FOR Colorectal Adenocarcinoma, NGS TESTING SHOULD NOT BE ROUTINE - - PowerPoint PPT Presentation

FOR Colorectal Adenocarcinoma, NGS TESTING SHOULD NOT BE ROUTINE

Howard Hochster, MD Associate Director for Clinical Research, Rutgers CINJ Distinguished Professor of Medicine Rutgers Robert Wood Johnson Medical School

Genes and Growth Factor Pathways That Drive the Progression of Colorectal Cancer.

Markowitz SD, Bertagnolli MM. N Engl J Med 2009;361:2449-2460.

HOW TO LEVERAGE THIS?

• MOLECULAR EVALUATION
• MOLECULAR TRIAGE

–MMR(MSI) –RAS –BRAF –HER-2 –RARE FUSIONS

• RIGHT vs. LEFT

Colorectal Cancer: 2018

à IHC à PCR à PCR à IHC à “EYEBALL”

MMR-D Identifies Resected Colon Cancer Patients With Low Recurrence Risk

Adapted from Ribic CM, et al. N Engl J Med. 2003;349:247-257.

Pooled Analysis of Stage II and III colon cancer patients (surgery alone)

MMR-D MMR-P

Overall Survival (%)

100 80 60 40 20 1 2 3 4 5 6 7 8

Years after Randomization

P = 0.004

No adjuvant chemotherapy, n = 287

Multiple studies have consistently demonstrated that the ~15% of colon cancer patients with MMR-D tumors have markedly lower recurrence risk, particularly for the stage II colon cancer patient.

Mismatch Repair Deficiency (MMR-D): Unique Biological Subgroup of Colon Cancer

Imai K, et al. Carcinogenesis. 2008;29:673-680. Umetani N, et al. Ann Surg Oncol. 2000;7:276-280. Rosen DG, et al. Mod Pathol. 2006;19:1414-1420.

PCR on tumor DNA for MSI (microsatellite instability) IHC for MMR protein status

MLH1+ MSH2+ MLH1- MSH2-

Thus, IHC for MMR proteins and PCR for MSI detect two manifestations of the same tumor biology:

• MMR-D is synonymous with MSI-H
• MMR-P is synonymous with MSI-L/MSS

MMR-D Has Consistently Been Shown to Be a Favorable Prognostic Marker

Source Stage / Treatment Endpoint MMR-D vs MMR-P HR (95% CI); p-value Ribic et al1 II/III Surgery alone Overall survival 0.31 (0.14-0.72) p=0.004 Sargent et al2 II/III Surgery alone Disease-free survival Overall survival 0.46 (0.22-0.95); p=0.03 0.51 (0.24-1.10); p=0.06 Gray et al3 (QUASAR) II Surgery alone Recurrence-free interval 0.31 (0.15-0.63) p<0.001 Roth et al4 (PETACC-3) II 5FU ± irinotecan Relapse-free survival 0.30 p=0.004

• 1. Ribic CM, et al. N Engl J Med. 2003;349:247-257.
• 2. Sargent DJ, et al. J Clin Oncol. 2010;28:3219-3226.
• 3. Gray R, et al. J Clin Oncol. In press.
• 4. Roth AD, et al. J Clin Oncol. 2009;27: abstract 288.

The ~15% of stage II colon cancer patients with MMR-deficient tumors have been found consistently to have a lower risk

• f recurrence and/or death

Mutations per tumor

Presented By Dung Le at 2015 ASCO Annual Meeting

Lung Cancer and Melanoma Le, et al. ASCO 2015

Slide 10

Presented By Dung Le at 2015 ASCO Annual Meeting

Le, et al. ASCO 2015

Slide 12

Presented By Dung Le at 2015 ASCO Annual Meeting

Le, et al. ASCO 2015

Phase 2 CheckMate 142 Study Design: MSI-H Cohort

Nivo 3 mg/kg (Q2W)

mStage 1

MSI-H

• Second-line colon MSI-

H

• ≥ 1 prior treatment for

metastatic disease

• ≥ 1 target lesion
• ECOG PS of 0-1

≥ 7/19 Nivo 3 mg/kg (Q2W)

mStage 2

Responsesa Responsesa

≥ 7/19

• Nivo 3 mg/kg + Ipi 1 mg/kg

(Q3W x 4 doses)

