Le prospettive nella ricerca

(1)

DALLA CAPECITABINA AL TAS 102

Milano 29 settembre 2016

LE PROSPETTIVE NELLA RICERCA Armando Santoro

Humanitas Cancer Center

(2)

THE 1 ° _,2 ° _{…….AND ≥ 3} ° LINE CHEMOTHERAPY IN CRC M+

FOLFOX FOLFIRI FOLFOXIRI

XELOX XELIRI BEVACIZUMAB

AFLIBERCET

CETUXIMAB

PANITUMUMAB

RAS wt RAS wt

RAS mu

…………..and after

(3)

Randomized Trial of TAS-102 for Refractory

Metastatic Colorectal Cancer

(4)

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

•TAS-102 combines Trifluridine, a nucleoside analogue which is incorporated into DNA and disrupts DNA synthesis and inhibits thymidylate synthetase

and the Thymidine

Phosphorylase inhibitor, Tipiracil that prevents the degradation of Trifluridine

•TAS-102 improved OS and PFS

in patients whose disease had

progressed after treatment with

fluorouracil-based combinations

(5)

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

Baseline Characteristics of the ITT Population

TAS-102 N=534

Placebo N=266 Primary site, % Colon

Rectum

63 37

61 39 KRAS mutational Wild-type

status, % Mutant

49 51

49 51 Time since diagnosis <18 months

of metastasis, % ≥18 months

21 79

21 79 Number of prior 2

regimens % 3

≥4

18 22 60

17 20 63 All prior systemic Fluoropyrimidine

cancer therapeutic Irinotecan agents, % Oxaliplatin

Bevacizumab

Anti-EGFR mAntibody Regorafenib

100 100 100 100 52 17

100 100 100

>99

54

20

(6)

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

100

0

0 2 4 6 8 10 12

Months from randomisation

Progress io n- free su rviv al

90

80

70

60 50

40

30

20

10

14 16

RECOURSE TAS -102

n = 534

Placebo n = 266

Median PFS, months 2.0 1.7

HR (95% CI) 0.48 (0.41-0.57)

Stratified log-rank

test: <0.001

(7)

Randomized Trial of TAS-102 for Refractory

Metastatic Colorectal Cancer

(8)

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

Time to ECOG Performance Status of 2 or Higher.

100

0

0 3 6 9 12 15

Months from randomisation

% with ECOG performanc e st atus <2

⁹⁰

80

70

60

50

40

30

20

10

18

n = 534

Placebo n = 266

Events # (%) 383 (72) 216 (81)

Median, months 5.7 4.0

HR (95% CI) 0.66 (0.56-0.78)

Stratified log-rank test: <0.001

(9)

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

O verall Surviv al %

TAS-102

Placebo

n = 534

Placebo n = 266

Median OS, months 7.1 5.3

HR (95% CI) 0.68 (0.51-0.84

P value .001

(10)

Randomized Trial of TAS-102 for Refractory

Metastatic Colorectal Cancer

(11)

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

Frequency of Adverse Events

Event TAS-102 (N=533) Placebo (N=265)

Any Gr. Gr. ≥3 Any Gr. Gr. ≥3

Any event, % 98 69 93 52

Any serious event, % 30 34

Most common events

^a

, %

Nausea 48 2 24 1

Vomiting 28 2 14 <1

Decreased appetite 39 4 29 5

Fatigue 35 4 23 6

Diarrhea 32 3 12 <1

Abdominal pain 21 2 18 4

Fever 19 1 14 <1

Asthenia 18 3 11 3

• AEs primary reason for discontinuation in 3.6% TAS-102 and 1.5% placebo treated patients

• Dose reductions due to AEs occurred in 14% of patients in the TAS-102 arm

(12)

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

Events TAS-102 (N=533) Placebo (N=265)

All Gr. Gr. 3 Gr. 4 All Gr. Gr. 3 Gr. 4

Febrile neutropenia 3.8 2.8 0.9 0 0 0

Stomatitis 7.9 0.4 0 6.0 0 0

Hand-foot syndrome 2.3 0 0 2.3 0 0

Alopecia 6.8 0 0 1.1 0 0

Proteinurea 4.1 0 0 1.9 0 0

Cardiac ischaemia events, % 0.4 0.2 0 0.4 0 0.4

Thromboembolic events, % 3.9 1.7 0.2 2.3 1.1 0.4

Pulmonary embolism 1.7 1.3 0.2 0 0 0

Adverse Events of Special Interest

(13)

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

Adverse Events of Special Interest

Event TAS-102 (N=533) Placebo (N=265)

