Managing mcrc Across Disease Continuum: Front-Line Therapy and Treatment Beyond Progression

Transcription

1 Managing mcrc Across Disease Continuum: Front-Line Therapy and Treatment Beyond Progression Guillermo Méndez, MD Sección Oncología Hospital de Gastroenterología Bonorino Udaondo Carlos B. Udaondo y Fundación Favaloro Buenos Aires, Argentina

2 Limited treatment options All cancers the same Dose intensity for all Changes in Colon Cancer Care Until Some cancers cured by surgery Minor cost impact Everybody can treat patients Screening implemented All patients and cancers are different Colon cancer as a chronic disease - Clear impact on survival Unreaveling molecular taxonomy Patient more central: QoL Major cost impact Understanding that expertise is crucial QoL, quality of life

3 First-Line Strategy Deeply Influences the Whole Story... The right treatment for the right patient with the aim of: 1) A chance of cure, if possible... 2) Longer and better survival 3) Maintenance of good performance status (PS) to get subsequent lines of therapy

4 Sidedness Tumoral behavior Drugs toxicity profile Oncologist preference Patient preference Economical issues Scientific evidence New Treatment Drivers BSC, best supportive care; CT, chemotherapy Van Cutsem E, et al. Ann Oncol. 2016;27(8):

5 Options Strategies Sequences FLUOROURACIL CAPECITABINE BEVACIZUMAB CETUXIMAB IRINOTECAN PANITUMUMAB OXALIPLATIN AFLIBERCEPT RAMUCIRUMAB TAS102 REGORAFENIB IMMUNOTHERAPY CLINICAL TRIALS First-line Maintenance Beyond progression Second-line Third-line Fourth-line Surgery/local therapies

6 FLUOROURACIL CAPECITABINE IRINOTECAN Options Strategies Sequences BEVACIZUMAB CETUXIMAB At the end, CONTINUUM OF PANITUMUMAB CARE has to be implemented IMMUNOTHERAPY CLINICAL TRIALS First-line Maintenance Beyond progression Second-line Third-line Fourth-line OXALIPLATIN AFLIBERCEPT in almost RAMUCIRUMAB 90% of patients in TAS102 REGORAFENIB daily clinical practice Surgery/local therapies

7 Choice Primum Movens a. Fit for chemo? PS? Age? Frail? b. Chance for cure? c. Extensive molecular characterization? d. Aggressive or indolent behavior? Symptomatic?

8 Chemo-Intensity Choice PATIENT: Age and Fitness UNFIT for combo and/or elderly patients FIT for combo DOUBLET MONOCHEMO TRIPLET

9 Chemo-Intensity Choice PATIENT: Age and Fitness UNFIT for combo and/or elderly patients MONOCHEMO

10 Previously untreated mcrc, age 70 years N = 280 Key inclusion criteria ECOG PS 0-2 The AVEX Trial Randomize 1:1 Stratification factors: ECOG PS (0-1 vs 2) Geographic region Capecitabine 1000 mg/m 2 bid days 1 14, q 21 d + Bevacizumab 7.5 mg/kg day 1, q 21 d Capecitabine 1000 mg/m 2 bid days 1 14, q 21 d Prior adjuvant chemotherapy allowed if completed >6 months before inclusion Not optimal candidates for a combination chemotherapy with irinotecan or oxaliplatin Key exclusion criteria Prior chemotherapy for mcrc or prior adjuvant anti-vegf treatment Clinically significant cardiovascular disease Current or recent use of aspirin (>325 mg/day) or other NSAID Use of full-dose anticoagulants or thrombolytic agents ECOG, Eastern Cooperative Oncoogy Group; mcrc, metastatic colorectal cancer; NSAID, nonsteroidal anti-inflammatory drug Cunningham D, et al. Lancet Oncol. 2013;14(11):

11 AVEX Trial: Overall Survival Overall Survival (%) P =.18 Time (Months) Cunningham D, et al. Lancet Oncol. 2013;14(11):

12 Chemo-Intensity Choice PATIENT: Age and Fitness FIT for combo DOUBLET TRIPLET

13 Does the Chemo Backbone Matter? NO PFS first-line 8.5 months vs 8.0 months PFS second-line 2.5 months vs 4.2 months OS: 21.5 months vs 20.6 months First-line RR: 56% vs 54% Second-line RR: 4% vs 15% OS, overall survival; PFS, progression-free survival; RR, response rate Tournigand C, et al. J Clin Oncol. 2004;22(2):