• Then Nivo 3 mg/kg (Q2W)

cStage 2b

3– 6/19

• Nivo 3 mg/kg +

Ipi 1 mg/kg (Q3W x 4 doses)

• Then Nivo 3 mg/kg

(Q2W)

cStage 1

Responsesa

aIn patients with centrally confirmed MSI-H status bCurrently enrolling

cStage 1 = combination therapy stage 1; cStage 2 = combination therapy stage 2; Ipi = ipilimumab; mStage 1 = monotherapy stage 1; mStage 2 = monotherapy stage 2; Nivo = nivolumab; Q2W = every 2 weeks; Q3W = every 3 weeks

11

Best Reduction in Target Lesion Size in Patients With MSI-H

*Asterisks denote confirmed responses

56% of patients with reduction 81% of patients with reduction

Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg Nivolumab 3 mg/kg

100 75 50 25

• 25
• 50
• 75
• 100

Best Reduction From Baseline in Target Lesion (%) Patients 100 75 50 25

• 25
• 50
• 75
• 100

Best Reduction From Baseline in Target Lesion (%) Patients

* * * * * * * * * * * * ** **** * **

% change truncated to 100% 12

Good Durability of Nivo and Nivo+Ipi

• Combination therapy provided improved long-term clinical benefit relative to

monotherapy during a similar follow-up perioda,e,f

Nivolumab 74 48 41 32 12 17 11 6 12 3 Nivolumab Months

• No. at Risk

119 Nivolumab + ipilimumab 95 86 78 12 39 10 3 11 100 90 80 70 60 50 40 30 20 10 3 6 9 15 12 21 24 18

Progression-free survival (%)c

27 30 Nivolumab + ipilimumab 100 90 80 70 60 50 40 30 20 10 3 6 9 15 12 21 24 18

Overall Survival (%)

2 7 30 33 Months 119 113 107 104 33 78 17 11 19 Nivolumab + ipilimumab 74 64 59 55 21 37 17 11 19 6 1 Nivolumab

Nivolumab + ipilimumaba,d Nivolumab1,

e,f

9-mo rate (95% CI), % 87 (80.0, 92.2) 78 [66.2, 85.7] 12-mo rate (95% CI), % 85 (77.0, 90.2) 73 [61.5, 82.1]

NE, not estimable; NR, not reached. aMedian follow-up was 13.4 (range, 9–25) months. bMedian PFS was NR [95% CI, NE]. cPFS per investigator

• assessment. dMedian OS was NR [95% CI, 18.0, NE].

Median follow-up was 13.4 (range, 10–32) months. fCheckMate-142 monotherapy and combination therapy cohorts were not randomized or designed for a formal comparison

• 1. Overman MJ, et al. Lancet Oncol 2017;18:1182–1191.

Nivolumab + ipilimumaba,b Nivolumab1,

e,f

9-mo rate (95% CI), % 76 (67.0, 82.7) 54 [41.5, 64.5] 12-mo rate (95% CI], % 71 (61.4, 78.7) 50 [38.1, 61.4]

1 3

~50% ~60%

Atezolizumab and bevaciuzmab for refractory MSI-high CRC

Hochster, et al. ASCO GI, 2017

Hochster, ASCO GI 2017

Schema of NRG-GI004/SWOG 1610 The COMMIT Study

MSI-high mCRC without prior systemic treatment for metastatic disease (N = 315)

Stratify: BRAF, met site, prior adj rx

R mFOLFOX6/Bevacizumab

(Arm 1: Control)

mFOLFOX6/Bevacizumab + Atezolizumab

(Arm 3: Combination)

