Cáncer colorrectal metastásico Hay diferencias entre los anti-egfr? Dra E. González-Flores HMQ Virgen de las Nieves Granada

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1 Cáncer colorrectal metastásico Hay diferencias entre los anti-egfr? Dra E. González-Flores HMQ Virgen de las Nieves Granada

2 Cetuximab vs Panitumumab

3 Cetuximab vs Panitumumab

4 Diferencias en la estructura molecular Cetuximab 1,2 Panitumumab 2,3 Mouse variable domains Human constant and variable domains Human constant domains Anticuerpo monoclonal quimerico IgG1 Anticuerpo monoclonal completamente humano IgG2 1. Erbitux SmPC June/2014; 2. Imai K, Takaoka A. Nat Rev Cancer 2006;6: ; 3. Vectibix SmPC February/2015.

5 Cetuximab Panitumumab x RAS EGF, epidermal growth factor. TGFα, transforming growth factor-α. VEGF, vascular endothelial growth factor. 1. Martinelli E, et al. Clin Exp Immunol 2009;158:1 9; 2. Brand TM, Wheeler DL. Small GTPases 2012;3:34 39.

6 CDC Complement-dependent cytotoxicity (CDC) EGFR Target tumor cell CDC y ADCC puede contribuir a la actividad citotoxica mediada por celulas dependientes de Ac para cetuximab Cetuximab Como anticuerpo IgG2, panitumumab no muestra actividad ADCC MAC, membrane attack complex. Antibody-dependent cell-mediated cytotoxicity (ADCC) Adapted from Imai K, Takaoka A. Nat Rev Cancer 2006;6:

7 Cetuximab vs Panitumumab

8 ESMO Draft mcrc treatment algorithm CLINICAL CONDITION OF THE PATIENT Fit GOAL Unfit (but may be suitable) FP ± bevacizumab; reduced dose doublet; anti-egfr Unfit BSC NED Cytoreduction (shrinkage) Disease control (control progression) Clearly resectable metastases WT RAS MOLECULAR PROFILE MT RAS MT BRAF WT RAS MOLECULAR PROFILE MT RAS MT BRAF Surgery alone; surgery with perioperative/ postoperative CT Doublet + anti-egfr Combination + bevacizumab Re-evaluation/assessment of response Q2M GOAL Progressive disease Triplet + bevacizumab CT + biological agent Second-line CT + bevacizumab Unusual, see text Re-evaluation/assessment of response Q2 3M Progressive disease Second-line Surgery Cytoreduction (shrinkage) Continue Disease control Continue; maintenance; or pause Continue; maintenance; or pause

9 Proportion, % Proportion, % Response rate Impact of anti-egfr mab therapy on outcomes (KRAS exon 2 WT, LLD) R0 resection rate P = P = CT alone CT+ EGFR mab 0 CT alone CT + EGFR mab Meta-analysis indicates EGFR inhibitors increase R0 resection rate by 60% in mcrc patients with unresectable liver-limited disease Petrelli F, Barni S. Int J Colorectal Dis 2012;27: CT, chemotherapy; mab, monoclonal antibody; R0, resection with microscopically negative margins.

10 Citorreducción CETUXIMAB Población no seleccionada CRISTAL OPUS CALGB Población seleccionada CELIM PANITUMUMAB Población no seleccionada PRIME PEAK Población seleccionada PLANET

11 AntiEGFR en Met hepáticas: población seleccionada N Criterios inclusión OR FOLFIRI FOLFOX Resecciones R0 FOLFOX FOLFIRI R0+ R1 FOLFOX FOLFIRI CETUXIMAB Estudio CELIM 70( K ras nativo) Técnicamente no resecables/>5 metastasis 70% 57% 68% 42% 34% 38% 30% 49% 46% 43% PANITUMUMB Estudio PLANET 53( RAS WT) Técnicamente no resecables/>4 meta/ >10cm 75,5% 73,1 % 77,8% 52,8% 39,6% 25,9% 53,8% Folprecht G, Gruenberger T. Lancet Oncol 2010; 11: Abad et al. Presented at the 2014 European Society of Medical Oncology Meeting, September 26-30, 2014, Madrid, Spain; Abstract # 7823

12 Proportion event-free (%) PLANET study RAS analysis (interim results) OS and resectability (WT RAS) In the overall group, surgery was associated with longer OS OS by resection status - Cuando el objetivo es la CITORREDUCCION la evidencia 60 apoya el uso de QT+ anti EGFR - PANI vs CETUXI HR = 0.20 (95% CI, ) Log-rank P = Abad A, et al. Eur J Cancer 2015;51(Suppl 3):S1 S810:abstract 2128 (and poster) Months Median, months (95% CI) Surgery done 51.5 ( ) Surgery not done 26.5 ( ) 4 8 N/S, not significant.

