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140 Background: HER2 ( ERBB2) over-expression and amplification (HER2+) is seen in a small but distinct subset (2-3%) of mCRC and is enriched in RAS/BRAF wild type (WT) tumors. This subset is characterized by a limited response to anti-epidermal growth factor receptor monoclonal antibody-based (anti-EGFR) therapy and a promising response to dual-HER2 inhibition. Methods: In this multicenter, open label, randomized, phase 2 trial, we enrolled 54 patients with RAS/BRAF WT HER2+ mCRC who had had disease progression after 1 or 2 previous therapies. HER2 status was confirmed centrally with immunohistochemistry (IHC) and in-situ hybridization (ISH). HER2+ was defined as IHC 3+ or 2+ and ISH amplified (dual-probe HER2/CEP17 ratio > 2.0). Patients were then randomly assigned in a 1:1 ratio to receive either TP (trastuzumab [loading 8 mg/kg then 6 mg/kg] + pertuzumab [loading 840 mg then 420 mg] every 3 weeks) or CETIRI (cetuximab 500 mg/m2 + irinotecan 180 mg/m2 every 2 weeks). Crossover was allowed for patients on CETIRI arm to TP (cTP) after progression. Restaging (per RECIST v1.1) was performed at 6 and 12 weeks and then every 8 weeks until progression. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), overall survival (OS) and safety. Results: A total of 54 (out of planned 62 due to low accrual) patients were randomized to TP (26) and CETIRI (28) between 10/2017 and 12/2021. By 8/18/2022, 20 patients had crossed over to cTP arm. One CETIRI patient was not analyzable. The results for key endpoints by protocol defined stratification factors, prior irinotecan (Piri) (yes or no) and HER2/CEP17 ratio (HCR) (>5 or ≤5), are summarized as of data cut-off of 9/6/2022. PFS did not vary significantly by treatment: medians 4.4 (95%CI: 1.9 – 7.6) months in TP group and 3.7 (95%CI: 1.6 – 6.7) months in CETIRI group (p = 0.35). Grade ≥3 adverse events occurred in 23%, 46% and 40% of patients in TP, CETIRI and cTP groups. Conclusions: Dual-HER2 inhibition with TP appears to be a safe and effective treatment option for patients with RAS/BRAF WT HER2+ mCRC with a promising response rate of 31%. Higher level of HER2 amplification may provide a greater degree of clinical benefit from TP compared to CETIRI. Future correlative efforts will explore biomarkers of response/resistance with this strategy. Clinical trial information: NCT03365882 . [Table: see text]

Introduction: Insomnia is a significant co-morbidity for cancer survivors, and can independently reduce lifespan, but there is currently no objective biochemical measure of insomnia. Circadian rhythms are 24 hour cycles that control physiologic processes including sleep. Disrupted circadian rhythms have been proposed as a cause of insomnia. Here, we describe the use of a novel biomarker, BloodCCD, to assess circadian rhythms from RNA-sequencing of blood samples from two independent clinical trials and one observational study. BloodCCD was adapted from Clock Correlation Distance (CCD), which assesses normal progression of the molecular circadian clock from gene expression in tissue samples. We used BloodCCD to interrogate whether 1) cancer patients and survivors with insomnia have disrupted circadian rhythms compared to healthy good sleepers, and 2) whether the degree of circadian disruption correlates with severity of insomnia in survivors. Methods: For BloodCCD analysis, time-series RNA-sequencing of human blood from healthy subjects were used to construct a reference correlation matrix of 42 genes which oscillate with 24-hour rhythms. To assess the Aims, RNA-sequencing from patient and survivor blood samples were compared to this reference correlation matrix to generate a BloodCCD score. A higher score indicates a further distance from a healthy clock, and thus clock disruption. For the first Aim, blood RNA-sequencing from cancer patients undergoing active treatment and survivors at least 2-months post-treatment and with insomnia were compared to healthy good sleepers. For the second Aim, blood RNA-sequencing from cancer survivors with insomnia were assessed, stratified by Insomnia Severity Index (ISI) Score into mild (ISI 10-14), moderate (ISI 15-21), and severe (ISI 22-28) insomnia. Results: Patients (n=28, 100% prostate cancer) and cancer survivors (n=497, ~72% breast cancer) had higher BloodCCD scores, indicating disrupted circadian clock, compared to healthy good sleepers (n=14), with scores of 9.98, 7.99, and 4.13, respectively. When cancer survivors were stratified by insomnia severity, those with severe insomnia (ISI 22-28) had the highest BloodCCD, 9.00, while those with moderate insomnia (ISI 15-21) had a score of 8.24 and those with mild insomnia (ISI 10-14) had the lowest score of 7.93, indicating that survivors with severe insomnia had a more disrupted circadian clock. All BloodCCD values were p < 0.001 for each value compared to reference correlation. Conclusions: BloodCCD shows promise as a biomarker to biochemically detect disrupted circadian rhythms in cancer patients and survivors, and as a readout for insomnia severity. Future studies should investigate whether BloodCCD improves in cancer survivors receiving interventions for insomnia. Funding: UG1CA189961-07S1 (NCI BIQSFP Program), UG1CA189961 (URCC NCORP), T32CA102618 (URCC T32 program), K07CA221931 Citation Format: Brian J. Altman, Javier Bautista, Eva Culakova, Kristina M. Morris, Rachel E. DeRollo, Elliot Outland, Amber Kleckner, Ian R. Kleckner, Nikesha J. Gilmore, Benjamin T. Esparaz, Charles S. Kuzma, Amy C. Vander Woude, Po-Ju Lin, Jacob J. Hughey, Karen M. Mustian. BloodCCD is a novel biomarker to detect circadian rhythm disruption in cancer survivors with insomnia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3215.