Atezolizumab

(Arm 2: Single Agent)

1º endpoint PFS

• - 90% power to detect HR <0.6

2º endpoints: OS, RR, safety, DCR, DOR

ATOMIC: Alliance Adjuvant Study: FOLFOX Atezolizumab as Adjuvant Therapy of Patients With Stage III MMR-Deficient CRC

• Phase III, n=700-750, proposed to explore Atezo as adjuvant in MSI-H

subpopulation

• Primary endpoints: DFS

– 90% power to detect HR of 0.60 (increase of 3-year DFS from 75% to 84%) – 175 events required – 2 interim analyses: 75% and 50% of events

• Secondary endpoints: OS, safety
• PI: Frank Sinicrope, Mayo Clinic

Patients with stage 3 MSI-H colon cancer (n=700-750) 1 year

24 weeks

mFOLFOX6 mFOLFOX6 Atezolizumab

Stratification factors

• Number of LN+ (1-4 vs

>4)

• T stage (T1-3 vs T4)
• Patient age

(< or >50 years)

MSI-H/dMMR status assessed locally

• MSI determined using a PCR-based assay
• dMMR status determined by IHC for MMR protein

expression (MLH1, MSH2, MSH6, PMS2) where loss of one

• r more proteins indicates dMMR.

HER-2 AMPLIFIED CRC

HER2 Amplification:

4% of CRC Tumors(~8% of RAS wild type)

19

Siena et al GI ASCO ‘14

HER2 and Apparent Lack of Benefit from EGFR Inhibition

5 1 0 1 5 2 0 2 5 5 0 1 0 0

M o n th s P e rc e n t s u r v iv a l

Median: 2.9 v 8.1 m (P < 0.001)

5 1 0 1 5 2 0 2 5 5 0 1 0 0

M o n th s P e rc e n t s u r v iv a l

Median: 2.9 v 9.3 m (P < 0.001)

HER2amp HER2NA HER2amp HER2NA

Cohort 1 Cohort 2

5 1 0 1 5 2 0 2 5 5 0 1 0 0

M o n th s P e rc e n t s u r v iv a l

Median: 9.7 v 10.1 m (P = 0.848)

5 1 0 1 5 2 0 2 5 5 0 1 0 0

M o n th s P e rc e n t s u r v iv a l

Median: 13.7 v 11.3 m (P < 0.616) HER2amp HER2NA HER2amp HER2NA

A A B B

EGFR-based regimen Non-EGFR-based regimen

MD Anderson

HERACLES: Trastuzumab + Lapatinib in HER2 2+/3+

*3 patients are not shown: 122026 (IHC 2+), not assessed yet; 121011 (IHC 3+) and 121013 (IHC 3+) early clinical PD.

Siena et al., Oral Presentation. ASCO 2015 (Abstract 3508)

HER2 3+ GCN≥20 HER2 2+ GCN<20 PD NEW LESION

• 2
• 1

1 8 9 7 2 6 5 4 3

• 3
• 4
• 5
• 6
• 7
• 8
• 9
• 10

Change to target lesions from baseline (%)

• 2
• 1

1 8 9 7 2 6 5 4 3

• 3
• 4
• 5
• 6
• 7
• 8
• 9
• 10

Change to target lesions from baseline (%)

Weeks from Treatment Start

8 1 6 3 2 2 4 4 4 8 4 1 2 2 3 6 2 8 4 4 5 2 5 6

1 2 5 5 1 2 4 2 1 1 2 1 1 5 1 2 1 2 3 1 2 1 1 6 1 2 2 2 1 2 1 1 1 2 2 2 5 1 2 1 6 1 2 2 2 2 1 2 1 2 4 1 2 1 1 8 1 2 5 1 7 1 2 1 1 9 1 2 1 1 4 1 2 1 3 1 2 1 9 1 2 1 4 1 2 1 2 1 2 4 7 1 2 1 1 2