13 CONTROL DE LA ENFERMEDAD CETUXIMAB Irinotecan CRYSTAL: fase III FIRE 3: (FASE III-Publicado) CALGB/SWOG (FASE III- Pendiente de publicación) Oxaliplatino COIN NORDIC OPUS: fase II CALGB/SWOG (FASE III- Pendiente de publicación) PANITUMUMAB Irinotecan Study : fase II Oxaliplatino PRIME : fase III PEAK (FASE II randomizado- Publicado)

14 OS probability PFS probability Evidencia de agentes anti-egfr en combinación en 1L con FOLFIRI (RAS wt) OS CRYSTAL trial (RAS wt*) 1 Study (RAS wt*) 2 Erbitux + FOLFIRI (n=178) FOLFIRI (n=189) HR=0.69 (95% CI: ) p= PFS Panitumumab + FOLFIRI (n=69) HR=0.758 (95% CI: ) p< Months EECC Fase III randomizado vs QT solo Beneficios significativos OS vs QT solo Months Estudio fase II de un solo brazo No hay datos OS disponible *Retrospective analysis. 1. Van Cutsem E, et al. J Clin Oncol 2015;33: ; 2. Karthaus M, et al. ESMO 2014 (Abstract No. 549P).

15 Proportion event-free, % OS estimate, % FOLFOX Ensayo fase III PRIME (RAS wt*) PFS Events, n/n (%) Median PFS, months (95% CI) Pani + FOLFOX4 156/259 (60) 10.1 ( ) FOLFOX4 170/253 (67) 7.9 ( ) OS Events, n/n (%) Median OS, months (95% CI) Pani + FOLFOX4 204/259 (79) 25.8 ( ) FOLFOX4 218/253 (86) 20.2 ( ) HR=0.72 (95% CI: ) p= HR=0.77 (95% CI: ) p= Months Months Douillard J-Y, et al. N Engl J Med 2013;369:

16 OPUS: RAS wt selection Patients RAS wt Cetuximab + FOLFOX4 FOLFOX4 (N=36) (N=46) OS months, median ,8 (IC 95%) (18,2; 26,8) (12,4; 23,9) HR (IC 95%) 0,94 (0,56-1,56) p value 0,80 PFS months, median 12,0 5,8 (IC 95%) (7,7; NE) (4,5; 7,5) HR (IC 95%) 0,53 (0,27-1,04) p value 0,0615 ORR % (IC 95%) (43,5; 76,9) (17,7; 45,8) OR 1. (IC Bokemeyer 95%) C, et al. Ann Oncol 2011;22: ; 3,33 (1,36-8,17) 2. Bokemeyer C, et al. ASCO GI 2010 (Abstract No. 428); p value 0, Bokemeyer C, et al. ASCO 2014 (Abstract No. 3505)

17 Qt+ anti EGFR vs QT+ Beva -Disponemos de mayor evidencia para la combinación de Irinotecan y Cetuximab vs Panitumumab -Disponemos de mayor evidencia para la combinación de Oxaliplatino y Panitumumab vs Cetuximab( si bien el estudio CALGB apoya el uso de Oxaliplatino + Cetuxi??) Khattak et al. Clin Colorectal Cancer 2015

18 Cetuximab vs Panitumumab

19 Fase III N=1300 pacientes EGFR + No bevacizumab previo Sobrero AF, et al. J Clin Oncol 2008; 26:2311. Ensayo EPIC (Erbitux Plus Irinotecan in Colorectal Cancer): Cetuximab ± Irinotecan tras progresión a FOLFOX

20 Peeters M, et al. J Clin Oncol 2010; 28:4706. Randomized Phase III Study of Panitumumab With FOLFIRI Compared With FOLFIRI Alone As Second-Line Treatment in Patients With Metastatic Colorectal Cancer

21 Cetuximab y Panitumumab en monoterapia -Disponemos de mayor evidencia para la combinación de Irinotecan y Panitumumab en segunda linea de CCRm -La evidencia apoya el uso de Cetuximab y panitumumab como monoterapia en pacientes refractarios a QT Jonker DJ, et al. N Engl J Med 2007; 357:2040. Van Cutsem E, et al. J Clin Oncol 2007;25:1658.

