Abstract
Background:
TAS-102, a novel antimetabolite, is approved for treatment refractory metastatic colorectal cancer (CRC). We aimed to determine whether the addition of TAS-102 to oxaliplatin (TAS-OX) was safe and effective in metastatic CRC previously treated with oxaliplatin.
Methods:
This investigator-initiated, open-label, single arm phase 1b study enrolled patients with metastatic CRC previously treated with 5-fluorouracil, irinotecan, and oxaliplatin. In dose escalation, TAS-102 was given at 3 dose levels: 25 mg/m2, 30 mg/m2, and 35 mg/m2 twice daily days 1–5 with oxaliplatin 85 mg/m2 on day 1 in 14-day cycles. The primary endpoint of dose escalation was the recommended dose for expansion, and in dose expansion the primary endpoint was overall response rate (ORR) by RECIST (version 1.1).
Results:
Forty-one patients were treated with TAS-OX. No dose limiting toxicities were observed in the 11 patients treated in escalation. The recommended dose for expansion was TAS-102 35 mg/m2 twice daily days 1–5 in combination with oxaliplatin 85 mg/m2 on day 1 in 14-day cycles. In the intention to treat population the ORR was 2.4% (95% Confidence interval [CI], 0–12.9%) with 1/41 patients having a partial response, although 12 (29%) had tumor shrinkage. The median progression-free survival (PFS) was 2.7 months (95% CI, 2.4–4.8) and median overall survival (OS) was 6.8 months (95% CI, 5.7–10).
Conclusion:
TAS-OX is safe with no unexpected toxicities at standard doses of each agent. The combination did not result in a clinically meaningful ORR, although PFS and OS were encouraging in this heavily pre-treated population.
Keywords: Colorectal cancer, TAS-102, Phase 1, Clinical trials, Oxaliplatin, Neutropenia
Lay Summary:
The TAS-OX clinical trial evaluated the safety and effectiveness of combining two chemotherapy agents for metastatic colorectal cancer: TAS-102 and oxaliplatin. The treatment combination was found to be well tolerated and revealed no unexpected side effects. The study did not meet its predetermined measure of success, however, 12 of 41 patients had reductions in the size of their tumor and the study treatment delayed the time to tumor growth compared to what would be expected.
Introduction
Colorectal cancer remains the second leading cause of cancer related mortality in the United States and globally.[1, 2] For metastatic colorectal cancer, the antimetabolite 5-fluorouracil (5-FU), which inhibits thymidylate synthase resulting in thymidine deficiency, has been the backbone of chemotherapy for decades. In the first or second line setting, 5-FU is combined with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) and is often used with biologic agents such as bevacizumab and panitumumab or cetuximab depending on RAS status and tumor sidedness.[3] Maintenance 5-FU is standard for metastatic colorectal cancer after initial combination chemotherapy such as FOLFOX, which may require dose reductions and ultimately the elimination of oxaliplatin due to treatment related neurotoxicity.[4, 5]
Oxaliplatin is a third-generation platinum compound. It is frequently reintroduced in the more advanced setting after progression on maintenance 5-FU, at the time of disease recurrence, post adjuvant treatment, or post metastasectomy. However, for patients that have progressed while receiving oxaliplatin containing-chemotherapy, FOLFOX is sometimes reintroduced on a case by case basis depending on the elapsed duration from prior oxaliplatin exposure. When oxaliplatin is used in first line therapy in the FOLFOX regimen, most patients have oxaliplatin discontinued for neuropathy or hypersensitivity reaction, rather than refractory disease. Although many patients derive clinical benefit from FOLFOX when oxaliplatin is reintroduced, the response rates are not as robust as during initial exposure. This may be at least in part due to prolonged exposure and resultant resistance to 5-FU, both when used in a combination regimen and alone during maintenance phase.[6] Moreover, patients with progression of disease on oxaliplatin-containing chemotherapy vs progression after discontinuation of oxaliplatin may represent separate patient populations in their responsiveness to the reintroduction of oxaliplatin combination chemotherapy.
After progression on 5-FU based therapies, patients with metastatic colorectal cancer are considered for TAS-102 or regorafenib. TAS-102 is an oral agent, which consists of a combination of a novel antimetabolite 5-trifluorothymidine and a thymidine phosphorylase inhibitor that prevents the degradation of 5-trifluorothymidine.[7] In chemorefractory metastatic colorectal cancer patients, TAS-102 has demonstrated activity, most notably in the randomized phase 3 RECOURSE trial which revealed an overall survival (OS) benefit of 7.1 months vs 5.3 months when compared to placebo with a hazard ratio 0.68 (95% confidence interval [CI], 0.58–0.81 P <0.001).[8] The overall response rate (ORR) was 1.6% with TAS-102, which highlights the cytostatic nature of the agent.
