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Prof Filippo de BraudFondazione IRCCS Istituto Naz Tumori Milano

Università di Milano

Wilson, P. M. et al. Nat. Rev. Clin. Oncol. 2014Courtesy Drssa Troiani

Wilson, P. M. et al. Nat. Rev. Clin. Oncol. 2014Courtesy Drssa Troiani

• TAS-102 is a combination of thethymidine analog trifluridine (FTD) andtipiracil. Tipiracil, a thymidinephosphorylase inhibitor, improves FTDbioavailability.

•Compared with 5-fluorouracil (5-FU),TAS-102 has a distinct mechanism ofaction and metabolism.

• TAS-102 has demonstrated efficacy in 5-FU-refractory cancers.

Mechanism of action matters

Lenz et al, Cancer Treat Rev 2015

Utsugi et al, JJCO 2013

Preclinical activity

Attività

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/m2 BID 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: 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/m2 BID 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)

Courtesy Dr Zaniboni

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 6 12 282 4 8 10 14 16 18 20 22 24 26

Su

rviv

al

dis

trib

uti

on

fu

nc

tio

n

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<0.0001HR: 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 01232 163 114 71 56 43 27 16 14 8 6 4534 04499 406 308 231 180 137 95 59 38 20 14 10

Courtesy Dr Zaniboni

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 1612 14

47.3%

20.8%

Pro

gre

ss

ion

-fre

e d

istr

ibu

tio

n f

un

cti

on

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<0.001HR: 0.48, 95% CI [0.41, 0.57]

52% reduction in risk of progression (HR 0.48)

266 51 10 2 2 1 012534 238 121 66 18 5 2430

Courtesy Dr Zaniboni

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/tipiracil vs. placebo (95% CI)

Most patients benefit from trifluridine/tipiracil treatment

Courtesy Dr Zaniboni

Results of the registrative trial of TAS-102 in mCRC

Mayer RJ et al., NEJM, 2015 & Mayer RJ et al., ASCO GI 2016 (abs #634)

Medication

Trial name

Setting Primary

outcome

PFScontrol

PFS gain

PFS HR OS control

OS gain OS HR

TAS-102vs placebo

RECOURSE

Third-line or beyondmetastatic

OS 1.7months

0.3 months

0.48(0.41-0.57)

5.3 months

1.8 months

0.68 (0.58–0.81)

A B

HR 0.68 (95%CI 0.58-0.81) <0.0001

HR 0.69 (95%CI 0.59-0.81) <0.0001

Courtesy Prof Mini

Courtesy Dr Zaniboni

Courtesy Dr Zaniboni

Subgroup analysis of RECOURSE

Mayer et al, NEJM 2015

The lack of efficacy in less pretreated patients may reflect agreater disease aggressiveness and chemo unresponsiveness.

The benefit observed independently of prior regorafenib doesNOT justify suggestions about the best sequence(nb different mechanism of action).

PFS curves of registration trials

Grothey et al, Lancet 2013; Mayer et al, NEJM 2015

Clinical trials in refractory mCRC showed how the benefit of different drugs waslimited to a subset of patients.

Regorafenib vs placebo TAS102 vs placebo

Patients clinicalselection

Biomarker-drivenselection

* The two values are, respectively, the 3rd and 1st quartiles of the variable distribution.

OR 95% CI P

ECOG Performance Status <0.0001

1 vs 0 2.73 1.58-4.70

2 vs 0 7.82 3.85-15.86

Primary tumor resection 0.027

No vs yes 2.01 1.08-3.71

Lactate Dehydrogenase, U/L 0.0001

480 vs 191* 1.64 0.96-2.80

Peritoneal metastases 0.081

Yes vs no 1.65 0.94-2.88

NOMOGRAM in refractory mCRC

The multivariable logistic model identified 4 independent variables.

Pietrantonio et al, ESMO World GI 2016

CONCLUSIONS

Four easy-to-collect information are useful to predict the probability of deathwithin 12 weeks in refractory mCRC patients.

Results obtained in the developing set have been adequately reproduced inthe validating set, thus supporting the reliability of these findings.

With increasing availability of new therapies in pretreated mCRC patients,decision making according to accurate prognostic assessment may help tospare costly and potentially toxic treatments in individual patients.

Our nomogram may significantly improve mCRC patients selection for later-lines therapies in the daily clinical practice and assist researchers forenrollment in early phase clinical trials.

Pietrantonio et al, ESMO World GI 2016

Somministrazione

LONSURF®A convenient oral dosing

• LONSURF® should be prescribed by physicians experienced in the administration of anticancer therapy

• The dose is 35 mg/m2/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)

• Drug pharmacokinetics was evaluated using a randomized, single-dose, two-treatment (fed versus fasting), two- period, two-sequence cross-over design, followed by repeated administration.

• 16 patients were given single doses of TAS-102 (35 mg ⁄ m2) in the pharmacokinetic phase and received twice-daily doses of TAS-102 in 28-day cycles in the repeated administration phase for evaluating efficacy and safety.

Yoshino T et al. Cancer Science 2016

• As TAS-102 is given orally, assessment of the effect of food on the pharmacokinetics of its constituents is required.

