Review of metastatic colorectal cancer treatment pathways and early clinical experience of trifluridine/tipiracil in the UK named patient programme

Patients eligible for inclusion in the NPP were adults (≥ 18 years) with histologically or cytologically confirmed mCRC who had been previously treated with, or were not deemed candidates for, available therapies including 5-fluorouracil (5-FU)/capecitabine- based combination therapies, anti-VEGF agents, and anti-EGFR agents. Female patients must have had a negative pregnancy test within 7 days of trifluridine/tipiracil initiation (or been post-menopausal) and all patients were required to use adequate contraception (where possible), during and up to 6 months after treatment. Patients with severe renal impairment, moderate or severe hepatic impairment and those with reduced neutrophil counts or unresolved prior grade 3 or 4 non-haematological clinically relevant toxicity from prior therapies were excluded, consistent with the United States Prescribing Information (USPI, provided in lieu of the summary of product characteristics [SmPC] [19]).

Eligible patients were proposed by their treating physician and provided written informed consent to participate in the NPP; data were collected as part of the routine management of the NPP using paper data collection forms. The data collected included patient demographics and clinical characteristics (including age, sex, disease duration, KRAS mutation status, Eastern Cooperative Oncology Group Performance Status [ECOG-PS] score at enrolment), prior CRC treatment and trifluridine/tipiracil treatment (where appropriate; including number of cycles of trifluridine/tipiracil provided, reason for discontinuation, AEs). The recommended starting dose of trifluridine/tipiracil was 35 mg/m² orally twice daily on Days 1 to 5 and on Days 8 to 12 in 28-day cycles, as indicated in the USPI/SmPC [19].

Data were collected routinely as part of the NPP and no formal sample size power calculation was carried out; all patients enrolled in the NPP were included in the present analysis. Quantitative variables are presented as mean (standard deviation [SD]) or median (inter-quartile range [IQR] or range); categorical variables are presented as frequencies and percentages. Treatment persistence was defined as the time from initiation of trifluridine/tipiracil to the date of last intake or, where date of last intake was not recorded, duration was estimated from the number of cycles (28 days per cycle) of trifluridine/tipiracil received; patients continuing on treatment or transferring to funded treatment were censored on the last day of the last cycle received as part of the NPP. Treatment persistence is presented as a Kaplan–Meier plot with median (95% confidence intervals [95% CI]). For patients who discontinued trifluridine/tipiracil due to disease progression, in the subgroup of patients with an available date of scan confirming disease progression (n = 58), the time from initiation to disease progression was highly correlated with treatment persistence (r = 0.984). Therefore, time to progression was defined as the time from initiation of trifluridine/tipiracil to the date of disease progression, or where date of disease progression was not recorded, treatment persistence was used as a proxy for time to progression; patients not discontinuing due to disease progression were censored on the last day of the last cycle received as part of the NPP. Progression-free status is presented as median (95% CI). For the purposes of treatment sequencing, treatments were grouped based on the primary treatment (e.g. FOLFIRI includes FOLFIRI only and FOLFIRI with additional agents).

A total of 250 patients enrolled in the NPP were included in the present analyses; of these, 194 received at least one dose of trifluridine/tipiracil and 56 patients were enrolled but did not receive trifluridine/tipiracil because they subsequently declined treatment or they rapidly became too unwell from their progressing disease to receive treatment. The patient demographics and clinical characteristics of patients receiving at least one dose of trifluridine/tipiracil and those not receiving this treatment are summarised in Table 1.

In patients receiving ≥1 dose of trifluridine/tipiracil, the median age at enrolment was 63.0 (IQR 54.0–69.0) years (43% female, n = 83/194) with a median disease duration (defined as the time from initial diagnosis of colorectal cancer to enrolment) of 35.7 (IQR 18.7–54.7) months; the median time from diagnosis of metastatic disease to enrolment was 25.4 (IQR 16.4–43.0) months. Twenty eight percent (n = 54/194) had an ECOG-PS score of 0, and 74% had prior colorectal surgery (n = 143/194); 39% (n = 75/194) of patients had received adjuvant therapy and 2% (n = 4/194) had received neoadjuvant therapy. Patients enrolled but not receiving trifluridine/tipiracil had broadly similar characteristics, with a median age of 62.0 (IQR 54.8–69.0) years (38% female, n = 21/56), a median disease duration of 33.4 (IQR 19.5–47.9) months and a median time from diagnosis of metastatic disease to enrolment of 22.4 (IQR 15.6–43.0) months. Of the patients enrolled but not receiving trifluridine/tipiracil, 14% (n = 8/56) had an ECOG-PS score of 0, and 64% (n = 36/56) had prior colorectal surgery; 29% (n = 16/56) of patients had received adjuvant therapy and 2% (n = 1/56) had received neoadjuvant therapy.

