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Gli studi clinici

Alberto Zaniboni

Oncologia Medica

Fondazione Poliambulanza - Brescia

Quali novità

(2)

It is a continuing source of humility to all of us who spend time trying to come up

with better, newer therapies for colorectal cancer that 5-fluorouracil (5-FU), an agent patented in 1957, remains at the center of

most colorectal regimens, and remains

arguably the single most active and important agent in the treatment of this disease.

Previous attempts to replace it with newer cytotoxics, such as irinotecan or oxali-

platin, have failed.

(L SALTZ 2008)

(3)

Trifluridine/tipira

cil

(4)

Japan May 2014 FDA September 2015 EMA April 2016

Change the story of pre-treated mCRC

LONSURF

®

(trifluridine/tipiracil) is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been

previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan based

chemotherapies, anti-VEGF agents, and anti-EGFR agents (EMA SmPC)

Trifluridine/tipiracil Summary of Product Characteristics.

LONSURF

®

approved

(5)

Trifluridine/tipiracil is a new treatment option for pre-treated mCRC patients

• Approval of trifluridine/tipiracil in Europe was based on the strength of the Phase 3 RECOURSE study

1

‒ Initiation of RECOURSE was based on the results from a Phase 2 Japanese registration study

2

• Trifluridine/tipiracil is a new treatment option

‒ Now included in these guidelines:

• ESMO (New)

3

• NICE

4

• NCCN (USA)

5

• Japanese (in process)

1. Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919;

2. Yoshino T, et al. Lancet Oncol. 2012;13:993-1001;

3. ESMO guidelines. Ann Oncol. 2016;27:1386–422 4. www.pathways.nice.org.uk/pathways/colorectal-cancer/

5. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site

(6)

Endpoints

• Primary: OS

• Secondary: PFS, TTF, DCR, RR, DOR, Safety, KRAS status treatment effect

Phase II Japanese registration study

BID = twice daily; BSC = best supportive care; DCR = disease control rate;

DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; OS = overall survival; PFS = progression free survival; PO = per os;

q4w = every 4 weeks; RR = response rate; TTF = time to treatment failure Yoshino T, et al. Lancet Oncol. 2012;13:993-1001.

R A N D O M I Z A T I O N

Trifluridine+tipiracil  + BSC

(N=113)

35 mg/m2BID PO D1–5, 8–12 q4w

Placebo + BSC (N=57)

D1–5, 8–12 q4w

mCRC

Patients refractory to 2 or more prior regimens

Refractory/intolerable

Fluoropyrimidine

Irinotecan

Oxaliplatin

ECOG PS 0–2

Age ≥20

Patients randomized, N=172

2:1

(7)

Japanese Phase II study: Overall survival

CI = confidence interval; HR = hazard ratio

Yoshino T, et al. Lancet Oncol. 2012;13:993-1001.

Survival distribution function

Months from randomization

0 3 6 9 12 15 18

0 0.5 1.0

57 46 31 18 4 1

112 104 77 55 23 6

Trifluridine/tipiracil No. at Risk:

Placebo

Trifluridine/tipiracil (N=112)

Placebo (N=57)

Median OS (months) 9.0 6.6

Stratified log-rank test: p=0.0011 HR: 0.56, 95% CI [0.39, 0.81]

44% reduction in the risk of death (HR 0.56)

(8)

Japanese Phase II study: Progression free survival (by independent assessment)

Yoshino T, et al. Lancet Oncol. 2012;13:993-1001.

Survival distribution function

Months from randomization

0 3 6 9 12 15 18

0 0.5 1.0

57 4 1 0 0

112 31 17 4 1

Trifluridine/tipiracil No. at Risk:

Placebo

Trifluridine/tipiracil (N=112)

Placebo (N=57)

Median OS (months) 2.0 1.0

Stratified log-rank test: p<0.0001 HR: 0.41, 95% CI [0.28, 0.59]

59% increase in preservation of PFS (HR 0.41)

(9)

0%

10%

20%

30%

40%

50%

60%

Trifluridine/tipiracil Placebo p<0.0001

Response rate

Japanese Phase II study: Overall response rate and disease control rate, by independent assessment

CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease; RR = response rate.