In an attempt to improve upon the efficacy described in the RECOURSE trial, there has been enthusiasm to combine TAS-102 with other drugs known to have activity in colorectal cancer. For example multiple clinical trials are evaluating TAS-102 combinations with agents such as irinotecan and bevacizumab.[9, 10] Furthermore, preclinical studies evaluating TAS-102 and oxaliplatin revealed synergistic activity between TAS-102 and oxaliplatin, which resulted in enhanced tumor cell death for in vitro and in in vivo colorectal cancer models.[11, 12] Given the potential for synergy between TAS-102 and oxaliplatin, and the limited efficacy with the reintroduction of oxaliplatin after progression on 5-FU based therapy, we designed the TAS-OX trial to explore the safety and efficacy of oxaliplatin in combination with the alternative anti-metabolite, TAS-102.
Methods
Study design and participants
The TAS-OX trial was a single arm, open label phase 1b/2 clinical trial performed at the Yale Cancer Center. Eligible patients had stage IV, histopathologically confirmed colorectal cancer with distant metastases that had progressed after standard therapy that included 5-FU, irinotecan, and oxaliplatin. The study consisted of two parts: 1) dose escalation and 2) dose expansion. To establish the recommended dose for expansion, dose escalation proceeded with a standard 3 + 3 design with a DLT evaluation period that lasted 28 days from treatment initiation. In part 2, enrollment proceeded at the recommended dose for expansion. Eligible patients were aged 18 years or older, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, had an estimated life expectancy of 3 months or more in the judgement of the investigator, and had adequate organ function (as assessed by renal, hepatic, hematological, and coagulation parameters). Patients were excluded if they had previously received TAS-102, had not progressed after standard therapies or had grade 2 or higher peripheral neuropathy. The complete study protocol, including a list of all eligibility criteria is included in the appendix. The Yale University Institutional Review Board approved the study, which adhered to Good Clinical Practice guidelines. All patients provided written, informed consent as a condition of study participation.
Procedures
In the phase 1 dose escalation portion of the study participants received escalating doses of TAS-102 twice daily on days 1–5 with fixed dose of oxaliplatin 85 mg/m2 on day 1 in 14-day cycles. The three dose levels of TAS-102 were 25 mg/m2, 30 mg/m2, and 35 mg/m2 with escalation proceeding in a 3+3 fashion. In the dose expansion portion of the study participants received the recommended dose for expansion of TAS-102 days 1–5 with fixed dosing oxaliplatin 85 mg/m2 in 14-day cycles. Pre-defined dose modifications were allowed to manage clinically significant toxicities related to individual agents as specified in the protocol (appendix). Up to 2 dose reductions were allowed for each agent, depending on the adverse event that led to the reduction, and all dose reductions were permanent. Participants received study treatments until radiographic or symptomatic progression, unacceptable toxicity, death, or withdrawal from the study. Radiographic tumor assessments were performed at baseline and every 8 weeks thereafter for the duration of the study.
Outcomes
The primary endpoint in the phase 1 dose escalation was the determination of the recommended dosage of TAS-102 to be used in combination with oxaliplatin. In the dose expansion portion of the study the primary endpoint was the ORR, defined as the proportion of patients with complete response or partial response as described by RECIST (version 1.1). Secondary endpoints included progression-free survival (PFS), OS, disease control rate, duration of response, and safety and tolerability of the combination.
Statistical analysis
The historical control when rechallenging patients with FOLFOX that have not progressed on prior oxaliplatin containing chemotherapy was assumed to be an ORR of 18% and an observed response rate of 35% or greater was assumed to be clinically meaningful and warrant further trials with the combination.[6] Furthermore, the study included early stopping rules with a Bayesian analysis plan for the ORR with at least 5 objective responses required in the first 30 patients treated in dose expansion in order to continue with full accrual to 50 patients in expansion. At least 12 objective responses in a full cohort of 50 patients was required to meet the primary endpoint in dose expansion.
The OS and PFS curves were generated using the Kaplan Meier method. The median OS and PFS were reported along with their 95% confidence intervals. Log-rank tests were used to compare different survival curves. All tests were 2-sided, with a significance level of 0.05.