Of the patients receiving ≥1 dose of trifluridine/tipiracil, 19% (n = 36/194) had received at least 4 prior therapies (Table 1); in patients who did not receive trifluridine/tipiracil, 25% (n = 14/56) had received at least 4 prior therapies.

The treatment regimens prior to enrolment in the NPP are summarised in Fig. 1. A total of 26 different first-line treatment regimens were recorded (see Additional file 1: Table S1). FOLFOX-, FOLFIRI- and CAPOX-based therapies were the most common first-line regimens in patients receiving ≥1 dose of trifluridine/tipiracil (37% [n = 71/194], 35% [n = 67/194] and 21% [n = 41/194], respectively (Fig. 1a)), and in patients not receiving trifluridine/tipiracil (41% [n = 23/56], 30% [n = 17/56] and 20% [n = 11/56], respectively (Fig. 1b)). Second-line treatment regimens in patients receiving and not receiving ≥1 dose of trifluridine/tipiracil were most commonly FOLFIRI-based (48% [n = 94/194] and 41% [n = 23/56], respectively) and FOLFOX-based (19% [n = 37/194] and 21% [n = 12/56], respectively). Treatment beyond the second-line was highly varied, with a wide range of different treatment regimens observed (Fig. 1). The most common third-line treatments in patients receiving ≥1 dose of trifluridine/tipiracil were FOLFIRI-, capecitabine- or cetuximab-based regimens (9% [n = 18/194], 8% [n = 15/194] and 8% [n = 16/194], respectively). Patients not receiving trifluridine/tipiracil most commonly received FOLFIRI- or FOLFOX-based regimens (9% [n = 5/56] each) at third line.

First- and second-line treatment sequencing is shown in Additional file 1: Figure S1. For those patients receiving trifluridine/tipiracil, 17% (n = 33/194) of patients had FOLFIRI-based first-line followed by FOLFOX-based second-line regimens, 30% (n = 58/194) had FOLFOX-based first-line followed by FOLFIRI-based second-line regimens and 13% (n = 26/194) had CAPOX-based first-line followed by FOLFIRI-based second-line regimens (Additional file 1: Figure S1A). Seven percent (n = 14/194) had FOLFIRI-based first-line regimens followed by trifluridine/tipiracil as second-line regimen. For those patients not receiving trifluridine/tipiracil, 14% (n = 8/56) of patients had FOLFIRI-based first-line followed by FOLFOX-based second-line regimens, 23% (n = 13/56) had FOLFOX-based first-line followed by FOLFIRI-based second-line regimens and 16% (n = 9/56) had CAPOX-based first-line followed by FOLFIRI-based second-line regimens (Additional file 1: Figure S1B). All other combinations of first- and second-line regimen were observed in < 5% of patients in each group.

Patients received a median of 2 cycles of trifluridine/tipiracil (range 1–20). The median treatment persistence was 1.8 (95% CI: 1.8–2.4) months (Fig. 2), with 30% (95% CI 24–37%) of patients persisting on treatment at 3 months, 10% (95% CI: 6–15%) at 6 months and 3% (95% CI: 1–8%) at 12 months. Overall, 92% (n = 179/194) of patients discontinued trifluridine/tipiracil, most commonly due to disease progression (79% [n = 142/179]); 3% (n = 5/179) discontinued due to AEs and 2% (n = 4/179) due to other reasons (16% [n = 28/179] reason for discontinuation unknown). Of the 15 patients remaining on trifluridine/tipiracil treatment at data collection, 87% (n = 13/15) had switched to commercial stock. In patients who discontinued treatment due to disease progression, the median progression-free duration was 2.8 (95% CI: 2.4–2.9) months.

Of the patients receiving ≥1 dose of trifluridine/tipiracil, 55% (n = 106/194) experienced at least one adverse event. Neutropenia (all grades) was the most commonly observed AE, reported in 30% (n = 59/194) of patients (Table 2).

Enrolment in the NPP required a clinician’s application, which may have introduced selection bias. Furthermore, patients treated as part of the NPP may not be representative of the patient population treated with trifluridine/tipiracil since marketing authorisation was granted and approval was received from NICE. The details of disease progression were only available in patients discontinuing trifluridine/tipiracil for disease progression and details of death were not available for the majority of patients, which precluded evaluation of progression-free survival and overall survival. Quality of life data was not collected during the NPP. Finally, all data were sourced retrospectively from data documented as part of the NPP, and therefore the quality of this analysis was reliant on the completeness and quality of the data recorded.