Gli studi clinici
Alberto Zaniboni
Oncologia Medica
Fondazione Poliambulanza - Brescia
Quali novità
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)
Trifluridine/tipira
cil
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
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
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
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)
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)
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
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
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
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)
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
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
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
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
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
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
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
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.
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
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
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
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
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.
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
Risposta alla terapia con TAS-102 nel tumore del colon retto avanzato
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
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
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
An overview of
trifluridine/tipiracil clinical data
Eric Van Cutsem, MD, PhD
Leuven, Belgium
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
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)