RAS Wt Research Articles

KRAS, NRAS and BRAF mutational status and first line treatment patterns in Slovenian population with metastatic colorectal carcinoma: Five year results.

e15546 Background: A phase IV non-interventional study was performed from 2013 till 2018 including 650 patients with primary aim to assess KRAS, NRAS and BRAF mutational status in Slovenian population with metastatic colorectal carcinoma (mCRC) suitable for first-line treatment. The evaluation of decisions for first-line treatment regarding the biomarkers status and assessing the possible impact of the time period of the biomarker status analysis report on the treatment decision were also incorporated in the analysis. The molecular analyses for KRAS and NRAS gene mutations were performed on exons 2, 3 and 4, and for BRAF gene mutations on exon 15. The first line systemic treatment options for RAS (KRAS/NRAS) wild type (wt) and mutated type (mt) mCRC subjects were as follows: chemotherapy - Fluoropyrimidine based systemic therapy combined with oxaliplatin and/or irinotecan with/without VEGF inhibitor bevacizumab and for RAS wt subjects, with/without EGFR inhibitors, cetuximab or panitumumab. Methods: To indicate the degree of certainty of KRAS, NRAS and BRAF status frequency as being wild type or mutant type 95% confidence interval was calculated. Results: The KRAS/NRAS/BRAF mutation rates were as follows - The distribution of subjects with KRAS mutated and wild-type tumors, was almost equal, 48.8% and 47.9% respectively. Eighty nine percent of the subjects had NRAS wild type tumours and 86.1% had BRAF wild type tumours. The most frequently used treatment regardless the biomarkers status and in accordance with the treatment guidelines was bevacizumab based combination therapy (53.1%). The EGFR inhibitor (cetuximab or panitumumab) based combination therapy was used in one third of mCRC subjects (30.9%), all with mCRC RAS wt. The time period from the initial presentation of the patient until the biomarker status analysis report was two weeks. Conclusions: With this study, we have proven that the distribution of the mutations in exons 2-4 of KRAS and NRAS genes and exon 15 in the BRAF gene in the Slovenian population with metastatic colorectal cancer matches historical data. Based on this, we conclude that the treatment decision in Slovenian population with metastatic colorectal carcinoma should be in the accordance with international treatment guidelines and on evidence based medicine. The molecular analysis performed at the Institute of Oncology Ljubljana was providing necessary biomarkers status report in an acceptable time that didn’t affect the treatment decision or delay the needed cancer treatment.

Phase II study of anti-EGFR rechallenge therapy with panitumumab driven by circulating tumor DNA molecular selection in metastatic colorectal cancer: The CHRONOS trial.

