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Más es posible: 3º línea en Cáncer Colorrectal metastásico P. García Alfonso Jefe de Sección de Oncología Médica HGU Gregorio Marañón de Madrid.

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Presentation on theme: "Más es posible: 3º línea en Cáncer Colorrectal metastásico P. García Alfonso Jefe de Sección de Oncología Médica HGU Gregorio Marañón de Madrid."— Presentation transcript:

1 Más es posible: 3º línea en Cáncer Colorrectal metastásico P. García Alfonso Jefe de Sección de Oncología Médica HGU Gregorio Marañón de Madrid

2 5-year Survival Rate for Stage IV CRC Remains Only 6% Overall Survival (months) 5-FU/LV bolus 5-FU/LV infusion IFL LVFU2/irinotecan FOLFOX IFL + bevacizumab FOLFOXIRI/FOLFIRI XELOX/FOLFOX + bevacizumab FOLFOX + cetuximab FOLFIRI + cetuximab FOLFOX + panitumumab FOLFIRI + cetuximab FOLFOXIRI + bevacizumab *KRAS wild-type tumors. Note: Informal comparison as these are not head-to-head clinical trials. Saltz LB, et al. N Engl J Med. 2000;343: ; Douillard JY, et al. Lancet. 2000;355: ; Goldberg RM, et al. J Clin Oncol. 2004;22:23-30; Hurwitz H, et al. N Engl J Med. 2004;350: ; Saltz LB, et al. J Clin Oncol. 2008;26: ; Falcone A, et al. J Clin Oncol. 2007;25: ; Bokemeyer C, et al. Ann Oncol. 2011;22: ; Van Cutsem E, et al. J Clin Oncol. 2011;29: ; Douillard J, et al. J Clin Oncol. 2011;29(suppl): abstract 3510; Heinemann V, et al. J Clin Oncol. 2013;31(suppl): abstract LBA3506; Falcone A, et al. J Clin Oncol. 2013;31(suppl): abstract Treatment Approaches to First-Line mCRC FOLFIRI + bevacizumab G.SM.ON

3 Regorafenib es un Inhibidor multiquinasa que actúa sobre múltiples vías tumorales Inhibition of neoangiogenesis Inhibition of stromal signalling Inhibition of proliferation of certain tumor cells Regorafenib is an oral multikinase inhibitor with a distinct profile targeting:  angiogenic (VEGFR1-3, TIE2)  stromal (PDGFR- , FGFR)  oncogenic (KIT, RAF1, BRAF and RET) receptor tyrosine kinases

4 Multicenter, randomized, double-blind, placebo-controlled, phase III  2:1 randomization  Strat. factors: prior anti-VEGF therapy, time from diagnosis of mCRC, geographical region  Global trial: 16 countries, 114 active centers  1,052 patients screened, 760 patients randomized within 10 months Secondary endpoints: PFS, ORR, DCR Tertiary endpoints: duration of response / stable disease, QOL, pharmacokinetics, biomarkers No crossover between treatment arms was allowed Progressive mCRC during or within 3 m of the last standard therapy R A N D O M I ZA T I O N Regorafenib + BSC 160 mg orally once daily 3 weeks on, 1 week off Placebo + BSC 3 weeks on, 1 week off 2 : 1 Primary Endpoint: OS 90% power to detect 33.3% increase (HR=0.75), with 1-sided overall  =0.025 Primary Endpoint: OS 90% power to detect 33.3% increase (HR=0.75), with 1-sided overall  =0.025 Grothey et al. Lancet 2013; 381:

5 Patient demographics

6 Baseline disease characteristics *KRAS status based on historical patient record

7 Overall survival (primary endpoint) Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p< at approximately 74% of events required for final analysis) Days from randomization Survival distribution function Placebo N=255 Regorafenib N=505 Median 6.4 mos 5.0 mos 95% CI 5.9– –5.8 Hazard ratio: 0.77 (95% CI: 0.64–0.94) 1-sided p-value: RegorafenibPlacebo

8 Days from randomization Survival distribution function Placebo N=255 Regorafenib N=505 RegorafenibPlacebo Median 1.9 mos 1.7 mos 95% CI 1.9– –1.7 Hazard ratio: 0.49 (95% CI: 0.42–0.58) 1-sided p-value: < PROGRESSION-FREE SURVIVAL (secondary endpoint)

