New TAS-102, oral; encouraging data for all groups/ Sep 2014

[Maia]

I've been following news about this agent since some time ago; thought about sharing the information here, in case it helps someone, and because it reached the Phase III status. We had a fellow here at the CC who mentioned starting this trial and then commented that she progressed on the drug ; that's the only reference I could find in this forum.
Personally, I'm not very interested in new chemotherapeutic agents (I favour immunological approaches) but some key points about this drug are noteworthy.

▸It's a nucleoside agent, oral administration (a pill); a Japanese development.
▸The drug was most effective in improving survival in patients with KRAS-mutant tumors and had less of an effect on KRAS wild-type tumors. (When it's well known there are less options and drug developments for KRAS +)
▸Improved overall survival (OS) (for a few months, we have to say, but with just that, regorafenib (Stivarga) got approved. So.) It's not that just improved progression free survival (PFS)
▸There is a big (116 locations), international Phase III trial ongoing: Study of TAS-102 in Patients With Metastatic Colorectal Cancer Refractory to Standard Chemotherapies (RECOURSE) http://clinicaltrials.gov/ct2/show/study/NCT01607957 Bad thing is that is randomized (and double-blind, two-arm, parallel).

(News from this November 2013, commenting the results of the phase II trial)

Novel Oral Agent Extends Survival in Relapsed/Refractory Colorectal Cancer, Phase II Study Shows

By Alice Goodman The ASCO Post http://www.ascopost.com/ViewNews.aspx?nid=10727
Posted: 11/7/2013

Hopes are high that TAS-102, a novel oral nucleoside agent, will turn out to be an advance in the treatment of advanced colorectal cancer, said Howard Hochster, MD, of the Gastrointestinal Cancer Program at Yale Cancer Center, New Haven, Connecticut, speaking at the Chemotherapy Foundation Symposium XXXI.

TAS-102 combines the cytotoxic agent trifluridine with the thymidine phosphorylase inhibitor tipiracil. TAS-102 is incorporated into DNA synthesis and inhibits DNA growth in cancer cells.

“This combination gives better pharmacology than either drug alone, and the compound is active in fluorouracil-resistant tumors,” Dr. Hochster noted.

Favorable Survival Results

A phase II study showed that TAS-102 improved overall survival by a median of 3 months in 172 patients with relapsed/refractory colorectal cancer; overall survival was 9 months in those treated with TAS-102 vs 6 months in the placebo group. Patients given TAS-102 were 44% less likely to die.

Additionally, 43% of patients receiving TAS-102 achieved stable disease vs 10% for those on placebo. Subgroup analysis showed favorable survival and progression-free survival outcomes for all subgroups independent of prior therapy and KRAS status.

Toxicities were mainly hematologic. In Dr. Hochster’s opinion, these were a primarily consequence of delayed neutrophil recovery.

The drug was most effective in improving survival in patients with KRAS-mutant tumors and had less of an effect on KRAS wild-type tumors.

Ongoing Phase III Study

“TAS-102 has entered phase III international study. It will be interesting to see if the KRAS results are replicated in the larger trial,” he said.

The hazard ratios for overall survival and progression-free survival in the phase II trial of TAS-102 were comparable with those in phase III trials comparing cetuximab (Erbitux), panitumumab (Vectibix), and regorafenib (Stivarga), respectively, vs best supportive care for third-line or greater treatment for metastatic colorectal cancer, Dr. Hochster said.

“If this holds up in phase III, TAS-102 may play an important role in colorectal cancer,” he said.

The phase III RECOURSE trial is enrolling patients with metastatic colorectal cancer who have been treated with two or more prior regimens and who are are refractory to fluoropyridines, irinotecan, oxaliplatin, bevacizumab (Avastin), and anti-EGFR therapy. Recruitment is being conducted in 13 countries and 122 cancer centers. Patients are randomly assigned to TAS-102 twice daily or best supportive care, and results are expected in 2014.

Wish the info brings some hope, specially to those KRAS mutants out there (like my friend), and also to those recently diagnosed. You never know what the next year may bring... for 'bad', yes, but for good too.

[Bev G]

Thank you for posting this! I missed it earlier, but it does look hopeful, especially for us "mutants"!

xox

Bev

[Maia]

UPDATE September 2014, from the ESMO 2014 this past weekend: Final analysis of primary endpoints from the phase III study


Take home message:
TAS-102 benefit (OS (=overall survival) and PFS (=progression free survival)) was observed in all defined subgroups , which included heavily treated patients, who received prior all the agents (even regorafenib) and included also KRAS mutant patients (the numbers are a little better for KRAS mutant, even).
**********************

ESMO 2014: TAS-102 Improves Overall- and Progression-Free Survival in Patients With Metastatic Colorectal Cancer Refractory to Standard Therapies

Date: 27 Sep 2014

Final analysis of primary endpoints from the phase III RECOURSE study

A final analysis of primary endpoints from the phase III RECOURSE study in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies showed a statistically significant overall survival (OS) and progression-free survival (PFS) benefit with TAS-102 in all prospectively defined subgroup analyses, including prior therapy with regorafenib. The results were presented during the Proffered Paper session in Colorectal Cancer at the ESMO Congress 2014, by Prof. Eric Van Cutsem of the Digestive Oncology Unit, University Hospital Leuven, Leuven, Belgium.