Role of the funding source
Yale Cancer Center was the study sponsor, and the study was funded by internal funds available through the cancer center. Both TAS-102 and oxaliplatin were commercially available and no external funds were used in support of this study.
Results
Between September 1 2016 and January 7 2020, 53 patients were screened, 12 of whom did not meet eligibility criteria (Figure 1). There were 41 eligible patients assigned to receive the study combination (11 in the part 1 dose escalation and 30 in part 2 dose expansion). The baseline demographic and disease characteristics are summarized in Table 1. All patients had previously received FOLFOX and 23 (56%) had progressed on active oxaliplatin based treatment; while 18 (44%) progressed after oxaliplatin discontinuation, including 4 patients who received oxaliplatin as part of prior adjuvant therapy. At the time of the July 7 2020 data cutoff all 41 patients had discontinued study treatment and 4 patients were still alive. The median follow up duration was 6.8 months (range: 0.93–37.5 months).
Figure 1.
Trial Profile.
Table 1.
Baseline Characteristics of the Intention to Treat Population
| Characteristic | TAS-102 + Oxaliplatin (N = 41) |
|---|---|
| Age | |
| Median | 62 |
| Range | 42 – 83 |
| Sex – no. (%) | |
| Male | 26 (63) |
| Female | 15 (37) |
| Race – no. (%) | |
| White | 38 (93) |
| Black | 1 (2) |
| Asian | 2 (5) |
| ECOG performance status – no. (%) | |
| 0 | 25 (61) |
| 1 | 16 (39) |
| Location of primary tumor – no. (%) | |
| Left side of colon, including rectum | 31 (76) |
| Right side of colon | 10 (24) |
| Stage at diagnosis – no. (%) | |
| I | 1 (2) |
| II | 2 (5) |
| III | 13 (32) |
| IV | 25 (61) |
| Histology – no. (%) | |
| Well differentiated | 2 (5) |
| Moderately differentiated | 30 (73) |
| Poorly differentiated | 9 (22) |
| High microsatellite instability – no. (%) | 2 (5) |
| KRAS / BRAF mutation – no. (%) | |
| KRAS mutation | 20 (49) |
| BRAF mutation | 1 (2) |
| Wildtype | 20 (49) |
| Number of prior therapies – no. (%) | |
| 1 | 1 (2) |
| 2 | 18 (44) |
| 3 | 15 (37) |
| ≥ 4 | 7 (17) |
| Progression during prior oxaliplatin – no. (%) | |
| Yes | 18 (44) |
| No1 | 23 (56) |
Includes 4 patients who received adjuvant oxaliplatin and 19 patients with progression on maintenance 5-FU based therapy after oxaliplatin discontinuation.
In part 1 dose escalation, 5 patients were treated at dose level 1, 3 at dose level 2, and 3 at dose level 3. Two patients at dose level 1 were not evaluable for DLT due to insufficient TAS-102 dosing in the 28-day DLT period. Of the 11 patients treated during dose escalation, no DLTs were observed at any dose level during the DLT period. Accordingly, the study proceeded to dose expansion where 30 patients were enrolled at the recommended dose for expansion. Dose expansion enrolled patients at the recommended dose for expansion of TAS-102 35 mg/m2 twice daily on days 1–5 with oxaliplatin 85 mg/m2 in 14-day cycles. In dose escalation there was one objective response by RECIST (version 1.1), but in dose expansion no objective responses were observed and the study was terminated early as defined by the prespecified futility analysis. The ORR for the intention to treat population was 2.4% (95% CI: 0–12.9%) with 1 of 41 patients achieving a partial response. The disease control rate at 8 weeks was 68% (95% CI: 51.9%−81.9%), and 12 patients (29%, 95% CI: 16.1%−45.5%) had a decrease in target lesion size (Figure 2; waterfall plot). The patient with a partial response had previously received FOLFOX + bevacizumab for metastatic colorectal cancer, but progressed after oxaliplatin discontinuation while on 5-FU/bevacizumab maintenance.
Figure 2.
Waterfall Plot.