3506 Background: Despite advances in molecular segmentation of metastatic colorectal cancer (mCRC), beyond RAS status therapeutic actionability remains confined to the limited subgroups of ERBB2 amplified, BRAF mutated and MSI-H patients. Optimization of available treatments is therefore warranted. Rechallenge with anti-EGFR monoclonal antibodies is often empirically used with some benefit as late-line therapy. We previously found that mutant RAS and EGFR ectodomain clones, which emerge in blood during EGFR blockade, decline upon antibody withdrawal leading to regain drug sensitivity. Based on this rationale, we designed CHRONOS, a multicenter phase II trial of anti-EGFR therapy rechallenge guided by monitoring of the mutational status of RAS, BRAF and EGFR in circulating tumor DNA (ctDNA). To our knowledge, this is the first interventional clinical trial of liquid biopsy for driving anti-EGFR rechallenge therapy in mCRC. Methods: Eligible patients were PS ECOG 0-2 RAS/BRAF WT mCRC having first achieved an objective response and then progression in any treatment line with an anti-EGFR antibody containing regimen, displaying RAS, BRAF and EGFR ectodomain WT status in ctDNA at molecular screening after progression to the last anti-EGFR-free regimen. Clonal evolution in ctDNA was analyzed by ddPCR and next generation sequencing. Panitumumab 6 mg/kg was administered IV every two weeks until progression. The primary endpoint was objective response rate (ORR) by RECIST version 1.1 with independent central review. 27 total patients and 6 responses were required to declare the study positive (power = 85%, type I error = 0.05). Results: Between Aug 19, 2019 and Nov 6, 2020 52 patients were screened by liquid biopsy and 36 (69%) were negative in ctDNA for RAS/BRAF/EGFR mutations. Of these, 27 patients were enrolled in 4 centers. Median age was 64 years (range: 42-80). PS ECOG was 0/50%, 1/46%, 2/4%. Previous anti-EGFR was administered in 1st line in 63%, 2nd in 15% and > 2nd in 22%. Median number of previous treatments was 3. The primary endpoint was met, with 8/27 partial responses (PR) observed (2 unconfirmed) (ORR = 30%, 95% CI: 12-47%). Stable disease (SD) was obtained in 11/27 (40%, 95% CI: 24-59%), lasting > 4 months in 8/11. Disease control rate (PR plus SD > 4 months) was therefore obtained in 16/27 (59%, 95% CI: 41-78%). Median progression-free survival was 16 weeks. Median duration of response was 17 weeks (1 ongoing). Maximal grade toxicity was G3, limited to dermatological and occurring in 19% of patients. ctDNA dynamics were studied in all patients. Conclusions: Liquid biopsy-driven rechallenge with anti-EGFR antibodies leads to further objective responses in one third of patients. Genotyping tumor DNA in the blood to direct therapy can be effectively incorporated in the management of advanced CRCs. Clinical trial information: 2016-002597-12.

Rationale for the utilization of biological targeted agents (bTAs) in the treatment of metastatic colorectal cancer (mCRC), single tertiary cancer center experience.

e15589 Background: Worldwide treatment for 1st line (1LTx) mCRC included doublet or triple chemotherapy with or without bTAs. In Quebec, the anti-EGFR therapy (panitumumab or cetuximab) was only recently approved in this setting for patients RAS WT, Bevacizumab (B) not eligible. In this study we evaluated the rational and outcomes using bTAs. Methods: Retrospective study assessing mCRC pts treated with or without bTAs at any time throughout the course of therapy at the Jewish General Hospital between 2010-2018. Pts were divided in 3 groups according to their 1LTx for analysis: Chemotherapy alone (1LChA), Chemotherapy plus B (1LChB), and anti-EGFR with or without chemotherapy (1LaEGFR). The primary objective was to assess the rational of bTAs prescription based in 1LTx selection. Secondary objectives included safety, PFS and OS. Results: Among a total of 463 pts with mCRC; 196 pts (42.3%) received 1LChA, 246 pts (53.2%) 1LChB, and 21 pts (4.5%) 1LaEGFR respectively. 1LChA group, 51% omitted bTAs for physician-patient preferences, 96 pts (49%) had contraindications for B, and 79 pts (40.3%) were potentially candidates for aEGFR, but did not receive it. 152/196 (77.5%) pts continued to 2LTx and 34.8% received bTAs. As for the 3LTx, 78/196 (40%) received a treatment, 48.7% received bTAs. The most common grade 3-4 adverse events (AEs) were hypertension and bowel perforation in B, gastrointestinal (GI) symptoms and skin reaction (SR) in aEGFR. 1LChB group, 31 pts (12.6%) presented AEs related to B. 191/246 pts (77.6%) continued to 2LTx with 48 pts (25%) receiving ChB despite progression in 1LTx on this bTA and 19 pts (10%) receiving aEGFR. The most common AEs reported in 2LTx were GI symptoms and neuropathy. In 3LTx, 54/91pts (59.3%) received aEGFR therapy and 8 pts (14.8%) had SR AEs. 46 pts (18.6%) continued to 4LTx, 13/46 pts (28.2%) received aEGFR. 1LaEGFR group, the most common AEs were SR and GI symptoms. 11/21 pts (52.3%) continued to 2LTx; 5 pts (45.4%) switching bTA class and receiving ChB. 81% pts started treatment between 2017-2018 and had at least two contraindication criteria for. The median PFS for the 1LChA and 1LChB groups were 10 and 11.5 months, respectively, and were not statistically significant (p=0.22). The OS with 1LChA and 1LChB was 33.26 vs. 27.80 months (p=0.27). The PFS and OS between 1LChA and 1LaEGFR were 10 vs 11 months (p= 0.27) and 33.26 vs. 35.07 months (p=0.13). Conclusions: The outcome and tolerability of bTAs in mCRC appear similar in our institution and randomised trials. We were not able to detect any significant difference among the three groups of comparison. The 1LaEGFR available data in this subset of patients are limited. Our data highlights the importance of optimal therapeutic sequencing to prolong OS. Dedicated studies are needed in order to determine the best bTAs therapeutic strategy in mCRC.