1 year

Patients

RR 32% (95% CI 16-53%)

My Pathway: Traztuzumab + Pertuzumab in HER2 Amp

22

ØRR 38% ; PFS: 4.6 m Ø5.7 months vs 1.4 months for concurrent KRAS WT vs MUT

Hurwitz et al. GI ASCO ’17 K=KRAS mutated

Dual HER2 inhibition in mCRC: SWOG 1613

RAS-WT and BRAF-WT Advanced/metastatic colorectal cancer Not treated with anti-EGFR therapy HER2 Amplified Advanced/Metastatic Colorectal Cancer Trastuzumab + Pertuzumab

Until PD

Cetuximab + Irinotecan Trastuzumab + Pertuzumab Stratification Factor(s): Prior Irinotecan: Yes vs. No HER2 IHC: 3+ vs. 2+ Randomization

FIRST MOLECULAR BREAKTHROUGH:

RAS STATUS A negative predictive test

Panitumumab: Progression-Free Survival

Patients at risk: Vectibix™ BSC 231 118 49 31 13 5 1 232 75 17 7 3 1 1

Event-Free Probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Weeks from Randomization 8 16 24 32 40 48 56

Stratified Log-rank test P < 0.0001

Primary analysis, all randomized analysis set, central radiology; timing of BSC patient measurements at investigator discretion Peeters M, et al. Proc Am Assoc Cancer Res. 2006;47:A CP-1; Presentation available at http://www.aacr.org/page6026.aspx#

Vectibix™ (panitumumab) + BSC vs BSC Alone in mCRC

Mean PFS Vectibix™ + BSC (n=231) 96 days BSC (n=232) 60 days

Panitumumab Pivotal Trial: Response by K-ras

Final Analysis, KRAS Evaluable Group

160 140 120 100 80 60 40 20 % Change

• 20
• 40
• 60
• 80

PR (0%) SD (12%) PD (70%)

Mutant

Patient

Pmab + BSC

160 140 120 100 80 60 40 20 % Change

• 20
• 40
• 60
• 80

PR (17%) SD (34%) PD (36%)

Wild-Type

Patient 160 140 120 100 80 60 40 20 % Change

• 20
• 40
• 60
• 80

PR (0%) SD (8%) PD (60%) Patient

BSC Alone

160 140 120 100 80 60 40 20 % Change

• 20
• 40
• 60
• 80

PR (0%) SD (12%) PD (75%) Patient

Amado et al. ECCO 2007

Increased PFS Observed in Patients with KRAS Wild-type Tumors

Mutant Wild-type

Hazard Ratio = 0.45 (95% CI: 0.34–0.59) Stratified Log Rank Test p < 0.0001 Percent Event-free Weeks

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 4 8 12 16 20 24 28 32 36 40 44 48 52

Median Events / n (%) (weeks) Pmab + BSC 115 / 124 (93) 12.3 BSC Alone 114 / 119 (96) 7.3

Hazard Ratio = 0.99 (95% CI: 0.73–1.36)

Median Events / n (%) (weeks) Pmab + BSC 76 / 84 (90) 7.4 BSC Alone 95 / 100 (95) 7.3

Percent Event-free Weeks

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 4 8 12 16 20 24 28 32 36 40 44 48 52

Amado, et al. J Clin Onc. 2008;26:1626-1634.

RAS status: Lessons

• Retrospective data from prospective clinical

trial with tissue

• Not necessarily a positive predictor
• Issues of prognostic vs. predictive

– Or both?

• Not formally tested prospectively
• Extended with additional trials

– KRAS and NRAS codons 2,3,4

Study Design

Presented By Scott Kopetz at 2017 Gastrointestinal Cancers Symposium

Primary Endpoint: Progression-free survival

Presented By Scott Kopetz at 2017 Gastrointestinal Cancers Symposium

Response Rate

Presented By Scott Kopetz at 2017 Gastrointestinal Cancers Symposium

CRC and “Sidedness”

Is it the “Poor Man’s” tumor profile

• r

good Clinical Judgment?