The median PFS was 2.7 months (95% CI: 2.4–4.8 months) and the median OS was 6.8 months (95% CI: 5.4–10 months) for the intention to treat population (Figure 3). At 4 months, 16 patients (39%, 95% CI: 0.27–0.57) were alive and progression-free. The median PFS was numerically longer in a subset of patients with grade 2 or greater neutropenia in the first 2 months of treatment, 5 months (95% CI: 3.5–9.8 months) compared to 2.4 months (95% CI: 2.2–4.6 months) for patients that did not develop this level of neutropenia (Supplementary Figure 1a, P=0.059) although this difference was not statistically significance. Furthermore, in the 2 month ≥ grade 2 neutropenia subset the median OS was 10 months (95% CI: 8.9-not reached) compared to 5.4 months (95% CI: 3.3-not reached) without this level of neutropenia (Supplementary Figure 1b, P=0.003). No differences in PFS or OS were noted when excluding patients in dose escalation that received TAS-102 at doses below the recommended dose for expansion (Supplementary Figure 2a and 2b). Moreover, no differences in PFS or OS were noted based on RAS/RAF status (Supplementary Figure 3a and 3b). Full subgroup analysis is outlined in Supplementary Tables 1 and 2.
Figure 3.
Progression-Free Survival (3a, left panel) and Overall Survival (3b, right panel) Curves for Intention To Treat Population.
In the combined dose escalation and dose expansion cohorts, the median number of cycles of TAS-OX was 4 (range, 1–21), with 13 (32%) of patients receiving 8 or more cycles. Dose reductions were needed in 16 patients (39%), 4 due to TAS-102 alone, 6 due to oxaliplatin alone, and 6 due to both study medications. Of the 10 TAS-102 dose reductions, 2 were by one dose level and 8 were by 2 dose levels with a median time to dose reduction of 4 cycles. Three patients (7%) discontinued study treatment for treatment related toxicities, which was attributed to both agents in 2 patients, and TAS-102 related recurrent neutropenia in 1 patient who resumed TAS-OX off trial and remains progression-free at data lock. Treatment related adverse events occurred in all 41 patients. The most frequently reported of these events at any grade occurring in more than 10% of patients are outlined in Table 2. Grade 3 or greater treatment-related adverse events occurred in 14 patients (34%) and were primarily treatment related cytopenias. There were no treatment related deaths.
Table 2.
Frequency of Treatment Related Adverse Events and Laboratory Abnormalities.
| Event | Any Grade | Grade ≥ 3 |
|---|---|---|
| Any event – no. (%) | 41 (100) | 14 (34) |
| Any serious event – no. (%) | 1 (2) | 1 (2) |
| Most common events – no. (%) | ||
| Fatigue | 24 (59) | 1 (2) |
| Nausea | 21 (51) | 0 |
| Anorexia | 10 (24) | 0 |
| Diarrhea | 9 (22) | 1 (2) |
| Vomiting | 9 (22) | 0 |
| Peripheral sensory neuropathy | 6 (15) | 1 (2) |
| Laboratory Abnormalities – no. (%) | ||
| Anemia | 19 (46) | 2 (5) |
| Neutrophil count decrease | 16 (39) | 8 (20) |
| Lymphocyte count decrease | 12 (29) | 4 (10) |
| Platelet count decreased | 13 (32) | 2 (5) |
| White blood cell count decreased | 10 (24) | 3 (7) |
| Alkaline phosphatase increased | 6 (15) | 0 |
AE with > 10% incidence
Discussion
In the United States, FOLFOX is frequently used as initial therapy for metastatic colorectal cancer and the reintroduction of oxaliplatin in later lines of therapy is standard clinical practice. This reintroduction is both considered for patients who previously progressed while receiving oxaliplatin-containing chemotherapy, and more commonly for patients that progressed on 5-FU maintenance after oxaliplatin discontinuation. For colorectal cancer, the optimal sequence of the available therapies is not clear and it is maximizing the exposure of all of the active agents that seems to be more important than the order of administration. Thus, the more treatments with existing therapies that can be offered to patients, the more benefit patients with metastatic colorectal cancer can derive in terms of survival and quality of life. The combination of TAS-102 and oxaliplatin is a novel treatment approach leveraging agents with activity in colorectal cancer.
No dose limiting toxicities were observed during dose escalation and the recommended dose for expansion was determined to be TAS-102 35 mg/m2 days 1–5 with oxaliplatin 85 mg/m2 in 14-day cycles. This dose intensity and schedule has also been confirmed in two additional phase 1 studies combining TAS-102 and oxaliplatin.[13, 14] In 41 patients with advanced metastatic colorectal cancer, TAS-102 in combination with oxaliplatin showed no unexpected safety findings. There were few patients that discontinued treatment because of treatment related adverse events and the majority of adverse events were grade 1 or 2 in severity and managed with supportive care, dose reductions or delays. All serious adverse events were of grade 3 or lower in severity, and only one was related to the study treatments. The safety results from this study do not reveal that either drug potentiates toxicity of the other, and full doses of each individual drug can safely be administered in combination.