Interim analysis of the AVETUXIRI Trial: Avelumab combined with cetuximab and irinotecan for treatment of refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC)—A proof of concept, open-label, nonrandomized phase IIa study.

80 Background: Immune checkpoint inhibitors have demonstrated poor efficacy in MSS mCRC. Previous research indicate that cetuximab (anti-EGFR chimeric monoclonal antibody) could initiate, independently from RAS mutation, an immunogenic tumor cell death and mediate antitumor immune response. In this trial, we aim to explore the clinical efficacy and safety of anti-PDL1 avelumab (AVE) combined with cetuximab (CET) and irinotecan (IRI) for treatment refractory MSS mCRC. Methods: AVETUXIRI (NCT03608046) is a multicenter academic study recruiting MSS, BRAFV600E wt, mCRC patients (pts) refractory to standard treatment (fluoropyrimidine, oxaliplatin, irinotecan and anti-EGFR treatment if RAS wt tumor) in 2 cohorts (cohort A: RAS wt – cohort B: RAS mut). In both cohorts, patients receive CET (400 mg/m2 W1, 250 mg/m2 W2, 500 mg/m2/2 weeks from W3), IRI (180 - 150 mg/m2/2 weeks from W1) and AVE (10 mg/kg/2 weeks starting from W3). Primary endpoints are overall response rate (ORR), defined as partial or complete response (PR or CR) according (i)RECIST1.1, and safety. Secondary endpoints include disease control rate (DCR), PFS and OS. Based on a Simon 2-stage design for ORR in each cohort (cohort A: P0=0.15, P1=0.33 / cohort B: P0=0.09, P1=0.25 / α = 0.1, β = 0.2 in both cohorts), 10 and 13 patients are required in the first stage of cohort A and B respectively. At least 2 pts have to reach PR or CR in each cohort to allow the continuation of the trial in the 2nd stage. Results: Between Oct 2018 and Jan 2020, 23 patients (median age 62 y-old, 86.9% male 78.3% left-sided, 91.3% synchronous mCRC) have been included in the first stage of the trial. No major or unexpected safety events were observed. 21.7% (5/23) of pts presented grade 3 diarrhea, all related to IRI, with complete resolution after IRI dose reduction or interruption. A reduced starting dose of IRI (150 mg/m2) was amended (09/2019) for the last included 8 pts without any grade 3-4 diarrhea occurrence. Grade 1-2 hypothyroidism was the only immune-related side effect. 3 PR were observed in cohort A and none in cohort B. DCR was 60.0% (6/10) and 61.5% (8/13) in cohort A and B respectively. Median PFS and OS were respectively 4.2 and 12.7 months (cohort A) and 3.8 and 14.0 months (cohort B). 6 months-PFS rate was 40.0% and 38.5% in cohort A and B. 12 months-OS rate was 53.3% and 57.7% in cohort A and B. The median follow-up of patients was 9.2 months. Conclusions: The AVETUXIRI trial met its primary efficacy endpoint for RAS wt mCRC pts justifying the study continuation in cohort A (2nd stage). No PR was observed in RAS-mut cohort. Nevertheless, encouraging data of DCR, PFS and OS observed in RAS mut cohort allow the opening of a new cohort for RAS-mut mCRC (cohort C) with PFS as primary endpoint. Clinical trial information: NCT03608046.

