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OPTIMAL MANAGEMENT OF CRC IN THE 3RD-LINE METASTATIC SETTING
Joleen Hubbard, MDAssociate Professor of Oncology, Mayo Clinic, Rochester, MN
October 18 th, 2019
11
DISCLAIMER
Dr. Joleen Hubbard is involved in research at the Mayo Clinic funded by Merck, Taiho and Bayer.
2
OBJECTIVES & LEARNING JOURNEY
• We will walk through the management of 4 actual cases of patients who have received 2 lines of prior therapy
• Discuss optimal sequencing of agents in third-line mCRC
• Learn promising new combinations of mCRC treatment
• Identify factors to choose a personalized approach for 3rd line treatment and beyond
mCRC, metastatic colorectal cancer 3
CASE 1
PT E.K. 35 YO F WITH METASTATIC RECTAL CANCER
• 6/16 – BRBPR, colonoscopy reveals a rectal mass, bx + moderately differentiated adenocarcinoma
– Pelvic MRI: T3N1 tumor 8 cm from anal verge
– CT CAP: 2 pulmonary nodules 1.2 cm RML & 1.4 cm RUL
– MSS, BRAF/KRAS wild type
• 7/16 – 11/16 – FOLFOX
• 12/16 –wedge resection of lung mets
• 2/17 – 3/17 – concurrent chemorads with capecitabine
• 6/17 – low anterior resection of primary rectal tumor, near CR on path
• 9/17 – recurrence in the lungs
5BRBPR, bright red bleeding per rectum; bx, biopsy; CAP, community-acquired pneumonia CR, colorectal; CT, computerized tomography; MRI, magneticresonance imaging; MSS, Microsatellite Stable; RML, right middle lobe; RUL, right upper lobe
PT E.K. 35 YO F WITH METASTATIC RECTAL CANCER, MSS, KRAS/BRAF WT
• 9/17 – recurrence in the lungs, bx confirmed recurrence
• 10/17 – started on therapy with FOLFIRI + bevacizumab
• 7/18 – transitioned to maintenance therapy with capecitabine + bevacizumab
• 6/19 – increase in size & number of lung lesions
6Bx, biopsy
WHAT IS THE NEXT STEP?
7EGFR, epidermal growth factor receptor; MSS, microsatellite stable; WT, wild type
PT E.K. 35 YO F WITH METASTATIC RECTAL CANCER, MSS, KRAS/BRAF WT
1. Reintroduce FOLFIRI + bevacizumab
2. Reintroduce FOLFOX and add bevacizumab
3. Regorafenib
4. Irinotecan + EGFR inhibitor
5. Single agent EGFR inhibitor
WHAT IS THE NEXT STEP?
8MSS, microsatellite stable; WT, wild type
PT E.K. 35 YO F WITH METASTATIC RECTAL CANCER, MSS, KRAS/BRAF WT
• Patient only had KRAS testing initially, so next-generation sequencing (NGS) testing sent
• Next-generation sequencing shows HER2 alteration (ERBB2 copy number gain)
WHICH OF THE FOLLOWING IS THE LEAST FAVORABLE OPTION FOR OUR PAT IENT?
9MSS, microsatellite stable; WT, wild type; EGFR, epidermal growth factor receptor
PT E.K. 35 YO F WITH METASTATIC RECTAL CANCER, MSS, KRAS/BRAF WT, ERBB2+
1. Reintroduce FOLFIRI + bevacizumab
2. Reintroduce FOLFOX + bevacizumab
3. Regorafenib
4. Irinotecan + EGFR inhibitor
5. Clinical trial with dual HER2 inhibition
WHICH OF THE FOLLOWING IS THE LEAST FAVORABLE OPTION FOR OUR PAT IENT?
10EGFR, Epidermal Growth Factor Receptor; MSS, Microsatellite Stable; WT, wild type
PT E.K. 35 YO F WITH METASTATIC RECTAL CANCER, MSS, KRAS/BRAF WT, ERBB2+
1. Reintroduce FOLFIRI + bevacizumab
2. Reintroduce FOLFOX + bevacizumab
3. Regorafenib
4. Irinotecan + EGFR inhibitor
5. Clinical trial with dual HER2 inhibition
EGFR inhibitors are unlikely to work in the setting of HER2 alterations
N=27MEDIAN PRIOR TREATMENT: 5
8 (30%) PATIENTS ACHIEVED OR: 1 CR + 7 PR
11
CR, complete response; mCRC, metastatic colorectal; OR, objective response; PR, partial response
Sartore-Bianchi A. et al.. Lancet Oncology 2016;17(6):738-746
HERACLES TRIAL, HER2+ mCRC:TRASTUZUMAB + LAPATINIB, RESPONSE RATES
HERACLES TRIAL, HER2+ mCRC: DURATION OF TREATMENT RESPONSE
12
mCRC, metastatic colorectal cancer
Sartore-Bianchi A. et al.. Lancet Oncology 2016;17(6):738-746
TRASTUZUMAB + LAPATINIB = ACTIVE AND WELL-TOLERATED IN PATIENTS WITH HER2+ mCRC
13
CR, complete response; mCRC, metastatic colorectal cancer; OR, objective response; PR, partial response
Meric-Bernstam F. et al. Lancet Oncol. 2019;20(4):518-530
MYPATHWAY BASKET TRIAL, HER2+ mCRC: TRASTUZUMAB + PERTUZUMAB, RESPONSE RATES
N=57MEDIAN PRIOR TREATMENT: 4
18 (32%) PATIENTS ACHIEVED OR: 1 CR + 17 PR
MYPATHWAY BASKET TRIAL, HER2+ mCRC: DURATION OF TREATMENT RESPONSE
14
mCRC, metastatic colorectal cancer
Meric-Bernstam F. et al. Lancet Oncol. 2019;20(4):518-530
TRASTUZUMAB + PERTUZUMAB = ACTIVE AND WELL-TOLERATED IN
PATIENTS WITH HER2+ mCRC
HER2+ mCRC AND EGFR INHIBITION
• 2nd line treatment with EGFR inhibitor in RAS/BRAF wild-type patients (similar PFS in 1st line therapy)
15
DISH, Dual in situ hybridization; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; mCRC, metastatic colorectal cancer; mPFS, median progression-free survival; PFS, progression-free survival
Raghav KPS, et al. ASCO 2016 (abstract 3517).
