How I Treat Metastatic Colorectal Cancer Making Sense of the Data - PowerPoint PPT Presentation

How I Treat Metastatic Colorectal Cancer – Making Sense of the Data Axel Grothey West Cancer Center, U Tennessee

The Luxury of So Many Options . . . How Do We Personalize? Patient X Patient Y Patient Z PD-1 mAb

What influences treatment choices in mCRC? Patient Molecular characteristics characteristics Prior adjuvant Comorbidities RAS BRAF treatment 1L Performance Age HER2 MSI-high status 2L Patient Tumor characteristics preference 3L Quality Toxicity Tumor Resectability of life profile burden 4L Tumor location Therapy tailored according to individual patient needs

Key points in the medical management of mCRC • We can “cure” some patients with limited metastatic disease • Collaboration within a MDT essential • For the majority of patients the treatment goal is to extend life and maintain quality of life as long as possible • Patients benefit from access to all active agents • Sequential therapy. It is a marathon, not a sprint • We have biomarkers who identify cancers which do NOT respond to certain therapies, i.e. EGFR mAbs • Routine testing for extended RAS/ BRAF mutations, now also HER-2 • Biomarkers that select patients FOR a specific therapy are emerging • MMR/ MSI-H for immunotherapy, HER-2 and BRAF for targeted approaches

Key Points To Consider • Outcome is not driven by first-line therapy for the majority of patients • Importance of subsequent lines of therapy • Continuum of care • We have refined the patient population which benefits from EGFR mAbs • Better benefit-risk ratio • Some patients need special treatment approaches • MSI-H cancers • BRAF mutated CRC (V600E vs non-V600E) • HER-2 overexpressors

Although OS Continues to Improve, PFS Has Been Mostly Stable With First- line Therapy in the Chemo-Biologic Era 35 30 25 20 Months PFS 15 OS 10 5 2004 2014 0 ) ) ) ) ) ) ) ) ) ) ) g L E 3 3 E 6 S E B B 7 A 6 U M E E B B G G 0 9 R R I P T I L L I R R 1 6 S O R I I A A F F 2 T T 1 Y P C C ( ( ( ( ( F O R ( ( ( x v x v v V C N n u x u e e e v A ( ( a B t e u t B B ( e x e P B t v + + + v C u C e e I - + I I t R y C e + + R R B e X p B X I I - I I + F R C O F X y + a O X L p + I L L O r F O F F O O I e a F L L F L R F h r I F O O F L O I e L F O t F F o h O F L F m t O F o F e m h e C h C 1. Hurwitz H, et al. N Engl J Med . 2004;350(23):2335-2342; 2. Saltz LB, et al. J Clin Oncol. 2008;26(12):2013-2019; 3. Bokemeyer C, et al. Ann Oncol . 2011;22(7):1535-1546; 4. Van Cutsem E, et al. J Clin Oncol . 2011;29(15):2011-2019; 5. Douillard JY, et al. N Engl J Med . 2013;369(11):1023-1034; 6. Heinemann V, et al. J Clin Oncol . 2013;(suppl 31):abstract LBA3506; 7. Falcone A, et al. J Clin Oncol . 2013;(suppl 31):abstract 3505.

Current Key Question: First-Line Choice of Biologics BEV vs EGFR mAbs Bevacizumab Cetuximab VS Panitumumab

Key Points on anti-VEGF Therapy • Duration of VEGF-inhibition matters • More cytostatic than cytotoxic MoA • Treatment to progression • Maintenance strategies • Treatment beyond progression • Clinical synergism between fluoropyrimidine + bevacizumab (see AVEX, CAIRO-3) • Three positive phase III trials for prolonged VEGF inhibition beyond progression • No compelling arguments for aflibercept or ramucirumab over bevacizumab

VEGFi Beyond PD - Phase III Trials Agent Bevacizumab Ziv-aflibercept Ramucirumab Study TML VELOUR RAISE 1 st Line Tx Chemo+BEV FP-Oxali+/- BEV FP-Oxali+BEV Chemo-BEV Chemo FOLFIRI + FOLFIRI + PL FOLFIRI + FOLFIRI + PL AFL RAM N pts 409 410 612 614 536 536 mOS (mos) 11.2 9.8 13.5 12.1 13.3 11.7 HR 0.81 HR 0.82 HR 0.84 p=0.0062 p=0.0032 p=0.022 mPFS (mos) 5.7 4.1 6.9 4.7 5.7 4.5 HR 0.68 HR 0.76 HR 0.79 p<0.0001 p=0.00007 p=0.0005 RR (%) 5.4 3.9 19.8 11.1 13.4 12.5 Bennouna et al., Lancet Oncol 2012 van Cutsem et al., JCO 2012 Tabernero et al., Lancet Oncol 2015 FP = fluoropyrimidine

Key Points To Consider • Outcome is not driven by first-line therapy for the majority of patients • Importance of subsequent lines of therapy • Continuum of care • We have refined the patient population which benefits from EGFR mAbs • Better benefit-risk ratio • Some patients need special treatment approaches • MSI-H cancers • BRAF mutated CRC (V600E vs non-V600E) • HER-2 overexpressors

Bettington, et al Histopathology , 2013

Metastatic Colorectal Cancer: Does Side Matter? Patients, Line of Molecular Study Treatment Outcome Right Left N Tx Selection O’Dwyer, et al. 5-FU 1 st J Clin Oncol. N = 1120 None OS (mo) 10.9 15.8 variations 2001. (E2290) ∆ 5 months Prognostic implication: Right-sided cancers have poorer prognosis