Maintenance treatment with cetuximab versus observation in RAS wild-type metastatic colorectal cancer: Results of the randomized phase II PRODIGE 28-time UNICANCER study.

15 Background: Compared to observation, maintenance therapy with a fluoropyrimidine +/- bevacizumab showed significant improvement in progression-free survival (PFS) but not in overall survival (OS) in patients with unresectable metastatic colorectal cancer (mCRC) and disease control after first-line doublet chemotherapy (CT) +/- bevacizumab. Few studies are available on the role of maintenance therapy after induction anti-EGFR-based CT, and the benefit from anti-EGFR maintenance monotherapy during CT-free intervals (CFI) in patients with RAS wild-type (wt) mCRC. Methods: RAS wt unresectable mCRC patients with controlled disease after FOLFIRI + cetuximab (8 cycles) were randomized (1:1) to receive maintenance with bi-weekly cetuximab alone (arm A) or observation (arm B) until disease progression (PD)/unacceptable toxicity/death. Randomization was stratified according to tumor response, center, baseline Köhne Score, CEA and platelet count. In case of tumor progression during the CFI, FOLFIRI + cetuximab was to be reintroduced for 8 cycles, followed by a new CFI. Tumor response was assessed per RECIST1.1 every 8 weeks. The primary objective of this multicenter non-comparative randomized phase II trial was 6-month PFS rate after initiation of maintenance therapy. A total of 134 randomized and evaluable patients (67 per arm) were required (Fleming’s one-step design, one-sided α=5%, β=20%, H0: 40%; H1: 55%). Secondary endpoints were overall response rate (ORR), time to strategy failure, PFS, OS, safety, quality of life, circulating tumor cells and circulating tumor DNA detection and dynamic changes during treatment. Results: From January 2014 to April 2019, 214 patients were included and 139 randomized (67 arm A/72 arm B) in 35 centers. Baseline characteristics were: males, 67%/69%; median age, 64/68 years; ECOG PS 0, 54%/46%; previous adjuvant therapy, 25%/14%; single metastatic site, 58%/47%; right-sided primary, 24%/18%. The ORR in the overall and the randomized population was 55% and 72%, respectively. The median follow-up was 30 months. The 6-month PFS rate after initiation of maintenance therapy was 30% 95%CI[19; 42] in the maintenance arm, and 6% 95%CI[2;14] in the observation arm, with a median PFS of 5.3 95%CI[3.7;6.5] and 2.0 95%CI[1.8;2.8] months, respectively. Any grade treatment-related toxicity, including skin rash (40%/4%), diarrhea (33%/8%), and hypomagnesemia (46%/10%) was more frequent in arm A. Conclusions: Based on the study hypothesis, the cetuximab maintenance arm did not meet the primary objective. However, the clinically meaningful difference in PFS without any overlap in the confidence intervals between the two arms warrants further investigation. Clinical trial information: NCT02404935.

Cost-effectiveness of cetuximab + FOLFIRI versus bevacizumab + FOLFIRI in the first-line treatment of RAS wild-type metastatic colorectal cancer in China.