9 Overall response and disease control rates (secondary endpoints)

10 Overall survival: Subgroup analysis according to prognostic variables

11 Drug-related, treatment-emergent adverse events occurring in ≥10% of patients at any grade Adverse event, % Regorafenib N=500 Placebo N=253 All grades G-3G-4All grades Grade 3Grade 4 Hand–foot skin reaction Fatigue Hypertension Diarrhea Rash/desquamation Anorexia Mucositis, oral Thrombocytopenia Fever Nausea Bleeding Voice changes Weight loss

12 Drug-related, treatment-emergent adverse events occurring in ≥10% of patients at any grade Adverse event, % Regorafenib N=500 Placebo N=253 All grades G-3G-4All grades G-3G-4 Hand–foot skin reaction Fatigue Hypertension Diarrhea Rash/desquamation Anorexia Mucositis, oral Thrombocytopenia Fever Nausea Bleeding Voice changes Weight loss

13 Common AEs Occur Early and Stabilize Over Time AE, adverse event. *If patients experienced the same AE in more than 1 cycle, this is recorded separately for each of cycles 1-8, but only once for the entire study category. Grothey A, Van Cutsem E, et al. ASCO GI; Abstract #467. Frequency of common AEs (all grades) over time* # Patients at risk HFSR Fatigue Diarrhea Hypertension Rash/Desquamation Treatment Cycle Frequency of AE (%) G.SM.ON

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16 Time-Adjusted Area Under the Curve Least-Squares Mean Health-related QoL analyses: Error bars represent the respective CI for each value BSC, Best Supportive Care; EORTC, European Organization for Research and Treatment of Cancer; QoL, Quality of Life; VAS, visual analog scale Grothey et al. Lancet 2012 Van Cutsem E, et al. Oral abstract presented at: ASCO; J Clin Oncol. 2012;30:(suppl; abstr 3502). Placebo + BSC Regorafenib + BSC No significant difference in health-related QoL with regorafenib vs placebo

17 Summary of CORRECT results  The study met its primary endpoint at the preplanned interim analysis  Regorafenib vs placebo: – Overall survival: 6.4 vs 5.0 months, HR=0.77, p= – Progression-free survival: 1.9 vs 1.7 months, HR=0.49, p< – Disease control rate (PR + SD): 44.8% vs 15.3%, p<  No new or unexpected safety findings: – Main treatment-related adverse events observed in the regorafenib arm were fatigue, hand–foot skin reaction, diarrhea, anorexia, voice changes, hypertension, oral mucositis, and rash/desquamation

18 Regorafenib 160 mg daily 3 weeks on / 1 week off (4-week cycle) n = 136 Placebo n = 68 Stratification Metastases: single vs multiple Time from mCRC diagnosis: >18 vs <18 months All patients received best supportive care Treat until progression, unacceptable toxicity, or withdrawal Asian patients with mCRC who progressed after standard therapies 25 Centers: mainland China, Hong Kong, South Korea, Taiwan, Vietnam Asian patients with mCRC who progressed after standard therapies 25 Centers: mainland China, Hong Kong, South Korea, Taiwan, Vietnam CONCUR trial design Clinicaltrials.gov NCT Primary endpoint: overall survival (OS) One-sided alpha 0.2 and assumed 33.3% OS improvement (HR=0.75 favoring regorafenib) with 154 events had 80% power Secondary endpoints: progression-free survival, response rate, disease control rate R 2:1 J. Li, et al. WCGI Abstract O Presented at WCGI 2014, Barcelona, Spain. Kim TW et al Presented at ESMO 2014, 26 – 30 September, Madrid

19 Key inclusion criteria  Pathologically proven mCRC  Measurable or non-measurable disease (RECIST v 1.1)  Failed >2 prior CRC treatment regimens, which included a fluoropyrimidine, oxaliplatin, and irinotecan  Progression during or within 3 months after the last approved standard therapy or during or within 6 months of completing adjuvant oxaliplatin-based therapy  Prior anti-VEGF or anti-EGFR targeted therapy allowed, but not mandatory  ECOG performance status 0 or 1 RECIST, response evaluation criteria in solid tumors J. Li, et al. WCGI Abstract O Presented at WCGIC 2014, Barcelona, Spain Kim TW et al. ESMO 2014, 26 – 30 September, Madrid

