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Prof Filippo de Braud
Fondazione IRCCS Istituto Naz Tumori Milano
Università di Milano
Wilson, P. M. et al. Nat. Rev. Clin. Oncol. 2014
Courtesy Drssa Troiani
Wilson, P. M. et al. Nat. Rev. Clin. Oncol. 2014
Courtesy Drssa Troiani
• TAS-102 is a combination of the thymidine analog trifluridine (FTD) and tipiracil. Tipiracil, a thymidine phosphorylase inhibitor, improves FTD bioavailability.
•Compared with 5-fluorouracil (5-FU), TAS-102 has a distinct mechanism of action 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/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: 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)
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 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
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 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
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/tipiracilvs. 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) Medicatio
n
Trial name
Setting Primary outcome
PFS control
PFS gain
PFS HR OS control
OS gain OS HR
TAS-102 vs placebo
RECOURS E
Third-line or beyond
metastatic
OS 1.7
months
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 a greater disease aggressiveness and chemo unresponsiveness.
The benefit observed independently of prior regorafenib does NOT 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 was limited to a subset of patients .
Regorafenib vs placebo TAS102 vs placebo
Patients clinical selection
Biomarker-driven
selection
* 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 death within 12 weeks in refractory mCRC patients.
Results obtained in the developing set have been adequately reproduced in the 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 to spare 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 for enrollment 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/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)
•
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 oral administration 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 following administration of TAS-102 under fasting and fed conditions, whereas those of tipiracil hydrochloride decreased by approximately 40%.•
Maximum concentrations of both drugs decreased by approximately 40%, indicating that food influenced the absorption and bioavailability 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 of the 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 because the maximum concentration of trifluridine decreased in neutrophils, which correlated with previous studies. These results suggest 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 (dihydropyrimidine dehydrogenase)
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, that contributes 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 were reported.
• 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 arms respectively, 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 that reported with 5FU in literature.
A potential limitation of our observation is that the patients who had
cardiotoxicity during previous treatments might have been excluded from TAS102 trials, which enrolled patients heavely pretreated with many previous lines 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 spontaneous reporting.
• The number of TAS-102 prescriptions and patients treated with TAS-102 during the study period are only estimated on the basis of a preregistration system, in which registration forms were faxed to the Patient Registration Center from the institute before drug administration
• Because the preregistration by fax was not
mandatory, the precise number of patients could not 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 diabetes mellitus, experienced congestive heart failure and atrial fibrillation after receiving TAS- 102