As initial treatment for metastatic colorectal cancer, FOLFOX and FOLFIRI are active regimens with response rates as high as 58% and 49% respectively.[15, 16] Treatment with second line FOLFOX after treatment failure on FOLFIRI reveals response rates of 10–15% in prospective clinical trials.[17–20] In contrast, approved third line treatments for metastatic colorectal cancer, TAS-102 and regorafenib, are associated with a modest 1.6% and 1% ORR respectively.[8, 21] Accordingly, these agents are largely considered cytostatic. A retrospective report of rechallenging patients with FOLFOX after a prior receipt of FOLFOX identified a response rate of 18% in 17 evaluable patients.[6] However, of the 3 patients (18%) that responded, none had previously progressed on oxaliplatin. Specifically, 2 patients that responded had only received prior oxaliplatin as neoadjuvant or adjuvant therapy and the third responding patient had previously stopped oxaliplatin while in complete response. For the TAS-OX trial, an observed response rate of at least 35% in dose expansion was determined to warrant further study of the combination, which was based on the 18% historical control for response rate. Given the fact that prospective clinical trials have demonstrated response rates in the single digits for treatment refractory CRC and the fact that we did not limit eligibility to retreatment for patients who had not progressed previously on oxaliplatin, our target response rates were overly ambitious. Furthermore, given the objective response rate with TAS-102, and its cytostatic properties, objective response was not the ideal endpoint to evaluate the efficacy of this combination in such a heavily pretreated patient population.
Here we report an objective response by RECIST (version 1.1) in 1 patient (2.4%, 95% CI: 0–12.9%) in the intention to treat population, and 0 objective responses in dose expansion. Moreover, we report a median PFS of 2.7 months (95% CI: 2.4–4.8 months) which exceeds the median PFS of 2 months for monotherapy TAS-102 described in the RECOURSE trial and 1.9 months with regorafenib in the CORRECT trial.[8, 21] Furthermore, we report a clinically meaningful 4 month PFS of 39% (95% CI: 27–57%) and 6 month PFS of 26% (95% CI: 15–44%). The median OS for TAS-OX of 6.8 months (95% CI: 5.4–10 months) is comparable with 7.1 months reported in both the RECOURSE and CORRECT trials.[8, 21] Our findings suggest at least similar efficacy to TAS-102 or regorafenib with TAS-OX. However, the major limitation of our study is that it is a non-randomized single arm study with a limited sample size, which makes definitive conclusions of efficacy endpoints such as PFS and OS challenging.
In an attempt to improve on the monotherapy activity of TAS-102 for metastatic colorectal cancer, numerous other combinations are currently being investigated. For example, the phase 2 study of TAS-102 and bevacizumab for metastatic colorectal cancer revealed a PFS of 4.6 months.[10] Given the non-overlapping toxicity profiles, the addition of bevacizumab to TAS-OX could be considered as a future direction for TAS-102 combinations in treatment refractory colorectal cancer. Furthermore, the combination of TAS-102, irinotecan, and bevacizumab was investigated in a phase 1 study, which included a colorectal cancer expansion cohort. The study demonstrated an impressive median PFS of 7.9 months with triplet therapy although grade 3 or greater adverse events were reported in 83% of participants.[9] Notably, patients without prior irinotecan were included, and this agent likely significantly contributed to the efficacy reported with this triplet therapy. In contrast, the study population in TAS-OX all had prior exposure to the agent being combined with TAS-102, oxaliplatin. Moreover, in addition to the majority of patients in TAS-OX having received 3 or more prior chemotherapies, 18 (44%) patients had prior progression on oxaliplatin, which highlights the heavily pre-treated population in our study. When comparing the patients that progressed on oxaliplatin chemotherapy to those with progression after discontinuation of prior oxaliplatin no statistically significant differences in PFS (median, 2.5 months vs 3.5 months P = 0.175) or OS (median, 6.3 months vs 8.4 months P = 0.240), survival curves are provided in Supplementary Figure 4a and 4b. However, given the small size of these subgroups it would be difficult to detect survival differences. Future studies in the third line setting may consider enrolling a more uniform patient population by limiting enrollment to either patients that progress on oxaliplatin chemotherapy vs maintenance 5-FU after oxaliplatin discontinuation, depending on the clinical question. Other future directions include evaluating TAS-OX in an earlier treatment setting such as the first or second line. It is highly likely there would be increased activity evaluating TAS-OX in a patient population that is not heavily pre-treated and has not received prior oxaliplatin. However due to the excellent outcomes of FOLFOX as initial treatment for metastatic colorectal cancer, an evaluation of TAS-OX in this setting would require a significant number of patients and follow up time to assess efficacy outcomes such as PFS and OS. Nevertheless, this is an important future direction under consideration for TAS-OX, and will require the thoughtful integration of biologic therapies such as bevacizumab, cetuximab, or panitumumab given their efficacy in early lines of therapy.