14 But Which Is the Best Combination Treatment?! Almost ten years of fight Anti-VEGF Anti-EGFR

15 Head-to-Head Clinical Trials Comparing Anti-EGFRs to Anti-VEGF in First-Line Treatment FIRE-3 1,2 RAS wt 1º endpoint Phase III Untreated KRAS (Exon2) wt mcrc N = 592 CALGB/SWOG ,4 Untreated KRAS (Exon2) wt mcrc N = 1137 R R Cet + FOLFIRI Bev + FOLFIRI Cet + FOLFOX/FOLFIRI Bev + FOLFOX/FOLFIRI N = 400 N = 526 ORR OS PEAK 5 RAS wt 1º endpoint Phase II Untreated KRAS (Exon2) wt mcrc N = 285 R Pani + mfolfox6 Bev + mfolfox6 N = 170 PFS Bev, bevacizumab; Cet, cetuximab; ORR, overall response rate; Pani, panitumumab; wt, wildtype 1. Heinemann V, et al. Lancet Oncol. 2014;15(10): Stintzing S, et al. Ann Oncol. 2014;25(Suppl 4): Abstract LBA Venook AP, et al. J Clin Oncol. 2014;32(5s): Abstract LBA3. 4. Lenz HJ, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 501O. 5. Schwartzberg LS, et al. J Clin Oncol. 2014;32(21):

16 But Which Is the Best Combination Treatment?! FIRE3: OS RASwt CALGB: OS in Expanded RAS Analysis HR % CI P =.011 Heinemann V, et al. Lancet Oncol. 2014;15(10): Venook AP, et al. JAMA. 2017;317(23):

17 Midgut vs Hindgut Fat Carbohydrate Protein Meat Calcium APC, adenomatous polyposis coli; CIMP, CpG island methylator phenotype; DCC, deleted in colorectal cancer; FAP, familial adenomatous polyposis; HNPCC, Hereditary nonpolyposis colorectal cancer; K-ras, Kirsten-ras Kim SE, et al. World J Gastroenterol. 2015;21(17):

18 Left-Sided RAS Wildtype mcrc Benefit From Anti-EGFR Treatment CALGB/SWOG Trial 1 OS (95% CI), Months Left Right HR (95% CI) P Value Cet (n = 173 vs 71) 39.3 ( ) 13.6 ( ) 0.55 ( ).001 Bev (n = 152 vs 78) 32.6 ( ) 29.2 ( ) 0.88 ( ).50 Benefit of anti-egfr therapy in left-sided RAS wildtype mcrc was also shown in retrospective analyses of other first-line trials (CRYSTAL 2, FIRE3 2 and PRIME 3 ). 1.Venook A, et al. J Clin Oncol. 2016;34(suppl): Abstract Tejpar S, et al. JAMA Oncol.2017;3(2): Boeckx N, et al. Ann Oncol. 2016;27(suppl 6): Abstract 89P.

19 The Relevance of Primary Tumor Location in Patients With mcrc: A Meta-Analysis of First-Line Clinical Trials RESPONSE RATE Holch JW, et al. Eur J Cancer. 2017;70:87-98.

20 WHAT ABOUT TRIPLETS?

21 TriBe: Study Design Primary endpoint: PFS Participating Centers: 34 Italian Oncology Units First patient in: July 2008 Last patient in: May 2011 PD, progressive disease Loupakis F, et al. N Engl J Med. 2014;371(17):

22 PFS: Primary Endpoint TriBe: PFS and OS OS: Secondary Endpoint HR: 0.80 [ ] P =.030 FOLFIRI + bev, median PFS: 9.7 months FOLFOXIRI + bev, median PFS: 12.1 months HR: 0.75 [ ] P =.003 Loupakis F, et al. N Engl J Med. 2014;371(17): Cremolini C, et al. Lancet Oncol. 2015;16(13):

23 TriBe: OS Outcome According to Molecular Subgroups N FOLFIRI + Bev Median OS, Months FOLFOXIRI + Bev Median OS, Months HR [95% CI] P RAS and BRAF evaluable [ ].159 RAS and BRAF wt [ ] RAS mutated [ ].522* BRAF mutated [ ] * P for interaction Cremolini C, et al. Lancet Oncol. 2015;16(13):