20 Baseline characteristics Regorafenib (n=136) Placebo (n=68) Age, median years (range)58 (31–79)56 (30–84) Male, n (%)85 (62.5)33 (48.5) ECOG PS, n (%) (25.7) 101 (74.3) 15 (22.1) 53 (77.9) KRAS status, n (%) Wild-type Mutant Unknown 50 (36.8) 46 (33.8) 40 (29.4) 29 (42.6) 18 (26.5) 21 (30.9) BRAF status, n (%) Wild-type Mutant Unknown 28 (20.6) (79.4) 14 (20.6) 1 (1.5) 53 (77.9) No prior targeted therapy * 56 (41.2)26 (38.2) >3 prior treatment lines73 (53.7)35 (51.5) >3 prior treatment lines for mCRC52 (38.2)27 (39.7) Intent-to-treat population *No prior anti-VEGF or anti-EGFR therapy Kim TW et al.Presented at ESMO 2014, 26 – 30 September, Madrid

21 Overall survival (OS) Primary endpoint OS probability Days from randomization Events, n (%) 95 (69.9)60 (88.2) Median, months HR [95% CI] [0.395 ‒ 0.765] P= (1-sided) Regorafenib (n=136) Placebo (n=68) 45% reduction in risk of death in the regorafenib group J. Li, et al. WCGI Abstract O Presented at WCGI 2014, Barcelona, Spain Kim TW et al. Presented at ESMO 2014, 26 – 30 September, Madrid

22 Subgroup analysis of OS

23 PFS probability Days from randomization Progression-free survival (PFS) Events, n (%) 120 (88.2)65 (95.6) Median, months HR [95% CI] [0.222 ‒ 0.435] P< (1-sided) Regorafenib (n=136) Placebo (n=68) 69% reduction in risk of progression or death in the regorafenib group J. Li, et al. WCGI Abstract O Presented at WCGI 2014, Barcelona, SpainPresented at Kim TW et al. ESMO 2014, 26 – 30 September, Madrid

24 Regorafenib (n=136)Placebo (n=68) Patients, % All gradesGrade 3Grade 4All gradesGrade 3Grade 4 Palmar-plantar erythrodysesthesia Blood bilirubin increased ALT increased Diarrhea Voice alterations/hoarseness Hypertension Fatigue Fever Hypokalemia Hypophosphatemia Rash, maculo-papular Platelet count decreased White blood cells decreased Adverse events in ≥ 10% of patients in either group (all grade ≥10% higher with regorafenib vs placebo) J. Li, et al. WCGI Abstract O Presented at WCGI 2014, Barcelona, Spain

25 Conclusions CONCUR met its primary endpoint showing that regorafenib provides a statistically significant improvement in OS, reducing the risk of death by 45% OS: HR=0.550, P= ; median 8.8 vs 6.3 months Regorafenib improves PFS and DCR PFS: HR=0.311, P <0.0001; median 3.2 vs 1.7 months DCR: 51.5% vs 7.4%, P < Adverse events are consistent with the known safety profile of regorafenib in mCRC CONCUR is the second phase 3 trial showing that regorafenib monotherapy improves survival in patients with mCRC who progress after standard therapy J. Li, et al. WCGI Abstract O Presented at WCGI 2014, Barcelona, Spain

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27 Treating CRC: ESMO Guidelines for Unresectable mCRC Oxaliplatin-Based First-LineIrinotecan-Based First-Line Chemo- Triplet Regorafenib Pan/cet a ± IRI 5-FU + bev 5-FU/IRI + bev 5-FU/OX + bev FOLFOX + pan or cet a (FOLF)IRI + pan/cet a FU/IRI + cet a 5-FU/OX 5-FU/IRI 5-FU/ OX/IRI Pan/cet a ± IRI or FU/bev FOLFIRI + aflib First line Second line Third line Fourth line Regorafenib 5-FU/IRI + bev FOLFOX + cet/(pan) a a KRAS wild type only. aflib, aflibercept; cet, cetuximab; pan, panitumumab; ESMO, European Society for Medical Oncology. Schmoll HJ, et al. Ann Oncol. 2012;23: Pan/cet a ± IRI Regorafenib G.SM.ON

