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Background MEK inhibition may overcome resistance to EGFR inhibition alone in patients (pts) with RAS wt mCRC. We evaluated the antitumor activity of T (MEK1/2 inhibitor) with Pmab (EGFR monoclonal antibody) in a phase II trial. Methods Pts with KRAS, NRAS, and BRAF wt mCRC with prior 5-FU, irinotecan, oxaliplatin, +/- bevacizumab and no prior EGFR therapy were treated with T 1.5mg oral daily and Pmab 4.8mg/kg IV every 2 weeks. Primary endpoint was clinical benefit (CB; CR, PR or SD ≥ 24 weeks) by RECIST v1.1. A 2-stage minimax design (p0=0.20, p1=0.45, 1-sided alpha=0.05, power=0.85) required ≥4/13 patients with CB in stage I and ≥8/26 patients with CB by end of stage II. Response assessments were performed every 4 cycles (C). Adverse events (AEs) were assessed by CTCAE v4.03. Tumor biopsies were performed before C1 and during C2. Plasma circulating free DNA (cfDNA) collected before C1, C2, C3 and every 2 subsequent C and were profiled using the Oncomine Lung cfDNA assay. Results There were 13 pts enrolled from Nov2015 to Dec2018. Of 12 evaluable patients, best response was confirmed PR (n = 3), unconfirmed PR (n = 5), and SD (n = 4) (unconfirmed ORR 67%). Two patients achieved CB ≥ 24 weeks (2/10; 20%) and two patients are still on trial with PR not yet evaluable for CB. The most common treatment-related AE (trAE) was acneiform rash (85%) including 31% with grade 3. Other trAEs were diarrhea (62%), mucositis (46%), maculopapular rash (54%), and vomiting (31%). Dose modifications and interruptions of T occurred in 69% of patients and 54% of patients receiving Pmab had dose modifications. Median PFS is 4.4 months (95% CI 2.9-7.1). Of 3 pts with serial cfDNA profiling results available, none had KRAS, NRAS, or BRAF mutations detectable before treatment, and 1 patient demonstrated polyclonal KRAS, NRAS, and BRAF mutations at C5 before radiographic progression at C9. Conclusions The addition of T to Pmab leads to a high rate of tumor shrinkage in RAS/RAF wt mCRC. Median PFS is similar to Pmab alone in the ASPECCT trial, which may be due to a high incidence of skin toxicity with the combination that leads to dose interruption and/or reduction. Additional results from cfDNA and tumor biopsies will be presented. Clinical trial identification NCT02399943. Legal entity responsible for the study Philippe Bedard. Funding Conquer cancer foundation of ASCO career development (Dr P. Bedard), Canadian Cancer Research Society Institute innovation grant (Dr P. Bedard), and drug supply from GlaxoSmithKline and Novartis. Disclosure A.R.R. Albiruni: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): CASI Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Genentech/ Roche; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Adaptimmune. A. Spreafico: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Oncorus; Research grant / Funding (institution): Symphogen AstraZeneca / Medimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Surface Oncology; Research grant / Funding (institution): Northern Biologics; Research grant / Funding (institution): Janssen Oncology/ Johnson & Johnson. A.R. Hansen: Advisory / Consultancy, Research grant / Funding (institution): Genentech/ Roche; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy, Research grant / Funding (institution): Boehringer-Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Medimmune. L.L. Siu: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/ MedImmune; Advisory / Consultancy: Morphosys; Advisory / Consultancy: Roche; Advisory / Consultancy: GeneSeeq; Advisory / Consultancy: Loxo; Advisory / Consultancy: Oncorus; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): AbbVie. P. Bedard: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): SERVIER; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): SignalChem; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly. All other authors have declared no conflicts of interest.

Background The goal of phase I trials is to determine adverse event (AE) profiles of new therapies. Typically, AEs are captured by clinicians, yet patient reported outcome (PRO) tools collect AEs which may be under reported. Our single center, prospective study aimed to validate PRO-CTCAE in phase I clinical trial patients (pts). Methods Pts eligible for phase I trials at Princess Margaret Cancer Centre were evaluated using tablet based, PRO-CTCAE with the full item library (n = 80) in addition to standard, matched clinician reported CTCAE grading of AEs at baseline (BL), mid cycle 1 (C1) and 2 (C2). Overall (BL + C1 + C2) totals were also assessed. Characteristics (age, gender, tumor group, ECOG, education), best response (using RECIST v1.1), and treatment information were collected. Comparative (kappa) statistics were used to assess agreement of patient and clinician reported AEs. Results Of 292 pts approached (05/2017 to 01/2019), 265 (91%) were consented and 243 (92%) were evaluable, with 552 surveys completed. Median age was 61 (range 18-82), 51% were female, and 79% were ECOG 1; with GI (31.7%), head and neck (13.2%), and breast (10.7%) as frequent tumor types. Pts were commonly treated with immune (66%) and/or targeted (21%), mono (35%) or combination (61%) therapy. PRO-CTCAE completion rates were high (98.7%), with fatigue (75%), pain (68%), and anxiety (54%) as often reported overall patient AEs. Common physician reported AEs were fatigue (41%), pain (39%) and insomnia (18%). Overall patient-clinician agreement (kappa), was poor for fatigue (0.12) and anxiety (0.08), and fair for pain (0.28). Clinician reported insomnia (0.2) was fair. Highest patient-clinician agreement was seen for dyspnea at BL (0.54), and edema (0.55) and rash (0.49) at C2. Despite patient reporting, clinicians did not report select AEs (palpitations, hiccups, vaginal dryness), and had poor overall agreement for cognitive (0-0.03), urinary (0.02-0.05), and mood (0.05-0.08) symptoms. Conclusions Completion of PRO-CTCAE was high in phase I trial pts. Clinician reported AEs had poor to fair agreement compared with PRO-CTCAE, suggesting under-reporting in phase I trials. This information could inform a phase I PRO survey to complement clinician reported AEs. Analyses are ongoing. Legal entity responsible for the study Drug Development Department, Princess Margaret Cancer Centre. Funding Has not received any funding. Disclosure A.A. Razak: Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (institution): CASI; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): BMS; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Amgen; Honoraria (self): Boehringer Ingelheim. A. Spreafico: Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: Oncorus; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Surface Oncology; Research grant / Funding (institution): Northern Biologics; Research grant / Funding (institution): Janssen Oncology/Johnson & Johnson. P. Bedard: Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Servier; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): SignalChem; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly; Research grant / Funding (self): Pfizer. L.L. Siu: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: Loxo; Advisory / Consultancy: Oncorus; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy: Morphosys; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy: GeneSeeq; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Boehringer-Ingelheim; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Intensity Therapeutics; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Mirati. A.R. Hansen: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): GSK; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Boehringer-Ingelheim; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Karyopharm. All other authors have declared no conflicts of interest.