BackgroundThe choice of treatment in patients with metastatic colorectal cancer (mCRC) is generally influenced by tumour and patient characteristics, treatment efficacy and tolerability, and quality of life. Better patient selection might lead to improved outcomes.MethodsThis post hoc exploratory analysis examined the effect of prognostic factors on outcomes in the Randomized, Double-blind, Phase 3 Study of trifluridine tipiracil (FTD/TPI) plus Best Supportive Care (BSC) versus Placebo plus BSC in Patients with mCRC Refractory to Standard Chemotherapies (RECOURSE) trial. Patients were redivided by prognosis into two subgroups: those with <3 metastatic sites at randomisation (low tumour burden) and ≥18 months from diagnosis of metastatic disease to randomisation (indolent disease) were included in the good prognostic characteristics (GPC) subgroup; the remaining patients were considered to have poor prognostic characteristics (PPC).ResultsGPC patients (n=386) had improved outcome versus PPC patients (n=414) in both the trifluridine/tipiracil and placebo arms. GPC patients receiving trifluridine/tipiracil (n=261) had an improved median overall survival (9.3 vs 5.3 months; HR (95% CI) 0.46 (0.37 to 0.57), p<0.0001) and progression-free survival (3.3 vs 1.9 months; HR (95% CI) 0.56 (0.46 to 0.67), p<0.0001) than PPC patients receiving trifluridine/tipiracil (n=273). Improvements in survival were irrespective of age, Eastern Cooperative Oncology Group Performance Status (ECOG PS), KRAS mutational status, and site of metastases at randomisation. In the trifluridine/tipiracil arm, time to deterioration of ECOG PS to ≥2 and proportion of patients with PS=0–1 discontinuing treatment were longer for GPC than for PPC patients (7.8 vs 4.2 months and 89.1% vs 78.4%, respectively).ConclusionLow tumour burden and indolent disease were factors of good prognosis in late-line mCRC, with patients experiencing longer progression-free survival and greater overall survival.

In oncology, there is a clinical need for novel combination therapy regimens that maximize efficacy and delay resistance to individual treatment modalities. Given the role of aberrant ErbB receptor signaling in the pathogenesis of many human cancers, there is rationale for incorporating afatinib, an irreversible pan-ErbB tyrosine kinase inhibitor, into such combinations. This review focuses on: pharmacological properties of afatinib that facilitate its use in combination; preclinical rationale for the combination of afatinib with other agents; and recently completed, and ongoing, clinical trials of afatinib-based combinations across tumor types. Based on these data, we emphasize a number of areas of high unmet medical need that could benefit from afatinib-based combinations, including patients with relapsed/refractory non-small-cell lung cancer.

677 Background: The Phase III RECOURSE trial, in patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard therapies, demonstrated that trifluridine/tipiracil (FTD/TPI) significantly extended overall survival (OS) and progression-free survival (PFS) versus placebo in all subgroups, regardless of age, geographical origin, or KRAS status, with acceptable safety. Literature reports have shown optimal benefit for pts with low tumor burden (< 3 metastatic sites), indolent disease (≥ 18 mo since diagnosis of first metastasis), ECOG PS 0-1, and no liver metastasis when treated in late line mCRC. Methods: This exploratory post hoc analysis of RECOURSE (all ECOG 0-1) compared pts on FTD/TPI or placebo with good prognostic characteristics (GPC; low tumor burden and indolent disease) and poor prognostic characteristics (PPC; high tumor burden and/or aggressive disease). These subgroups were then analyzed by liver metastasis at baseline, ECOG PS, KRAS status and age. Results: Baseline characteristics were generally similar between the two groups. GPC placebo pts performed better than the PPC placebo pts, but worse than the GPC pts treated with FTD/TPI. GPC pts treated with FTD/TPI showed median OS of 9.3 mo versus 5.3 mo in PPC pts (HR 0.46; 95% CI: 0.37, 0.57; p < 0.0001); there was a similar effect for PFS. GPC pts had significantly better mOS and mPFS regardless of age (≥ 65 vs. < 65 y), ECOG PS (0–1), KRAS status (mutant vs. wildtype), and liver metastasis (y/n). No liver metastasis was the best prognostic factor: mOS in such pts treated with FTD/TPI was 16.4 mo and 7.6 mo in the GPC (n = 97) and PPC (n = 35) groups, respectively (HR 0.42; 95% CI: 0.24, 0.74; p < 0.0019); there was a similar effect for PFS. Pts with ECOG PS 0 at baseline remained PS 0-1 at discontinuation in 96% of the GPC group. Conclusions: Low tumor burden and indolent disease indicate good prognosis in late line mCRC. Pts with no liver metastasis have the best prognosis and are likely to have longer OS. GPCs might explain the percentage of long-term responders on FTD/TPI in RECOURSE. Maintenance of ECOG PS 0–1 during treatment is crucial in the continuum of care, allowing pts to benefit from further treatment options. Clinical trial information: NCT01607957.

