novedades recientes en cáncer colo-rectal metastásico€¦ · colo-rectal metastásico ana mª...

Novedades Recientes en Cáncer Colo-rectal Metastásico

Ana Mª López Muñoz Hospital Universitario de Burgos

!1. Triple-Drug Chemotherapy + Biologics!!2. Molecular Landscape-Biomarkers!

BRAF HER-2 NTRK and Non-TRK fusions

!3. Immunotherapy

TRIPLE-DRUG CHEMOTHERAPY!+!

BIOLOGICS

Pilar García-Alfonso et al. Expert Opin Biol Ther. 2019 May;19(5):411-422

Pilar García-Alfonso et al. Expert Opin Biol Ther. 2019 May;19(5):411-422

FOLFOXIRI- CETUXIMAB

FOLFOXIRI- PANITUMUMAB

FII

FIIR

FIIR

FII

FI

FI

" The administration of a biologic agent in combination with FOLFOXIRI results in high survival and response rates!!

" Only selected patients can receive this aggressive treatment due to toxicity issues.!!" FOLFOXIRI with bevacizumab has currently more solid evidence than combination with anti-EGFR in

both conversion and palliative settings. However, the true value of bevacizumab in the combination remains to be established as it has not been evaluated in a randomized setting yet. (Guidelines)!!" FOLFOXIRI-anti-EGFR combinations have shown promising results in phase II trials, with higher

response rates in certain patients. Panitumumab is the only biologic that has proved its value when added to FOLFOXIRI in a randomized clinical trial. Data from large phase III trials are still lacking.!!" Impact of sidedness and impact of biomarkers, should be observed with caution due to the small

numbers of patients in these subgroup analyses.

Results of ongoing head-to-head studies will shed additional light on this

issue

Matos I et al. Expert Opinion on Investigational Drugs 2019 May;28(5):463-471

Promising response rates (are likely to become an important option in conversion therapy and/or in the first line setting of mCRC).

!The safety profiles of these combinations (incidences of grade 3-4 gastrointestinal toxicities were high).

!There are unresolved questions with these combinations, for example:

* Doses of irinotecan and fluorouracil * Maintenance strategies with anti-EGFR +/- with fluorouracil * The appropriate control arm in a phase III clinical * Which is the second line after progression

“We need to improve patient selection for these combinations, not only at the molecular level to obtain high response rates, but also in terms of the safety profile”

Presented By Javier Sastre at 2019 ASCO Annual Meeting

Presented By Javier Sastre at 2019 ASCO Annual Meeting

OS by treatment arm

Presented By Javier Sastre at 2019 ASCO Annual Meeting

Presented By Chiara Cremolini at 2019 ASCO Annual Meeting

Slide 10

Presented By Chiara Cremolini at 2019 ASCO Annual Meeting

Presented By Chiara Cremolini at 2019 ASCO Annual Meeting

Presented By Chiara Cremolini at 2019 ASCO Annual Meeting

Michael Geissier. ASCO 2019 # 3511

Michael Geissier. ASCO 2019 # 3511

MOLECULAR LANDSCAPE

BIOMARKERS

STANDARD OF CARE 2019 EVOLVING BIOMARKERS

KRAS/NRAS BRAF (V600E) dMMR/MSI-H HER-2?

NTRK Fusions Non-TRK Fusions POLE CMS TMB ctDNA

mCRC

BRAF

BRAF inhibition results in rapid feedback activation of epidermal growth factor receptor (EGFR), permitting sustained MAPK activation and continued cell proliferation; however, combined inhibition of BRAF and EGFR resulted in synergistic inhibition of tumor growth in BRAF V600E–mutant CRC xenograft models.

Vemurafenib!Dabrafenib!Encorafenib

Trametinib!Binimetinib

Cetuximab!Panitumumab

F IIRa SWOG S1406 (S. Kopetz ASCO-17): Cetuximab-Irinotecan vs Vemurafenib-Irinotecan-Cetuximab!! - VIC: ORR* 16% (4%), DCR* 67% (22%), PFS* 4.3 m (2), OS 9.6 (5.9, crossover 48%)

F I (R.B. Corcoran. Cancer Discov. 2018): 3 cohortes (Dabrafenib(D)-Trametinib (T)-Panitumumab(P), D-P, T-P.!! - DTP: ORR 21%, DCR 86%, PFS 4.2 m OS 9.1 m

F II (J. Tabernero. JCO 34 (15_Suppl) 3544): Encorafenib- Cetuximab +/- Alpelisib! - E-C-A: ORR 27%,PFS 5.4 m, OS 15.2 m

Eric Van Cutsem et al. J Clin Oncol 2019; 37:1460-1469

Thirty patients were enrolled in the SLI of BEACON CRC between November 1, 2016, and April 24, 2017

Eric Van Cutsem et al. J Clin Oncol 2019; 37:1460-1469

Eric Van Cutsem et al. J Clin Oncol 2019; 37:1460-1469

Among the 17 patients treated with one prior therapy, ORRs per local and central assessment were 59% (95% CI, 32.9% to 81.6%) and 53% (95% CI, 27.8% to 77.0%),!respectively. !!Among the 12 patients treated with two prior therapies, the local ORR was 33% (95% CI, 9.9% to 65.1%), with corresponding rates from central assessment of 25% (95% CI, 5.5% to 57.2%).

