Novità

Chiara Cremolini University of Pisa

Azienda Ospedaliero-Universitaria Pisana

Novità e sequenze terapeutiche nel tumore del colon retto

NOVITA’

Supernovae in oncologia

20 settembre 2019

1st-line tx of mCRC: Keep it easy!

Untreated mCRC patients FIT FOR COMBO CT

LEFT SIDED RAS/BRAF wt

HER2 neg MSS

ALL THE OTHERS

1st CHOICE:

Doublet + anti-EGFR

1st CHOICE:

Chemo (Triplet if feasible)

+ bevacizumab

One step back: the TRIBE study

Phase III random TRIBE study

Jul 2008 – May 2011

Primary endpoint: PFS

Bevacizumab + FOLFIRI Bevacizumab + FOLFOXIRI HR=0.75 (95% CI: 0.62–0.90) p=0.003

PFS

Bevacizumab + FOLFIRI Bevacizumab + FOLFOXIRI HR=0.80 (95% CI: 0.65–0.98) p=0.030

OS

Cremolini et al. Lancet Oncol 2015 Loupakis et al. N Engl J Med 2014

ORR: 53% vs 65%, p=0.006

Is FOLFOXIRI/bev better than the pre- planned sequential exposure to the

same agents (FOLFOX→FOLFIRI)?

A re treatments after progression feasible and efficacious?

FAQs about FOLFOXIRI/Bev

Due to the higher toxicity, is it feasible

in every oncology unit?

TRIBE2: Study design

R 1:1

FOLFOX + bev*

FOLFOXIRI + bev*

5FU/bev PD1

5FU/bev

PRIMARY ENDPOINT: Progression Free Survival 2

FOLFIRI +

bev* _5FU/bev PD2

PD1 FOLFOXIRI +

bev* _5FU/bev PD2

Arm A

Arm B

* Up to 8 cycles

Cremolini et al, WCGIC ’19 – LBA-007 and ASCO Ann Meeting ‘19

679 pts in 58 Italian sites

Key eligibility criteria

▪ Histologically proven adenocarcinoma

▪ Unresectable (locally assessed) mCRC not pre-treated for mets

▪ Measurable disease according to RECIST v1.1

▪ Age 18-75

▪ ECOG PS ≤ 2 (ECOG PS = 0 if age = 71-75 years)

▪ Adjuvant oxa-containing chemotherapy NOT allowed

▪ Adjuvant fluoropyrimidine monotherapy allowed if more than 6 months elapsed between the end of adjuvant and first relapse

▪ Adequate bone marrow, liver and renal functions

Cremolini et al, WCGIC ’19 – LBA-007 and ASCO Ann Meeting ‘19

Patients’ characteristics – ITT population

N=679

Characteristic, % patients

Arm A N = 340

Arm B N = 339

Sex (M / F) 61 / 39 54 / 46

Median Age (range) 61 (30 – 75) 60 (33 – 75)

ECOG PS (0 / 1-2) 85 / 15 86 / 14

Synchronous Metastases (Y / N) 89 / 11 89 / 11

Prior Adjuvant CT (Y / N) 2 / 98 2 / 98

Number Metastatic Sites (1 / >1) 38 / 62 45 / 55

Liver Only Disease (Y / N) 29 / 71 32 / 68

Primary Tumor Side (right / left) 38 / 62 38 / 62

RAS/BRAF (RAS mut / BRAF mut / wt / NE) 65 / 10 / 20 / 5 63 / 10 / 22 / 5 Right AND/OR RAS/BRAF mut / Left AND RAS/BRAF wt / NA 79 ^{/ 16 / 5} 78 ^{/ 17 / 5}

Cremolini et al, WCGIC ’19 – LBA-007 and ASCO Ann Meeting ‘19

Median follow up = 30.6 mos

Arm A N = 340

Arm B N = 339 Events, N (%) 272 (80%) 242 (71%)

