• Real-world data (RWD) of the use of trifluridine/tipiracil hydrochloride (TFT) in patients with metastatic colorectal cancer: The Greater Manchester experience

      Alchawaf, A.; Dawod, M.; Al-Ani, M.; Barriuso, Jorge; Ferrera, A.; Ho, A.; Braun, Michael S; Paton, Nina; Saunders, Mark P; Wilson, G.; et al. (2020)
      Background Trifluridine/tipiracil hydrochloride has shown to improve progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC). Exploratory analysis suggested that patients with good prognostic characteristics GPC (18 months since first diagnosis) carry better prognosis vs. poor prognostic characteristics (PPC). We report the Greater Manchester experience of the use of TFT. Methods All consecutive patients who received TFT between August 2016 and August 2019 were included. Data were collected from electronic records. Univariate survival analysis was performed with Kaplan-Meier curve and log-rank test. Cox regression was used for multivariable analysis. Results All consecutive pts (n=188) were included; median follow up was 7.1 months. Median age was 66 IQR (59-72); 60% were male; 22% had right; 43% had left; 35% had rectal cancers. RAS mutation was identified in 29.8%. Twenty-nine (16%) received bevacizumab and 23.4% received anti-EGFR treatment. Seventy-eight (41%) had ≤ 3 sites of metastases; 134 (74%), 120 (66%) and 70 (40%) had liver, lung and peritoneal metastasis respectively; 123 (65.4%) had ≤18months since diagnosis of first metastasis, 64 patients (34%) had GPC while 122 (64.9%) had PPC. Median time from stage IV diagnosis to starting treatment was 23.9 months IQR (14.9-38.5). Thirty-six (19%) had HB < 0.001. Patients with GPC had better OS of 12.9 months (95% CI 10.11-15.77) compared to 7.45 months in patients with PPC (95% CI 10.1 to 15.7), p< 0.001. Patients with liver metastasis had a shorter median PFS 2.7 months and OS 7.5 months (95% CI 6.3-8.8) when compared with patients with no liver metastasis with PFS 4.3 months (95% CI: 2.5 to 2.9), p=0.002 and OS of 12 months (95% CI: 9.3-14.7), p=0.001. Patients who were in the GPC group and had no liver metastasis had an improved median OS of 13.9 months when compared with the rest of patients in whom median OS was 7.8 (95% CI 7.2 to 20.7), p=0.002. Multivariable analysis showed that GPC was an independent prognostic factors for OS (HR 0.582; 95% CI 0.3-0.8; p=0.005). Grade 3 neutropenia was an independent prognostic factor for PFS (HR 0.55; 95% CI 0.39-0.79; p=0.001) and OS (HR0.4; 95% CI 0.2-0.6; P< 0.001). Conclusion Our RWD on TFT was associated with a better OS than expected. This RWD study was able to validate GPC, GPC with no liver metastases and grade ≥ 3 neutropenia as subgroups benefiting the most from TFT.
    • Triple wild-type' co-mutational profile in early-stage KRAS-mutant lung cancer

      Lindsay, Colin R; Nicola, P.; Jamal-Hanjani, M.; Wallace, A.; Wilson, G.; Burghel, G.; Schlecht, H.; Baker, K.; Baker, E.; Priest, Lynsey; et al. (2020)
      Introduction: Kirsten rat sarcoma viral oncogene (KRAS) is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC), occurring in approximately 30% of cases. Recent work suggests KRAS -mutant (KRASm) NSCLC is a microcosm for diverse immune checkpoint inhibitor responses, partly dictated by its co-mutation with TP53 (?KP? group=~1/3 cases, ?immune hot?), STK11 (?KL? group=~1/3 cases, ?immune cold?) or CDKN2A (?KC? group=~1/3 cases). Here we identify and describe genomic and clinical associations of a further subset of KRASm NSCLC defined by ?triple WT? status for common KRASm co-mutations. Method: Sequencing results from 364 early-stage NSCLC cases from the Cancer Research UK TRACERx program (whole-exome sequencing) and the Genomics England 100,000 genome program (whole-genome sequencing) were analyzed for KRASm, associated co-mutations in TP53, STK11 and CDKN2A, copy number changes in the RAS-RAF-MEK-ERK axis, tumor mutational burden (TMB) and mutational signatures. Clinical demographics and factors including tumor size, nodal status and stage were ascertained and assessed for statistical associations with sequencing data using the Mann-Whitney and Fisher?s exact tests. Results: Overall, 143/364 lung cancer cases (39%) were KRASm with 65/143 (45%) tumors identified as ?KP,? 26/143 (18%) as ?KL,? and 3/143 (2%) as ?KC.? There were 49/143 KRASm cases (34%) with no co-mutation in TP53, STK11 or CDKN2A, defined as ?triple wild-type? (triple WT). Relative to the KP, KL and KC genotypes, there was a positive association of the KRAS G12D mutation with triple WT status: 10/49 cases, 20%; KP/KL/KC: 6/94 cases, 6%; p=0.022). In the 100,000-genome cohort, TMB was similar for the triple WT and KL groups but significantly lower than that observed for KP (KP: median 10.55 mut/Mb, 95% CI 8.8-15.33; triple WT: median 6.96, 95% CI 4.87-12.53; p=0.036). Despite this lower median TMB, smoking-associated mutational signature 4 was common in triple WT tumors (triple WT: 13/14 pts, 93%; overall 76/114 pts, 67%). In the triple WT group overall, there was a reduction of >50% in cancers with copy number changes of NF1 and NRAS. There was an inverse association between pathologic stage III tumors and KRASm triple WT genotype (p=0.0014). Conclusion: There are a significant proportion of KRASm NSCLC patients whose tumors are triple WT for TP53, STK11 and CDKN2A. Despite their high frequency of smoking-associated mutational signatures, these tumors are characterized by low TMB and are more common in early-stage disease. They also associate more commonly with KRAS G12D. Our observations suggest a discrete KRASm subset that may have implications for stratification in trials of immune checkpoint inhibitors and/or targeted therapeutics of KRASm tumors.