

tumours

JACCRO CC-05

JACCRO CC-06

Objective: to assess the prognostic impact of primary tumour location on clinical outcomes of Japanese patients with KRAS exon 2 WT mCRC enrolled in the JACCRO CC-05 or -06 trials

PFS in ITT population OS in ITT population

Time (months)0 6 12 18 2430 36 42

5.6 11.1

Left-sided tumours (n=90)Right-sided tumours (n=20)HR=0.47 (95% CI: 0.28–0.80); p=0.0041

1.0

PFS

estim

ate

0.8

0.6

0.4

0.2

0

Time (months)

12.6 36.2

Left-sided tumours (n=90)Right-sided tumours (n=20)HR=0.28 (95% CI: 0.15–0.52); p<0.0001

0 6 12 18 2430 36 42 48

1.0

OS e

stim

ate

0.8

0.6

0.4

0.2

0

Primary tumour location: combined analysis of JACCRO CC-05 and -06 studies

Sunakawa, et al. ASCO GI 2016. Abstract 613

PFS in FOLFOX groupLeft-sided tumours (n=43)Right-sided tumours (n=9)HR=0.15 (95% CI: 0.06–0.37); p<0.0001

Time (months)

5.7 42.8

0 6 12 18 2430 36 42 48

1.0

OS e

stim

ate

0.8

0.6

0.4

0.2

0

OS in FOLFOX group

Primary tumour location may be a negative predictive factor in patients with mCRC and KRAS WT tumours who receive

cetuximab + oxaliplatin-based therapy

Left-sided tumours (n=43)Right-sided tumours (n=9)HR=0.26 (95% CI: 0.12–0.56); p=0.0002

Time (months)

3.0

11.3

0 6 12 18 2430 36 42

1.0

PFS

estim

ate

0.8

0.6

0.4

0.2

0

Proc ASCO, 2016, 3505.Association of primary (1°) site and molecular

features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor

(αEGFR) therapy. Michael Sangmin Lee

Association of primary (1°) site and molecular features with progression-free survival (PFS) and

overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor


Proc ASCO, 2016, 3505.

Proc ASCO, 2016, 3505.Association of primary (1°) site and molecular

features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor


E• Nacido en 04/1955. • Síntomas obstructivos• Cáncer de colon ascendente pT4a cN1c cM1b estadío iv

(metastásico a pulmón, hígado, retropritoneo, óseo ?). Adenocarcinoma bien diferenciado.

• KRAS no mutado• Colectomía parcial en 08/05/2014 (con colostomía temporal). • Se inició quimioterapia con FOLFOX- bevacizumab en 04/06/2014. • Se suspende el oxaliplatino en 01/2015 por neuropatía periférica. • Estable en TAC de 25/02/2015: con progresión documentada en

pulmón e hígado, y química en 29/07/2015.

F• Nacido en 04/1955. • Síntomas obstructivos• Cáncer de colon ascendente pT4a cN1c cM1b estadío iv (metastásico a pulmón,

hígado, retropritoneo, óseo ?). Adenocarcinoma bien diferenciado. • KRAS no mutado• Colectomía parcial en 08/05/2014 (con colostomía temporal). Se inició

quimioterapia con folfox - bevacizumab en 04/06/2014. • Se suspende el oxaliplatino en 01/2015 por neuropatía periférica. • Estable en TAC de 25/02/2015: con progresión documentada en pulmón e hígado, y

química en 29/07/2015. • Inició FOLFIRI + panitumumab en 10/08/2015. Con respuesta parcial en 04/03/2016.

En 19/08/2016 TAC de tórax y abdomen contrastado que muestra incremento de las lesiones hepáticas de hasta 18 en múltiples segmentos y lóbulos, estabilidad de la lesiones metastásicas pulmonares y lesiónes costales en la parrilla 6, 7 y 9 derecha (posiblemente, por trauma).