The data from the RECOURSE study was first reported at the ESMO World Congress in Gastrointestinal Cancer earlier this year in Barcelona, Spain. At the ESMO Congress in Madrid, Prof. Van Cutsem presented new data, in particular subgroup analyses of OS and PFS by KRAS status, stratification factors and patient characteristics, and time to worsening of ECOG performance status (PS) to 2 or more.

TAS-102 is a combination of a novel oral nucleoside, trifluridine (FTD) with the thymidine phosphorylase inhibitor, tipiracil hydrochloride (TPI), which prevents the degradation of FTD, enabling sustained and effective FTD levels.

TAS-102 vs placebo in refractory mCRC

RECOURSE was conducted to evaluate the efficacy and safety of TAS-102 in patients with mCRC refractory to standard therapies. Patients with ECOG PS 0-1 who failed two or more prior treatments with fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and cetuximab/panitumumab (in case of KRAS wild-type disease) were eligible for the study.

Treatment continuation was foreseen until progression, intolerant toxicity or patient refusal. It was a multicenter, randomised, double-blind, placebo-controlled, phase III study with stratification by KRAS status, time from diagnosis to metastatic disease, and geographical region. It was performed in 13 countries around the world. Enrollment started in June 2012 and finished in October 2013.

The study primary endpoint was OS and the key secondary efficacy endpoint was PFS. Other secondary endpoints included safety, tolerability, time to treatment failure (TTF), overall response rate (ORR), disease control rate (DCR), duration of response (DoR), OS and PFS in subgroups determined by KRAS status.

The OS and PFS were evaluated by using univariate and multivariate analyses for prospectively defined subgroups and a retrospectively defined subgroup of patients with prior treatment with regorafenib.

In total 800 patients were randomised to TAS-102 (534 patients) or placebo (266 patients). In intent to treat population, patient demographics and characteristics were balanced between two arms with one third of Asian patients in each group.

The hazard ratios for OS and PFS were 0.68 (p < 0.0001) and 0.48 (p < 0.0001), respectively, both favouring TAS-102. The OS in TAS-102 group was 7.1 month vs 5.3 month in placebo group. Median PFS was 2.0 months in TAS-102 treated patients and 1.7 month in the placebo arm.

The OS and PFS benefit with TAS-102 was consistent across all subgroups. In particular, the HRs for OS in subgroups were 0.58 in patients with KRAS wild-type tumours and 0.80 in KRAS mutated tumours; 0.64 in Western population and 0.75 in Asian patients; 0.73 in patients with PS 0 and 0.61 in patients with PS 1; and 0.69 for patients who have already received or not regorafenib.

In patients with time from diagnosis to first metastasis shorter than 18 months, the HR for OS was 0.84 and 0.64 in those with ≥ 18 months. In patients younger than 65, this HR was 0.74 and 0.62 in the group ≥ 65 years old. In patients who received three prior treatments, the HR was 0.74 and 0.59 in those who received ≥ 4 treatment lines.


Overall survival treatment effect remained similar in the multivariate model

The OS treatment effect remained the same in the multivariate model. No predictive factors were identified. Statistically significant prognostic factors (p < 0.05) in final model based on stepwise selection were:

- time since diagnosis of first metastasis,
- ECOG performance status,
- and number of metastatic sites.

Time to worsening of ECOG PS status to 2 or more was significantly delayed with TAS-102 vs placebo with medians of 5.7 vs 4.0 months (HR = 0.66, p < 0.0001). Post-study treatment was similar between arms (41.2% in TAS-102, 42.5% in placebo).

Safety results were previously presented at the ESMO World Congress on Gastrointestinal Cancer 2014. The most frequently observed toxicities were gastrointestinal and haematologic. Serious adverse events were observed in 29.6% patients in TAS-102 and 33.6% patients in placebo group. Primary reason for treatment discontinuation due to adverse events was 3.6% in TAS-102 and 1.5% in the placebo group. One treatment-related death was observed in TAS-102 group. The rate of febrile neutropenia was 3.8% and frequency of G-CSF usage 9.4% in TAS-102 and 0% in placebo group.

Conclusion

Prof. Van Cutsem concluded that TAS-102 demonstrated a clinically relevant improvement in OS and PFS compared with placebo in patients with mCRC refractory/intolerant to standard therapies. Improved OS benefit was statistically significant or trended favorably for TAS-102 across all stratification factors and predefined subgroups. Consistent with OS results, PFS improvement for TAS-102 was statistically significant across all stratification factors and predefined subgroups. The OS benefit was maintained irrespective of regorafenib use.

Discussant Dr. Christophe Tournigand said that in the RECOURSE study TAS-102 significantly improved OS and PFS in patients with metastatic colorectal cancer, refractory or intolerant to standard therapies. However, questions for the future would be: identifying biomarkers, addressing the question of QoL improvement, and seeing efficacy/tolerance in combination therapy, and efficacy in earlier lines of therapy.

