BRAF Mutated mCRC: Specific Considerations for Treatment Dustin - - PowerPoint PPT Presentation

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Sep 01, 2023 323 likes •543 views

BRAF Mutated mCRC: Specific Considerations for Treatment Dustin Deming, MD McArdle Laboratory of Cancer Research Carbone Cancer Center University of Wisconsin EGFR PI3K RAS AKT P BRAF P BRAF P MEK MAPK P N u Transcription factors

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BRAF Mutated mCRC: Specific Considerations for Treatment

Dustin Deming, MD McArdle Laboratory of Cancer Research Carbone Cancer Center University of Wisconsin

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PI3K AKT EGFR RAS MEK P MAPK P BRAF P BRAF P Survival Migration Cell growth Cell cycle progression Transcription factors N u c l e u s

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BRAF Mutations

Occur in ~8-10% of colorectal cancers

80% are BRAF V600E mutations

Concomitant Alterations include:

APC
TP53
PIK3CA
CTNNB1
Hypermethylation resulting in loss of MLH1
Less common missense mutations in MLH1, MSH2
Largely mutually exclusive with KRAS/NRAS mutations

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Cl Clinical Ch Characteri ristics

More common in female and elderly
Right-sided predominance with larger primary

tumors

Associated with:
MMR deficiency
High grade
Peritoneal disease
Metastatic lymph node involvement

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BRAF BRAF V600E 600E – Prognostic c Implications

(Cremolini, et al., Lancet, 2015)

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No Not t Al All BRAF BRAF Mutati tions are e Cr Crea eated ed Equally y

(Jones, JCO, 2017)

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In Vitro Kinase Activity

(Jones, JCO, 2017)

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Fi First-lin line treatment for

r BRAF V600E

mCR mCRC

Only a third of patients go on to second-line

therapy

FOLFOXIRI + Bevacizumab (TRIBE and CHARTA

studies)

FOLFOX or FOLFIRI +/- Bevacizumab

(Seligmann, Ann Oncol, 2017; Cremolini, Lancet, 2015; Schnoll, ASCO, 2017)

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N=32 FOLFOXIRI + Bev FOLFIRI + Bev OS 19 mos 10.7 mos PFS 7.5 mos 5.5 mos RR 56% 42% (Cremolini, et al., Lancet, 2015)

TR TRIBE Study

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ORR DCR Ref Nivolumab (n=12) 25%

Overman, JCO, 2018

Nivolumab and Ipilimumab (n=29) 55% 79% Overman, JCO, 2018

BRAF V6 V600E MMR deficient Se Secon

nd-lin

line e Trea eatm tmen ent

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BRAF Targeted Th Therapeutic Op Options

1. Single agent BRAF inhibition
2. Doublet therapy
3. Doublet therapy plus chemotherapy
4. Triplet therapy

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n RR PFS Ref Vemurafenib 21 5 2.1 Kopetz, JCO, 2015 Dabrafenib 9 11

Falchook, Lancet,

2012 Encorafenib 18 16.7 4 Gomez Roca, ESMO, 2014

Si Single A Agent BR BRAF T Targeted Th Therapy

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EG EGFR Feedback Signaling

(Corcoran, et al., Cancer Discovery, 2018)

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n RR PFS Ref BRAF/EGFR Inhibition Vemurafenib/Panitumumab 15 13 3.2 Yeager, CCR, 2015 Vemurafenib/Cetuximab 27 4 4.5 Hyman, NEJM, 2015 Dabrafenib/Panitumumab 20 10 3.5 Corcoran, Cancer Discov, 2018 Encorafenib/Cetuximab 26 19.2 3.7 van Geel, Cancer Discov, 2017 BRAF/MEK Inhibition Dabrafenib/Trametinib 43 12 3.5 Corcoran, JCO, 2015 MEK/EGFR Inhibition Trametinib/Panitumumab 31 2.6 Corcoran, Cancer Discov, 2018

Doublet BRAF Targeted Th Therapy

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Ve Vemurafenib, Cetuximab, Irinotecan

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Ve Vemurafenib, Cetuximab, Irinotecan

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n RR PFS Ref Dabrafenib, trametinib, panitumumab 91 21 4.1 Corcoran, Cancer Discovery, 2018 Encorafenib, binimetinib, cetuximab 30 48 8 Van Cutsem, GI ASCO, 2018

Triplet BRAF Targeted Th Therapy

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Su Summa mmary

BRAF V600 mutant cancers are a distinct subtype of

CRC with unique clinical characteristics and a poor prognosis

Current treatment strategies include chemotherapy

and targeted therapies.

Anti-PD1 therapies should be used in the setting of

mismatch repair deficiency.

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Futur Future e Dir irec ectio tions ns

Awaiting results of the BEACON phase III study of

encorafenib, binimetinib and cetuximab.

First-line use of immunotherapy or targeted

therapies

Anticipate studies examining the combination of

these approaches

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