Disease control rate = CR+PR+SD more than 6 weeks from initiation of treatment Yoshino T, et al. Lancet Oncol. 2012;13:993-1001

Disease control rate

43.8%

10.5%

Placebo Trifluridine/tipiracil

Trifluridine/ tipiracil (N=112) %

Placebo (N=57) %

CR 0 0

PR 0.9 0

SD 42.9 10.5

PD 47.3 77.2

NE 8.9 12.3

RR (%) 0.9 0.0

(10)

Japanese Phase II study: Adverse events with frequency of ≥3%

Yoshino T, et al. Lancet Oncol. 2012;13(10):993-1001

Trifluridine/tipiracil N=113

Placebo N=57 Any Grade %

Grade

3 or 4, % Any Grade %

Grade

3 or 4, % P value Hematological

Neutropenia 72 50 2 0 <0.0001

Leukopenia 76 28 4 0 <0.0001

Anemia 73 17 16 5 <0.0001

Lymphopenia 35 10 12 4 0.0019

Thrombocytopenia 39 4 2 0 <0.0001

Non-hematological

Fatigue 58 6 42 4 0.052

Diarrhea 38 6 21 0 0.037

Nausea 65 4 28 0 <0.0001

Anorexia 62 4 33 4 0.0006

Febrile neutropenia 4 4 0 0 0.170

Vomiting 34 4 25 0 0.290

(11)

Japanese Phase II study: Conclusions

• In pre-treated mCRC patients, trifluridine/tipiracil provided the following benefits versus placebo:

‒ Significant improvement in OS (HR 0.56)

‒ Significant improvement in PFS (HR 0.41)

‒ 44% vs 11% of patients achieved disease control

• The promising results observed in this Phase II Japanese study were the basis of the global RECOURSE Phase III trial

Yoshino T, et al. Lancet Oncol. 2012;13(10):93-1001

(12)

RECOURSE: Refractory colorectal cancer study

• Multicentre, randomized, double-blind, placebo-controlled, Phase 3 study

‒ Stratification: KRAS status, time from diagnosis of metastatic disease, geographical region

• Treatment continuation until progression, intolerant toxicity or patient refusal

• Sites: 13 countries, 101 sites

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919.

mCRC

Patients previously received 2 or more prior regimens Refractory / intolerable to

Fluoropyrimidine Irinotecan

Oxaliplatin Bevacizumab

Anti-EGFR if wild-type KRAS

Known KRAS status

ECOG PS 0-1

Adequate bone marrow and organ function

2:1

R A N D O M I Z A T I O N

Trifluridine/tipiracil + BSC

(N=534)

35 mg/m2BID PO d1–5, 8–12 q4w

Placebo + BSC (N=266)

BID PO d1–5, 8–12 q4w

Endpoints

Primary: OS

Secondary: PFS, Safety, Tolerability, Time to ECOG PS≥2, ORR, DCR, DoR, Subgroup by KRAS (OS and PFS)

(13)

RECOURSE: Baseline demographics and disease characteristics

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919.

Trifluridine/tipiracil (N=534)

Placebo (N=266)

Age in years, median (range) 63 (27–82) 63 (27–82)

Gender, % Male 61 62

Race, % White

Asian Black

57 34

<1

58 35 2

Geographic region, % Japan

US, Europe, Australia

33 67

33 67

ECOG PS, % 0

1

56 44

55 45

Primary site, % Colon

Rectum

63 37

61 39

KRAS mutational status, % Wild-type

Mutant

49 51

49 51

Time since diagnosis of metastasis,% <18 months

≥18 months

21 79

21 79

Number of prior regimens % 2

3

≥4

18 22 60

17 20 63 All prior systemic cancer therapeutic agents, % Fluoropyrimidine

Irinotecan Oxaliplatin Bevacizumab Anti-EGFR mAntibody

Regorafenib

100 100 100 100 52 17

100 100 100

>99 54 20

Refractory to fluoropyrimidine (as part of any prior regimen), % 98 >99

(14)

RECOURSE: Overall survival

*Analysis conducted after 574 events

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919.