n HER2+ HER2- p
mPFS Cohort I14/97 (HER2+ by IHC/DISH)
2.9 months 8.1 months <0.0001
mPFS Cohort II37/99 (HER2+ by NGS)
2.8 months 9.3 months <0.0001
• Needs further validation
• but HER2+ in mCRC may be another marker with negative predictive value for EGFR inhibitor treatment
SIMILAR LACK OF RESPONSE TO EGFR INHIBITION SEEN IN THE HERACLES STUDY:
Previous therapy with panitumumab or cetuximab 27 (100%)
Patients eligible to be assessed for sensitivity to panitumumab or cetuximab
15 (65%)
Previous response to panitumumab or cetuximab 0
16
EGFR, epidermal growth factor receptor
Sartore-Bianchi A. et al.. Lancet Oncology 2016;17(6):738-746
TAKE HOME POINT: NEXT GENERATION SEQUENCING SHOULD BE PERFORMED ON ALL mCRC PATIENTS!!
• ERBB2 (HER2) alterations occur in 4.8% of mCRC
• EGFR inhibitors are unlikely to be effective in KRAS mutant patients
I recommend NGS at diagnosis
– Planning for subsequent lines of therapy is essential to identify candidates for targeted therapy
• All RAS, BRAF, immunotherapy, HER2, NTRK
– Identify clinical trials early
• Some exclude a certain # of lines of therapy
17
mCRC, metastatic colorectal cancer; NGS, next generation sequencing
Ross JS. Et al. Cancer 2018;124(7):1358-1373
CASE 2
PT J.K. 54 YO M WITH mCRC, MSS, BRAF/RAS WT
• 5/15: colonoscopy for 3 month h/o BRBPR shows large ulcerated tumor 5 cm from anal verge. Bx confirms adenocarcinoma, MSS, BRAF/RAS WT
• CT shows multiple liver metastases
• 6/15: starts FOLFOX + bevacizumab
• 8/15: Hypersensitivity reaction to oxaliplatin
– Repeat imaging studies show marked response to treatment
• Proceeded with 5 x 5 Gy radiation
• 9/15: combined primary resection (APR) and liver metastatectomy/RFA
• 11/15 – 1/16 adjuvant therapy with capecitabine
• 4/16: 2 new liver masses – treated with RFA
19
APR, abdominal perineal resection; BRBPR, bright red bleeding per rectum; bx, biopsy; CT, computerized tomography; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; RFA, radiofrequency ablation; WT, wild type
PT J.K. 54 YO M WITH mCRC, MSS, BRAF/RAS WT
• 7/16 – new liver and retroperitoneal metastases (deemed unresectable), started on FOLFIRI + bevacizumab with marked response
• 3/17 – transitioned to maintenance therapy with capecitabine + bevacizumab
• 12/17 – increase in size of retroperitoneal lymphadenopathy
20
mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type
WHAT IS THE NEXT STEP?
21EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type
PT J.K. 54 YO M WITH mCRC, MSS, BRAF/RAS WT
1. Reintroduce FOLFIRI + bevacizumab
2. Reintroduce FOLFOX + bevacizumab (with oxaliplatindesensitization protocol)
3. Trifluridine/tipiricil
4. Regorafenib
5. Irinotecan + EGFR inhibitor
6. Single agent EGFR inhibitor
WHAT IS THE NEXT STEP?
22EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type
PT J.K. 54 YO M WITH mCRC, MSS, BRAF/RAS WT
1. Reintroduce FOLFIRI + bevacizumab
2. Reintroduce FOLFOX + bevacizumab (with oxaliplatindesensitization protocol)
3. Trifluridine/tipiricil
4. Regorafenib
5. Irinotecan + EGFR inhibitor
6. Single agent EGFR inhibitor
Patient was restarted on FOLFIRI + bevacizumab given the marked response previously and 9 months since discontinuing irinotecan
WHAT IS THE NEXT STEP?
23EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type
PT J.K. 54 YO M WITH mCRC, MSS, BRAF/RAS WT
1. Reintroduce FOLFOX + bevacizumab (with oxaliplatindesensitization protocol)
2. Trifluridine/tipiricil
3. Regorafenib
4. Irinotecan + EGFR inhibitor
5. Single agent EGFR inhibitor
• 4/18 – progression on FOLFIRI + bevacizumab, patient asymptomatic
WHAT IS THE NEXT STEP?
24EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; IV, intravenous; WT, wild type
PT J.K. 54 YO M WITH mCRC, MSS, BRAF/RAS WT
1. Reintroduce FOLFOX + bevacizumab (with oxaliplatindesensitization protocol)
2. Trifluridine/tipiricil
3. Regorafenib
4. Irinotecan + EGFR inhibitor
5. Single agent EGFR inhibitor
I chose regorafenib since he was asymptomatic and EGFR inhibitor will retain activity in later lines of therapy (and the patient wanted pills instead of IV treatment)
• 4/18 – progression on FOLFIRI + bevacizumab, patient asymptomatic
WHY REGORAFENIB FIRST?
• Patients benefit from access to all active agents (ie, regorafenib AND TAS-102)
• Regorafenib appears to provide more benefit in less pretreated patients
25
REVERCE STUDY:STUDY DESIGN AND ENDPOINTS
26
*Exclusion of RAS mutation after protocol amendment concurrent with the approval of RAS testing in JapanAEs, adverse events; C, cetuximab; EGFR, epidermal growth factor receptor; PFS, progression-free survival, PFS1, progression-free survival of treatment 1; PFS2, progression-free surival of treatment 2; QoL, quality of life; R, regorafenib; TTF, time to sequential treatment failure; WT, wild type;Shitara. K et al. Ann Oncol. 2019;30(2):259-265
Stratified by intent to use irinotecan with cetuximab at enrollment, prior history of bevacizumab, and institutions
Treatment 1 (Tx1)
C-R arm
R-C arm
1:1
Treatment 2 (Tx2)
Study registered at the University Hospital MedicalInformation Network (UMIN) Clinical Trials Registry
(Protocol ID: UMIN000011294)
• Histopathologically provenunresectable metastatic or locallyadvanced colorectal adenocarcinoma
• Treatment failure with fluoropyrimidines, oxaliplatin, and irinotecan
• Anti-EGFR naïve• KRAS exon 2 WT• Pts with minor RAS mutations* are
excluded since March 2015•KRAS exon 3 (codon 59/61), exon 4 (codon 117/146), NRAS exon 2 (codon 12/13), exon 3 (codon 59/61), and exon 4 (codon 117/146)
N=101
Regorafenib160 mg
3 weeks on 1 week offN= 51
Cetuximab initial dose: 400mg/m2
subsequent dose: 250mg/m2
(+irinotecan 120mg/m2)N=50
Cetuximab initial dose: 400mg/m2
subsequent dose: 250mg/m2
(+irinotecan 120mg/m2)
Regorafenib160 mg
3 weeks on 1 week off
Disease Progression
or unacceptable toxicities
Disease Progression
or unacceptable toxicities
Primary endpoint: overall survivalSecondary endpoints: TTF, PFS of sequential therapy, PFS1, PFS2, response rate and disease controle rate of Treatment 1 (Tx1) and 2 (Tx2), incidence of AEs and QoL
SECONDARY ENDPOINTS: PFS1 AND PFS2
27
C, cetuximab; CI, confidence interval; HR, hazard ratio; PFS1, progression-free survival for treatment 1; PFS 2, progression-free survival for treatment 2; R, regorafenib;
Shitara. K et al. Ann Oncol. 2019;30(2):259-265
REVERCE STUDY: PFS
PRIMARY ENDPOINT: OVERALL SURVIVAL
28
REVERCE STUDY: OS
C, cetuximab; CI, confidence interval; HR, hazard ratio; OS, overall survival; R, regorafenib
Shitara. K et al. Ann Oncol. 2019;30(2):259-265
Regorafenib followed by cetuximab associated with longer OS than the current standard sequence
IMBLAZE370: PHASE III ATEZOLIZUMAB WITH OR WITHOUT COBIMETINIB VS REGORAFENIB IN PREVIOUSLY TREATED mCRC
29mOS, median overall survival; mPFS, median progression-free survival
Eng C: et al. Lancet Oncol. 2019 Jun;20(6):849-861; 1Grothey A. et al. Lancet. 2013;381(9863):303-12; 2Li J. et al. Lancet Oncol. 2015:619-29.
Atezolizumab(n=90)
Cobimetinib + atezolizumab
(n=163)
Regorafenib(n=90)
mPFS mOS(months) (months)
1.91 8.87
1.94 7.10
2.00 8.51
Compare to 6.4 months mOS in CORRECT1
study and 8.8 months mOS in CONCUR2 study
R2:1:1
• Unresectable locally advanced or metastatic colorectal cancer
• Received ≥2 regimens in the metastatic setting (not including maintenance)
(n=363)
WHY REGORAFENIB FIRST?
