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. HOW TO LEVERAGE THIS? Markowitz SD, Bertagnolli MM. N Engl J Med 2009;361:2449-2460.
Colorectal Cancer: 2018 • MOLECULAR EVALUATION • MOLECULAR TRIAGE à IHC –MMR(MSI) à PCR –RAS à PCR –BRAF à IHC –HER-2 –RARE FUSIONS • RIGHT vs. LEFT à “EYEBALL”
MMR-D Identifies Resected Colon Cancer Patients With Low Recurrence Risk Pooled Analysis of Stage II and III colon cancer patients (surgery alone) MMR-D 100 Overall Survival (%) 80 60 MMR-P 40 20 No adjuvant chemotherapy, n = 287 P = 0.004 0 0 1 2 3 4 5 6 7 8 Years after Randomization 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. Adapted from Ribic CM, et al. N Engl J Med . 2003;349:247-257.
Mismatch Repair Deficiency (MMR-D): Unique Biological Subgroup of Colon Cancer IHC for MMR protein status MLH1+ MSH2- Thus, IHC for MMR proteins and PCR for MSI detect two MLH1- MSH2+ manifestations of the same tumor biology: • MMR-D is synonymous with MSI-H • MMR-P is synonymous with MSI-L/MSS PCR on tumor DNA for MSI (microsatellite instability) 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.
MMR-D Has Consistently Been Shown to Be a Favorable Prognostic Marker Stage / MMR-D vs MMR-P Source Treatment Endpoint HR (95% CI); p-value II/III 0.31 (0.14-0.72) Overall survival Ribic et al 1 Surgery alone p=0.004 II/III Disease-free survival 0.46 (0.22-0.95); p=0.03 Sargent et al 2 Surgery alone Overall survival 0.51 (0.24-1.10); p=0.06 Gray et al 3 II 0.31 (0.15-0.63) Recurrence-free interval (QUASAR) Surgery alone p<0.001 Roth et al 4 II 0.30 Relapse-free survival (PETACC-3) 5FU ± irinotecan p=0.004 The ~15% of stage II colon cancer patients with MMR-deficient tumors have been found consistently to have a lower risk of recurrence and/or death 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.
Mutations per tumor Lung Cancer and Melanoma Le, et al. ASCO 2015 Presented By Dung Le at 2015 ASCO Annual Meeting
Slide 10 Le, et al. ASCO 2015 Presented By Dung Le at 2015 ASCO Annual Meeting
Slide 12 Le, et al. ASCO 2015 Presented By Dung Le at 2015 ASCO Annual Meeting
Phase 2 CheckMate 142 Study Design: MSI-H Cohort mStage 2 mStage 1 Responses a MSI-H Nivo 3 mg/kg (Q2W) ≥ 7/19 • Second-line colon MSI- H • ≥ 1 prior treatment for metastatic disease cStage 1 Nivo 3 mg/kg cStage 2 b (Q2W) • ≥ 1 target lesion Responses a Responses a • ECOG PS of 0-1 • Nivo 3 mg/kg + • Nivo 3 mg/kg + Ipi 1 mg/kg Ipi 1 mg/kg 3– ≥ (Q3W x 4 doses) 6/19 (Q3W x 4 doses) 7/19 • Then Nivo 3 mg/kg (Q2W) • Then Nivo 3 mg/kg (Q2W) a In patients with centrally confirmed MSI-H status b Currently 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 Nivolumab 3 mg/kg Nivolumab 3 mg/kg + 100 100 Ipilimumab 1 mg/kg 75 75 56% of patients with reduction 81% of patients with reduction 50 50 Best Reduction From Baseline Best Reduction From Baseline 25 25 in Target Lesion (%) in Target Lesion (%) 0 0 -25 -25 ** * * * * * * -50 * -50 **** * * * * -75 -75 * * ** % change truncated to 100% -100 -100 Patients Patients *Asterisks denote confirmed responses 12
Good Durability of Nivo and Nivo+Ipi Nivolumab + Nivolumab + Nivolumab 1, Nivolumab 1, e,f e,f ipilimumab a,d ipilimumab a,b 9-mo rate (95% 9-mo rate (95% 76 (67.0, 82.7) 54 [41.5, 64.5] 87 (80.0, 92.2) 78 [66.2, 85.7] CI), % CI), % 12-mo rate (95% 12-mo rate (95% 71 (61.4, 78.7) 50 [38.1, 61.4] 85 (77.0, 90.2) 73 [61.5, 82.1] Progression-free survival (%) c CI], % 100 CI), % 100 90 90 Overall Survival (%) 80 80 70 70 60 60 50 50 40 40 ~60% 30 30 ~50% 20 20 Nivolumab + ipilimumab Nivolumab + ipilimumab 10 10 Nivolumab Nivolumab 0 0 0 3 6 9 12 15 18 21 24 27 30 0 3 6 9 12 15 18 21 24 2 7 30 33 Months Months