F• Nacido en 04/1955. • Síntomas obstructivos• Cáncer de colon ascendente pT4a cN1c cM1b estadío iv (metastásico a pulmón, hígado,

retropritoneo, óseo ?). Adenocarcinoma bien diferenciado. • KRAS no mutado• Colectomía parcial en 08/05/2014 (con colostomía temporal). Se inició quimioterapia con

folfox - bevacizumab en 04/06/2014. • Se suspende el oxaliplatino en 01/2015 por neuropatía periférica. • Estable en TAC de 25/02/2015: con progresión documentada en pulmón e hígado, y

química en 29/07/2015. • Inició FOLFIRI + panitumumab en 10/08/2015. Con respuesta parcial en 04/03/2016. En

19/08/2016 TAC de tórax y abdomen contrastado que muestra incremento de las lesiones hepáticas de hasta 18 en múltiples segmentos y lóbulos, estabilidad de la lesiones metastásicas pulmonares y lesiónes costales en la parrilla 6, 7 y 9 derecha (posiblemente, por trauma).

• Inició FOLFOX - Bevacizumab en 06/09/2016:



BRAF p.V600 (BRAF c.1799 [p.V600]) position mutational analysis should be performed in CRC

tissue in selected patients with colorectal carcinoma for prognostic stratification.




There is insufficient evidence to recommend BRAF c.1799 (p.V600) mutational status as a predictive molecular biomarker for response to anti-EGFR inhibitors.

There is insufficient evidence to recommend PIK3CA mutational analysis of colorectal carcinoma tissue for therapy selection outside of a clinical trial.

There is insufficient evidence to recommend PTEN analysis (expression by immunohistochemistry [IHC] or deletion by fluorescence in situ hybridization [FISH]) in colorectal carcinoma tissue for patients who are being considered for therapy selection outside of a clinical trial.





OS (mo)

PFS (mo)

ORR (%)

FOLFOXIRI + BevacizumabFOLFIRI + Bevacizumab

65

29.8*

12.2*

9.7*

25.8*

53

BRAF+ OS (mo)

N=508* Statistically significant

10.7*19*

90CONFIDENTIAL – for internal use only

Retrospective analysis of two RAS/BRAF WT, mCRC cohorts:- Cohort 1: HER2 tested by IHC / ISH, 14/97 HER2 amplified- Cohort 2: all patients HER2 tested by next generation sequencing (n=37)

HER2 amplification as a negative predictor of efficacy of anti-EGFR inhibitors

In this retrospective analysis, HER2 amplification was indicated to be a negative predictive biomarker of efficacy of anti-EGFR inhibitors

Raghav, et al. ASCO 2016. Abstract 3517

Cohort 1: PFS on anti-EGFR txMedian 2.9 vs 8.1 months(p<0.001)

Cohort 2: PFS on anti-EGFR txMedian 2.9 vs 9.3 months(p<0.001)

Months Months

Perc

ent s

urvi

val

Perc

ent s

urvi

val

HER2 amplifiedHER2 non-amplified

HER2 amplifiedHER2 non-amplified

C• Nacido en 12/1969. • Adenocarcinoma moderadamente diferenciado de colon derecho, con metástasis hepáticas no resecables, pero

convertibles, diagnosticado en 06/02/2015. cT4a cN2 cM1a. • Mutación del KRAS en codón 2. • Inició FOLFOX + Bevacizumab en 12/03/2015, seguido por Bevacizumab. • En 07/07/2015 TAC de abdomen contrastado: respuesta parcial por RECIST de las lesiones en el segmento VI, VII y

II de 15, 14 y 11 mm respectivamente. No aparición de nuevas lesiones. Respuesta parcial por RECIST (luego de ciclo 4).

• En 05/10/2015 Metastasectomía hepática R0 (se resecan 3 lesiones de los segmentos VI x2, III de 25, 8 y 3 mm, respectivamente) CEA (Normal <4): 1.4.