Median PFS2, mos 17.5 19.1

HR = 0.74 [95% CI: 0.62-0.88] p<0.001

Primary endpoint: Progression Free Survival 2

Cremolini et al, WCGIC ’19 – LBA-007 and ASCO Ann Meeting ‘19

Median follow up = 30.6 mos FOLFOX + bev N = 340

FOLFOXIRI + bev N = 339

Events, N (%) 303 (89%) 291 (86%)

Median 1^stPFS, mos 9.8 12.0

HR = 0.75 [95% CI: 0.63-0.88] p<0.001

1st line FOLFOXIRI/Bev vs FOLFOX/bev

FOLFOX + bev N = 340

FOLFOXIRI + bev

N = 339 p

Response Rate 50% 62% p=0.002

R0 Resection Rate 12% 17% p=0.047

Arm A N = 340

Arm B N = 339

PD events 291 (86%) 272 (80%)

Death before PD 12 (4%) 19 (6%)

Any 2nd-line therapy 86%

(251/291)

81%

(219/272)

2nd line therapy

Cremolini et al, WCGIC ’19 – LBA-007 and ASCO Ann Meeting ‘19

Median follow up = 30.6 mos

Arm A N = 289*

Arm B N = 270*

Events, N (%) 258 (89%) 221 (82%)

Median 2

PFS, mos 5.6 6.2

HR = 0.87 [95%CI: 0.73-1.04] p=0.122

* 2 pts in arm A and 2 pts in arm B died the same day of PD1 and were not included in the 2nd-PFS analysis

2nd line - Progression Free Survival

(Patients alive at the time of PD1)

Arm A N = 340

Arm B N = 339

PFS events 291 (86%) 272 (80%)

Death before PD 12 (4%) 19 (6%)

Any 2nd-line therapy 86%

(251/291)

81%

(219/272)

2nd-line therapy N=251 N=219

FOLFIRI + bev, %

195 (78%) ^{16 (7%)}

FOLFIRI, %

26 (10% ^{) 6 (3%)}

FOLFOXIRI + bev, %

1 (0%) 129 (59%)

FOLFOXIRI, %

0 (0%) 20 (9%)

FOLFOX +/- bev, %

6 (2%) 16 (7%)

Anti-EGFR +/- chemo, %

4 (2%) 9 (4%)

Other, %

19 (8%) 23 (11%)

2nd line therapy

Per Protocol 2nd line - Progression Free Survival

Median follow up = 30.6 mos

FOLFIRI + bev N = 195

FOLFOXIRI + bev N = 129

Events, N (%) 178 (91%) 104 (81%)