22 ASPECCT: efficacy of panitumumab versus cetuximab for previously treated WT KRAS mcrc Efficacy Panitumumab Cetuximab Hazard/odds ratio Median OS, months (95% CI) 10.4 (9.4, 11.6) 10.0 (9.3, 11.0) HR=0.97 (0.84, 1.11) Median PFS, months (95% CI) 4.1 (3.2, 4.8) 4.4 (3.2, 4.8) HR =1.00 (0.88, 1.14) ORR, % (95% CI) 22.0 (18.4, 26) 19.8 (16.3, 23.6) OR=1.15 (0.83, 1.58) Panitumumab was assessed to be non-inferior to cetuximab for OS based on a 50% retention rate* of the OS benefit of cetuximab Actual OS retention rate was 106% (95% CI: 82%,130%) *Fraction of cetuximab OS benefit that is retained by panitumumab Peeters, et al. Lancet Oncology 2014

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24 Retratamiento con anti EGFR Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI- GOIM): a randomized phase 2 trial of FOLFOX plus cetuximab versus FOLFOX 6,8 vs 5,5( p=0,36). RAS WT( N: 75) NRAS,KRA, BRAF, PI3KCA WT: 6,9 VS 5,3( P=0,025)( N: 66) Annals of Oncology Advance Access published March 21, 2016 Liu X, George GC, Tsimberidou AM, et al. Retreatment with anti-egfr based therapies in metastatic colorectal cancer: impact of intervening time interval and prior anti-egfr response. Retratamiento con cetuximab: 86 Median PFS on cetuximab-based retreatment was 4.9 months vs 2.5 months in prior non-responders (p=0.064). Análisis multivariante: No significant difference in PFS on cetuximab retreatment according to prior anti-egfr response, interval length between prior anti-egfr-based therapy and cetuximab retreatment, or other demographic or clinical variables. BMC Cancer 2015;15:713

25 Retratamiento con anti EGFR Metges Retrospectiva 106 respondedores CET: 31% OR/ 16% EE ESMO 2012 Resistentes Cet: 14% BC

26 Cetuximab vs Panitumumab

27 Tasas de Reacciones cutaneas de grado 3/4 y diarrea con cetuximab y panitumumab en ensayos randomizados 1 5 CRYSTAL 1,2 OPUS 3,4 PRIME 5 Patients with grade 3/4 AEs, % Cetuximab + FOLFIRI (n=317) KRAS wt RAS wt KRAS wt RAS wt KRAS wt FOLFIRI (n=350) Cetuximab + FOLFIRI (n=178) FOLFIRI (n=189) Cetuximab + FOLFOX4 (n=82) FOLFOX4 (n=97) Cetuximab + FOLFOX4 (n=38) FOLFOX4 (n=49) Panitumumab + FOLFOX4 (n=322) FOLFOX4 (n=327) Any AE Neutropenia Diarrhea Fatigue Skin reactions (all) Infusion-related reaction 21 < <1 0 Anti-EGFR therapy is approved in patients with RAS wt mcrc. 6,7 Anti-EGFR therapy is not indicated for the treatment of patients with mcrc whose tumors have RAS mutations or for whom RAS tumor status is unknown. 6, Van Cutsem E, et al. J Clin Oncol 2011;29: ; 2. Van Cutsem E, et al. J Clin Oncol 2015;33: ; 3. Bokemeyer C, et al. Ann Oncol 2011;22: ; 4. Bokemeyer C, et al. Eur J Cancer 2015;51: ; 5. Douillard J-Y, et al. J Clin Oncol 2010;28: ; 6. Erbitux SmPC June/2014; 7. Vectibix SmPC February/2015.

28 ASPECCT: safety Adverse events Panitumumab Cetuximab Any Grade Grade 3/4 Any Grade Grade 3/4 Infusion reactions, % Skin toxicity, % Hypomagnesaemia, % Treatment-related adverse events led to discontinuation of treatment in 3% of patients in each arm Fatal adverse events occurred in 6% of panitumumab patients and 10% of cetuximab patients, most were attributable to disease progression. The only treatment-related fatal adverse event was a lung infection, which occurred in the cetuximab arm Peeters, et al. Lancet Oncology 2014

29 Cetuximab vs Panitumumab

30 ASPECCT Hypomag analysis 30

31 RAS mutational analysis:

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33 ASPECCT S492R analysis 33

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36 Cetuximab vs Panitumumab TRATAMIENTO ANTI EGFR Población RAS WT EFICACIA DEMOSTRADA en citorreducción EFICACIA EN OS en PRIMERA LINEA y en refractarios No inferioridad de P vs C en pretratados Mecanismo de acción no idéntico Mejor esquema de combinación?? Perfil de toxicidad similar pero no idéntico: Reacciones de HPS Retratamiento: estudios retrospectivos? Factores predictivos de respuesta: Mutaciones Hipomagnesemia BIOPSIA LIQUIDA??