CRYSTAL: FOLFIRI +/- Cetuximab L R PFS L R OS Tejpar et al., JAMA Oncol 2016

OS and PFS by Sidedness in PRIME (FOLFOX +/- Pmab) OS PFS Boeck, et al. Ann Oncol 2017

CALGB/SWOG 80405: OS by Tumor Location ( RAS WT) 100 OS (95% CI), Months HR P Value* (95% CI) Left Right Cetux 39.3 13.6 0.55 80 0.001 (n=173 vs 71) (32.9-42.9) (11.3-19.0) (0.39-0.79) % Event Free Bev 32.6 29.2 0.88 0.50 (n=152 vs 78) (28.3-36.2) (22.4-36.9) (0.62-1.25) 60 ∆R vs L Tx significant (mos) 40 Cetux 25.7 BEV 3.4 20 not significant 0 0 12 24 36 48 60 72 84 96 108 Time From Study Entry, Months *Adjusted for biologic, protocol CT, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary, liver metastases. Venook A, et al. Presented at: ESMO. 2016.

The Truth on Sidedness RAS/ RAF wt Treatment recommendations Location ESMO NCCN AG primary Left EGFR mAbs are No clear preference EGFR mAbs are Standard of Care in for EGFR mAbs or preferred, BEV can first-line BEV in first line be used in select patients in first line Right EGFR mAbs can be No EGFR mAbs in No EGFR mAbs in considered in first first line and first line (if RR is line if response is potentially not in goal, consider goal any line triplet), but allow EGFR mAbs in later line

The Truth on Sidedness RAS/ RAF wt Treatment recommendations Location ESMO NCCN AG primary Left EGFR mAbs are No clear preference EGFR mAbs are Standard of Care in for EGFR mAbs or preferred, BEV can first-line BEV in first line be used in select patients in first line Right EGFR mAbs can be No EGFR mAbs in No EGFR mAbs in considered in first first line and first line (if RR is line if response is potentially not in goal, consider goal any line triplet), but allow EGFR mAbs in later line

The “Perfect” Candidate for First-Line EGFR mAbs Negative selection (mutually exclusive) • KRAS/ NRAS/ HRAS exon 2, 3, 4 wild-type - 55% • No BRAF V600E mutation - 8% • (No HER-2 amplification -2.5%) Further exclusion criteria (not mutually exclusive) • Right-sided cancers 30%

Sidedness and Tumor Response Based on published / presented results, not individual patient data. Mix of first- and second-line trials, with or without BEV P=0.089 Arnold et al., Ann Oncol 2017

Efficacy of triplet CT: Incremental response rates Biomarker Incremental Trial n Treatment arms ORR (%) selection response rate (%) FOLFOXIRI 60 Falcone et al 1 244 Unselected 26 FOLFIRI 34 FOLFOXIRI 43 Souglakos et al 2 283 Unselected 9 FOLFIRI 34 FOLFOXIRI + bevacizumab 65 TRIBE 3 508 Unselected 12 FOLFIRI + bevacizumab 53 FOLFOXIRI + bevacizumab 81 OLIVIA 4 80 Unselected 19 mFOLFOX6 + bevacizumab 62 Saridaki 5 30 KRAS wt FOLFOXIRI + cetuximab 70 N/A ERBIRINOX 6 24 KRAS wt FOLFIRINOX + cetuximab 83 N/A Folprecht et al 7 14 KRAS wt FOLFOXIRI + cetuximab 71 N/A MACBETH 8 72† RAS/BRAF wt mFOLFOXIRI‡ + cetuximab 71 N/A Fornaro 9 37 RAS/BRAF wt FOLFOXIRI + panitumumab 89 N/A BELIEF 138 RAS wt FOLFOX/FOLFIRI + cetuximab 62.2% 33 1. Falcone A, et al. J Clin Oncol 2007;25:1670-1676; 2. Souglakos J, et al. Br J Cancer 2006;94:798–805; †Interim analysis of patients completing induction therapy. 3. Loupakis F, et al. N Engl J Med 2014;371:1609–1618; 4. Gruenberger T, et al. Ann Oncol 2015;26:702–708; ‡Compared with standard FOLFOXIRI, mFOLFOXIRI includes a reduced dose of 5. Saridaki Z, et al. Br J Cancer 2012;107:1932–1937; 6. Assenat E, et al. Oncologist 2011;16:1557–1564; irinotecan (130 vs 165mg/m 2 ) and 5-FU (2400 vs 3200mg/m 2 ). 7. Folprecht G, et al. BMC Cancer 2014;14:521; 8. Cremolini C, et al. ASCO 2014 (Abstract No. 3596); 9. Fornaro L, et al. Ann Oncol 2013;24:2062–2067; 10. Erbitux SmPC, June/2014.

Best Conversion Therapy Sidedness Molecular status Right (30%) Left (70%) RAS/BRAF wt FOLFOXIRI +/- BEV FOLFOX + EGFR mAb (35-40%) (FOLFOX +/- BEV) (FOLFOXIRI + EGFR mAb) RAS mut FOLFOXIRI +/- BEV FOLFOXIRI +/- BEV (50-55%) (FOLFOX +/- BEV) (FOLFOX +/- BEV) BRAF V600E mut FOLFOXIRI + BEV FOLFOXIRI + BEV (8-10%) BRAF non-V600E mut FOLFOXIRI +/- BEV FOLFOX + EGFR mAb (2%) (FOLFOX +/- BEV) (FOLFOXIRI + EGFR mAb)