• Patients benefit from access to all active agents (ie, regorafenib AND TAS-102)
• Regorafenib appears to provide more benefit in less pretreated patients
• Side-effects can be managed
– Especially if using ReDos approach – stay tuned for tomorrow’s session!!
• Cytotoxic therapy (eg, TAS-102) can be active after regorafenib
30
No further therapyn=98 (57%)
Standard treatmentn=33
Clinical trialn=31
MC, MDA, AND USC EXPERIENCE:CHEMOTHERAPY AFTER REGORAFENIB IN mCRC
31MC, Mayo Clinic; mCRC, metastatic colorectal cancer; MDA, MD Anderson; USC, University of Southern California.
Kidd MT, et al. J Clin Oncol. 2015;33 (abstract 678)
Post-regorafenib therapy
n=64 (37%)
Continue regorafenibn=11 (6%)
Regorafenib treatment(MC=59, MDA=95, USC=19)
EFFICACY OF CHEMOTHERAPY AFTER REGORAFENIB (N=33)
32CI, confidence intervals; OR, objective response; OS, overall survival; PD, progression disease; SD, stable disease
Kidd MT, et al. J Clin Oncol. 2015;33 (abstract 678)
Best response, n(%)Efficacy of chemotherapy afterregorafenib (n=33)
OR or SD 20 (61%)
Reintroduction: Stable disease or response to a treatment previously discontinued without definitive PD
8 (24%)
Re-challenge: Response to re-challenge withchemotherapy previously discontinued owing to PD
4 (12%)
New Treatment: Response to receiving an agent not administered prior to regorafenib
8 (24%)
PD 11 (33%)
Not evaluable 2 (6%)
OS post regorafenib discontinuation, median (95% CI)Probability of OS
6 months 12 months
6.5 months (CI 4.9–9.4) 52% 27%
WHY REGORAFENIB FIRST?
• Patients benefit from access to all active agents (ie, regorafenibAND TAS-102)
• Regorafenib appears to provide more benefit in less pretreated patients
• Side-effects can be managed
– Especially if using ReDos approach – stay tuned for tomorrow’s session!!
• Cytotoxic therapy (eg, TAS-102) can be active after regorafenib
• EGFR inhibitors still have efficacy in later lines of therapy
33
HR OF PFS/DFS FOR EGFR mAbs PHASE III TRIALS IN KRAS WT CRC
34
EGFR, Epidermal Growth Factor Receptor; DFS, disease-free survival; HR, hazard ratio,; PFS, progression-free survival; WT, wild type
COIN: Maughan Lancet 2011; 377: 2103–14; Crystal: VanCutsem J Clin Oncol 33:692-700. 2015; PRIME: Douillard, J Clin Oncol 28:4697-4705. 2010; NORDIC: Tveit, J Clin Oncol 30:1755-1762. 2012; N0147: Alberts JAMA. 2012;307(13):1383-1393; 181: Peeters J Clin Oncol. 2010 Nov 1;28(31):4706-13; Cetuximab single agent: JonkerN Engl J Med 2007; 357:2040-2048; Panitumumab single agent: VanCutsem J Clin Oncol 25:1658-1664 2007
Hazard ratio
1.2 1 0.8 0.6 0.4 0.2 0
First-Line
Second-Line
Adjuvant
Salvage(single agent)
HOW DO I CHOOSE REGORAFENIB VS. TAS-102?
• Regorafenib and TAS-102 have similar effect on OS but different toxicities
• Also take into account side effect profile
– Examples
• Contraindications to anti-angiogenic therapy TAS-102
• Problems with cytopenias regorafenib
35OS, overall survival
GOOD ECOG PS ASSOCIATED WITH INCREASED CLINICAL BENEFIT OF REGORAFENIB
36ECOG PS, Eastern Cooperative Oncology Group - performance status; OS, overall survival; PFS, progression-free survival
Tougeron D. et al.. ESMO 2014 (poster 602P)
PFS OS
Pro
babili
tyof P
FS
Pro
babili
tyof O
S
WHAT IS THE NEXT STEP?
37EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; IV, intravenous; WT, wild type
PT J.K. 54 YO M WITH mCRC, MSS, BRAF/RAS WT
1. Reintroduce FOLFOX + bevacizumab (with oxaliplatindesensitization protocol)
2. Trifluridine/tipiricil (TAS-102)
3. Irinotecan + EGFR inhibitor
4. Single agent EGFR inhibitor
• 10/18 – progression on regorafenib with back pain related to retroperitoneal lymph node progression
WHAT IS THE NEXT STEP?
38EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; IV, intravenous; WT, wild type
PT J.K. 54 YO M WITH mCRC, MSS, BRAF/RAS WT
1. Reintroduce FOLFOX + bevacizumab (with oxaliplatindesensitization protocol)
2. Trifluridine/tipiricil (TAS-102)
3. Irinotecan + EGFR inhibitor
4. Single agent EGFR inhibitor
I chose irinotecan + EGFR inhibitor because the patient needed a response
• 10/18 – progression on regorafenib with back pain related to retroperitoneal lymph node progression
RESPONSE RATES WITH REGORAFENIB, TAS-102
Regorafenib TAS-102
Study CORRECT1 CONCUR2 RECOURSE3
Priorbiologics
100% BEV43% EGFR mAbs
60% 100% BEV*53% EGFR mAbs
Regorafenib Placebo Regorafenib Placebo TAS-102 Placebo
Patients, n 505 255 136 68 534 266
mOS, months 6.4 5.0 8.8 6.3 7.1 5.3
HR 0.77p=0.0052
HR 0.55p=0.00016
HR 0.68p<0.0001
mPFS, months 1.9 1.7 3.2 1.7 2.0 1.7
HR 0.49p<0.0001
HR 0.31p<0.0001
HR 0.48p<0.001
RR, % 1.0 0.4 4.4 0 1.6 0.4
P=0.19 P=0.045 P=0.29
Relevant AEs HFSRFatigue
NeutropeniaDiarrhea
39
AEs, adverse events; BEV, bevacizumab; EGFR, epidermal growth factor receptor; HFSR, hand-foot skin reaction; HR, hazard ratio; mAbs, monoclonal antibodies; mOS, median overall survival; mPFS, median progression-free survival; Rego, regorafenib; RR, response rate
* All patients in the TAS-102 group and 265/266 patients (99.6%) had previously received BEV1Grothey A. et al. Lancet. 2013;381(9863):303-12; 2Li J. et al. Lancet Oncol. 2015:619-29. 3Mayer RJ, et al. N Engl J Med. 2015;372(20):1909-19
CETUXIMAB MONOTHERAPY AND CETUXIMABPLUS IRINOTECAN IN IRINOTECAN-REFRACTORY METASTATIC COLORECTAL CANCER
40PFS, progression-free survival; RR, response rate
Cunningham. D, et al. N Engl J Med. 2004 Jul 22;351(4):337-45.
cetuximab Cetuximab+irinotecan p value
RR 10.8% 22.9% p=0.007
PFS 1.5 months 4.1 months P<0.001
PT J.K. 54 YO M WITH MCRC, MSS, BRAF/RAS WT
• 10/18 – progression on regorafenib with back pain related to retroperitoneal lymph node progression
• 10/18 started irinotecan + panitumumab with good response and reduction in back pain
• 3/19 Transitioned to single agent EGFR inhibitor
• Still have options of:
– Reintroduction of FOLFOX + bevacizumab (with oxaliplatindesensitization protocol)
– Trifluridine/tipiricil
41EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type
CASE 3
PT L.S. 66 YO F WITH mCRC, MSS, BRAF MUTANT/RAS WT
• 10/16 – sigmoid colectomy, pT4aN2b (9/33 lymph nodes +), pMMR
• NGS: BRAF V600e, TP53, MSS
• 11/16 – 4/17 XELOX
• 10/17 –New ascites and omental nodularity. Biopsy confirms recurrent CRC
• 11/17 – 5/18 – FOLFIRI + bev, progressive disease
43
Bev, bevacizumab; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; NGS, next generation sequencing; pMMR, mismatch repair proficient; WT, wild type
WHAT IS THE NEXT STEP?
44EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type
PT L.S. 66 YO F WITH mCRC, MSS, BRAF MUTANT/RAS WT
1. Reintroduce FOLFOX + bevacizumab
2. Regorafenib
3. TAS-102
4. Irinotecan + EGFR inhibitor
5. Irinotecan + EGFR inhibitor + BRAF inhibitor
6. MEK inhibitor + EGFR inhibitor + BRAF inhibitor
WHAT IS THE NEXT STEP?
45EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type
PT L.S. 66 YO F WITH mCRC, MSS, BRAF MUTANT/RAS WT
1. Reintroduce FOLFOX + bevacizumab
2. Regorafenib
3. TAS102
4. Irinotecan + EGFR inhibitor
5. Irinotecan + EGFR inhibitor + BRAF inhibitor
6. MEK inhibitor + EGFR inhibitor + BRAF inhibitor
I chose MEK inhibitor + EGFR inhibitor + BRAF inhibitor because we had the BEACON study open at our institution
OS IS AFFECTED BY BRAF MUTATIONS IN CALGB 80405 (72/504, 14%)
46
HRadj, Hazard ration adjusted; OS; overall survival
HRadj 1.67
(95% CI 1.20-2.33)
p 0.0035
Without adjusting for sidedness:
HRadj 1.82
(95% CI 1.37-2.44)
p 0.0001
0 12 24 36 48 60 72
0.00
0 12 24 36 48 60 72
Months From Randomization
Prop
orti
on W
itho
ut E
vent
34.2 months (31.0-36.4)N=432Wildtype
12.9 months (11.1-19.0)N=72Mutant
Median OS (95% CI)BRAF
0.25
0.50
0.75
1.00
BRAF MUTATIONS AND EGFR INHIBITORS
47OS, overall survival; PFS, progression-free survival
Pietrantonio, et al. Eur J Cancer. 2015 Mar;51(5):587-94
463 RAS-wt/BRAF-mut CRC patients from:
9 phase II trials and1 phase II trial
were analysed
0.88
PFS
OS0.91
BRAF V600E INHIBITOR: PLX4032 (VEMURAFENIB)
48
1Flaherty KT, et al. N Engl J Med. 2010;363(9):809-19. Kopetz S, et al. J Clin Oncol. 2015 Dec 1;33(34):4032-8,
Source figure: oral presentation from Kopetz S. at the Clinical Trials Planning Meeting (CTPM) Jan 2011.