• Inició FULV. Inicia en fecha: 09/11/2015. Terminó curso programado en 11/04/2016. • En 12/07/2016 TAC que muestra lesión de 21 x 22 mm en la unión de los segmentos IV y VII, adenopatía

aortocava. • Inicia quimioterapia con FOLFIRI + Bevacizumab. Inicia en fecha: 10/08/2016. • En 17/08/2016 se establece deficiencia de MLH1 y PMS2 en inmunohistoquímica.• En 31/10/2016 PET-CT: Estabilidad de las lesiones hepáticas que ahora miden 3.3 y 1.8 cm, con necrosis central,

adenopatía retroperitoneal de 1.3 cm y mesentérica de 1.2 cm, así como la lesión de tejidos blandos subctostal en niveles 11 y 12 de 4 cm.

• En 31/01/2017 PET-CT: Estabilidad de las lesiones hepáticas, mesentéricas y retroperitoneales.• Qué sigue?

Le DT et al. N Engl J Med 2015;372:2509-2520.

Clinical Benefit of Pembrolizumab Treatment According to Mismatch-Repair Status.

Concluding remarks

@onconerd


BRAF

KRAS

EREG or AREG

PI3K PTEN

EGFR

PIP1

PIP3


Low expression of EGFR ligands → decreased response to EGFR-targeted agents

Mutant BRAF → decreased response to EGFR-targeted agents


Mutant KRAS → decreased response to EGFR-targeted agents


The consensus molecular subtypes of colorectal cancer

Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350-1356. doi:10.1038/nm.3967.

Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350-1356. doi:10.1038/nm.3967.

The consensus molecular subtypes of colorectal cancer


ESMO Consensus Guidelines for the Management of Patients with Metastatic

Colorectal Cancer• Biologicals (targeted agents) are indicated in the first-line treatment of most patients unless contraindicated [I, A]. • The VEGF antibody bevacizumab should be used in combination with:

° the cytotoxic doublets FOLFOX/CAPOX/FOLFIRI, ° the cytotoxic triplet FOLFOXIRI in selected fit and motivated patients

where cytoreduction (tumour shrinkage) is the goal—and potentially also in fit patients with tumour BRAF mutations [II, B],

° fluoropyrimidine monotherapy in patients unable to tolerate aggressive treatment [I, B]. • EGFR antibodies should be used in combination with:

° FOLFOX/FOLFIRI [I, A], ° capecitabine-based and bolus 5-FU based regimens should not be

combined with EGFR antibodies [I, E].



Colorectal Cancerrecommendation 13: conversion therapy.

• In potentially resectable patients (if conversion is the goal), a regimen leading to high RRs and/or a large tumour size reduction (shrinkage) is recommended [II, A].• There is uncertainty surrounding the best combination to use as only few trials have addressed this specifically:

° In patients with RAS wild-type disease, a cytotoxic doublet plus an anti-EGFR antibody seems to have the best benefit risk/ratio, although the combination of FOLFOXIRI plus bevacizumab may also be considered and, to a lesser extent, a cytotoxic doublet plus bevacizumab [II, A].

° In patients with RAS-mutant disease: a cytotoxic doublet plus bevacizumab or FOLFOXIRI plus bevacizumab [II, A]. • Patients must be re-evaluated regularly in order to prevent the overtreatment of resectable patients as the maximal response is expected to be achieved after 12–16 weeks of therapy in most patients



Colorectal CancerRecommendation 19: maintenance therapy.

• Patients receiving FOLFOX or CAPOX plus bevacizumabbased therapy as induction therapy should be considered for maintenance therapy after 6 cycles of CAPOX and 8 cycles of FOLFOX. The optimal maintenance treatment is a combination of a fluoropyrimidine plus bevacizumab. Bevacizumab as monotherapy is not recommended [I, B].

• Patients receiving FOLFIRI can continue on induction therapy—at a minimum—for as long as tumour shrinkage continues and the treatment is tolerable [V, B]. • For patients receiving initial therapy with FOLFOXIRI plus or minus bevacizumab, a fluoropyrimidine plus bevacizumab may be considered as maintenance therapy (as was done in the pivotal trials examining FOLFOXIRI).

• For patients receiving initial therapy with a single-agent fluoropyrimidine ( plus bevacizumab), induction therapy should be maintained [V, A].

• Individualisation and discussion with the patient is essential [V, A].