Median 2^ndPFS, mos 5.8 6.5

HR = 0.76 [95%CI: 0.60-0.97] p=0.025

FOLFIRI + bev N = 195

FOLFOXIRI + bev

N = 129 p

Response Rate 12% 19% p=0.057

Disease

Control Rate 64% 77% p=0.037

Safety Profiles

1st line

G3/4 adverse events,

% patients

FOLFOX + bev N = 336

FOLFOXIRI + bev

N = 336

p

Nausea 3 6 0.140

Vomiting 2 3 0.419

Diarrhea 5 17 <0.001

Stomatitis 3 5 0.299

Neutropenia 21 50 <0.001

Febrile neutropenia 3 7 0.050

Neurotoxicity 1 2 0.505

Asthenia 6 7 0.633

Hypertension 10 7 0.223

Venous thromboembolism 6 4 0.204

Cremolini et al, WCGIC ’19 – LBA-007 and ASCO Ann Meeting ‘19

Safety Profiles

1st line 2nd line

G3/4 adverse events,

% patients

FOLFOX + bev N = 336

FOLFOXIRI + bev

N = 336

p

FOLFIRI + bev N = 195

FOLFOXIRI + bev

N = 129

p

Nausea 3 6 0.140 3 6 0.263

Vomiting 2 3 0.419 2 3 0.718

Diarrhea 5 17 <0.001 6 9 0.269

Stomatitis 3 5 0.299 3 5 0.356

Neutropenia 21 50 <0.001 24 24 1.000

Febrile neutropenia 3 7 0.050 2 2 0.686

Neurotoxicity 1 2 0.505 0 5 0.004

Asthenia 6 7 0.633 6 8 0.654

Hypertension 10 7 0.223 2 3 0.443

Venous thromboembolism 6 4 0.204 1 1 1.000

Cremolini et al, WCGIC ’19 – LBA-007 and ASCO Ann Meeting ‘19

Median follow up = 30.6 mos

Arm A N = 340

Arm B N = 339

Events, N (%) 217 (64%) 191 (56%)

Median OS, mos 22.6 27.6

HR = 0.81 [95%CI: 0.67-0.98] p=0.033

Overall Survival – preliminary results

FOIB¹ n=57

TRIBE² n=252

OPAL³ n=97

STEAM⁴ n=93

MOMA⁵ n=232*

CHARTA⁶ n=125

QUATTRO⁷ n=69

JACCRO CC- 11⁸ n=62**

TRIBE-2⁹ n=679*

VISNU¹⁰ n=349

Regimen

FOLFOXIRI/

Bev → FU/Bev maintenance

FOLFIRI/B ev +/- Oxa

FOLFOXIRI/

Bev → FU/Bev maintenance

FOLFOXIRI /Bev vs FOLFOX/Be

v

FOLFOXIRI/

Bev

→ Bev ± metroCT

FOLFOX/

Bev

± IRI

FOLFOXIRI/

Bev → FU/Bev maintenance

mFOLFOXIR I/

Bev → FU/Bev maintenance

FOLFOX/Bev +/- iRI

FOLFOX/Bev +/- iRI CTC≥3

Response rate 77% 65% 64% 72% 63% 69% 72% 76% 62% 59%

Disease control

rate ^{100% 90% 87% 91% 91% N/A 99% 97% 91% NA}

Median PFS,

mos ^{13.1 12.3 11.1 11.9 9.4 v 10.3 12.0 13.3 11.5 12.0 12.4}

Median OS,

mos ^{30.9 29.8 32.2 34.0 28 vs 23 28.0} Not reached Not reached 27.6 22.3

1. Masi et al. Lancet Oncol 2010; 2. Cremolini et al. Lancet Oncol 2015 3. Stein et al. Br J Cancer 2015; 4. Hurwitz et al. Oncologist 2018

5. Cremolini et al. EJC 2018; 6. Schmoll et al. ESMO GI 2018 7. Oki et al. Clin Color Cancer 2018; 8. 7. Satake et al. Oncotarget 2018 9. Cremolini et al. ASCO 2019 10. Sastre et al. ASCO 2019

*>70% patients with RAS or BRAF mutation

** only RAS mutant

FOLFOXIRI + bev: consistent efficacy results

Grade 3/4 Adverse Events, %

TRIBE¹ n=252

OPAL² n=97

STEAM³ n=93

MOMA⁴ n=232

CHARTA⁵ n=125

QUATTRO⁶ n=69

JACCRO CC-11⁷

n=62**

TRIBE2⁹ n=679

VISNU⁹ n=349

Diarrhoea 19% 11% 22% 13% 16% 10% 13% 17% 21%

Stomatitis 9% 4% 2% 4% 3% NA 3% 5% 9%

Neutropenia 50% 26% 57% 55% 21% 73% 54% 50% 35%

Hypertension 5% 3% 22% 4% 7% 35% 32% 7% 4%

VTE events 7% 5% 7% 4% 2% 1% NA 4% NA

FOLFOXIRI + bev: consistent safety results

1. Cremolini et al. Lancet Oncol 2015 2. Stein et al. Br J Cancer 2015; 3. Hurwitz et al. Oncologist 2018

4. Cremolini et al. EJC 2018; 5 Schmoll et al. ESMO GI 2018 6. Oki et al. Clin Col Can 2018; 7. Satake et al. Oncotarget 2018 8. Cremolini et al. ASCO 2019 9. Sastre et al. ASCO 2019

