From negative to positive selection What can we really target now? - PDF document

From negative to positive selection

What can we really target now? Alterations Prevalence Targetability Enrichment NO 55-60% - RAS mutations (> if right colon, RAS wt, 8-10% YES BRAF V600E mutation MSI) ? 8% - PIK3CA/ PTEN mutations (> if right colon, BRAF 5% 5% YES YES Microsatellite instability Microsatellite instability mut) (> if left/rectum colon, 2% NO BRAF non- V600E mutations RAS mut, MSS) ( if l ft/ (> if left/rectum colon, t l 2% YES HER2 amplification RAS/BRAF w t) ? 2% - MET amplification 1% YES (> if right colon, MSS) POLE mutations TRK1- 3 , ALK , ROS1 (> if right colon, <1% <1% YES YES RAS/BRAF wt, MSI) translocations (> if right colon, <1% YES RET translocations RAS/BRAF wt, MSI)

From negative to positive selection RAS mut Wild- type BRAF V600E mut MSI BRAF non V600 mut PIK3CA/ PTEN mut MET amplification HER2 HER2 amplification lifi ti Gene fusions POLE mut

HER2: a successful story HER2+ mCRC pts mCRC pts MyPATHWAY TRIAL HERACLES TRIAL Trastuzumab + Trastuzumab + Lapatinib Lapatinib Pertuzumab Pertuzumab ORR ORR 30% 38% Sartore Bianchi et al, Lancet Oncology 2016 Hainsworth et al, J Clin Oncol 2018

The latest step: trastuzumab deruxtecan (DS- 8201a) ORR 16% 16% Yoshino et al, ESMO 2018

From negative to positive selection RAS mut Wild- type BRAF V600E mut MSI BRAF non V600 mut PIK3CA/ PTEN mut MET amplification HER2 HER2 amplification lifi ti Gene fusions POLE mut

Entrectinib in NTRK - rearranged tumors Combined analysis of ALKA, STARTRK- 1 e STARTRK- 2 Demetri et al, ESMO 2018

Gene fusions: similarities with “ BRAF story” ALK/ ROS/ NTRKs RET BEST RESPONSE TO BEST RESPONSE TO BEST RESPONSE TO BEST RESPONSE TO PREVIOUS ANTI- EGFR: PREVIOUS ANTI- EGFR: PROGRESSIVE DISEASE PROGRESSIVE DISEASE 100% (1/ 1) 100% (1/ 1) 100% (4/ 4) 100% (4/ 4) Pietrantonio et al, J Natl Can Inst ’17; Pietrantonio et al, Ann Oncol ‘18

Larotrectinib in RET - rearranged tumors Combined analysis of 1 Phase I, 1 Phase I/ II and 1 Phase II trials Drilon et al, NEJM 2018

From negative to positive selection …in advanced lines

NGS use: when? Survey conducted among 1281 oncologists in the USA Freedman et al, JCO Precision Oncology ‘18

Escalating the funnel up to first- line First- line Second- line Third- line Fourth- Fourth line Courtesy of Carlotta Antoniotti

From negative to positive selection RAS mut Wild- type BRAF V600E mut MSI BRAF non V600 mut PIK3CA/ PTEN mut MET amplification HER2 HER2 amplification lifi ti Gene fusions POLE mut

CheckMate- 142: 1 st line cohort Lenz et al, ESMO Congress 2018

• CheckMate 142 CheckMate 142: first ‐ line Ipi+Nivo Objective Response Rate: 60% Nivolumab + ipilimumab NIVO3 (Q2W) + IPI1 NIVO3 (Q2W) + IPI1 (Q6W) (Q6W) PFS OS N = 45 N 45 N = 45 N 45 Median PFS, months (95% Median OS, months (95% NR ( 14.1– NE) NR (NE) CI) CI) 9 ‐ mo rate (95% CI), % 77 (62.0–87.2) 9 ‐ mo rate (95% CI), % 89 (74.9–95.1) 100 12 ‐ mo rate (95% CI), % 12 t (95% CI) % 77 (62.0–87.2) 77 (62 0 87 2) 12 12 ‐ mo rate (95% CI), % t (95% CI) % 83 (67 6 91 7) 83 (67.6–91.7) rvival (%) 100 90 90 (%) 80 80 gression-free sur Overall survival 70 70 60 60 50 50 40 40 30 30 30 30 O Prog 20 20 10 10 0 0 0 3 6 9 12 15 18 0 3 6 9 12 15 18 21 Months Months Months Months No. at risk 45 37 34 24 15 7 7 45 42 40 38 24 13 1 0 Lenz et al, ESMO 2018 40