Survival distribution function

Months from randomization

0 3 6 9 12 15 18

0 0.5 1.0

266 198 107 47 24

534 459 294 137 64

Trifluridine/tipiracil No. at Risk:

Placebo

Trifluridine/tipiracil (N=534)

Placebo (N=266)

Median OS (months)* 7.1 5.3

Stratified log-rank test: p<0.0001 HR: 0.68, 95% CI [0.58, 0.81]

Alive at 12 months, % 27 18

• 32% reduction in the risk of death (HR 0.68)

• Improved 1 year survival rate vs. placebo (27% vs. 18%)

23 7

9 3

(15)

RECOURSE: Updated overall survival

Carried out at 89% of events (138 additional events) Cut off October 8th, 2014: 712 events Mayer R, et al. ASCO GI 2016 Abstract 634

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Survival distribution function

Months from randomization 0

50 100

Trifluridine/tipiracil No. at Risk:

Placebo

Trifluridine/tipiracil (N=534)

Placebo (N=266)

Median OS (months) 7.2 5.2

Stratified log-rank test: p<0.0001 HR: 0.69, 95% CI [0.59, 0.81]

Alive at 12 months, % 27 17

• 2-month improvement in median OS and 31% reduction in risk of death (HR 0.69)

• Improvement in 1 year survival was maintained in this updated analysis

266 232 163 114 71 56 43 27 16 14 8 6 4 1 0

534 499 406 308 231 180 137 95 59 38 20 14 10 4 0

(16)

RECOURSE: OS subgroup analyses

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919.

Subgroup Favours trifluridine/tipiracil Favours placebo Events / N HR (95% CI)

All patients 574 / 800 0.68 (0.58-0.81)

KRAS status Wild type Mutant

280 / 393 294 / 407

0.58 0.80

(0.45-0.74) (0.63-1.02) Time since diagnosis of first metastasis

<18 months

≥18 months 131 / 166

443 / 634

0.84 0.64

(0.58-1.21) (0.53-0.78) Geographic region

Japan

US, Europe & Australia

227 / 266 347 / 534

0.75 0.64

(0.57-1.00) (0.52-0.80) Age

<65 years

≥65 years

316 / 448 258 / 352

0.74 0.62

(0.59-0.94) (0.48-0.80) Gender

Male Female

348 / 491 226 / 309

0.69 0.68

(0.56-0.87) (0.51-0.90) ECOG performance status

0 1

298 / 448 276 / 352

0.73 0.61

(0.58-0.93) (0.48-0.79) Primary tumor site

Colon Rectum

361 / 499 213 / 301

0.68 0.64

(0.55-0.85) (0.48-0.85) Number of prior regimens

2 3

≥4

106 / 140 137 / 173 331 / 487

1.05 0.74 0.59

(0.68-1.63) (0.51-1.08) (0.47-0.73) Prior use of regorafenib

Yes No

94 / 144 480 / 656

0.69 0.69

(0.45-1.05) (0.57-0.83) Refractory to fluoropyrimidine

part of last prior regimen 329 / 455 0.75 (0.59-0.94)

0.3 0.5 1 2.0

Hazard ratio: Trifluridine/tipiracilvs. placebo (95% CI)

Most patients benefit from trifluridine/tipiracil treatment

(17)

RECOURSE: PFS

CT scan performed every 8 weeks from month 2

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919.