May 21, 2019!BEACON CRC Interim Results

Triplet vs Control

Doublet vs Control

BRAF codon 594 or 596 mutated mCRCs are different from BRAF V600E ones in terms of molecular features, pathological characteristics and clinical outcome

BRAF 594 or 596 mutated were more frequently rectal, non-mucinous and with no peritoneal spread. All BRAF 594 or 596 mutated tumors were microsatellite stable. Patients with BRAF codons 594 or 596 mutated tumors had markedly longer overall survival (OS)

C. Cremolini et al. Annals of Oncology 2015; 26: 2092–2097.

Jeremy C. Jones et al. J Clin Oncol 2017; 35:2624-2630.

Cancers with non-V600BRAF mutations, compared with cancers with V600E BRAF (V600EBRAF) mutations, were found in patients who were significantly younger (58 v 68 years, respectively), fewer female patients (46% v 65%, respectively), and patients who had fewer high-grade tumors (13% v 64%, respectively) or right-sided primary tumors (36% v 81%, respectively). Median overall survival was significantly longer in patients with non-V600BRAF-mutant metastatic CRC compared with those with both V600EBRAF-mutant and wild-type BRAF metastatic CRC (60.7 v 11.4 v 43.0 months, respectively; P , .001).

Schirripa M. et al. Clin Cancer Res. 2019

V600E597 601

594 596

Patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care (including cetuximab or panitumumab)

Andrea Sartore-Bianchi. Lancet Oncology 2016; 17: 738-46

ORR 30%

HER-2

Median progression-free survival was 21 weeks (95% CI 16–32)!Median overall survival calculated post hoc was 46 weeks (95% CI 33–68)

Funda Meric-Bernstam et al.Lancet Oncol 2019; 20: 518–30

ORR: 32%!2% Complete Response 30% Partial Response

Analysis of activity by NGS-derived HER2 copy number suggested that more patients with higher-than-median copy number achieved objective response than did those with lower copy number, which is consistent with results from HERACLES

Funda Meric-Bernstam et al.Lancet Oncol 2019; 20: 518–30

HER2 amplification in RAS/RAF wild-type mCRC seems to be a predictive biomarker for lack of efficacy of anti-EGFRab therapy.

Kanwal Raghav et al JCOPO 2019

We correlated ERRB2 pCN with progression-free survival (PFS) and best objective response (BOR)

Clin Cancer Res; 25(10) May 15, 2019

In this study, an observed pCN of 2.4 and an adjusted pCN of 25.82 copies of ERBB2 areproposed to select patients who will benefit from HER2-targeted therapy

HER2-A RAS WT

Driolon A. et al. N Engl J Med. 2018, 378(8):731-739

In November 2018, the US Food and Drug Administration granted accelerated approval to Larotrectinib for adult and pediatric patients with solid tumors

harboring NTRK gene fusions without known acquired resistance mutation.

NTRK!Non-TRK FUSIONS

Biagio Ricciuti et al. OncoTargets and Therapy 2019:12 3171–3179

.- Different studies have shown that TPM3–NTRK1 gene rearrangement is a recurrent event in colorectal carcinoma (0.5-2%) .- TPR-NTRK1, LMNA-NTRK1,…

Colorectal cancer

.- In a single-institution retrospective study in heavily pretreated colorectal cancer patients, NTRK fusion was detected in 2.5% of cases (Sartore-Bianchi A, Target Oncol. 2017; 12)

Pietrantonio et al found a nearly doubled incidence (4%) of NTRK fusions in a cohort of 346 colorectal cancer patients. Of note, ten of 13 patients with NTRK fusion (76.9%) also had high microsatellite instability (J Natl Cancer Inst. 2017;109)

Kinase Fusions in Colorectal Cancers: A Unique Biologic Subset

R. Madison. ESMO-18 # 3509

Kinase rearrangements (KRE) were identified in 126 CRC tissue specimens (0.68%) and 7 CRC ctDNA samples (1.36%).

The most frequently altered kinases were RET (22%), NTRK1 (16%), and ALK (13%)

Of all KRE cases, NTRK1 and RET KRE cases were 85% and 50% MSI high, respectively

Silvia Marsoni. ESMO 2018

Slide 7

IMMUNOTHERAPY

H. J. Lenz. ASCO-19 # 3521

IMMUNOTHERAPY FOR MSI CRC

IMMUNOTHERAPY FOR MSS CRC

Cathy Eng, et al. Lancet Oncol 2019; 20: 849–61

Shota Fukuoka et al. ASCO-19 # 2522

Shota Fukuoka et al. ASCO-19 # 2522

PFS

1. Consolidación de los tripletes de QT + Biológicos 1ª

línea CCRm “SELECCIÓN DE PACIENTES”

2. Tripletes en BRAF mutados (Fase III BEACON).

Caracterización de las mut BRAF.

3. HER-2 A: predictivo doble bloqueo HER-2, ¿Tatamiento

con Ac anti-EGFR?

4. ¿NGS? (NTRK)

5. Inmunoterapia:!MSI: Datos prometedores en primera línea.

Pendientes Fase III

MSS: Pequeños avances en combinaciones con ICP y

BK

mCRC