229 Background: Metastatic gastroesophageal cancer (GC/GEJC) is an aggressive disease with poor prognosis and a median overall survival (mOS) of around 1 year. While new treatments have emerged, the need for better understanding of the biology and patient profiling is essential given the heterogeneity of the disease. Previously, the TAGS study showed an improved OS with trifluridine/tipiracil (FTD/TPI) vs placebo in heavily pretreated metastatic GC/GEJC patients with a 31% risk reduction in death. This exploratory subgroup analysis of TAGS aims to assess the efficacy, safety, and quality of life (QoL) results observed in patients who received FTD/TPI or placebo in third line (3L) and those who received FTD/TPI beyond the third line (4L+). This analysis will help provide physicians a clearer view of what is expected in the third-line setting in terms of outcomes and to confirm the efficacy of FTD/TPI in later lines. Methods: Patients were divided into two groups: (i) patients who had received FTD/TPI or placebo after two lines of previous systemic therapy (3L) (n = 126 vs 64); and (ii) patients who had received FTD/TPI or placebo (n = 211 vs 106) after three or more lines of previous systemic therapy (4L+). Patient demographics/baseline characteristics, efficacy (OS, progression-free survival [PFS], and time to ECOG deterioration to 2 or more), safety, and QoL were assessed accordingly in these two groups. Results: Patient baseline characteristics in both groups were well balanced between FTD/TPI and placebo. The mOS for FTD/TPI vs placebo in 3L was 6.8 vs 3.2 months (HR, 0.67; 95% CI, 0.47-0.97; P= 0.0318); whereas, in 4L+, it was 5.2 vs 3.7 months (HR, 0.72; 95% CI, 0.55-0.95; P= 0.0192). The mPFS for FTD/TPI vs placebo in 3L was 3.1 vs 1.9 months (HR, 0.54; 95% CI, 0.38-0.77; P= 0.0004); whereas, in 4L+, it was 1.9 vs 1.8 months (HR, 0.57; 95% CI, 0.44-0.74; P< 0.0001). Time to deterioration of ECOG to 2 or more for FTD/TPI vs placebo in 3L was 4.8 vs 2.0 months (HR, 0.60; 95% CI, 0.42-0.86; P= 0.0049); whereas, in 4L+, it was 4.0 vs 2.5 months (HR, 0.75; 95% CI, 0.57-0.98; P= 0.0329). No relevant clinical differences were found in the impact on QoL in the overall study population. The safety profile of FTD/TPI remained consistent through all subgroup analyses. Conclusions: This analysis confirms the efficacy and safety of using FTD/TPI vs placebo in GC/GEJC patients in third and later lines with a survival benefit that seems to be slightly superior in 3L. Results of QoL in both 3L and 4L+ were consistent with previously published subgroup analyses and with the overall TAGS study population. When FTD/TPI is taken in 3L as recommended in the international guidelines, physicians can expect to provide their patients with a mOS of 6.8 and mPFS of 3.1 months. Clinical trial information: NCT02500043.

639 Background: Trifluridine/tipiracil (FTD/TPI) is indicated and recommended for the treatment of previously treated metastatic colorectal cancer (mCRC). Previous evaluations used pooled clinical evidence from the Phase III (RECOURSE) and Phase II trials to model cost-effectiveness, but FTD/TPI specific utilities were not available and alternative data sources were used. The aim of this study was to utilize EQ-5D data from an ongoing Phase IIIb trial (PRECONNECT) within an updated cost-effectiveness model to validate health-related quality of life (HRQoL) outcomes for mCRC patients receiving FTD/TPI. Methods: EQ-5D-3L data from PRECONNECT trial were analyzed with UK utility tariff applied. Pre- and post-progression health state utilities were estimated using a linear mixed effects regression model. Indirect comparison versus regorafenib was based on evidence from the CORRECT trial. Utilities and UK costs (GBP, 2018) were then implemented into the existing economic model. Results: Mean pre-progression and post-progression utilities were 0.72 and 0.59, respectively, with discounted incremental quality adjusted life years gain of 2.1 months versus best supportive care (BSC) and 0.8 versus regorafenib. Use of FTD/TPI based on PRECONNECT data, as in the previous analysis, was associated with improved mean survival pre-progression (by 1.8 months) and post-progression (by 1.4 months) for the total OS gain of 3.2 months versus BSC. The mean OS gain versus regorafenib was 1.4 months. Updated cost-effectiveness analysis using PRECONNECT derived inputs showed that results remained broadly unchanged with a negligible increase in ICER from £51,589 to £51,792 (£51,101 in the probabilistic sensitivity analysis) when compared to BSC, while FTD/TPI remained dominant (more effective and less costly) versus regorafenib. Conclusions: New HRQoL data from the PRECONNECT study collected in a real-world setting validated previous HRQoL inputs used to model cost-effectiveness of FTD/TPI in previously treated metastatic colorectal cancer. Clinical trial information: NCT03306394.