28 Indicación en Europa Aprobación por la EMA en Septiembre de 2013 Indicación: Tratamiento de pacientes adultos con cáncer colorrectal metastásico, que han sido previamente tratados con las terapias disponibles o no se les considera candidatos a dichas terapias. Esto incluye terapias basadas en fluoropirimidinas, anti-VEGF y anti-EGFR

29 Posicionamiento Terapéutico

30 Targeted therapyStudyTreatment arms Absolute OS improvement HR Second-line studies Aflibercept 1 VELOUR FOLFIRI + aflibercept (vs FOLFIRI + placebo) 1.4 months 0.82 p= Bevacizumab 2 E3200 FOLFOX4 + bevacizumab (vs FOLFOX4) 2.1 months 0.75 p =.0011 Bevacizumab 3 TMLCT + Bev (vs CT)1.4 months0.81 p= Cetuximab 4, *EPIC Irinotecan + cetuximab (vs irinotecan) 0.7 months0.98 p=0.71 Panitumumab 5 (KRAS wt subgroup) 181 FOLFIRI + panitumumab (vs FOLFIRI) 2.0 months0.85 p=0.12 Studies in third line or later Regorafenib 6 CORRECTRegorafenib (vs placebo)1.4 months0.79 p=0.038 Perifosine 7 X-PECT Perifosine + capecitabine (vs capecitabine + placebo) −0.5 months † 1.11p=0.315 OS improvements with targeted therapies *Pt population includes KRAS wt and mutant patients. No KRAS wt subgroup analysis available. † OS analysis favoured capecitabine + placebo. Note: indirect comparison of major trials – as with any indirect comparison differences exist in study designs and study populations. 1. Van Cutsem E et al. J Clin Oncol 2012;30:3499–506; 2. Giantonio BJ et al. J Clin Oncol 2007;25:1539–44; 3. Arnold D et al. ASCO 2012; abstract CRA3503; 4. Sobrero AF et al. J Clin Oncol 2008;26:2311–19; 5. Peeters M et al. J Clin Oncol 2010;28:4706–13; 6. Van Cutsem E et al. ESMO 2012;abstract LBA18; 7. Bendell J et al. ASCO 2012; abstract LBA3501.

31 Approved agents with OS BENEFIT in 3rd line os QT Antiangiogenic agents Anti-EGFR agents Mitomycin C Gemcitabine Capecitabine Raltitrexed Bevacizumab Aflibercept Regorafenib Cetuximab Panitumumab Only in (K) RAS wt

32 Insight from MDACC Retrospective Analysis of Oxaliplatin Retreatment Prior Oxali use Median duration between end of first Oxali and retreatment (range), mo Mean number of retreatment cycles received, (range) RECIST response n (%) Biochemical response (where available) Median time to progression/ withdrawal of Oxali (range), mo Adjuvant (n = 29) 25.9 (6.5–71.0) 2.8 (1–8) 4 (14%) PR 11 (38%) SD 4 (14%) PD 10 (34%) NE 4/16 (25%) 3.3 (1.4–11.7) Unresectable mCRC (n = 75) 12.5 (1.3–63.8) 7.5 (1–53) 4 (5%) PR 29 (39%) SD 12 (16%) PD 30 (40%) NE 9/48 (19%) 3.1 (0.2–36.5) Perioperative for metastasectomy (n = 22) 19.1 (3.2–43.0) 9 (1–16) 0 (0%) PR 11 (50%) SD 1 (5%) PD 10 (45%) NE 3/5 (60%) 3.3 (1.2–16.2) “Retreatment with Oxali demonstrated minimal clinical efficacy and is limited by cumulative neurotoxicity and hypersensitivity reactions” NE, non-evaluable; Oxali, oxaliplatin. Bhadkamkar N, et al. J Clin Oncol. 2013;31(4 suppl): Abstract 500; Levels per Van Cutsem E, et al. Ann Oncol. 2014; epub ahead of print. doi: / annonc / mdu260.. Level IV Evidence