77% Response Rate
-100
-75
-50
-25
0
25
50
75
100
%Ch
ange
Fro
m B
asel
ine
(Sum
of L
esio
n Si
ze)
-100
-75
-50
-25
0
25
50
75
100
5% Response Rate
REFRACTORY MELANOMA1 REFRACTORY COLORECTAL2
Oncogene mutation does not imply oncogene dependence
Flaherty et al NEJM ‘10 Kopetz et al ASCO ‘10
Understand the biological context in which particular mutations occur
Low AKT activation
Minimal hypermethylation
High AKT activation
Extensive hypermethylation
%Ch
ange
Fro
m B
asel
ine
(Sum
of L
esio
n Si
ze)
BRAF INHIBITORS + EGFR INHIBITORS HAVE IN VIVO ACTIVITY IN BRAFV600E MUTATED CRC XENOGRAFTS
49CRC, colorectal cancer; PLX, PLX4032
Prahallad A, et al. Nature. 2012;483(7387):100-103.
ClinicalTrials.gov Identifier: NCT02164916
50Bid, twice daily; IV, intravenous; PO, per os; q2weeks, once every two weeks
Presented By Scott Kopetz at 2017 Gastrointestinal Cancers Symposium.
SWOG STUDY S1406 STUDY DESIGN
Progression
Progression Off Study
BRAFV600EMutation
Off Study
CentralTestingPerformed
Wild-type(off-study)
LocalBRAFtesting
No localBRAFtesting
RANDOMIZATION
REGISTRATION
Vemurafenib 960 mg PO bid continuousCetuximab 500 mg/m2 IV q2weeksIrinotecan 180 mg/m2 IV q2weeks
ARM 2:Vemurafenib +Cetuximab +Irinotecan
ARM 1:Cetuximab +Irinotecan STEP 3: Cross-
over to addVemurabinib
SWOG STUDY S1406 PRIMARY ENDPOINT: PFS
51
PFS, progression-free survival
Kopetz S. Presented at ASCO 2017.
Source data: from published results at ClinicalTrials.gov Identifier: NCT02164916
N Events Median 95% Conf IntCetuximab + Irinotecan 50 48 2.0 (1.8 – 2.1)Vemurafenib + Cetuximab 49 40 4.4 (3.6 – 5.7)
+ Irinotecan
HR = 0.48 (95% CI 0.31 – 0.75)P = 0.001
0 3 6 8 10 12 14
Months after randomization
80%
100%
60%
40%
20%
0%
April 18. 2017 data cutoff
7.3 months of median follow up
SWOG STUDY S1406 SECONDARY ENDPOINT: RESPONSE RATE
Cetuximab +Irinotecan
(n=47)a
Vemurafenib+ Cetuximab +
Irinotecan(n=44)a
P-valuec
Partial responseb 4.2% 16.0%
P=0.001Stable disease 17.0% 50.0%
Progressionc 66.0% 18.2%
Disease Control 22% 67%Rate
a93 patients had measurable disease; bConfirmed and unconfirmed; PR for patients previously treated with irinotecan was 0% and 18%, respectively; cIncluding symptomatic deterioration; c Chi-squared
Cetuximab + Irinotecan
Vemurafenib + Cetuximab + Irinotecan
April 18. 2017 data cutoff
100%
52
20%
0%
-30%
-100%
100%
20%
0%
-30%
-100%
Kopetz S. Presented at ASCO 2017.
Source data: from published results at ClinicalTrials.gov Identifier: NCT02164916
BINIMETINIB, ENCORAFENIB, AND CETUXIMAB TRIPLET THERAPY FOR PATIENTS WITH BRAF V600E–MUTANT METASTATIC COLORECTAL CANCER: SAFETY LEAD-IN RESULTS FROM THE PHASE III BEACON COLORECTAL CANCER STUDY
53mCRC, metastatic colorectal cancer
VanCutsem. E, et al. J Clin Oncol. 2019 Jun 10;37(17):1460-1469.
• Unresectable mCRC• BRAF V600E mutation• Received at least one but
no more than 2 prior lines of therapy
n=30
encorafenib 300 mg daily
+binimetinib 45 mg
twice daily +
weekly cetuximab
Most common grade 3 or 4 adverse events: • Fatigue (13%)• Anemia (10%),• Increased creatine
phosphokinase (10%)• Increased AST (10%)• Urinarytract infections (10%)
BEACON SAFETY LEAD IN: EFFICACY ENDPOINT: ORR
54
CI, confident interval; CR, complete response; ORR, overall response rate; PR, partial response
VanCutsem. E, et al. J Clin Oncol. 2019 Jun 10;37(17):1460-1469.
