Lessons from Tarceva in pancreatic cancer: where are we now, and how should future trials be designed in pancreatic cancer?

PURPOSE OF REVIEW: The recent advances in the use of targeted therapy in pancreatic cancer are based on the knowledge of genetic alterations that occur during pancreatic carcinogenesis. We describe the repository of frequent alterations targeting tumour suppressor genes and oncogenes. We focus our attention on the epidermal growth factor receptor signalling pathway, which can be activated through different alterations and seems to play a central role in the cell transformation. Multiple targeted drugs have been developed against different partners of this network trying to improve the treatment of pancreatic cancer patients. RECENT FINDINGS: Tarceva has obtained approval in the USA and Europe for metastatic pancreatic cancer with a modest increase of median survival and a 6% increase in 1-year survival rates, suggesting that only a small fraction of patients truly benefit from it. The comparison with lung and colon cancer suggests that Kras mutations could be a predictive marker of resistance. Other promising drugs targeting different partners of the epidermal growth factor receptor signalling pathway could play a synergistic role with Tarceva as inhibitors of mTOR, mitogen-activated protein kinase kinase 1, and nuclear factor-kappaB or can directly turn down Ras. SUMMARY: The biology of the epidermal growth factor receptor, mitogen-activated protein kinase, PI3K/mTOR network suggests that a combination of drugs targeting simultaneously different partners should improve survival

0328: Assessment of radiation exposure during cardiac device implantation: lessons learned from a multicenter registry

BackgroundFew data exist about radiation exposure during implantation of cardiac electrical device. No dose reference levels (DRLs) were reported.Purpose to define DRLs and to analyze factors related to an increased radiation dose delivered to patients and medical staff.Methods the Raypace study is a multicenter, prospective observational registry. Using a national database, patient demographic, procedural and radiation data were collected. Fluoroscopy time (FT) and dose-area product (DAP) were registered. Physician/staff exposure was measured using 2 real-time personal dosimeters, one worn under the lead apron and the other one worn outside the apron. Statistical analysis used log-transformation of DAP, FT and DAP/FT ratio.ResultsA total of 657 procedures from 9 institutions were reviewed. Pacemaker (PM) and cardioverter-defibrillator (ICD) implantation was performed in 481 and 176 patients, respectively. A cardiac resynchronization device was implanted in 153 patients. Fluoroscopy time was similar for PM and ICD implantations. Median fluoroscopy time was 836, 117 and 101 second and median DAP was 1410, 150 and 129 cGy.cm2 for biventricular, dual chamber and ventricular device implantation, respectively. LAO projection, in addition to AP projection, was used in 47% of the procedures. Five centers out of 9 used collimation. The median Hp (10) effective dose measured outside the lead apron was 4.6 µSv and 0.1 µSv under the lead apron.Regarding CRT implant procedures, four systems out of 6 were responsible for an increased exposure (p<0.001). DRLs were 2600, 338 and 332 cGy.cm2 for biventricular, dual chamber and ventricular device implantation, respectively.ConclusionsDAP reduction was improved with the use of latest generators but needed customized settings. Biventricular device implantation was responsible for the highest radiation exposure. However, radiation exposure during those procedures have decreased as compared to previously reported values

Duration of adjuvant chemotherapy for stage III colon cancer

BACKGROUND Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. METHODS We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. RESULTS After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). CONCLUSIONS Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.

The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration: Prospective Combined Analysis of Phase III Trials Investigating Duration of Adjuvant Therapy with the FOLFOX (FOLFOX4 or Modified FOLFOX6) or XELOX (3 versus 6 months) Regimen for Patients with Stage III Colon Cancer: Trial Design and Current Status