33 Limited Evidence for Retreatment with Anti-EGFR in mCRC AuthornStudy DesignPopulationOutcomeComments Saif M, et al. 1 15Retrospective case review of cases at 2 institutions (Yale and St Francis) Patients who had tolerated panitumumab with clinical benefit after failure on cetuximab therapy MR in 3/11; SD in 3/11. Median duration of SD: 4 mo Grade 3/4 skin rash in 5 (33%) patients and asthenia in 1 patient Metges J, et al. PANERB 2 106Prospective case series of on-label therapy in 22 institutions in Canada Patients with KRAS WT mCRC who had received a CETUX-based regimen and, after progression, monotherapy with panitumumab Prior response to CETUX-based regimen correlated with better response to panitumumab (n=48; ORR=31%; SD=16%) vs no prior response (n=28; ORR=7%; SD=7%) Panitumumab monotherapy has limited benefit for mCRC that did not respond to prior CETUX-based regimen Liu X, et al Retrospective analysis of patients re-treated with an anti-EGFR agent in phase I/II studies KRAS wild type mCRC; prior cetuximab or panitumumab therapy; retreatment anti-EGFR agents were cetuxumab + oxaloplatin or iritonecan based regimen (n= 77) or cetuxumab + erlotinib (n=15) or cetuxumab + sirolimus (n=12). Median interval between prior anti-EGFR and retreatment was 4.55 mo CR/PR/SD rate was 56% for anti- EGFR retreatment, and had been 38% for initial anti-EGFR therapy. Prior CR/PR/SD with anti-EGFR correlated with ~3.5× higher ORR; longer interval between initial and retreatment correlated with ~2× higher ORR. Prior responders to cetuximab-based treatment with longer interval length between initial and retreatment were more likely to respond to anti-EGFR therapy when re-treated (P <.001) Santini D, et al. 4 39Phase II multicenter single-arm trial in patients retreated with CETUX-IRI after prior clinical benefit with the same regimen Patients with clinical benefit after a line of CETUX + IRI-based therapy and then PD (“IRI-refractory”) who had received a new line of therapy after PD, and then progressed after treatment with this new line of therapy. ORR was 53.8%; 19 (49%) PRs and 2 (5%) CRs; SD in 36% pts median PFS: 6.6 mo (must have had at least SD with prior CETUX + IRI-based therapy) Correlation between skin tox during first CETUX + IRI-based therapy and rechallenge (P = 0.01) CETUX, cetuximab; ORR, objective response rate. 1. Saif M, et al. Clin CRC. 2010;9: ; 2. Metges J, et al. ESMO. 2012: Ab 572P; 3. Liu X, et al. ASCO Ab 3607; 4. Santini D, et al. Ann Oncol. 2012;23: ; Levels per Van Cutsem E, et al. Ann Oncol. 2014; epub ahead of print. doi: / annonc / mdu260. Level IV Evidence Level III Evidence

34 Updated ESMO 2014 Guidelines for mCRC Regorafenib is a standard option in pre-treated mCRC patients A: Scenario 1B: Scenario 2C: Scenario 3 1 st line 2 nd line 3 rd line 4 th line 5 th + line Cytotoxic doublet 1 + bevacizumab Cytotoxic doublet 1 + bevacizumab or aflibercept 3 Irinotecan or FOLFIRI + anti- EGFR antibody 2 Regorafenib Cytotoxic doublet 1 + bevacizumab Cytotoxic doublet 1 + anti- EGFR antibody 2 Regorafenib Cytotoxic doublet 1 + anti- EGFR antibody 2 Cytotoxic doublet 1 + bevacizumab or aflibercept 3 Regorafenib 1.Cytotoxic doublets: fluoropyrimidine + oxaliplatin or irinotecan; 2. RAS wild type; 3. Aflibercept only in combination with FOLFIRI. Adapted from Van Cutsem E, et al. Ann Oncol. doi: /annonc/mdu260. Epub before print; 4. Stivarga EU SmPC. Consideration of reintroduction of antitumor therapy

35 Biomarcador pronóstico y predictivo

36 Regorafenib Improves OS and PFS in Both KRAS WT and KRAS MT Disease KRAS mutational status was neither prognostic nor predictive in the study population Van Cutsem E, et al. Oral abstract presented at ASCO J Clin Oncol. 2012;30:(suppl): Abstract Regorafenib n = 505 Placebo n = 255 HR (95% CI) KRAS mutation, % No NA Yes NA Median OS, months KRAS wildtype (0.476–0.895) KRAS mutant (0.670–1.123) Median PFS, months KRAS wildtype (0.362–0.623) KRAS mutant (0.425–0.649)