• The primary objective of this study was to assess the effect of food on the pharmacokinetics of FTD and TPI after a single oraladministration of TAS-102.

• The secondary objective was to investigate the efficacy and safety of repeated TAS-102 administration.

• A high-fat, high-calorie meal was used to evaluate the maximal effect of food intake on pharmacokinetics.

Yoshino T et al. Clinical colorectal Cancer 2016

• Food showed no effect on the area under the curve from 0 to 12 h or 0 h–infinity values of trifluridine followingadministration of TAS-102 under fasting and fed conditions, whereas those of tipiracil hydrochloride decreased byapproximately 40%.

• Maximum concentrations of both drugs decreased by approximately 40%, indicating that food influenced the absorption andbioavailability of trifluridine and tipiracil hydrochloride, respectively.

• During the repeated administration, stable disease was observed in nine patients with rectal, small-cell lung, breast, thymic,duodenal and prostate cancers.

• Major adverse events were neutropenia, leukopenia, anemia, and nausea. G4 neutropenia were resolved by prolongation ofthe washout period (n = 5 ⁄ 5 patients), and reduction of TAS-102 dose (n = 4 ⁄ 5 patients) or administration of GCSF or both(n = 3 ⁄ 5 patients). No febrile neutropenia was observed in any patient in the study.

(no. JapicCTI-111482).

• Postprandial administration was optimal for TAS-102 because trifluridine’s area under the curve was not changed by food,indicating that its clinical efficacy would not be affected. Additionally, postprandial administration was reasonable becausethe maximum concentration of trifluridine decreased in neutrophils, which correlated with previous studies. These resultssuggest that TAS-102 would be an effective treatment for small-cell lung, thymic, and colorectal cancers.

Tossicità

Courtesy Drssa Troiani

Wilson, P. M. et al. Nat. Rev. Clin. Oncol. 2014

80% of 5FU catabolism is mediated by DPD (dihydropyrimidinedehydrogenase)

The primary catabolite is fluoro-β-alanine, that contributes to:

Neurotoxic events +Cardiotoxic events ++Hand and foot syndrome +++

Phosphorylation of 5FU leads to the production of FUMP, thatcontributes to:Gastrointestinal events +++

S1 , an other oral FP, combining tegafur (a 5FU pro drug), gimeracil ( CDHP , DPD inhibitor) and oteracil potassium (OPRT inhibitor), shows reduced incidence of HFS and GI events

Safety data

In an assessment of TAS-102 group after two cycles:• 53% had a delay of 4 days or more in beginning their next

cycle owing to toxicity• the delay in approximately half of this subgroup extended

for 8 days or more.

In the TAS-102 group a total of 73 patients (14%) required dose reductions:• 53 patients [10%] having a single dose reduction• 18 [3%] having two reductions• 2 [<1%] having three reductions)

Adverse events resulted in the withdrawal of 4% of the patients receiving TAS-102 and 2% of the patients receiving placebo.

In TAS-102 group:• 38% G≥3 neutropenia • 18% G≥3 anemia• 5% G≥3 thrombocytopenia

• 2% G≥3 nausea • 2% G≥3 vomiting • 3% diarrhea

• 7% alopecia

no clinically meaningful differences were noted with respect to the development of serious hepatic or renal dysfunction, anorexia, stomatitis, hand–foot syndrome, or cardiac events.

Mayer RJ et al. NEJM 2015

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

Courtesy Dr Zaniboni

Petrelli et al. BMC Cancer 2016

• In phase I studies, no cardiotoxic events were reported, including 3 single agent TAS 102 trials and a phase I study of a combination of TAS 102 with a fixed dose of irinotecan (121 patients overall).

• In the phase II trials comparing TAS 102 (at the labeled dose) with placebo, 112 patients were randomized but no cardiotoxic events werereported.

• In the phase III study by Mayer et al. n = 3 and n = 2 cardiac events(cardiac ischemia) were recorded in the experimental and control armsrespectively, with no rate of cardiac arrhythmia observed. The rate of cardiotoxicity is 0.5 %

• That represents from 2 to 40-fold numerically less frequent of thatreported with 5FU in literature.

A potential limitation of our observation is that the patients who hadcardiotoxicity during previous treatments might have been excluded from TAS102 trials, which enrolled patients heavely pretreated with many previouslines of therapies.

Petrelli et al. BMC Cancer 2016

Yoshino T et al. Clinical colorectal Cancer 2016

Yoshino T et al. Clinical colorectal Cancer 2016

• This was a postmarketing surveillance study; ADR collection was dependent upon spontaneousreporting.

• The number of TAS-102 prescriptions and patientstreated with TAS-102 during the study period are only estimated on the basis of a preregistrationsystem, in which registration forms were faxed to the Patient Registration Center from the institutebefore drug administration

• Because the preregistration by fax was notmandatory, the precise number of patients couldnot be determined.

• 370 total ADRs were reported

Three ADRs of cardiac disorders were observed in 2 patients• 1 patient with concurrent cardiac ischemia developed

decreased left ventricular function• 1 patient with a history of myocardial infarction and

complications of hypertension, hyperlipidemia and diabetesmellitus, experienced congestive heart failure and atrialfibrillation after receiving TAS- 102

Futuro

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

Courtesy Dr Zaniboni

Grazie