0 2 4 6 8 10 12 14 16

47.3%

20.8%

Progression-free distribution function

Months from randomization 0

50 100

Trifluridine/tipiracil No. at Risk:

Placebo

Trifluridine/tipiracil (N=534)

Placebo (N=266)

Median PFS (months) 2.0 1.7

Stratified log-rank test: p<0.001 HR: 0.48, 95% CI [0.41, 0.57]

52% reduction in risk of progression (HR 0.48)

266 51 10 2 2 2 1 1 0

534 238 121 66 30 18 5 4 2

(18)

RECOURSE: Overall response rate and disease control rate

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919.

Significant improvement in disease control achieved

0%

10%

20%

30%

40%

50%

60%

Trifluridine/tipiracil Placebo p<0.001

Response rate Disease control rate

44%

16%

Placebo Trifluridine/tipiracil

Trifluridine/tipiracil (N=112) %

Placebo (N=57) %

CR 0 0

PR 1.6 0

SD 42.4 15.9

ORR (%) 1.6 0.4

(19)

RECOURSE: Time to ECOG Performance Status ≥2

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919.

Trifluridine/tipiracil (N=534)

Placebo (N=266)

Median PFS (months) 5.7 4.0

Stratified log-rank test: p<0.001 HR: 0.66, 95% CI [0.56, 0.78]

Patients stay in PS 0–1 significantly longer (5.7 vs. 4.0 months)

% with ECOG performance status <2

Months from randomization

0 3 6 9 12 15 18

0 50 100

266 134 57 21 11

534 352 188 84 28

Trifluridine/tipiracil No. at Risk:

Placebo

7 0

3 1

(20)

Additional systemic therapy

• 42% of patients in each group received further systemic therapy after the trial

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919.

(21)

RECOURSE: Frequency of adverse events

Per NCI CTCAE version 4.03

aAdverse events of any grade that occurred in ≥10% of patients in the trifluridine/tipiracil group and in a greater percentage in that group than in the placebo group.

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919.

Event, %

Trifluridine/tipiracil (N=533)

Placebo (N=265)

Any Grade Grade ≥3 Any Grade Grade ≥3

Any event, % 98 69 93 52

Any serious event, % 30 34

Most common eventsa, %

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

(22)

RECOURSE: Adverse events of special interest*

*as-treated population

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919; Data on File.

Event, %

Trifluridine/tipiracil (N=533)

Placebo (N=265)

Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 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

Proteinuria 4.1 0 0 1.9 0 0

Cardiac ischemia 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

(23)

RECOURSE: Frequency of laboratory abnormalities

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919; Data on File.

Laboratory abnormalities, %

Trifluridine/tipiracil (N=533)

Placebo (N=265)

Any Grade Grade ≥3 Any Grade Grade ≥3

Neutropenia 67 38 <1 0

Leukopenia 77 21 5 0

Anemia 77 18 33 3

Thrombocytopenia 42 5 8 <1

Increases 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

(24)

RECOURSE: Overview of adverse events and dosing modifications

• 4% of the patients receiving trifluridine/tipiracil and 2% of the patients receiving placebo had to withdraw due to adverse events

• 86% of patients taking trifluridine/tipiracil did not require a dose reduction

• 53% of patients treated with trifluridine/tipiracil tablets had a dose delay

(25)

RECOURSE: Summary

• Compared with placebo, trifluridine/tipiracil demonstrated a clinically meaningful and statistically significant improvement in:

• OS – 32% reduction in risk of death (HR 0.68)

• Updated OS – median OS 2-month improvement vs. placebo

• 1 year survival rate – improvement vs. placebo (27% vs.18%)

• PFS – 52% reduction in the risk of progression (HR 0.48)

• Disease control rate improved (44% Trifluridine/tipiracil vs 16% placebo)

• ECOG PS – patients stay in PS 0–1 significantly longer (5.7 vs. 4.0 months)

• Trifluridine/tipiracil has an acceptable toxicity profile, with low

discontinuation rates due to AEs (4%), and 42% of patients were able to receive an additional line of therapy

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919.