133 Background: Adding cetuximab to FOLFIRI chemotherapy (cet+CT) as first-line (1L) treatment for RAS wild-type (wt) metastatic colorectal cancer (mCRC) has been reported as cost-effective vs bevacizumab + FOLFIRI (bev+CT) in multiple jurisdictions. This study determined the cost-effectiveness (CE) of cet+CT for patients with mCRC in China. Methods: A published 3–health-state (nonprogressive, progressive, death) CE model was adapted to reflect Chinese patient characteristics, health state utilities, unit costs, and discounting rates, applying FIRE-3 trial–based resource utilization and adverse event rates. Progression-free and overall survival estimates were based on published FIRE-3 trial simulations to statistically adjust for available later-line treatment modalities in China vs those observed in FIRE-3. [1] Cetuximab and bevacizumab costs were based on up-to-date prices after the 2019 national reimbursement drug listing negotiations. Incremental CE ratios (ICERs) are given as cost (Chinese Yuan [¥]) per life-year (LY) and quality-adjusted LY (QALY) gained. The willingness-to-pay (WTP) threshold was ¥193,931, equivalent to 3 times the gross domestic product per capita, following WHO guidance. Results: Overall costs/costs restricted to 1L treatment were ¥483,771/¥249,619 (cet+CT) and ¥366,036/¥156,802 (bev+CT). Health effects were 3.32/2.68 (cet+CT) and 2.39/1.94 (bev+CT) LYs/QALYs gained. Discounted ICERs for cet+CT vs bev+CT were ¥148,311 and ¥186,517 per LY and QALY gained in deterministic analysis. cet+CT had a 71.8% (LY) and 52.5% (QALY) probability of being cost-effective. Treatment duration with a biologic in 1L, utilities in 3L treatment, and duration of 2L treatment were the main outcome drivers. Conclusions: Projections suggest that cet+CT is cost-effective vs bev+CT for 1L treatment of patients with RAS wt mCRC in China, with ICERs below the current WTP threshold in deterministic and probabilistic sensitivity analyses. [1] Van Oostrum I, et al. Value Health. 2020;23(Suppl 1): S8.

Safety analysis of the randomized phase II study of FOLFOXIRI plus cetuximab versus FOLFOXIRI plus bevacizumab as the first-line treatment in metastatic colorectal cancer with RAS wild-type tumors: The DEEPER trial (JACCRO CC-13).

86 Background: Triplet regimens, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab have been shown to be superior in terms of early tumor shrinkage (ETS) and depth of response (DpR) compared to doublet regimen plus bev or triplet regimen in patients with RAS wild-type metastatic colorectal cancer (mCRC), in the TRIBE trial ( N Engl J Med 2014) or VOLFI trial ( J Clin Oncol 2019), respectively. There have been few studies which directly compared cetuximab (cet) with bev when combined with triplet regimen. Therefore, we investigated the efficacy and safety of bev vs. cet in combination with FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as first-line treatment in terms of the DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC (ClinicalTrials.gov Identifier: NCT02515734). The experimental arm with cet was considered to be active if the difference of median DpR was over 12.5% compared with the bev arm, under the conditions of significance level of 0.05 and power of 0.85. Secondary endpoints included the ETS at week 8, progression-free survival, overall survival, secondary resection rate, and toxicity. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the safety analysis set (median age 65y, 64% male, PS0/1:91%/9%, left/right primary:83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively, some patients were excluded for the safety analysis due to the violation of inclusion criteria (6 for cet arm and 5 for bev). On the cutoff date of September 2020, median number of cycles administered was 10 (range, 1-51) for the cet arm and 12 (range, 1-51) for the bev arm. The incidence of severe adverse events (AEs) was 25.4% (44/173) for the cet arm and 25.7% (45/175) for the bev arm, respectively. The following AEs of grade 3-4 were observed more frequently in the cet arm compared to the bev arm: oral mucositis (9.2% vs. 2.3%), diarrhea (12.1% vs. 8.0%), dermatitis acneiform (12.1% vs. 0%), and hypomagnesemia (4.0% vs. 0%). The treatment-related death occurred in 2 patients of the cet arm, while no patients in the bev arm. The rate of treatment discontinuation due to AEs of any cause was comparable between the cet and bev arms (7% vs. 9%). Conclusions: This safety analysis indicated that both regimens of m-FOLFOXIRI plus cet or bev were tolerable in RAS wt mCRC patients although some frequent severe AEs were observed. Clinical trial information: UMIN000018217.