We have previously identified the development of ≥ grade 2 neutropenia in the first two cycles to be a favorable prognostic factor with TAS-102.[22] For that reason we evaluated survival endpoints for TAS-OX patients in the subgroup of patients that developed ≥ grade 2 neutropenia in the first 8 weeks of treatment. Here we confirm this to be a favorable prognostic factor, and a potential biomarker of efficacy. The rationale for improved survival in the ≥ grade 2 neutropenia subgroup is thought to be pharmacokinetic, and the effect seems to persist even when combined with a second chemotherapeutic, in this case oxaliplatin. However, at this time the pharmacokinetic principles of this effect are not yet fully elucidated and it remains to be seen whether increasing the dose of TAS-102 and/or oxaliplatin is safe or improves outcomes for patients that do not develop neutropenia.
In conclusion, the TAS-OX trial confirmed the safety of TAS-102 35 mg/m2 twice daily on days 1–5 with oxaliplatin 85 mg/m2 on day 1 in 14-day cycles, even in heavily pretreated patients. The expansion phase of the study closed early for futility due to response rates that were not appreciably different from other prospective clinical trials in the third line setting. However, the PFS and OS with TAS-OX does suggest some patients may derive more benefit from this combination than monotherapy with TAS-102 or regorafenib although more studies are needed to select patients most likely to benefit. Thus, TAS-OX is safe and future clinical investigations are warranted, which may include the addition of biologics such as bevacizumab with careful attention to the appropriate selection of clinical endpoints.
Supplementary Material
Supplemental Figure 1. Progression-Free Survival (1a, left panel) and Overall Survival (1b, right panel) Curves For ≥ Grade 2 Neutropenia Cohort.
Supplemental Figure 2. Progression-Free Survival (2a, left panel) and Overall Survival (2b, right panel) Curves For Patients Treated in Dose Expansion Only.
Supplemental Figure 3. Progression-Free Survival (3a, left panel) and Overall Survival (3b, right panel) Curves For KRAS/RAF mutated vs KRAS/RAF wildtype (WT).
Supplemental Figure 4. Progression-Free Survival (4a, left panel) and Overall Survival (4b, right panel) Curves For Patients that Progressed on Oxaliplatin Chemotherapy vs Progression After Discontinuation of Oxaliplatin.
Funding/Support:
This clinical trial was supported by funding available through the Yale Cancer Center and the treatments were commercially available. Dr. Michael Cecchini receives research support as part of the Yale Cancer Center Calabresi Immuno-oncology Training Program. Research reported in this publication was supported by the National Cancer Institute of the National Institute of Health under Award Number K12 CA215110.
Footnotes
Conflicts of Interest Disclosures:
Dr. Cecchini reports consulting fees from Eisai inc, Agios Pharmaceuticals, AstraZeneca and Parthenon Therapeutics; Dr. Uboha reports consulting fees from Taiho, AstraZeneca, Eli Lilly, Incyte, Ipsen and research support from Taiho, Eli Lilly, Ipsen, and EMD Serono. No other disclosures are reported.
Prior presentations:
The phase 1 safety data was presented at the 2019 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.
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Supplementary Materials
Supplemental Figure 1. Progression-Free Survival (1a, left panel) and Overall Survival (1b, right panel) Curves For ≥ Grade 2 Neutropenia Cohort.
Supplemental Figure 2. Progression-Free Survival (2a, left panel) and Overall Survival (2b, right panel) Curves For Patients Treated in Dose Expansion Only.
Supplemental Figure 3. Progression-Free Survival (3a, left panel) and Overall Survival (3b, right panel) Curves For KRAS/RAF mutated vs KRAS/RAF wildtype (WT).
Supplemental Figure 4. Progression-Free Survival (4a, left panel) and Overall Survival (4b, right panel) Curves For Patients that Progressed on Oxaliplatin Chemotherapy vs Progression After Discontinuation of Oxaliplatin.