(26)

Conclusion

Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:1909-1919.

Yoshino T, et al. Lancet Oncol. 2012;13(10):993-1001.

In two large randomized trials, trifluridine/tipiracil demonstrated a clinically meaningful and statistically significant improvement in OS and PFS compared with

placebo in pre-treated mCRC patients

(27)
(28)
(29)
(30)
(31)
(32)
(33)
(34)

Risposta alla terapia con TAS-102 nel tumore del colon retto avanzato

(35)

35

Study Design Indication Phase Number of

patients Timing

1st-line Non-intensive TAS-102/Bev vs. Cap/Bev

CRC RP2 150 Start: April 2016

Expected end: Q3 2018

2nd-line TAS-102/Oxali/Bev CRC P1 DE +36Exp Start: April 2016

Expected end: Dec 2016

TAS-102, 2nd-line: TAS-102/CPT- 11/Bev

CRC P1 36 Start: Q1 2015

Expected end: Jan 2016

2nd-line: CPT-11 combination or Oxali combination

(study design: to be determined)

CRC P3 800 TBD

Current clinical development plan in mCRC

CRC: ColoRectal Cancer

DE+Exp: Dose Escalation plus EXPansion Cohort

(36)

36

Study Design Indication Phase Number of

patients Timing

3rd/4th-line: TAS-102 vs.

Placebo GC P3 500 Start: Dec 2015

Expected end: Q1 2018

TAS-102 Safety confirmation (hepatic

impairment)

Solid tumor P1 32 Start: Q1 2015

Expected end: Q1 2018

TAS-102 safety

confirmation (renal impairment) Solid tumor P1 48 Start: Q1 2015

Expected end: Q2 2017

Current clinical development plan other than mCRC

CRC: ColoRectal Cancer GC: Gastric Cancer

(37)

caratteristiche popolazione (28pt)

età mediana (anni) 58

femmine

10 (36%) maschi

18 (64%)

localizzazione primitivo pt

colon dx 9

colon sx 14

colon trasverso 1

retto 4

stato mutazionale RAS mutato

19 (67%)

RAS wt 9 (33%)

secondarismi pt

fegato 22

polmone 13

osso 2

peritoneo 9

linfonodi 13

snc 0

>=3 sedi 7

trattamenti pregressi pt

5FU 28

oxaliplatino 28

cpt11 27

erbitux/panitumumab 9

bevacizumab 23

aflibercept 2

regorafenib 18

TAS-102

linea di terapia (mediana)

4 (range 2- 4)

numero di cicli (mediana)

2 (range 1- 8)

riduzioni di

dosaggio 6pt (21%)

risposte

PD 19 (67%)

SD 5 (19%)

RP 0 (0%)

non riv 4 (14%)

sopravvivenza

PFS (mo) 2,1

OS (mo) 3,2

(38)

An overview of

trifluridine/tipiracil clinical data

Eric Van Cutsem, MD, PhD

Leuven, Belgium

(39)

Trifluridine/tipiracil: Studies in progress

Indication Treatment Phase Study status

mCRC, 1L Trifluridine/tipiracil + bevacizumab vs capecitabine + bevacizumab

Randomized Phase II In progress

mCRC, 2L Trifluridine/tipiracil + oxaliplatin + bevacizumab

Phase I In progress

mCRC, 2L Trifluridine/tipiracil + irinotecan + bevacizumab

Phase I In progress

Metastatic gastric cancer, 3/4L

Trifluridine/tipiracil vs placebo Phase III In progress

(40)

LONSURF®

A convenient oral dosing

• LONSURF

®

should be prescribed by physicians experienced in the

administration of anticancer therapy

• The dose is 35 mg/m

2

/dose twice daily

• Tablets are available in two strengths:

LONSURF®Summary of Product Characteristics

To be taken with a glass of water within 1 hour after completion of morning and evening meals

LONSURF® is administered over a 4-week cycle (28 days)

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