Amphiregulin Expression Is a Predictive Biomarker for EGFR Inhibition in Metastatic Colorectal Cancer: Combined Analysis of Three Randomized Trials

Amphiregulin (AREG) and epiregulin (EREG) are ligands of EGFR. Predictive information for anti-EGFR treatment in metastatic colorectal cancer (mCRC) was observed, but data for other agents is limited. Ligand mRNA expression; RAS, BRAF, PIK3CA mutations; and EGFR expression were assessed by qRT-PCR, pyrosequencing, and IHC, respectively, in mCRC tumor tissue of patients participating in the randomized controlled trials FIRE-1, CIOX, and FIRE-3. Normalized mRNA expression was dichotomized using median and third quartile. Overall (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method including univariate and multivariate Cox regression analyses. Penalized spline regression analysis tested interaction of mRNA expression and outcome. Of 688 patients with available material, high AREG expression was detected in 343 (>median) and 172 (>3rd quartile) patients. High AREG expression was associated with significantly higher OS [26.2 vs. 21.5 months, HR = 0.80; 95% confidence interval (CI), 0.68-0.94; P = 0.007], PFS (10.0 vs. 8.1 months, HR = 0.74; 95% CI, 0.63-0.86; P = 0.001), and objective response rate (63.1% vs. 51.6%, P = 0.004) compared to low expression at both threshold values. This effect remained significant in multivariate Cox regression analysis (OS: P = 0.01, PFS: P = 0.002). High AREG mRNA expression interacted significantly with the efficacy of cetuximab compared with bevacizumab (OS: P = 0.02, PFS: P = 0.04) in RAS WT mCRC. High AREG mRNA expression is a favorable prognostic biomarker for mCRC which interacted significantly with efficacy of anti-EGFR treatment.

Implications of RAS Mutational Status in Subsets of Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) across Therapy Groups

Implications of RAS Mutational Status in Subsets of Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) across Therapy Groups

449P Randomized phase II study comparing pathological responses of resected colorectal cancer metastases (CRCM) after bevacizumab (BEV) with FOLFOX or FOLFIRI (BEV-ONCO trial)

Pathological response (PR) of resected CRCM after preop treatment is a recognized prognostic factor. Retrospective studies reported that BEV + oxaliplatin-based chemotherapy increased PR compared to irinotecan-based chemotherapy. In this trial, we aim to demonstrate that preop BEV + FOLFOX would increase PR. BEV-ONCO (NCT01858649) is a multicenter prospective randomized (1/1) phase II trial evaluating PR on resected CRCM after 3 to max 6 cycles of mFOLFOX (ARM A) or FOLFIRI (ARM B) + BEV (5mg/kg/2 weeks). Primary endpoint is the major pathological response rate (MPRR) defined as the % of patients presenting CRCMs with a mean tumor regression grade (TRG) <3. Secondary endpoints include DFS, OS, safety, complete PR, R0 resection rate and liver toxicity comprising sinusoidal obstruction syndrome (SOS) and nodular regenerative hyperplasia (NRH). 54 pts (27 per arm) are needed to detect a difference (alpha=0.05; beta=0.2) of MPRR proportion of 0.40 between treatment arms (two-sided Fisher's Exact test). Among 65 pts included between 06/2013 and 09/2018, 57 pts (28 ARM A / 29 ARM B) have had CRCM resection. Clinical and treatment characteristics were similar in both treatment arms (median age 60 y-old, 51% male, 33% RAS wt, 98% liver CRCM, 75% synchronous, median 2 CRCM/pt, median of 4 chemo cycles and 3 BEV cycles). 11/28 pts presented 1-month postop surgical complications in ARM A (39%, grade 3-4: 17.9%) and 9/29 pts in ARM B (31%, grade 3-4: 6.9%, p=0.58). MPRR was 32% in ARM A and 21% in ARM B (p=0.38). 4 pts presented complete PR (ARM A/B: 14%/0%, p=0.05). No difference between treatment arms was observed for R0 resection (ARM A/B: 89%/93%, p=0.80), SOS (ARM A/B: 54%/38%, p=0.50), NRH (ARM A/B: 21%/17%, p=0.75), DFS (ARM A/B: HR=1.14, 95%CI:0.58-2.21, p=0.71) and OS (ARM A/B: HR=1.38, 95%CI:0.48-4.00, p=0.55). Pts with PR among all CRCM (Max TRG≤3; 44% of pts) had a lower risk of relapse/death (DFS: HR=0.41, 95%CI=0.20-0.82, p=0.01) and death (OS: HR=0.34, 95%CI=0.10-1.11, p=0.07). This trial fails to demonstrate any significant difference of PR between BEV with FOLFOX or FOLFIRI but confirms PR as a prognostic factor.

