optimal management of crc in the 3rd-line metastatic … · 2019. 11. 14. · optimal management of...

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.

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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


1. Reintroduce FOLFIRI + bevacizumab

2. Reintroduce FOLFOX and add bevacizumab

3. Regorafenib

4. Irinotecan + EGFR inhibitor

5. Single agent EGFR inhibitor


8MSS, microsatellite stable; WT, wild type


• 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+


2. Reintroduce FOLFOX + bevacizumab

3. Regorafenib


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+



3. Regorafenib


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

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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


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)

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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


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

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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

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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


• 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

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mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type


21EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type



2. Reintroduce FOLFOX + bevacizumab (with oxaliplatindesensitization protocol)

3. Trifluridine/tipiricil

4. Regorafenib









4. Regorafenib



Patient was restarted on FOLFIRI + bevacizumab given the marked response previously and 9 months since discontinuing irinotecan






3. Regorafenib



• 4/18 – progression on FOLFIRI + bevacizumab, patient asymptomatic


24EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; IV, intravenous; WT, wild type




3. Regorafenib



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

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*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

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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

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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)


• Patients benefit from access to all active agents (ie, regorafenib AND TAS-102)


• 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

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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%


• Patients benefit from access to all active agents (ie, regorafenibAND TAS-102)


• 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





2. Trifluridine/tipiricil (TAS-102)



• 10/18 – progression on regorafenib with back pain related to retroperitoneal lymph node progression





2. Trifluridine/tipiricil (TAS-102)



I chose irinotecan + EGFR inhibitor because the patient needed a response


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

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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 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


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

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Bev, bevacizumab; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; NGS, next generation sequencing; pMMR, mismatch repair proficient; WT, wild type





2. Regorafenib

3. TAS-102


5. Irinotecan + EGFR inhibitor + BRAF inhibitor

6. MEK inhibitor + EGFR inhibitor + BRAF inhibitor





2. Regorafenib

3. TAS102


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


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


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




• 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


60mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type



2. Regorafenib

3. TAS-102


61mCRC, metastatic colorectal cancer; MSS, microsatellite stable; WT, wild type



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?


PT E.D. 63 YO FEMALE WITH METASTATIC RECTAL CANCER, BILAT LUNG METS, BRAF/RAS WT, MSS

1. Reintroduce FOLFIRI and add bevacizumab


3. Regorafenib




NEXT STEP?





3. Regorafenib




I chose to give an EGFR inhibitor. Concern about anti-angiogenesis with prior fistula and low volume of disease not needing response


• 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?





3. Regorafenib




NEXT STEP?





3. Regorafenib




I chose trifluridine/tipiricil due to patient preference of oral agent and again concern with anti-angiogenic therapy


• 6/17 – 10/17 trifluridine/tipiricil. Stable disease 1st scan, progression 2nd scan


NEXT STEP?





3. Regorafenib



NEXT STEP?





3. Regorafenib



I chose irinotecan + EGFR inhibitor because of increasing tumor burden


• 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


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

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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!

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optimal management of crc in the 3rd-line metastatic … · 2019. 11. 14. · optimal management of...

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