The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration was established to prospectively combine and analyze data from several randomized trials conducted around the world to answer whether a three-month course of oxaliplatin-based adjuvant therapy (FOLFOX4/modified FOLFOX6 or XELOX) is non-inferior to the current standard six-month treatment for patients with stage III colon cancer, with a primary endpoint of three years disease-free survival. The IDEA steering committee comprises two members from each group coordinating an individual trial and two members from a secretariat who coordinate combining of the data and management of the joint analysis. Members of the IDEA agreed to combine the data from their individual trials to enable definitive analysis consisting of at least 10,500 patients. With accrual of 8,797 patients at the end of February 2013, the IDEA is on track to achieve its accrual objective of at least 10,500 patients by the end of 2013

Trifluridine/tipiracil with or without bevacizumab in metastatic colorectal cancer: results of a systematic review and meta-analysis

Background: Trifluridine/tipiracil plus bevacizumab (FTD/TPI + BEV) has shown efficacy and tolerability in refractory metastatic colorectal cancer (mCRC). Because randomized controlled trial (RCT) data comparing FTD/TPI + BEV with FTD/TPI are lacking, this meta-analysis evaluated outcomes with both regimens. Data Sources and Methods: Electronic databases, congress proceedings (past 3 years), trial registries, systematic review bibliographies, gray literature, and guidelines through June 2021 were searched for RCTs, non-RCTs, and prospective observational studies involving &gt;20 previously treated patients with mCRC receiving FTD/TPI + BEV or FTD/TPI. Absolute and relative disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse event (AE) rates, and discontinuation rates due to AEs were evaluated using fixed-effects and random-effects models. Study quality, heterogeneity, and publication bias were assessed. Results: In all, 29 of 875 screened publications were selected (26 studies: 5 RCTs, 11 non-RCTs, and 10 prospective observational studies). One RCT compared FTD/TPI + BEV with FTD/TPI. FTD/TPI + BEV versus FTD/TPI had a higher absolute DCR [64% (6 studies; n = 289) versus 43% (10 studies; n = 2809)], median PFS [4.2 (5 studies; n = 244) versus 2.6 (6 studies; n = 1781) months], 12-month PFS [9% (5 studies; n = 244) versus 3% (6 studies; n = 1781)], median OS [9.8 (5 studies; n = 244) versus 8.1 (6 studies; n = 1814) months], and 12-month OS [38% (5 studies; n = 244) versus 32% (6 studies; n = 1814)]. Grade ⩾3 febrile neutropenia, asthenia/fatigue, diarrhea, nausea, and vomiting rates were similar (1%–7%). Grade ⩾3 neutropenia rate was higher with FTD/TPI + BEV than with FTD/TPI [43% (6 studies; n = 294) versus 29% (12 studies; n = 7139)]. Discontinuation rates due to AEs were similar [8% (5 studies; n = 244) and 7% (10 studies; n = 3724)]. Low study quality, heterogeneity, and/or publication bias were detected in certain instances. Conclusion: Despite fewer patients treated with the combination, this meta-analysis consistently suggested that FTD/TPI + BEV provides benefits over FTD/TPI in refractory mCRC and has similar safety, except for more frequent grade ⩾3 neutropenia

SEAMARK: phase II study of first-line encorafenib and cetuximab plus pembrolizumab for MSI-H/dMMR BRAFV600E-mutant mCRC

Immunotherapy; Metastatic colorectal cancer; Targeted therapyImmunoteràpia; Càncer colorectal metastàtic; Teràpia dirigidaInmunoterapia; Cáncer colorrectal metastásico; Terapia dirigidaPatients with both BRAF V600E mutations and microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) have poor prognosis. Currently, there are no specifically targeted first-line treatment options indicated for patients with mCRC whose tumors harbor both molecular aberrations. Pembrolizumab is a checkpoint inhibitor approved for the treatment of MSI-H/dMMR mCRC, and the BRAF inhibitor encorafenib, in combination with cetuximab, is approved for previously treated BRAF V600E-mutant mCRC. Combination of pembrolizumab with encorafenib and cetuximab may synergistically enhance antitumor activity in patients with BRAF V600E-mutant, MSI-H/dMMR mCRC. SEAMARK is a randomized phase II study comparing the efficacy of the combination of pembrolizumab with encorafenib and cetuximab versus pembrolizumab alone in patients with previously untreated BRAF V600E-mutant, MSI-H/dMMR mCRC.The SEAMARK study was sponsored by Pfizer, Inc. This study is in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Merck KGaA Darmstadt, Germany, and Eli Lilly and Company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed

Plain language summary of SUNLIGHT: trifluridine/tipiracil and bevacizumab for refractory metastatic colorectal cancer

Colorectal; Metastasis; RefractoryColorrectal; Metástasis; RefractarioColorrectal; Metàstasi; RefractariThis study was sponsored by Servier and Taiho Oncology, Inc. GWP has been an expert witness for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Hoffmann-La Roche, Merck KGaA, MSD, Novartis, Pierre Fabre, and Servier and has received consulting fees from Bayer. JT has received consulting fees from Amgen, Astellas, Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, and Servier. MW has received consulting fees from Amgen, Array BioPharma, AstraZeneca, Bayer, Bristol Myers Squibb, Genentech, Incyte, Mirati Therapeutics, Nouscom, PsiOxus Therapeutics, Taiho Oncology, Inc., and Xenthera. FC has received a research grant from Amgen, Bayer, AstraZeneca, Hoffmann-La Roche, and Merck KGaA and has received consulting fees from Bayer, Hoffmann-La Roche, Merck KGaA, Pfizer, Pierre Fabre, and Servier. EVC has received consulting fees from AbbVie, ALX Oncology, Amgen, Array BioPharma, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, Hoffmann-La Roche, GlaxoSmithKline, Incyte, Ipsen, Merck, Mirati Therapeutics, Nordic Pharma, Novartis, Pfizer, Pierre Fabre, Seattle Genetics, Servier, Taiho Pharmaceutical Co., Takeda Oncology, Terumo, and Zymeworks. EE has received speaker fees from Amgen, Merck, Organon, Pierre Fabre, Sanofi Aventis, and Servier and has received consulting fees from Bayer, Hoffmann-La Roche, and Novartis. GL has received consultancy fees from Danone and funding for an educational workshop from Servier. DPM has received honoraria for lectures from Amgen, AstraZeneca, Bristol Myers Squibb, Lilly Deutschland, Merck, Pierre Fabre., Seagen, Servier, and Taiho Pharmaceutical Co., consultancy fees from Amgen, Onkowissen, Pierre Fabre, and Takeda Oncology, grants from Amgen and Servier, funds toward travel from Amgen and Servier, and funding as a member of an endpoint review committee from Servier. JT has received consultancy fees from Array BioPharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly and Company, Hoffmann-La Roche, Genentech, HalioDX SAS, Hutchinson MediPharma, Ikena Oncology, Inspirna, IQVIA, Menarini, Merck Serono, Merus, MSD, NeoPhore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, SOTIO Biotech, Taiho Pharmaceutical Co., Tessa Therapeutics, and TheraMyc, has received support for an educational collaboration from Imedex /HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource (PER), and has stock in Oniria Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed

A phase Ia study of the MEK1/2 inhibitor PD-0325901 with the c-MET inhibitor crizotinib in patients with advanced solid cancers