Awaited data from phase III studies

Microsatellite Microsatellite i i instability instability t bilit t bilit MSS MSI- high Immunotx HER2 HER2 pos pos neg neg pos pos

Pol Ɛ proofreading domain mutations Prevalence: ≈ 0.5 ‐ 2.0% Young g Right colon Right colon MSS MSS Male TCGA colorectal cancers TCGA colorectal cancers 4% POLE ‐ mutant “Ultramutated” Microsatellite stable TGCA, Nature 2012; Giannakis et al, Cell Rep 2016 Domingo et al, Lancet Gastroenterol Hepatol 2016

“High” Tumor Mutational Burden Immunoscore positivity Open question Microsatellite instability

Liquid biopsy in colorectal cancer TICE PRACT NICAL P EARLY DETECTION LOCALIZED DISEASE REFRACTORY DISEASE CLIN  Diagnosis of  Prognostication;  Monitoring response and cancer or pre-  Detection of residual tracking resistance; cancer earlier  Identification of disease and treatment through screening. personalization in p mechanisms of acquired q macroscopically resected resistance. patients.

CRICKET: Study Design Phase II, non comparative, study Target accrual: 27 pts PD PD FOLFOX/XELOX FOLFOX/XELOX FOLFIRI/ / Irinotecan mCRC pts FOLFOXIRI RAS and BRAF wt FOLFOXIRI + Cetuximab + Cetuximab + Bevacizumab • At least a RECIST 1.1 partial • Time between the end of response 1 st ‐ line therapy and the start Study treatment: • 1st ‐ line PFS ≥ 6 months of 3 rd ‐ line ≥ 4 months Irinotecan 180 mg/sqm iv PD to 1 st ‐ line cetuximab • Cetuximab 500 mg/sqm iv within 4 weeks after the last within 4 weeks after the last cetuximab administration Primary endpoint: Response Rate Cremolini et al, JAMA Oncology 2018

CRICKET: Results according to ctDNA Progression ‐ Free Survival Overall Survival p=0.24 p=0.03 p Cremolini et al, JAMA Oncology 2018

28 pts included 25 pts with evaluable ctDNA evaluable ctDNA RAS wt ctDNA RAS mut ctDNA N=13 N=12 Confirmed Confirmed responders d responders N=4 (31%) N=0 (0%)

CRICKET: results according to RAS status in ctDNA Progression Free Survival Overall Survival Cremolini et al, JAMA Oncology 2018

The latest step: the E- RECHALLENG- E trial Trial registration: UMIN000016439

Primary endpoint: ORR RECIST Response Rate: 15% (5/ 33) Disease Control Rate: 55% (18/ 33) Osawa et al, ESMO 2018

CRICKET: Results according to ctDNA Other “ongoing” mechanisms of acquired resistance?

Later lines’ algorithm Pre ‐ treated* mCRC pt p Candidate to receive another YES line of therapy? NO MSI ‐ high? YES NO Checkpoint inhibitor Initial benefit and then resistance to anti ‐ EGFR? YES RAS/BRAF wt ctDNA? BSC Consider anti Consider anti ‐ NO NO EGFR rechallenge ECOG PS 0 AND age < 65 ‐ 70 ys AND no severe liver YES YES impairment NO Regorafenib flexible dosing flexible dosing * Progressed or not candidate to fluoropyrimidines, oxaliplatin, irinotecan, an antiangiogenic agent, an anti ‐ TFD/TPI EGFR MoAb if RAS wt

Take home message: clinical applications of a deeper molecular characterization of CRC  Negative hyperselection (ex. PRESSING panel) g yp ( p )  Positive prediction … hopefully upfront  Positive prediction hopefully upfront   Dynamic monitoring to inform tx choices (liquid biopsy) f ( )  Inclusion in clinical trials and prospective collection of outcome data with targeted off-label therapies

ROME trial: from histology to target PI: Prof. Marchetti Università la Sapienza

Grazie per l’attenzione!