Optimizing the use of FOLFOXIRI/bev:

Elderly pts (70-75 ys, PS=0)

Pooled analysis of TRIBE and TRIBE2 (N=1187 pts)

✓ Same magnitude of benefit as younger pts

✓ More chemo-related adverse events independently of chemo- intensity

✓ 27% G3/4 diarrhoea and 16% febrile neutropenia with FOLFOXIRI/bev

✓ Initial reduction of 5FU (2400 mg/sqm) and irinotecan (165 mg/sqm) dose

OR

✓ G-CSF as primary prophylaxis

Marmorino et al, Ann Oncol in press

Optimizing the use of FOLFOXIRI/bev:

Males vs Females

Pooled analysis of TRIBE and TRIBE2 (N=1187 pts)

✓ Same magnitude of benefit independently of gender

✓ Females experience more chemo-related adverse events independently of chemo- intensity (nausea, vomiting, stomatitis, asthenia, alopecia, G3/4 neutropenia, anemia)

✓ ^{68% nausea and} 50% vomiting with FOLFOXIRI/bev

Careful management of the anti-hemetic prophylaxis

Marmorino et al, Ann Oncol in press

AtezoTRIBE trial

R

1:2

mCRC pts 1st line

unresectable

FOLFOXIRI+bev

(up to max 8 cycles)

FOLFOXIRI+bev +atezo

(up to max 8 cycles)

5FU/LV +Bev

5FU/LV +Bev +Atezo

PD

INDUCTION MAINTENANCE

Phase II random

Stratification factors:

• Center

• PS 0 vs 1-2;

• primary tumor location (right vs left or rectum);

• Previous adjuvant CT

Primary endpoint: PFS Target accrual: 201 patients

Ar m A Ar m B

Poor prognosis

Poor sensitivity to available tx

Best choice in 1st line: FOLFOXIRI + bev

BRAF mutant mCRC

Subgroup analyses - clinical characteristics- PFS2

N pts HR Pinteraction

582 97

15 664

346 333 75 604

205 472

0.70 1.13

1.05 0.73

0.68 0.74

0.67 0.79

0.74 0.75

0.59 0.05

0.93 0.75

0.35 HR (95% CI)

 Favours arm B Favours arm A→

0 .1 1 1 0

N o Y e s L i v e r - o n l y d i s e a s e N o Y e s S u r g e r y o n p r i m a r y t u m o u r S y n c h r o n o u s M e ta c h r o n o u s T i m e t o m e t a s t a s e s N o Y e s P r e v i o u s a d j u v a n t t h e r a p y 1 o r 2 0 E C O G P e r f o r m a n c e S t a t u s

Cremolini et al, WCGIC ’19 – LBA-007

0 . 1 1 1 0 L e f t c o lo n a n d R A S a n d B R A F w t a n d / o r E C O G P S 1 - 2

R ig h t c o lo n a n d / o r R A S o r B R A F m u t a n d E C O G P S 0 P r i m a r y t u m o u r s i t e & R A S a n d B R A F s t a t u s & E C O G P S L e f t c o lo n a n d R A S a n d B R A F w t R ig h t c o lo n a n d / o r R A S o r B R A F m u t P r i m a r y t u m o u r s i t e & R A S a n d B R A F s t a t u s M S I- h ig h M S S M i c r o s a t e l l i t e s t a t u s B R A F m u t R A S m u t R A S a n d B R A F w t R A S a n d B R A F s t a t u s L e f t c o lo n o r re c t u m R ig h t c o lo n P r i m a r y t u m o u r s i t e