ORR 48% (95% CI, 29.4% to 67.5%)
BEACON SAFETY LEAD IN: OTHER EFFICACY ENDPOINTS: mPFS-mOS
55mOS, median overall survival; mPFS, median progression-free survival
VanCutsem. E, et al. J Clin Oncol. 2019 Jun 10;37(17):1460-1469.
mPFS: 8.0 months mOS: 15.3 months
• August 2018: The FDA granted breakthrough therapy designation for encorafenib in combination with binimetiniband cetuximab for the treatment of patients with BRAFV600E–mutant metastatic colorectal cancer (mCRC), as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease
56
BINIMETINIB, ENCORAFENIB, AND CETUXIMAB TRIPLET THERAPY FOR PATIENTS WITH BRAF V600E–MUTANT METASTATIC COLORECTAL CANCER: THE PHASE III BEACON COLORECTAL CANCER STUDY
57
• Unresectable mCRC• BRAF V600E mutation• Received at least one but no
more than 2 prior lines of therapy
R1:1:1
Doublet ArmEncorafenib + Cetuximab
N=205
Triplet ArmEncorafenib + Binimetinib +
CetuximabN=205
Control ArmIrinotecan + Cetuximab
ORFOLFIRI + Cetuximab
N=205ClinicalTrials.gov Identifier: NCT02928224
Source: Presentation from Kopetz S. et al. at ESMO World Congress on Gastrointestitnal Cancer 2019; Kopetz S. et al. N Engl J Med. 2019; 381:1632-1643
BEACON: BINIMETINIB, ENCORAFENIB, AND CETUXIMAB TRIPLET THERAPY FOR PATIENTS WITH BRAF V600E–MUTANT mCRC:
58CI, confidence intervalKopetz S. et al. N Engl J Med. 2019; 381:1632-1643
WHAT IS THE NEXT STEP?
59EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type
PT L.S. 66 YO F WITH mCRC, MSS, BRAF MUTANT/RAS WT
• 5/18 – 4/19 treated with MEK inhibitor + EGFR inhibitor + BRAF inhibitor on the BEACON study
– Had disease response through 2/19
• 4/19 – disease progression with new peritoneal nodules
WHAT IS THE NEXT STEP?
60mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type
PT L.S. 66 YO F WITH mCRC, MSS, BRAF MUTANT/RAS WT
1. Reintroduce FOLFOX + bevacizumab
2. Regorafenib
3. TAS-102
WHAT IS THE NEXT STEP?
61mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type
PT L.S. 66 YO F WITH mCRC, MSS, BRAF MUTANT/RAS WT
1. Reintroduce FOLFOX + bevacizumab
2. Regorafenib
3. TAS-102
I chose regorafenib given she has a good performance status and pre-existing neuropathy and I’m hoping it will “resensitize” the tumor to cytotoxic chemo in future
CASE 4
PT E.D. 62 YO FEMALE WITH METASTATIC RECTAL CANCER
• Original diagnosis 6/14
• Concurrent chemorads with 5-FU resection
• 10/15 Postop imaging showed liver metastases
• Started on FOLFOX + bevacizumab
– After 3 cycles developed pelvic fistula/abscess requiring I&D and permanent colostomy
• 2/15 treatment changed to FOLFIRI. Received 6 cycles, good response, and then had resection of liver metastases 5/15
• 11/15 appearance of multiple small bilateral pulmonary metastases
• MSS, BRAF/RAS wild type
• Next step in management?
63MSS, microsatellite stable
NEXT STEP?
64EGFR, epidermal growth factor receptor; MSS, microsatellite stable; WT, wild type
PT E.D. 63 YO FEMALE WITH METASTATIC RECTAL CANCER, BILAT LUNG METS, BRAF/RAS WT, MSS
1. Reintroduce FOLFIRI and add bevacizumab
2. Reintroduce FOLFOX + bevacizumab
3. Regorafenib
4. Trifluridine/tipiricil
5. Irinotecan + EGFR inhibitor
6. Single agent EGFR inhibitor
NEXT STEP?
65EGFR, epidermal growth factor receptor; MSS, microsatellite stable; WT, wild type
PT E.D. 63 YO FEMALE WITH METASTATIC RECTAL CANCER, BILAT LUNG METS, BRAF/RAS WT, MSS
1. Reintroduce FOLFIRI and add bevacizumab
2. Reintroduce FOLFOX + bevacizumab
3. Regorafenib
4. Trifluridine/tipiricil
5. Irinotecan + EGFR inhibitor
6. Single agent EGFR inhibitor
I chose to give an EGFR inhibitor. Concern about anti-angiogenesis with prior fistula and low volume of disease not needing response
PT E.D. 64 YO FEMALE WITH METASTATIC RECTAL CANCER, BILAT LUNG METS, BRAF/RAS WT, MSS
• 1/16 – 2/17 Panitumumab with good response
• 2/17 – 6/17 treatment holiday (due to travelling and tired of skin toxicity)
• 6/17 CT scan shows progression in the lungs
66CT, computerized tomography; MSS, microsatellite stable; WT, wild type
NEXT STEP?