The sponsor of the RECOURSE trial is Taiho Oncology Inc./Taiho Pharmaceutical Co. Ltd.

***************
LBA13 - Phase III RECOURSE trial of TAS-102 vs. placebo, with best supportive care (BSC), in patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard therapies

Aim

TAS-102 is a combination of a novel oral nucleoside, trifluridine (FTD) with the thymidine phosphorylase inhibitor, tipiracil hydrochloride (TPI), which prevents the degradation of FTD, enabling sustained and effective FTD levels. RECOURSE (Sponsor: Taiho Oncology Inc. / Taiho Pharmaceutical Co. Ltd.) was conducted to evaluate the efficacy and safety of TAS-102 in pts with mCRC refractory to standard therapies.

Methods

mCRC-patients (ECOG PS 0-1) who failed fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and cetuximab/panitumumab (if KRAS wild-type) were eligible. The primary endpoint (overall survival, OS) and the key secondary efficacy endpoint (progression-free survival, PFS) were evaluated using univariate and multivariate analyses for prospectively defined subgroups and a retrospectively defined subgroup with prior regorafenib.

Results

800 pts were randomized to TAS-102 (534 pts) or placebo (266 pts). The hazard ratios for OS and PFS were 0.68 (95% CI: 0.58 - 0.81; p < 0.0001) and 0.48 (95% CI: 0.41 - 0.57; p < 0.0001), respectively, both favoring TAS-102. OS and PFS benefit for TAS-102 was consistent across all subgroups. OS treatment effect in the multivariate model remained the same. Safety results were previously presented [Yoshino T. et al., Ann Oncol 2014; 25 (Suppl 2; abstr O-0022)]. Time to worsening of ECOG PS status to 2 or more was significantly delayed with TAS-102 vs. placebo [medians of 5.7 vs. 4.0 months, HR = 0.66 (95% CI: 0.56–0.78)]. Post-study treatment was similar between arms (41.2% in TAS-102, 42.5% in placebo).



Conclusions

OS and PFS benefit was observed in all prospectively defined subgroup analyses, including prior regorafenib therapy.

[Stanfordmom]

Thanks so much, Maia! You are such a great researcher.

When do you think this drug will get approved In the US? Thanks!

[Maia]

Taiho is preparing the submission of the NDA (New Drug Application) and MAA (marketing authorization application) of TAS-102 in the United States now, these days, before 2014 ends, and maybe in the European Union in the first quarter of 2015. I really know nothing about times and this kind of thing (pharma business), maybe others (ahem, GrouseMan ) have more idea. Just extrapolating what happened with regorafenib.. I'd say that during the next year TAS-102 will be available in USA. Hope that it's something better than regorafenib...

[mstults]

There is an expedited process for some drugs but I don't remember the details

[WifeOfMike]

New Drug Boosts Survival in Metastatic CRC.
The results of the Phase III trial of TAS-102 were reported at ESMO and indicated that this drug does increase survival in metastatic patients who have received 2 or more prior lines of treatment.
see: http://www.practiceupdate.com/news/6133

Broad points discussed:
The RECOURSE phase III trial- 800 patients with metastatic colorectal cancer who had failed at least two prior chemotherapy regimens.
32% cut in mortality during a median 8 months follow-up
improvement in progression-free survival was 5.7 months among patients who received TAS-102 and 4.0 months among placebo patients.
Most common side effects (usually grade 1-2) were nausea, fatigue, diarrhea, vomiting and low level of grade 3-4 adverse event

You may have to register (as I did) to see the latest results of this Study- takes about a minute
I would have copied it here, but their website threatens to come find me & break both of my legs if I did
Hopefully the drug company applies for approval in the US SOON .
Vicki

[dxycn]

it have been approved in japan

[sjring]

There is an expedited process for some drugs but I don't remember the details

The expedited process I believe relates to the Agency's review of Clinical Trial data and the application. From what I saw on Clinicaltrials.gov, the Phase 3 studies (there are a couple of them) are active but not recruiting new patients. Bodes well that they may be near the end of patient participation, There are a couple of actively recruiting Phase 1 studies one looks like an ascending dose study to find maximum safe dose and another PK study and 2 Asian based Phase 1's (China and Korea). The phase 1's all appear to be open label (so you would know if you were getting the study drug). So timing would also depend on whether the agency needs the data from these Phase 1 studies to approve the drug.

Once the patients complete the study the database has to lock which can take 4-6 weeks, and then the biometrics or clinical pharmacology teams do the statistical analysis, etc and write the study report which can take a couple of months. Then FDA looks at the application and results of the trials, and may want additional safety or efficacy data which could result in another trial.

[Ratepo]

Hmm, though nice to hear a new medicine is on its way the results are not too impressive. OS 7,1 months versus 5,3 for placebo. Kras mutants a bit better. Well anyway lets hope that it will come soon and more results will be available. Seems a bit like regorafenib. But many many thanks for keeping us updated of course!

[singingholly]

Thank you Maia, as usual.