477P Genomically-matched therapy in refractory CRC according to ESCAT

Next Generation Sequencing (NGS) emerges as an actionability-searching strategy in the molecularly heterogeneous context of colorectal cancer (CRC)1, but its clinical impact remains unknown in a refractory setting. We aim to determine the value of NGS in terms of enrolment in genomically-guided clinical trials (gCT) in a cohort of metastatic CRC (mCRC) patients (pts) according to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT[E]) 2. 1Muzny et al, Nature 2012; 2Mateo et al, Ann Oncol 2018. Target population are pts with refractory mCRC included in NGS program (DNA seq for mutations [mut], amplifications [amp] or deletions [del] and RNA seq for fusions [fus]) for therapeutic purposes from 2015-2019. 159 pts have been identified, 122 left-sided (LC) vs 37 right-sided (RC). Basal molecular profile locally performed showed: 80 pts RAS WT (E IA), all treated with anti-EGFR; 9 pts BRAF V600E (E IA), 6/9 received BRAF-inhibitors; 3 pts MSI (E IB), 2/3 received immunotherapy. NGS (149 mut panel, 29 amp/del panel, 27 fus panel) was performed on archival FFPE samples of primary tumors (85%) and metastases (15%) of 113 LC and 36 RC. 10 pts have insufficient material. NGS unveiled druggable alterations different from basal profile in 24 pts (16%): 2 ERBB2 amp (EIB), 6 KRAS G12C mut (EIIIA), 3 ERBB2 mut (EIIIA), 5 PIK3CA mut in RAS –BRAF WT (EIVA), 3 BRAF nonV600E mut (EIVA), 4 RNF43 mut (EIVA), 1 MET amp (EIVA), distributed as 7 RC (19%) and 17 LC (15%). Only 4 pts were included in gCT, 5 deteriorated clinically and 15 were enrolled in other unmatched trials or received SoC because lack of slots in gCT. NGS unravels 16% of ESCAT-defined druggable alterations with final inclusion rate in gCT of 4/159 pts. Further data is needed to better define the value of NGS in mCRC, considering the evolving landscape of gCT and biomarkers, as well as basal tumor biology and clonal selection.

Abstract 2701: Patient-derived colorectal cancer organoid therapeutic escalation: Tracking resistance to EGFR inhibition for predicting therapeutic sensitivity