67EGFR, epidermal growth factor receptor; MSS, microsatellite stable; WT, wild type
PT E.D. 64 YO FEMALE WITH METASTATIC RECTAL CANCER, BILAT LUNG METS, BRAF/RAS WT, MSS
1. Reintroduce FOLFIRI and add bevacizumab
2. Reintroduce FOLFOX + bevacizumab
3. Regorafenib
4. Trifluridine/tipiricil
5. Irinotecan + EGFR inhibitor
6. Single agent EGFR inhibitor
NEXT STEP?
68EGFR, epidermal growth factor receptor; MSS, microsatellite stable; WT, wild type
PT E.D. 64 YO FEMALE WITH METASTATIC RECTAL CANCER, BILAT LUNG METS, BRAF/RAS WT, MSS
1. Reintroduce FOLFIRI and add bevacizumab
2. Reintroduce FOLFOX + bevacizumab
3. Regorafenib
4. Trifluridine/tipiricil
5. Irinotecan + EGFR inhibitor
6. Single agent EGFR inhibitor
I chose trifluridine/tipiricil due to patient preference of oral agent and again concern with anti-angiogenic therapy
PT E.D. 65 YO FEMALE WITH METASTATIC RECTAL CANCER, BILAT LUNG METS, BRAF/RAS WT, MSS
• 6/17 – 10/17 trifluridine/tipiricil. Stable disease 1st scan, progression 2nd scan
69MSS, microsatellite stable; WT, wild type
NEXT STEP?
70EGFR, epidermal growth factor receptor; MSS, microsatellite stable; WT, wild type
PT E.D. 65 YO FEMALE WITH METASTATIC RECTAL CANCER, BILAT LUNG METS, BRAF/RAS WT, MSS
1. Reintroduce FOLFIRI and add bevacizumab
2. Reintroduce FOLFOX + bevacizumab
3. Regorafenib
4. Irinotecan + EGFR inhibitor
5. Single agent EGFR inhibitor
NEXT STEP?
71EGFR, epidermal growth factor receptor; MSS, microsatellite stable; WT, wild type
PT E.D. 65 YO FEMALE WITH METASTATIC RECTAL CANCER, BILAT LUNG METS, BRAF/RAS WT, MSS
1. Reintroduce FOLFIRI and add bevacizumab
2. Reintroduce FOLFOX + bevacizumab
3. Regorafenib
4. Irinotecan + EGFR inhibitor
5. Single agent EGFR inhibitor
I chose irinotecan + EGFR inhibitor because of increasing tumor burden
PT E.D. 66 YO FEMALE WITH METASTATIC RECTAL CANCER, BILAT LUNG METS, BRAF/RAS WT, MSS
• 10/17 – 1/18 – irinotecan plus panitumumab
• Good response but significant fatigue with irinotecan
• 3/18 – continued single agent panitumumab
– Stable disease through 5/19
– Asymptomatic, exercises 5 days per week
72MSS, microsatellite stable; WT, wild type
IS THERE A RATIONALE FOR RE-CHALLENGE WITH EGFR INHIBITORS?
• Retrospective cohort of patients with RAS/BRAF/EGFRWT mCRC treated with an EGFR inhibitor
– 135 patients identified
– sequencing of ctDNA from plasma samples with Guardant360 platform
• Inverse relationship between RAS and EGFR and time since last treatment
– no change in truncal APC and TP53 inactivating mutations.
• RAS and EGFR MT alleles decayed after EGFR inhibitor discontinuation
– half-life of 3.4 months and 6.9 months, respectively
• Potential molecular explanation for the efficacy of EGFR inhibitor re-challenge
73
APC, adenomatous polyposis coli; ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MT, mutant; WT, wild type
Parseghian. ASCO 2018. (abstract 3511)
MOLECULAR EXPLANATION FOR THE EFFICACY OF EGFR INHIBITOR RE-CHALLENGE
74Parseghian. ASCO 2018. (abstract 3511)
CONCLUSIONS
CONCLUSIONS
• Careful consideration of patient factors can optimize patient management to get the most benefit out of each drug/regimen
• NGS at diagnosis:
– Quickly identify HER2 & BRAF mutant tumors
– Line up trials
• May gain more efficacy with regorafenib if used earlier on
• Rationale for rechallenge with EGFR inhibitors
• Remember EGFR inhibitors retain activity even in the salvage setting
76EGFR, epidermal growth factor receptor; NGS, next generation sequencing
CONCLUSIONS
• These cases demonstrate the opportunity for improvement of survival outcomes:
– Case 2 – alive 4 years + 2 months with metastatic disease
– Case 3 – alive nearly 2 years with metastatic BRAF mutant disease
– Case 4 – alive over 5 years with metastatic disease!
77