Lenz, Heinz‐Josef

TPS252 Background: Tucatinib (TUC), a highly selective HER2-directed TKI recently approved for HER2+ metastatic breast cancer (MBC), is being developed as a novel therapy for patients (pts) with metastatic colorectal cancer (mCRC) and other GI tumors. While trastuzumab (Tras) with chemotherapy is standard in the 1st-line setting for metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC), no anti-HER2 therapy has demonstrated an OS benefit over chemotherapy in 2nd-line, possibly due to loss of HER2 expression following Tras-based therapy. In GEC xenograft models, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone. Interim results from the MOUNTAINEER study have shown promising activity for TUC and Tras in HER2+ mCRC. The MOUNTAINEER-02 study is evaluating the efficacy and safety of TUC in combination with Tras, ramucirumab (Ram), and paclitaxel (Pac) in pts with HER2+ GEC. Methods: MOUNTAINEER-02 (NCT04499924) is a phase 2/3 study evaluating TUC and Tras with the 2nd-line standard of care, Ram and Pac. Pts receive TUC 300 mg or placebo PO BID, Tras (6 then 4 mg/kg) or placebo (IV on Days 1 and 15 of each 28-day cycle), Pac (IV on Days 1, 8, 15), and Ram (IV on Days 1 and 15). Eligible pts have locally-advanced unresectable or metastatic HER2+ GEC, have received a HER2-directed antibody, and 1 prior line of therapy for advanced disease. Pts must be ≥18 years of age, with an ECOG ≤1, and have had no prior exposure to Ram, anti-HER2 or anti-EGFR TKI, HER2-directed antibody-drug conjugates, or taxanes ≤12 months before enrollment. Due to the potential impact of TUC on Pac metabolism, the study will include an initial Pac dose finding stage. The open-label phase 2 part will determine the recommended dose of Pac (60 or 80 mg/m²) combined with TUC, Tras, and Ram in 6-12 patients, and evaluate the safety and activity of the regimen in Cohorts 2A and 2B (30 patients each). The randomized, double-blind, phase 3 part will compare the efficacy and safety of TUC and Tras (Arm 3A; ~235 patients) vs. placebo (Arm 3B; ~235 patients), both in combination with Ram and Pac, and also evaluate activity of TUC with Ram and Pac (Arm 3C; ~30 patients). The dual primary phase 3 endpoints are OS and PFS per investigator, with confirmed ORR as a key secondary endpoint. HER2 status is determined at baseline using a blood-based NGS assay, and IHC/ISH of fresh or archival tumor biopsies, if available. Pts must be HER2+ by blood-based NGS in Cohort 2A and phase 3; in Cohort 2B, pts must be HER2+ in a biopsy taken post-progression during/after 1st-line therapy, but HER2-negative by blood-based NGS. Disease assessments per RECISTv1.1 will occur q6 weeks for 36 weeks, then q9 weeks. The pharmacokinetics of TUC, Pac, and their metabolites will be evaluated in a subset of pts, including a cohort with gastrectomies. Enrollment is ongoing in the U.S. Clinical trial information: NCT04499924.

TPS155 Background: Chemotherapy in combination with targeted agents are standard-of-care options for patients for mCRC with response rates > 50% in first line. In the second line setting, efficacy of chemotherapy and targeted agents are much lower with response rates of 5% for FOLFIRI (5-fluorouracil, leucovorin, irinotecan) + bevacizumab (anti-VEGF). New treatment options are urgently needed in particular for the 50 % of patients harboring a KRAS mutation. PLK1 is a serine/threonine kinase, master regulator of the mitotic checkpoint and cell division. PLK1 is overexpressed in CRC and its overexpression is associated with poor prognostic. A genome wide RNAi screen identified PLK1 as a synthetic lethal target in KRAS mutant CRC cells, inducing cell cycle arrest and apoptosis upon inhibition. Onvansertib is an oral, highly selective PLK1 inhibitor that demonstrates single agent and synergistic activity with irinotecan and 5-FU in preclinical CRC models. Additionally, KRAS mutated versus wild-type cells showed higher sensitivity to onvansertib. PLK1 inhibition is a potential target in KRAS-mutated mCRC, and the combination of onvansertib + FOLFIRI + bevacizumab may provide a new second-line treatment option. Methods: The primary objective of this single-arm Phase 1b/2 study is to assess the safety and preliminary efficacy of onvansertib in combination with FOLFIRI and bevacizumab in the second line setting for KRAS-mutated mCRC patients. For the Phase 1b segment, a standard 3 + 3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase 2 dose (RP2D) of onvansertib. As of September 15th 2020, the first two dose levels have been cleared for safety and the third is enrolling. Efficacy will be determined by objective response rate (ORR) according to RECIST v1.1 (primary endpoint), progression-free survival and reduction in KRAS allelic burden in liquid biopsies (secondary endpoints). Biomarker analyses include genomic profiling of circulating tumor DNA genomic to evaluate altered pathways that correlate with patient clinical response. Based on a one-sided one sample log-rank test with 10% Type I error, there will be at least 90% power to detect an improvement in ORR from 5% to 20% with 32 patients. Clinical trial information: NCT03829410.