24 First-Line Guided by Patient Status, Molecular Profile, Aim of Treatment, and Sidedness Right colon OS is the goal (Continum of care) Left colon OS is the goal (Continum of care) Right colon RR is the goal Left colon RR is the goal RAS wt BRAF wt Monotherapy ± Bev Doublet ± Bev Triplet ± Bev (Fit Pts) Monotherapy ± Bev Doublet ± antiegfr Doublet ± Bev Triplet ± Bev Triplet ± Bev (Pte Fit) Doublet ± antiegfr Doublet ± Bev Doublet + antiegfr Triplet ± Bev (Fit Pts) Doublet ± Bev RAS wt BRAF mut Triplet ± Bev (Fit Pts) Doublet ± Bev Triplet ± Bev (Fit Pts) Doublet ± Bev Triplet ± Bev (Fit Pts) Doublet ± Bev Triplet ± Bev (Fit Pts) Doublet ± Bev

25 Second-Line Means WHICH CHEMO? WHICH BIOLOGIC? The first question is what did he get in first-line?

26 The Standard Option to SWITCH chemo! Tournigand C, et al. J Clin Oncol. 2004;22(2):

27 Which Second-Line Treatment? WHICH BIOLOGIC? After BEV After anti-egfr

28 What After Bevacizumab? Bevacizumab Majority of patients Aflibercept Only with FOLFIRI Ramucirumab Only with FOLFIRI Bennouna J, et al. Lancet Oncol. 2013;14(1): Tabernero J, et al. Lancet Oncol. 2015;16(5): Van Cutsem E, et al. J Clin Oncol. 2012;30(28): Peeters M, et al. Clin Cancer Res. 2015;21(24): Sobrero AF, et al. J Clin Oncol. 2008;26(14):

29 Which Second-Line Treatment? WHICH CHEMO? WHICH BIOLOGIC? After BEV After anti-egfr

30 Probability of Survival Bevacizumab After Cetuximab Progression OVERALL SURVIVAL FIRE-3 Trial FOLFORI + Cet FOLFORI + Bev Months Since Start of Treatment Events n/n (%) 158/297 (53.2%) 185/295 (62.7%) Median (Months) 95% CI HR 0.77 (95% CI: ) Log-rank P =.017 Alive after first-line therapy Any second-line therapy Second-line substances, % SECOND-LINE TREATMENT FOLFORI + Cet N = % (260/297) 78.5% (204/260) FOLFORI + Bev N = % (250/295) 76.4% (191/250) n = 204 (100) n = 191 (100) Fluoropyrimidine % Oxaliplatin % Irinotecan % Bevacizumab % Numbers at Risk Anti-EGFR mab % Treatment with a substance not being part of first-line therapy mab, monoclonal antibody Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506. Heinemann V, et al. Lancet Oncol. 2014;15(10):

31 Which Biologic After Anti-EGFR? Bevacizumab Majority of patients

32 Phase II CAPRI-GOIM Study Previously untreated, unresectable mcrc KRAS exon 2 WT (N = 356) Primary Endpoint PFS Cetuximab Beyond Progression FOLFIRI+ Cetuximab (n = 340) PD FOLFOX4 + Cetuximab FOLFOX4 ARM1 ARM2 ARM1 ARM2 OS, months PFS, months HR 0.57 ( ) HR 0.56 ( ) P =.056 P = Cascinu S, et al. Eur J Cancer. 2017;83:

33 Advanced Disease Later Lines

34 Treatment Options in Later Lines Anti-EGFR (pani, cet +/- irinotecan) In patients who are RAS wt and not previously treated with anti-egfr Chemo Rechallenge No prospective evidences Carefully consider previous benefit and toxicity Small molecules: Regorafenib Chemotherapy: Trifluridine/tipiracil (TAS-102) Target therapy: AntiHER-2

35 Treatment Options in Later Lines Anti-EGFR (pani, cet +/- irinotecan) In patients who are RAS wt and not previously treated with anti-egfr Chemo Rechallenge No prospective evidences Carefully consider previous benefit and toxicity Small molecules: Regorafenib Chemotherapy: Trifluridine/tipiracil (TAS-102) Target therapy: AntiHER-2