CALGB/SWOG 80405: FINAL DESIGN N = 1140

1 Endpoint: Overall Survival

Chemo + Cetuximab Chemo + Bevacizumab

mCRC 1st-line KRAS wild type (codons 12,13) STRATA:

FOLFOX/FOLFIRI Prior adjuvant Prior XRT

FOLFIRI

• r

FOLFOX

MD choice

CALGB/SWOG 80405: Overall Survival

Venook, ASCO 2014

Arm N (Events)

OS (m) Median

95% CI

Chemo + Cetux 578 (375) 29.9 27.0-32.9 Chemo + Bev 559 (371) 29.0 25.7-31.2

P=0.34 HR 0.925 (0.78-1.09)

80405: Sidedness is Prognostic

Progression Free Survival (PFS)

All RAS wt N=474 Right 1° Median PFS (mos) Left 1° Median PFS (mos) Hazard Ratio Left vs Right 95% CI (adjusted*) P (adjusted*)

All pts 8.9 11.7

0.81 (0.64, 1.01) 0.06

Cet 7.5 12.7

0.61 (0.45, 0.84) 0.002

BV 10.2 11.2

0.99 (0.71, 1.37) 0.96 *Adjusted for biologic, protocol chemotherapy, prior adjuvant therapy, prior RT, age, sex , synchronous disease, in place primary, liver metastases

80405: Sidedness is Prognostic

Overall Survival (OS)

All RAS wt N=474

Right 1° Median OS (mos) Left 1° Median OS (mos) Hazard Ratio Left vs Right 95% CI (adjusted*) P (adjusted*) All pts 21.9 35.2 0.72 (0.56,0.92) 0.009 Cet 13.6 39.3 0.55 (0.39, 0.79) 0.001 Bev 29.2 32.6 0.88 (0.62, 1.25) 0.50

*Adjusted for biologic, protocol chemotherapy, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary, liver metastases

Median OS by Sidedness (all RAS wt):

80405 and FIRE-3*

Right 1°

Median OS (mos)

Left 1°

Median OS (mos) P (adjusted)

N = 149 N = 325

Cet

13.6 39.3

0.001 Bev

29.2 32.6

0.50

N = 88 N = 306

Cet

18.3 38.3

P < 0.00001 Bev 23.0 28.0 P = 0.038

All RAS wt N=474 All RAS wt N=394

FIRE-3

* Sebastian Stintzing,MD, personal communication

Heinemann, et al, ASCO, 2014

KRAS NRAS BRAF Her2 MSI Remainder

Snapshot of Molecularly-Directed Therapy for CRC

KRAS NRAS BRAF HER2 MSI Undefined

MD Anderson

RAS mutated BRAF mutated, MSS MSI-High RAS/BRAF wild type

• “Left Sided”
• “Right Sided”

FOLFOXIRI + Bev

Vemurafenib/ Cetuximab/Irinotecan

• r Clinical Trial

FOLFOX + Bev PD-1 inhibition FOLFOX + Bev FOLFIRI + Bev Salvage Oral agents:

Regorafenib

TAS-102 FOLFOX + Cet/Pan (or Bev) FOLFOX + Bev FOLFIRI + Bev

Irinotecan + Cmab/Pmab

FOLFIRI + Bev (or Cet/Pan)

CURRENT TREATMENT APPROACH

Novel subgroups: HER2 amp, ALK, TRK Fusions, RNA-based subgroups

CONCLUSIONS

• NGS gives few actionable mutations
• Most important for treatment are MMR,

RAS, BRAF status and HER-2 amplification

• None of these require NGS
• Sidedness is a “freebie”
• These can be done by IHC, PCR and

visual inspection at lower cost, which should be standard for now