TPS143 Background: Patients with KRAS and NRAS ( RAS) wild-type mCRC benefit from the epidermal growth factor receptor (EGFR) monoclonal antibodies (Abs) panitumumab and cetuximab, but nearly all patients experience resistance. Blood-based profiling of cell free DNA (cfDNA) can identify genomic alterations that drive acquired EGFR Ab resistance. After discontinuation of anti-EGFR Abs, acquired genomic alterations decay over time to undetectable levels. Some studies have suggested clinical benefit from EGFR Ab rechallenge, but there is limited evidence that EGFR Ab rechallenge improves survival compared to standard of care (SOC) therapies. We hypothesize that cfDNA profiling will identify patients appropriate for panitumumab rechallenge, and that these molecularly selected patients will have improved survival compared to current SOC therapies. Methods: This is a randomized phase II, open label study designed to compare the overall survival (OS) of panitumumab rechallenge versus SOC (investigator choice TAS-102 or regorafenib). Secondary objectives include comparisons of progression free survival, objective response rate, clinical benefit rate, and quality of life as measured by the linear analogue self-assessment (LASA) questionnaire. Eligible patients have radiographically measurable KRAS, NRAS, and BRAF codon 600 wild-type mCRC based on tumor tissue testing, and must have experienced progression or intolerance to treatment with a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF Ab, and an anti-PD-1 Ab if the tumor has mismatch repair deficiency or is MSI-H. Progression after at least 4 months treatment with an anti-EGFR Ab is required. All patients must be enrolled in the COLOMATE cfDNA screening protocol (NCT03765736) and meet molecular eligibility based on Guardant360 cfDNA profiling (absence of amplification of ERBB2, KRAS, NRAS, and MET; absence of mutations of BRAF, EGFR, ERBB2, KRAS, NRAS, and MET [mutant allele frequency > 0.5%]). Greater than 90 days must have elapsed between the most recent treatment with an anti-EGFR Ab and cfDNA profiling. Dosing for all study drugs is according to clinical SOC. 120 patients will be randomized 1:1 to panitumumab rechallenge or SOC. With 83 OS events, this study will have 80% power to detect an improvement in median OS from 6.5 to 10 months (HR=0.65; 1-sided α= 0.15). This study began enrollment in 6/2020. Recruitment is ongoing at 16 sites in the Academic and Community Cancer Research United (ACCRU) network (ACCRU-GI-1623). Clinical trial information: NCT03992456.

Abstract Purpose: Irinotecan/5-fluorouracil (5-FU; FOLFIRI) or oxaliplatin/5-FU (FOLFOX), combined with bevacizumab or cetuximab, are approved, first-line treatments for metastatic colorectal cancer (mCRC). We aimed at identifying germline variants associated with survival in patients with mCRC treated with these regimens in Cancer and Leukemia Group B/SWOG 80405. Experimental Design: Patients with mCRC receiving either FOLFOX or FOLFIRI were randomized to either cetuximab or bevacizumab. DNA from peripheral blood was genotyped for approximately 700,000 SNPs. The association between SNPs and overall survival (OS) was tested in 613 patients of genetically estimated European ancestry using Cox proportional hazards models. Results: The four most significant SNPs associated with OS were three haplotypic SNPs between microsomal glutathione S-transferase 1 (MGST1) and LIM domain only 3 (LMO3, representative HR, 1.56; P = 1.30 × 10−6), and rs11644916 in AXIN1 (HR, 1.39, P = 4.26 × 10−6). AXIN1 is a well-established tumor suppressor gene in colorectal cancer, and rs11644916 (G>A) conferred shorter OS. Median OS for patients with the AA, AG, or GG genotypes was 18.4, 25.6, or 36.4 months, respectively. In 90 patients with stage IV colorectal cancer from The Cancer Genome Atlas (TCGA), rs11649255 in AXIN1 [in almost complete linkage disequilibrium (LD) with rs11644916], was associated with shorter OS (HR, 2.24, P = 0.0096). Using rs11648673 in AXIN1 (in very high LD with rs11644916 and with functional evidence), luciferase activity in three colorectal cancer cell lines was reduced. Conclusions: This is the first large genome-wide association study ever conducted in patients with mCRC treated with first-line standard treatment in a randomized phase III trial. A common SNP in AXIN1 conferred worse OS and the effect was replicated in TCGA. Further studies in colorectal cancer experimental models are required.