36 mcrc:third-line and Beyond: Regorafenib and TAS-102 Improve Survival CORRECT 1 CONCUR 2 RECOURSE 3 a PO b PO PO HR, 0.77; 95% CI, ; P =.0052 HR for death, 0.68; 95% CI, ; P<.001 HR, 0.55; 95% CI, ; P = a Standard therapies include fluropyrimidine, oxaliplatin, irinotecan-based chemotherapies, bevacizumab and anti-egfr antibodies if KRAS wildtype b In Asian patients. Prior anti-vegf or anti-egfr targeted therapy permitted, but not mandatory 1. Grothey A, et al. Lancet. 2013;381(9863): Li J, et al. Lancet Oncol. 2015;16(6): Mayer RJ, et al. N Engl J Med. 2015;372(20):

37 Different Toxicity Profile of Regorafenib and TAS-102 Adverse Events (AEs) ( 10%) Associated With Regorafenib in the CORRECT Trial AE, % Hand-foot skin reaction (HFSR) Regorafenib (n = 500) All Grades Grade 3 Grade Fatigue Hypertension Diarrhea Rash/desquamation Anorexia Voice changes Weight loss Mucositis, oral Thrombocytopenia Fever Nausea Bleeding AE, % Any Grade Grade 3 Neutropenia Leukopenia Anemia Thrombocytopenia 42 5 Increase in ALT level 24 2 Increase in AST 30 4 Increase in total bilirubin 36 9 Increase in alkaline phosphatase level ALT, alanine aminotransferase; AST, aspartate transaminase Grothey A, et al. Lancet. 2013;381(9863): Mayer RJ, et al. N Engl J Med. 2015;372(20): Common AEs Associated With TAS-102 in the RECOURSE Trial 39 8 Increase in creatinine level 13 <1

38 Starting Dose of Regorafenib: ReDos Study Proportion of Patients Who Complete 2 Cycles of Tx And Initiate Cycle 3 (Primary Endpoint) Overall survival (Secondary endpoint) A strategy with weekly dose escalation of regorafenib from 80 mg/day to 160 mg/day seems superior to a starting dose of 160 mg/day A trend for improved OS P =.0943 Bekaii-Saab TS, et al. J Clin Oncol. 2018;36(suppl 4S): Abstract 611.

39 Nothing New on the Puzzle? HER-2 3% RAS/BRAF wildtype BRAF mutation 40% 10% MSI 5% RAS mutations 50% MSI, microsatellite instability

40 Microsatellite Instability in mcrc Although approximately 15% of early CRCs display a high degree of microsatellite instability (MSI-H), indicating a deficient DNA mismatch repair system (dmmr), 1,2 MSI-H status is found in approximately 4% of metastatic CRC 3 MSI Frequency, % Colon Cancer Stage 1. Aaltonen LA, et al. N Engl J Med. 1998;338(21): Popat S, et al. J Clin Oncol. 2005;23(3): Goldstein J, et al. Ann Oncol. 2014;25(5):

41 Where it all Started Type of Response MSI (n = 10) MSS (n = 18) Complete Response 0% 0% Partial Response 40% 0% Objective Response Rate 40% 0% Disease Control Rate 90% 11% MSS, microsatellite stable Le DT, et al. N Engl J Med. 2015;372(26):

42 Immune Checkpoint Blockade in MSI-H mcrc: CheckMate-142 No. at Risk Progression-Free Survival, % c Nivolumab + ipilimumab Nivolumab Months Nivolumab + ipilimumab Nivolumab Overall Survival, % Nivolumab + ipilimumab Nivolumab Months With similar follow-up, combination therapy provided improved PFS and OS relative to monotherapy ORR with nivolumab alone 31%, with nivolumab + ipilimumab 55% André T, et al. J Clin Oncol. 2018;36(suppl 4S): Abstract 553. Overman MJ, et al. Lancet Oncol. 2017;18(9):

43 Colon cancer care is improving Conclusions Improvements in the efficacy of systemic therapies and better patient selection Better understanding of molecular tumorigenesis Implementation of continum of care treatment strategies impact on OS Treatment guided by PS, molecular profile, and sidedness (NO DOGMA ON THAT) STILL MANY UNMET NEEDS (eg, treatment of RAS mutant, BRAF mutant, immunotherapy in earlier treatment lines and beyond MSI-H tumors)

44 GRACIAS

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