Any Gr. Gr. ≥3 Any Gr. Gr. ≥3

Laboratory abnormalities^a, %

Neutropenia 67 38 <1 0

Leukopenia 77 21 5 0

Anemia 77 18 33 3

Thrombocytopenia 42 5 8 <1

Increase in alanine aminotransferase 24 2 27 4

Increase in aspartate aminotransferase 30 4 35 6

Increase in total bilirubin 36 9 26 12

Increase in alkaline phosphatase 39 8 45 11

Increase in creatinine 13 <1 12 <1

• Bone marrow toxicities higher in TAS-102 group as expected

• 9% of patients in the TAS-102 group received granulocyte colony-stimulating factor

(14)

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

• TAS-102 vs placebo was significantly better in:

OS PFS

across essentially all stratification factors and predefined subgroups

• A statistically significant prolongation of time to ECOG PS ≥2 was observed

• TAS-102 has an acceptable toxicity profile

The most frequently observed toxicities were gastrointestinal and hematologic; rate of febrile neutropenia was 3.8%

Conclusions

(15)

CORRECT Regorafenib n = 505

Placebo n = 255

Median OS, months 6,4 5,0

HR (95% CI) 0.77 (0.64–0.94)

P value .0052

CONCUR Regorafenib

n = 136

Placebo n = 68

Median OS, months 8,8 6,3

HR (95% CI) 0.55 (0.39-0.76)

P value .0002 (1-sidded)

CONCUR

²

CORRECT

¹

45% reduction in the risk of death

0 300 400 500 600 200

100 1,0

0,6 0,4 Ov erall Su rviv al % 0,2

0 0,8

Regorafenib 160 mg + BSC Placebo + BSC

Days Since Randomization 0

6 8 10 14

4 2 12

100 75 50 Ov erall Surv iva l % 25

23% reduction in the risk of death

0 REGORAFENIB: PHASE 3 TRIALS

(16)

0 6 8 10 12

4 2

1,00 0,75 0,50 PF S Prob ab ilit y 0,25

51% reduction in risk of progression or death

0 CORRECT

¹

Time from Randomization, months

CONCUR

²

69% reduction in risk of progression or death

0,00

300 400 500

200 100

1,00

0,50 PF S prob ab ilit y 0,25

0 0,75

CORRECT Regorafenib

n = 505

Placebo n = 255

Median PFS, months 1,9 1,7

HR (95% CI) 0.49 (0.42 – 0.58)

P value <.0001

CONCUR Regorafenib

n = 136

Placebo n = 68

Median PFS, months 3,2 1,7

HR (95% CI) 0.31 (0.22 ‒ 0.43)

P value <.0001 (1-sided)

REGORAFENIB: PHASE 3 TRIALS

(17)

Trial Therapy RR PFS (mo) OS (mo)

Yoshino Lancet Onc 2012

phase II

Pl + BSC TAS-102+BSC

n=169

– 0% vs 1%

 1.0 vs 2.0

HR 0.41 (central assessment)

 6.6 vs 9.0

HR 0.56

Van Cutsem RECOURSE, ESMO 2014

Pl + BSC TAS-102+BSC

n=800

–

0.4% vs 1.6%

 1.7 vs 2.0

HR 0.48;

 5.3 vs 7.1

HR 0.68

Grothey, CORRECT Lancet 2013

BSC Regorafenib

n=753

– 0% vs 1%

 1.7 vs 1.9

HR 0.49

 5.0 vs 6.4

HR 0.77

Li, CONCUR ESMO-GI 2014

BSC Regorafenib

n=204

0% vs 4.4%

 1.7 vs 3.2

HR 0.31

 6.3 vs 8.8

HR 0.55

NEW DRUGS IN CHEMORESISTANT MCRC

(18)

Pro e contro di lonsurf vs regorafenib

TAS-102 2

New dilemma in CRC treatment: how to use and

sequence TAS-102 and regorafenib?

(19)

New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib?

Patient selection is crucial

Trial Therapy RR

Mayer, N Eng J Med 2015 BSC vs TAS-102

0.4% vs 1.6%

Grothey, Lancet 2013 BSC vs Regorafenib 0% vs 1%

Li, Lancet Oncol, 2015 BSC vs Regorafenib 0% vs 4.4%

Patients with poor performance status and rapidly progressive disease are

less likely to benefit from both drugs

(20)

New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib?

Patient selection is crucial

• Significant improvements in OS in pts ≥65y receveing TAS-102 vs placebo (7.0 vs 4.6 m, P=0.0002).

