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

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

Nov 15, 2022 226 likes •547 views

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

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From negative to positive selection

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What can we really target now?

Alterations Prevalence Targetability Enrichment RAS mutations 55-60%

  • BRAF V600E mutation

8-10% (> if right colon, RAS wt, MSI)

NO

YES

PIK3CA/ PTEN mutations 8%

  • Microsatellite instability

5% (> if right colon, BRAF

?

YES

Microsatellite instability 5% mut) BRAF non- V600E mutations 2% (> if left/rectum colon, RAS mut, MSS) ( if l ft/ t l

NO

YES

HER2 amplification 2% (> if left/rectum colon, RAS/BRAF wt) MET amplification 2%

  • ?

YES

POLE mutations 1% (> if right colon, MSS) TRK1- 3, ALK, ROS1 <1% (> if right colon,

YES YES

translocations <1% RAS/BRAF wt, MSI) RET translocations <1% (> if right colon, RAS/BRAF wt, MSI)

YES YES

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From negative to positive selection

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

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HER2: a successful story

HER2+ mCRC pts

Trastuzumab + Lapatinib

mCRC pts

Trastuzumab + Pertuzumab

HERACLES TRIAL MyPATHWAY TRIAL

Lapatinib Pertuzumab

ORR 30% ORR 38%

Sartore Bianchi et al, Lancet Oncology 2016 Hainsworth et al, J Clin Oncol 2018

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The latest step: trastuzumab deruxtecan (DS- 8201a)

ORR 16% 16%

Yoshino et al, ESMO 2018

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From negative to positive selection

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

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Entrectinib in NTRK- rearranged tumors

Combined analysis of ALKA, STARTRK- 1 e STARTRK- 2

Demetri et al, ESMO 2018

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Gene fusions: similarities with “BRAF story”

ALK/ ROS/ NTRKs RET BEST RESPONSE TO BEST RESPONSE TO BEST RESPONSE TO PREVIOUS ANTI- EGFR: PROGRESSIVE DISEASE 100% (4/ 4) BEST RESPONSE TO PREVIOUS ANTI- EGFR: PROGRESSIVE DISEASE 100% (1/ 1) 100% (4/ 4)

Pietrantonio et al, J Natl Can Inst ’17; Pietrantonio et al, Ann Oncol ‘18

100% (1/ 1)

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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

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From negative to positive selection …in advanced lines

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NGS use: when? Survey conducted among 1281 oncologists in the USA

Freedman et al, JCO Precision Oncology ‘18

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Escalating the funnel up to first- line

First- line Second- line Fourth- Third- line Fourth line

Courtesy of Carlotta Antoniotti

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From negative to positive selection

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

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CheckMate- 142: 1 st line cohort

Lenz et al, ESMO Congress 2018

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  • CheckMate 142

CheckMate 142: first‐line Ipi+Nivo

Objective Response Rate: 60%

Nivolumab + ipilimumab

PFS NIVO3 (Q2W) + IPI1 (Q6W) N 45 OS NIVO3 (Q2W) + IPI1 (Q6W) N 45 N = 45 Median PFS, months (95% CI) NR (14.1–NE) 9‐mo rate (95% CI), % 77 (62.0–87.2) 12 t (95% CI) % 77 (62 0 87 2) N = 45 Median OS, months (95% CI) NR (NE) 9‐mo rate (95% CI), % 89 (74.9–95.1) 12 t (95% CI) % 83 (67 6 91 7)

100 90 80 rvival (%) (%) 100 90 80

12‐mo rate (95% CI), % 77 (62.0–87.2) 12‐mo rate (95% CI), % 83 (67.6–91.7)

70 60 50 40 30 gression-free sur Overall survival 70 60 50 40 30 30 20 10 3 6 9 12 15 18 Prog Months 3 6 9 12 15 18 21 O Months 30 20 10

40

Months

  • No. at risk 45

37 34 24 15 7 7 Months 45 42 40 38 24 13 1

Lenz et al, ESMO 2018

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Awaited data from phase III studies

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Microsatellite i t bilit Microsatellite i t bilit instability instability MSS MSI- high Immunotx

HER2 HER2 neg neg pos pos pos pos

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PolƐ proofreading domain mutations

Prevalence: ≈0.5‐2.0%

Young Right colon MSS

4% POLE‐mutant TCGA colorectal cancers TCGA colorectal cancers

g Male Right colon MSS

“Ultramutated” Microsatellite stable TGCA, Nature 2012; Giannakis et al, Cell Rep 2016 Domingo et al, Lancet Gastroenterol Hepatol 2016

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Open question

“High” Tumor Mutational Burden Microsatellite instability Immunoscore positivity

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Liquid biopsy in colorectal cancer

TICE PRACT

REFRACTORY DISEASE LOCALIZED DISEASE

NICAL P

EARLY DETECTION

 Monitoring response and tracking resistance;  Identification of mechanisms of acquired  Prognostication;  Detection of residual disease and treatment personalization in

CLIN

 Diagnosis of cancer or pre- cancer earlier through screening. q resistance. p macroscopically resected patients.

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CRICKET: Study Design

Phase II, non comparative, study

FOLFOX/XELOX

Target accrual: 27 pts PD PD

mCRC pts RAS and BRAF wt

FOLFIRI/ FOLFOXIRI + Cetuximab FOLFOX/XELOX / FOLFOXIRI + Bevacizumab Irinotecan + Cetuximab

  • At least a RECIST 1.1 partial

response

  • 1st‐line PFS ≥6 months
  • PD to 1st‐line cetuximab

within 4 weeks after the last

  • Time between the end of

1st‐line therapy and the start

  • f 3rd‐line ≥4 months

Study treatment: Irinotecan 180 mg/sqm iv Cetuximab 500 mg/sqm iv

within 4 weeks after the last cetuximab administration

Primary endpoint: Response Rate Cremolini et al, JAMA Oncology 2018

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CRICKET: Results according to ctDNA

Progression‐Free Survival Overall Survival

p=0.03 p=0.24 p

Cremolini et al, JAMA Oncology 2018

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

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CRICKET: results according to RAS status in ctDNA

Progression Free Survival Overall Survival Cremolini et al, JAMA Oncology 2018

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The latest step: the E- RECHALLENG- E trial

Trial registration: UMIN000016439

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Primary endpoint: ORR

RECIST Response Rate: 15% (5/ 33) Disease Control Rate: 55% (18/ 33)

Osawa et al, ESMO 2018

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CRICKET: Results according to ctDNA

Other “ongoing” mechanisms of acquired resistance?

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Later lines’ algorithm

Pre‐treated* mCRC pt p

NO

Candidate to receive another line of therapy?

YES MSI‐high? YES NO Checkpoint inhibitor Initial benefit and then

BSC

resistance to anti‐EGFR? RAS/BRAF wt ctDNA? YES Consider anti‐ NO Consider anti EGFR rechallenge NO ECOG PS 0 AND age < 65‐ 70 ys AND no severe liver YES impairment YES Regorafenib flexible dosing NO

* Progressed or not candidate to fluoropyrimidines,

  • xaliplatin, irinotecan, an antiangiogenic agent, an anti‐

EGFR MoAb if RAS wt

flexible dosing TFD/TPI

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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  f ( )  Dynamic monitoring to inform tx choices (liquid biopsy)  Inclusion in clinical trials and prospective collection of

  • utcome data with targeted off-label therapies
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ROME trial: from histology to target

PI: Prof. Marchetti Università la Sapienza

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Grazie per l’attenzione!