Abstract Extensive biological and clinical evidence supports the notion many CRC tumors are addicted to EGFR/KRAS/MAPK signaling. For example, mutations in KRAS, BRAF and other MAPK pathway components confer intrinsic or acquired resistance to anti-EGFR therapy. However, a significant proportion of acquired resistance cases have remained unexplained. ARID1A mutations are found in approximately 11% of CRC tumors, but a connection between ARID1A mutations and EGFR/MAPK signaling activation in CRC has not been previously suspected. By leveraging the genomic biomarker data collected from 333 patients at baseline and at progression who participated in the CALGB/SWOG 80405 trial, we found that mutations in ARID1A, a key component of SWI/SNF complex, were enriched in the cell free DNA of 6/16 of the patients whose tumors had become resistant to anti-EGFR therapy with ARID1A mutations detected at either timepoint (adj. p = 0.03, OR = 0.09, two-tailed fisher's exact test). In contrast, there was no evidence of enriched ARID1A mutations in patients treated with bevacizumab. To investigate the potential role of a broader ARID1A deficiency phenotype in resistance to cetuximab therapy, we developed an ARID1A mutant-like signature from TCGA that captures the transcriptional profile characteristic of ARID1A mutants. Using this signature to stratify CALGB patients based on gene expression data collected on tissue at diagnosis, we also found patients with an ARID1A mutant-like gene expression profile had worst outcome in patients treated with cetuximab than bevacizumab with adjustment for established clinical variables for both OS [p = 0.0002, hazard ratio (HR) 6.2, 95% confidence interval (CI) 2.4-16], and PFS [p = 0.0008, HR 4.7 (1.9 -12)], suggesting that ARID1A mutations may be also a mechanism of intrinsic resistance to anti-EGFR therapies. Gene expression analysis demonstrated that ARID1A deficiency leads to re-activation of an EGFR-like signature, suggesting reactivation of this pathway as a possible mechanism of resistance. Furthermore, CRISPR knockout of ARID1A in the cetuximab-sensitive CRC cell line NCI-H508 conferred elevated MAPK signaling relative to parental line and resistance to cetuximab in culture. Consistent with these findings, we also observed strong mutual exclusivity between ARID1A mutations and mutations in the EGFR/MAPK signaling pathway in more than 40,000 lung and colorectal cancer patients profiled in the FoundationCore® database. Strikingly, in lung cancers where EGFR mutations structural variants (SV) are more prevalent, EGFR SV was the top mutually exclusive alteration with ARID1A mutations in lung cancers. Of 5980 lung cancer patients with ARID1A and/or EGFR SVs, only 100 patients (1.7%) had both SVs. Taken together, our data suggest that ARID1A loss-of-function mutations may promote resistance to cetuximab by driving an EGFR-like transcription program in the absence of ligand-dependent activation of EGFR. Our results suggest that ARID1A defects could be potentially used as an exclusion biomarker for cetuximab treatment decisions, and they provide a rationale for exploring therapeutic MAPK inhibition in ARID1A mutant CRC patients. Citation Format: Radia Marie Johnson, Xueping Qu, Joshua Thomas, Yvonne Kschonsak, Ling-Yuh Huw, Fang-Shu Ou, Ethan Sokol, Nnamdi Ihuegbu, Oliver Zill, Omar Kabbarah, Anneleen Daemen, Richard Bourgon, Alan Venook, Federico Innocenti, Heinz-Josef Lenz, Felipe de Sousa e Melo, Carlos Bais. ARID1A mutations induce an EGFR-like gene expression signature and confer intrinsic and acquired resistance to cetuximab treatment in first line metastatic CRC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-063.