• PFS HR was 0.41 for pts ≥65y, favoring TAS-102 (P<0.0001). I

• In pts ≥65y, DCR was 48.7% with TAS-102 vs 15.5%.

• An age-related difference in overall incidence of AEs wasn’t observed in either

(21)

New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib?

Patient selection according to AE

(22)

New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib?

Patient selection according to AE

•TAS-102 is not catabolized by DPD, with consequently reduced formation of FBAL and other cardiotoxic 5FU catabolites (F-citrate)

•TAS- 102, may represent a drug of choice for patients with known cardiac disease.

Cardiotoxicity of capecitabine, 5-Fuoruracile, TAS 102 and S1

(23)

New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib?

Patient selection according to prior therapy

RECOURSE trial TAS-102

N=534

Placebo N=266

All prior systemic Fluoropyrimidine cancer therapeutic Irinotecan

agents, % Oxaliplatin Bevacizumab

Anti-EGFR mAntibody Regorafenib

100 100 100 100 52 17

100 100 100

>99 54 20

• During patient accrual into the RECOURSE study, regorafenib became available: the clinical benefit associated with TAS-102 was maintained regardless of prior treatment with regorafenib

• Although both agents have an OS benefit, in clinical practice oncologists

often fail to incorporate them into treatment in favor of recycling prior lines of

chemotherapy or other unproven approaches.

(24)

New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib?

Perspectives …and challenges

• The favorable toxicity profile of TAS 102 makes it an ideal partner for combination with:

• Irinotecan [Doi T, et al. Phase I study of TAS-102 and irinotecan combination therapy in Japanese patients. Invest New Drugs. 2015 ]

• Oxaliplatin [Nukatsuka M, et al. Efficacy of combination chemotherapy using, TAS-102, with oxaliplatin on human colorectal and gastric cancer xenografts.

Anticancer Res. 2015 ]

• Targeted agents [Kuboki Y, et al. An investigator initiated multicenter phase I/II study of TAS-102 with bevacizumab for metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE). J Clin Oncol. 2015]

• Indeed, a number of trials are ongoing, evaluating the role of TAS-102

in earlier lines of therapy, and in the maintenance and/or second line

settings

(25)

ONGOING CLINICAL TRIALS OF TAS-102 IN mCRC

Trial Identifier Phase I Study of TAS-102 and Radioembolization With 90Y Resin Microspheres for Chemo-

Refractory Colorectal Liver Metastases

NCT02602327

Phase I/II Study for the Safety and Efficacy of Panitumumab in Combination With TAS-102 for Patients With RAS Wild-Type Metastatic Colorectal Cancer Refractory to Standard

Chemotherapy (APOLLON

NCT02613221

An Open-Label, Multi-Center, Phase 2 Study of Switch Maintenance With TAS-102 Plus

Bevacizumab Following Oxaliplatin or Irinotecan-Based Fluoropyrimidine-Containing Induction Chemotherapy in Patients With Metastatic Colorectal Cancer (ALEXANDRIA)

NCT02654639

Randomized, Double-Blind, Phase III Study of TAS-102 Versus Placebo in Asian Patients With

Metastatic Colorectal Cancer refractory or Intolerable to Standard Chemotherapies (TERRA)

NCT01955837

A Phase I Study of SGI-110 Combined With Irinotecan Followed by Randomized Phase II Study of SGI-110 Combined With Irinotecan Versus Regorafenib or TAS-102 in Previously Treated Metastatic Colorectal Cancer Patients

NCT01896856

A Multicenter Phase 1/2 Trial of TAS-102 With Bevacizumab for Metastatic Colorectal Cancer

Refractory to Standard Therapies (C-TASK FORCE

UMIN000012883

Multicenter Phase 1b/2 Trial of Nintedanib With TAS-102 in Patients With Metastatic Colorectal Cancer (mCRC) Who Had Progression on or Were Intolerant to Standard Therapies (N-TASK FORCE)

UMIN000017114

Randomized Phase II Study of Regorafenib Followed by Cetuximab versus Reverse Sequence for Wild-Type KRAS Metastatic Colorectal Cancer Previously Treated with Fluoropyrimidine, Oxaliplatin, and Irinotecan (REVERECE

UMIN000011294

A Phase I/II Study for the Safety and Efficacy of Panitumumab in Combination With TAS-102 for Patients With Wild-Type Metastatic Colorectal Cancer Refractory to Standard Chemotherapy (APOLLON

UMIN000019876

(26)

Le prospettive nella ricerca

DALLA CAPECITABINA AL TAS 102

Milano 29 settembre 2016