• Initial induction therapy or a second-line therapy have to be reintroduced at radiological or first signs of symptomatic progression. If a second-line therapy is chosen, re-introduction of the initial induction treatment should be a part of the entire treatment strategy as long as no relevant residual toxicity is present [III, B].



Colorectal CancerRecommendation 20: second-line combinations with targeted agents.

• Patients who are bevacizumab naïve should be considered for treatment with an antiangiogenic (bevacizumab or aflibercept) second line [I, A].

The use of aflibercept should be restricted to combination with FOLFIRI for patients progressing on an oxaliplatin-containing regimen [I, A]. • Patients who received bevacizumab first line should be considered for treatment with: ° Bevacizumab post-continuation strategy [I, A].

° Aflibercept or ramucirumab (in combination with FOLFIRI) when treated in first line with oxaliplatin [I, A].

° EGFR antibodies in combination with FOLFIRI/irinotecan for patients with RAS wild-type (BRAF wild-type) disease • Relative benefit of EGFR antibodies is similar in later lines compared with second line [II, A].



Colorectal CancerConsensus recommendation for patients where cytoreduction with ‘conversion’ and/or the integration of local ablative treatment is the goal

• A1a. For those patients who have RAS wild-type disease, a cytotoxic doublet plus an EGFR antibody should be the treatment of choice

• A1b. For those patients with RAS mutant disease, a cytotoxic doublet plus bevacizumab or cytotoxic triplet plus bevacizumab are the preferred options

• A1c. Patients should be revaluated for their disease status every 2 months in order to ensure that resectable patients are not over- treated

• A1d. If, after the first re-evaluation at 2 months, there is evidence of tumour shrinkage, patients should be recommended for either potentially curative surgery or the most suitable LAT strategy—with a view to eliminating all evidence of disease (i.e. R0 resection, NED)



Colorectal CancerConsensus recommendation for patients where cytoreduction with ‘conversion’ and/or the integration of local ablative treatment is the goal

• A1e. If no response is evident at first evaluation, it is suggested that the cytotoxic doublet is changed in order to maximise the chance of resection [5]

• A1f. Where there is evidence for cytoreduction but the patients are not suitable for surgery, they should continue on combination chemotherapy plus the appropriate biological dependent on RAS and BRAF mutation status as indicated in Figure 4.

• A1g. Where there is evidence of disease progression, patients should continue to second-line therapy (Figure 5).

• A1h. Toxicity might also require a change to an alternative regimen.



Colorectal CancerConsensus recommendation for patients where cytoreduction is needed because of aggressive biology and/or risk of developing or existing severe symptoms

• A2a. For those patients who have RAS wild-type disease, a cytotoxic doublet plus an EGFR antibody is a preferred option, although a cytotoxic doublet plus bevacizumab is an equally valid alternative. A cytotoxic triplet plus or minus bevacizumab may be an alternative for selected, very fit and motivated patients

• A2b. For those patients with RAS mutant disease, a cytotoxic doublet plus bevacizumab is the preferred option. A cytotoxic triplet plus or minus bevacizumab may be an alternative for selected, very fit and motivated patients

• A2c. Patients should be revaluated for their disease status every 2 months

• A2d. Treatment should not be changed in patients without tumour progression and not suffering from major toxicity



Colorectal CancerConsensus recommendation for patients where disease control is the goal

• B1a. For these patients, a cytotoxic doublet in combination with bevacizumab or in patients with RAS wild-type tumours, a cytotoxic doublet plus an EGFR antibody are recommended

• B1b. Patients should be revaluated for their disease status every 2–3 months

• B1c. In patients with a good response or at least disease control, active maintenance therapy should be considered. A fluoropyrimidine plus bevacizumab is the preferred option if they started their treatment with a cytotoxic doublet plus bevacizumab

• B1d. Where there is evidence of disease progression, patients should continue to second-line therapy (Figure 5)

• B1e. Toxicity might also require a change to second-line therapy.

Controversias actuales en el manejo de cáncer colorrectal metastàsico

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Transcript of Controversias actuales en el manejo de cáncer colorrectal metastàsico