No. at Risk Nivolumab + 119 95 86 78 39 12 11 10 3 0 0 119 113 107 104 78 33 19 17 11 0 0 0 ipilimumab 74 64 59 55 37 21 19 17 11 6 1 0 Nivolumab 74 48 41 32 17 12 12 11 6 3 0 • Combination therapy provided improved long-term clinical benefit relative to monotherapy during a similar follow-up period a,e,f NE, not estimable; NR, not reached. a Median follow-up was 13.4 (range, 9–25) months. b Median PFS was NR [95% CI, NE]. c PFS per investigator assessment. d Median OS was NR [95% CI, 18.0, NE]. Median follow-up was 13.4 (range, 10–32) months. f CheckMate-142 monotherapy and combination therapy cohorts were not randomized or designed for a formal comparison 1 1. Overman MJ, et al. Lancet Oncol 2017;18:1182–1191. 3
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 mFOLFOX6/Bevacizumab (Arm 1: Control) MSI-high mCRC without prior systemic treatment for metastatic Atezolizumab R disease (Arm 2: Single Agent) (N = 315) Stratify: BRAF, met site, prior adj rx mFOLFOX6/Bevacizumab + Atezolizumab 1º endpoint PFS (Arm 3: Combination) -- 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 24 weeks Stratification factors Patients with mFOLFOX6 • Number of LN+ (1-4 vs stage 3 MSI-H >4) colon cancer • T stage (T1-3 vs T4) Atezolizumab (n=700-750) • Patient age (< or >50 years) mFOLFOX6 MSI-H/dMMR status assessed locally • MSI determined using a PCR-based assay 1 year • dMMR status determined by IHC for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicates dMMR. • 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
HER-2 AMPLIFIED CRC
HER2 Amplification: 4% of CRC Tumors(~8% of RAS wild type) Siena et al GI ASCO ‘14 19
HER2 and Apparent Lack of Benefit from EGFR Inhibition EGFR-based regimen Non-EGFR-based regimen Median: 2.9 v 8.1 m Median: 9.7 v 10.1 m 1 0 0 1 0 0 (P < 0.001) (P = 0.848) Cohort 1 P e rc e n t s u r v iv a l P e rc e n t s u r v iv a l HER2amp HER2amp 5 0 5 0 HER2NA HER2NA B A 0 0 0 5 1 0 1 5 2 0 2 5 0 5 1 0 1 5 2 0 2 5 M o n th s M o n th s Median: 2.9 v 9.3 m 1 0 0 1 0 0 Median: 13.7 v 11.3 m (P < 0.001) (P < 0.616) Cohort 2 P e rc e n t s u r v iv a l P e rc e n t s u r v iv a l HER2amp HER2amp HER2NA HER2NA 5 0 5 0 A B 0 0 0 5 1 0 1 5 2 0 2 5 0 5 1 0 1 5 2 0 2 5 M o n th s M o n th s
MD Anderson HERACLES: Trastuzumab + Lapatinib in HER2 2+/3+ HER2 2+ HER2 3+ PD NEW GCN<20 GCN≥20 LESION 1 year Change to target lesions from baseline (%) Change to target lesions from baseline (%) 9 9 0 8 0 8 0 7 7 0 6 0 0 6 0 5 5 0 0 4 4 0 0 3 0 3 2 0 2 0 1 0 0 1 0 0 0 0 - - 1 - 1 - 2 - 0 2 - 0 - 3 3 0 - 0 4 - 0 4 - 0 5 0 - 5 - 0 RR 32% (95% CI 16-53%) 6 0 - 6 0 - - 7 0 - 7 0 8 - 0 8 0 - 0 9 - 9 0 - 5 4 2 7 2 4 9 3 4 9 7 8 2 6 5 1 0 6 3 5 1 10 0 2 1 0 0 0 0 0 1 1 1 1 2 0 2 0 2 1 2 1 2 0 10 0 4 8 1 1 2 2 2 3 3 4 4 4 5 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5 1 1 4 1 1 1 1 1 1 5 1 2 1 2 1 2 1 1 1 4 2 0 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 6 0 4 8 2 6 0 4 8 2 6 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Patients Weeks from Treatment Start *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)
My Pathway: Traztuzumab + Pertuzumab in HER2 Amp K=KRAS mutated Ø RR 38% ; PFS: 4.6 m Ø 5.7 months vs 1.4 months for concurrent KRAS WT vs MUT Hurwitz et al. GI ASCO ’17 22
Dual HER2 inhibition in mCRC: SWOG 1613 RAS-WT and BRAF-WT Advanced/metastatic colorectal cancer Not treated with anti-EGFR therapy Stratification Factor(s): HER2 Amplified Advanced/Metastatic Prior Irinotecan: Yes vs. No Colorectal Cancer HER2 IHC: 3+ vs. 2+ Randomization Trastuzumab + Pertuzumab Cetuximab + Irinotecan Until PD Trastuzumab + Pertuzumab
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