MEK1/2 inhibitor; C-MET inhibitor crizotinib; Advanced solid cancersInhibidor de MEK1/2; Inhibidor de c-MET crizotinib; Cáncer sólido avanzadoInhibidor de MEK1/2; Inhibidor de c-MET crizotinib; Càncer sòlid avançatBackground: Single-agent MEK1/2 inhibition has been disappointing in clinical trials targeting RAS mutant (MT) cancers, probably due to upstream receptor activation, resulting in resistance. We previously found that dual c-MET/MEK1/2 inhibition attenuated RASMT colorectal cancer (CRC) xenograft growth. In this study, we assessed safety of MEK1/2 inhibitor PD-0325901 with c-MET inhibitor crizotinib and determined the optimal biological doses for subsequent clinical trials. Methods: In this dose-escalation phase I trial, patients with advanced solid tumours received PD-0325901 with crizotinib, using a rolling-6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. Blood samples for pharmacokinetics and skin biopsies were collected. Results: Twenty-five patients were recruited in 4 cohorts up to doses of crizotinib 200 mg B.D continuously with PD-0325901 8 mg B.D, days 1-21 every 28 days. One in six patients exhibited a dose-limiting toxicity at this dose level. Drug-related adverse events were in keeping with single-agent toxicity profiles. The best clinical response was stable disease in seven patients (29%). Conclusions: PD-0325901/crizotinib can be given together at pharmacologically-active doses. The MTD for PD-0325901/crizotinib was 8 mg B.D (days 1-21) and 200 mg B.D continuously in a 28-days cycle. The combination was further explored with an alternate MEK1/2 inhibitor in RASMT CRC patients. Eudract-number: 2014-000463-40.Funding was supported by MErCuRIC, funded by the European Commission’s Framework Programme 7, under contract ♯602901, research grants from Pfizer as well as the Tom Simms Memorial Fund in Queen’s University Belfast. SVS was supported by Cancer Research UK (C13749/A7261). VP was supported from Programme JAC - project SALVAGE (CZ.02.01.01/00/22_008/0004644) financed by MEYS – Co-funded by the European Union, and thanks the RECETOX Research Infrastructure (No LM2023069) financed by the Ministry of Education, Youth and Sports for supportive background. The research leading to these results has received funding from: AIRC under 5 per Mille 2018 - ID. 21091 program – P.I. Bardelli Alberto (A.B.); International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK (A26825 and A28223), FC AECC (GEACC18004TAB) and AIRC (22795) (A.B.); AIRC under IG 2023 - ID. 28922 project – P.I. Bardelli Alberto (A.B.); PRIN 2022 - Prot. 2022CHB9BA (A.B.). The study was sponsored by the University of Oxford

Impact of Treatment With Trifluridine/Tipiracil in Combination With Bevacizumab on Health-Related Quality of Life and Performance Status in Refractory Metastatic Colorectal Cancer: An Analysis of the Phase III SUNLIGHT Trial

Chemotherapy; Patient-reported outcomes; VEGF inhibitorQuimioteràpia; Resultats informats pels pacients; Inhibidor de VEGFQuimioterapia; Resultados informados por los pacientes; Inhibidor de VEGFBackground: The efficacy of trifluridine/tipiracil (FTD/TPI) + bevacizumab compared to FTD/TPI for treatment of refractory metastatic colorectal cancer (mCRC) was demonstrated in the SUNLIGHT trial. This analysis of SUNLIGHT investigated the impact of treatment with FTD/TPI + bevacizumab on patient quality of life (QoL) and Eastern Cooperative Oncology Group performance status (ECOG PS). Methods: Questionnaires (EORTC QLQ-C30 and EQ-5D-5L) and ECOG PS assessments were conducted at baseline and on Day 1 of each treatment cycle. Time to definitive deterioration (TTDD) of QoL and time to ECOG PS worsening between treatment arms was assessed. A repeated-measures mixed-effects model was used to compare changes in QoL and ECOG PS from baseline. Kaplan-Meier and Cox regression methods were used to assess TTDD of QoL, time to ECOG PS worsening to ≥ 2, and overall survival (OS) and progression-free survival (PFS) in patients maintaining an ECOG PS of 0-1. Results: Both treatment arms showed similar QoL scores from baseline to cycle 6, with no clinically relevant change over time. Patients receiving FTD/TPI + bevacizumab had a longer TTDD of QoL than patients receiving FTD/TPI, as well as longer time to ECOG PS worsening. In patients with maintained ECOG PS, median OS and PFS was prolonged in the FTD/TPI + bevacizumab arm compared to the FTD/TPI arm. Conclusion: This analysis of SUNLIGHT showed that patients treated with FTD/TPI + bevacizumab had no clinically relevant changes in QoL, and prolonged TTDD and time to ECOG PS worsening, compared to patients treated with FTD/TPI