Subgroup analyses – sidedness and molecular characteristics- PFS2

 Favours arm B Favours arm A→

N pts HR Pinteraction

259 420

0.72 0.74

0.91 HR (95% CI)

144 435 66

0.71 0.70 1.13

0.26

547 109

0.72 0.76

0.84 528

26

0.67 0.85

0.64

470 186

0.68 0.87

0.23

BRAF targeted inhibition

BEACON: study design

66%

Kopetz et al, WCGIC ’19 – LBA006

Primary endpoint: OS

Triplet vs control

Doublet vs control

Triplet vs Doublet

Kopetz et al, WCGIC ’19 – LBA006

Response Rate: 2%

Response Rate: 26% Response Rate: 20%

Co-primary endpoint: Response Rate

Kopetz et al, WCGIC ’19 – LBA006

Triplet vs control Doublet vs control

Secondary endpoint: Progression Free Survival

Kopetz et al, WCGIC ’19 – LBA006

Toxicity profile

Overall G3/4 AEs 58% 50% 61%

Serious AEs 42% 33% 37%

Kopetz et al, WCGIC ’19 – LBA006

Precision medicine in mCRC: we got it!

BRAF V600E mutation:

from negative prognosis to positive prediction

Cetuximab + Encorafenib + Binimetinib: a new standard?

Added value of binimetinib?

BRAF V600E mut and MSI-high (only around 5% in this study vs

“expected” 30% of BRAF mut): what’s next?

Primary endpoint: PFS

Efforts of personalized medicine in mCRC

Pietrantonio et al, WCGIC ’19 – O025

CAPTEM: outcome results

Overall survival Progression free survival

Response Rate

Pietrantonio et al, WCGIC ’19 – O025

CAPTEM: outcome results according to MGMT IHC

Pietrantonio et al, WCGIC ’19 – O025

Alkylating agents in mCRC

MGMT methylation MGMT methylation +

immunohistochemistry

Later lines of tx: Which is the best option?

Phase III options

Regorafenib Trifluridine/

Tipiracil

Regorafenib dose optimization: REARRANGE

Argiles et al, WCGIC ’19 – O026

Overall survival

Progression free survival

REARRANGE : no impaired survival with the escalating approach

Argiles et al, WCGIC ’19 – O026

Regorafenib dose optimization: ReDOS

Bekaii-Saab et al, Lancet Oncol ‘19

Overall survival Progression free survival

9.8 6.0

HR=0.72, p=0.12 HR=0.84, p=0.38

2.0 2.8

Bekaii-Saab et al, Lancet Oncol ‘19

ReDOS : no impaired survival with the escalating approach

Regorafenib flexible dosing?

• To improve compliance to the treatment

• To reduce the incidence of adverse events

• To preserve patients’ quality of life in a palliative setting

…without impairing treatment efficacy

REGONIVO: study design

Hara et al, WCGIC ‘19 – SO-007 Fukuoka et al, ASCO Ann Meeting ‘19

Colorectal cohort: signals of activity

Hara et al, WCGIC ‘19 – SO-007 Fukuoka et al, ASCO Ann Meeting ‘19

Safety profile

Hara et al, WCGIC ‘19 – SO-007 Fukuoka et al, ASCO Ann Meeting ‘19

Two inactive drugs

become active when

combined together?

Hoff et al, ESMO Meeting ‘17

Why?

Regorafenib is able to reduce/reprogramme tumor-associated macrophages with immunosuppressive effect (Treg)

Fukuoka et al, ASCO Ann Meeting ‘19

Later lines of tx: Which is the best option?

Phase III options

Regorafenib Trifluridine/

Tipiracil

Primary endpoint: Progression Free Survival

Danish Lonsurf trial: study design

Pfeiffer et al, WCGIC ‘19 – O-014

Danish Lonsurf trial: outcomes

Response Rate: 0% vs 2%

Disease Control: 51% vs 67%

Progression Free Survival

Overall Survival

Pfeiffer et al, WCGIC ‘19 – O-014

Vs. TASCO1 (1st-line) Response Rate 34%

Disease Control Rate 86%

Danish Lonsurf trial: safety

Pfeiffer et al, WCGIC ‘19 – O-014

Take home messages

Do not give up!

Targets matter (also in mCRC)

Hit hard in first-line

Be flexible in later lines

Thank you!