Abstract Background: Chemotherapy in combination with targeted agents are standard-of-care options for patients for mCRC with response rates >50% in first line. In the second line setting, efficacy of chemotherapy and targeted agents are much lower with response rates of 5% for FOLFIRI (5-fluorouracil, leucovorin, irinotecan) + bevacizumab (anti-VEGF). New treatment options are urgently needed in particular for the 50 % of patients harboring a KRAS mutation. Polo-like kinase 1 (PLK1) is a serine/threonine kinase, master regulator of the mitotic checkpoint and cell division. PLK1 is overexpressed in CRC and its overexpression is associated with poor prognostic. A genome wide RNAi screen identified PLK1 as a synthetic lethal target in KRAS mutant CRC cells, inducing cell cycle arrest and apoptosis upon inhibition. Onvansertib is an oral, highly selective PLK1 inhibitor that demonstrates single agent and synergistic activity with irinotecan in preclinical CRC models. Additionally, KRAS mutated vs wild-type cells showed higher sensitivity to onvansertib. PLK1 inhibition is a potential target in KRAS-mutated mCRC and onvansertib + FOLFIRI + bevacizumab may provide a new second-line treatment option. Trial design: The primary objective of this single-arm Phase 1b/2 study is to assess the safety and preliminary efficacy of onvansertib in combination with FOLFIRI and bevacizumab in the second line setting for KRAS-mutated mCRC patients. For the Phase 1b segment, a standard 3 + 3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase 2 dose (RP2D) of onvansertib. As of January 24th 2020, enrollment in the second dose level is ongoing. Efficacy will be determined by objective response rate (ORR) according to RECIST v1.1 (primary endpoint), progression-free survival and reduction in KRAS allelic burden in liquid biopsies (secondary endpoints). In the phase 2, based on a one-sided one sample log-rank test with 10% Type I error, there will be at least 90% power to detect an improvement in ORR from 5% to 20% with 26 patients. Exploratory endpoints include genomic studies of circulating tumor cells and ctDNA to evaluate altered pathways that correlate with patient response. Clinical trial identification NCT03829410. Citation Format: Afsaneh Barzi, Heinz-Josef Lenz, Errin Samuëlsz, Maya Ridinger, Mark Erlander, Tanios S. Bekaii-Saab, Daniel H. Ahn. A phase 1b/2 study of onvansertib (PCM-075) in combination with FOLFIRI and bevacizumab for second line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT235.

AbstractBackgroundEnergy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study.MethodsBaseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute–sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided.ResultsMedian follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; Pnonlinearity < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; Ptrend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; Ptrend < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; Ptrend < .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (Pnonlinearity = .03).ConclusionsAmong patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.

TPS4116 Background: Chemotherapy in combination with targeted agents are standard-of-care options for patients for mCRC with response rates >50% in first line. In the second line setting, efficacy of chemotherapy and targeted agents are much lower with response rates of 5% for FOLFIRI (5-fluorouracil, leucovorin, irinotecan) + bevacizumab (anti-VEGF). New treatment options are urgently needed in particular for the 50 % of patients harboring a KRAS mutation. PLK1 is a serine/threonine kinase, master regulator of the mitotic checkpoint and cell division. PLK1 is overexpressed in CRC and its overexpression is associated with poor prognostic. A genome wide RNAi screen identified PLK1 as a synthetic lethal target in KRAS mutant CRC cells, inducing cell cycle arrest and apoptosis upon inhibition. Onvansertib is an oral, highly selective PLK1 inhibitor that demonstrates single agent and synergistic activity with irinotecan in preclinical CRC models. Additionally, KRAS mutated vs wild-type cells showed higher sensitivity to onvansertib. PLK1 inhibition is a potential target in KRAS-mutated mCRC, and the combination of onvansertib + FOLFIRI + bevacizumab may provide a new second-line treatment option. Methods: The primary objective of this single-arm Phase 1b/2 study is to assess the safety and preliminary efficacy of onvansertib in combination with FOLFIRI and bevacizumab in the second line setting for KRAS-mutated mCRC patients. For the Phase 1b segment, a standard 3 + 3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase 2 dose (RP2D) of onvansertib. As of January 24, 2020, enrollment in the second dose level is ongoing. Efficacy will be determined by objective response rate (ORR) according to RECIST v1.1 (primary endpoint), progression-free survival and reduction in KRAS allelic burden in liquid biopsies (secondary endpoints). In the phase 2, based on a one-sided one sample log-rank test with 10% Type I error, there will be at least 90% power to detect an improvement in ORR from 5% to 20% with 26 patients. Exploratory endpoints include genomic studies of circulating tumor cells and ctDNA to evaluate altered pathways that correlate with patient clinical response. Clinical trial information: NCT03829410 .