37 Jeffers M, et al. ASCO GI Abstract 381. Evaluation of biomarker populations Clinical outcome in the overall study population and biomarker subpopulations in CORRECT The subpopulations of patients providing plasma and tumor tissue for mutational analysis are representative of the overall CORRECT patient population in terms of both OS and PFS

38 Correlative subgroup analyses demonstrated that regorafenib mediated a trend for OS benefit vs placebo in all biomarker subgroups Interaction P values indicated no significant efficacy differences among biomarker subgroups that were compared BRAF was not analysed due to the small number of BRAF-mutant samples Regorafenib showed a trend for improved OS vs placebo in all biomarker subgroups Jeffers M, et al. ASCO GI Abstract 381. Interaction P=0.561 Interaction P=0.723 Interaction P=0.933 Interaction P= KRAS-WT + PIK3CA-WT (plasma) Overall study population KRAS-MU + PIK3CA-WT (plasma) KRAS-MU + PIK3CA-MU (plasma) PIK3CA-MU (tumor) PIK3CA-WT (tumor) PIK3CA-MU (plasma) PIK3CA-WT (plasma) KRAS-MU (tumor) KRAS-WT (tumor) KRAS-MU (plasma) KRAS-WT (plasma)n=154 (71) n=349 (205) n=99 (55) n=140 (82) n=419 (224) n=84 (52) n=207 (123) n=29 (15) n=67 (40) n=282 (165) n=137 (59) n=760 (432) Hazard ratio (regorafenib/placebo)

39 EGF, epidermal growth factor. Lenz H-J, et al. ASCO Abstract Additional analysis of biomarkers considered relevant for CRC was performed Not for distribution. For medical education only, not promotional use.

40 EGF, epidermal growth factor. Lenz H-J, et al. ASCO Abstract Additional analysis of biomarkers: Predictive Factors Not for distribution. For medical education only, not promotional use.

41 EGF, epidermal growth factor. Lenz H-J, et al. ASCO Abstract Additional analysis of biomarkers: prognostic indicators Not for distribution. For medical education only, not promotional use.

42 REBECCA: a LARGE COHORT STUCY OF REGORAFENIB IN THE REAL LIFE SETTING IN PATIENTS PRE TREATED FOR mCRC

43 REBECCA: A large cohort study of regorafenib (REG) in the real-life setting in patients (pts) previously treated for metastatic colorectal cancer (mCRC) (D. Tougeron, et al. Poster Display Session: 602P) Patients lived longer with REG therapy: Delay from initial diagnosis more than 18 mo < 3 metastatic sites No liver mets ECOG 0-1 Dose > 120 mg/day Patients lived longer with REG therapy: Delay from initial diagnosis more than 18 mo < 3 metastatic sites No liver mets ECOG 0-1 Dose > 120 mg/day REBECCA: OS Multivariate Analysis

44 El 19% de los pacientes tratados con Rego tuvieron PFS > 4 meses Mayor mediana de duración de tratamiento Mayor toxicidad ¾ de diarrea e hipertensión Grothey A et al. ASCO-GI 2015

45 Dexametasona oral profilactica para evitar la fatiga por regorafenib (n: 91 pacientes retrospectivo) Fukuoka S. et al. ASCO-GI 2015

46 Conclusiones Regorafenib es el primer inhibidor multiquinasa oral con actividad demostrada en el CCRm (EC fase III CORRET Y CONCUR) Es una alternativa terapéutica para pacientes que han progresado a todos los tratamientos convencionales Las Guías Internacionales lo recomiendan con un nivel de evidencia I Perfil de toxicidad previsible que debe ajustarse en el primer ciclo en función de la toxicidad El mayor beneficio clínico se obtiene en PS 0 y 1

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48 Estudio fase II de Regorafenib como agente único para el tratamiento de pacientes con cáncer colorrectal metastásico (CCRm) con mutaciones en cualquier RAS o BRAF previamente tratados con FOLFOXIRI más bevacizumab TTD PREVIUM Coordinadores: Dra. Pilar García Alfonso. H. Gregorio Marañón. Madrid Dr. Manuel Benavides. H. Carlos Haya. Málaga

49 ¡ Muchas Gracias!


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