Abstract Background: Precision oncology requires translational tools predictive of clinical benefit. Epidermal growth factor receptor inhibition (EGFRi) yields a survival advantage in RAS/RAF wildtype (wt) colorectal cancer (CRC), however clinical tools do not predict individual patient response or resistance mechanisms. Patient-derived cancer organoids (PDCOs) allow for an ex vivo method to track subclonal response. Here, we examine the development of PDCO EGFRi resistance as a novel biomarker to differentiate treatment sensitivities. Methods: Fresh CRC tissue was obtained following consent to an IRB-approved protocol. Molecular profiling was performed on expanded PDCOs and in parallel to clinical hotspot sequencing. Cultures were treated with stepwise (20%) increases in panitumumab (46ug/mL per escalation) up to the physiologic Cmax (230ug/mL). A HER2 amplified culture was also assessed by escalation of trastuzumab with 20% stepwise increase to physiologic Cmax (180ug/mL). Threshold for escalation to the next dose level was a median relative growth of 20% at 96h. Time to resistance (TTR) was defined from start to persistent PDCO growth at 100% Cmax. Treatment studies assessed the longest diameter of individual spheres, assessed at 48h and compared to control using effect size (Glass's (G) Δ). TTR was compared to molecular profiles of primary resistance and clinical outcomes. Results: CRC PDCOs were derived from 10 patients (5 localized and 5 metastatic samples). PDCOs had diverse molecular profiles: 3 KRAS mutant (mt), 1 PTEN mt, 7 TP53 mt, and 7 RAS/RAF wt. TTR ranged from 26-226 days, with 90% of PDCOs lines achieving resistance. RAS mt PDCOs had a homogeneous TTR of 27.0±1.4 days. RAS wt PDCOs displayed marked variation in therapeutic response with TTR of 51.5±61.7 days (p=0.06, compared to RAS mt). A HER2-amplified PDCO (copy number 14) showed intermediate sensitivity to EGFRi (TTR 55 days), similar to dose escalation of HER2-targeting trastuzumab (TTR of 51 days). This HER2-amplified PDCO showed intermediate sensitivity to single agent trastuzumab (GΔ = 0.56), yet no sensitivity to trastuzumab following EGFRi resistance (GΔ = 0.09). Prospective clinical correlation was possible for 1 PDCO line, a RAS wt PDCO derived prior to EGFRi which showed marked sensitivity with growth and metabolic arrest achieved at 40% CMax consistent with clinical response. Conclusions: We present therapeutic dose escalation using PDCOs as a translational tool to track the clonal dynamics of resistance to EGFRi in CRC. This technique provides an objective measure of TTR to differentiate culture specific sensitivity in a clinically relevant timeframe. Molecular profiling of resistant cultures is ongoing which may provide an ex vivo tool for predicting individual resistance as cancers evade therapeutic pressure of targeted selection. Citation Format: Jeremy D. Kratz, Aishwarya Sunil, Meghan Conroy, Cheri A. Pasch, Nicole Lassen, Hannah Houtler, Kayla K. Lemmon, Linda Clipson, Daniel E. Abbott, Evie H. Carchman, Elise H. Lawson, Noelle K. Loconte, Sam J. Lubner, Kristina A. Matkowskyj, Daniel L. Mulkerin, Nataliya Uboha, Dustin A. Deming. Patient-derived colorectal cancer organoid therapeutic escalation: Tracking resistance to EGFR inhibition for predicting therapeutic sensitivity [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 2701.

Controversies in the treatment of RAS wild-type metastatic colorectal cancer

ObjectiveTo provide guidance for the management of RAS wild-type (wt) metastatic colorectal cancer (mCRC) in daily practice.MethodsNominal group and Delphi techniques were used. A steering committee of seven experts analyzed the current management of RAS wt mCRC, through which they identified controversies, critically analyzed the available evidence, and formulated several guiding statements for clinicians. Subsequently, a group of 30 experts (the expert panel) was selected to test agreement with the statements, through two Delphi rounds. The following response categories were established in both rounds: 1 = totally agree, 2 = basically agree, 3 = basically disagree, 4 = totally disagree. Agreement was defined if ≥ 75% of answers were in categories 1 and 2 (consensus with the agreement) or 3 and 4 (consensus with the disagreement).ResultsOverall, 71 statements were proposed, which incorporated the following areas: (1) overarching principles; (2) tumor location; (3) triplets; (4) maintenance; (5) second-line and beyond treatments; (6) Rechallenge and liquid biopsy. After the two Delphi rounds, only six statements maintained a lack of clear consensus.ConclusionsThis document aims to describe the expert’s attitude when dealing with several common clinical questions regarding patients with RAS wt mCRC.

Abstract 2577: AGO2 interaction limits wild type RAS activation yet essential for disease progression in oncogenic KRAS driven cancers

Abstract KRAS mutations drive over 30% of all cancers and 90% of pancreatic cancer. To investigate additional potential modulators of RAS-mediated oncogenesis, we previously performed a screen for direct interactors of RAS in a panel of cancer cell lines and identified a direct interaction between KRAS and Argonaute 2 (AGO2), independent of KRAS mutation status. To define the effects of conditional loss of AGO2 in KRASG12D-driven cancer, we employed a genetically engineered mouse model of pancreatic cancer (KC model). Genetic ablation of AGO2 did not interfere with development of the normal pancreas or KRASG12D-driven early precursor pancreatic intraepithelial neoplasia (PanIN) lesions. However, AGO2 loss prevented progression from early to late PanIN lesions, development of pancreatic ductal adenocarcinoma (PDAC), and metastatic progression. This resulted in increased of KRASG12D mutant mice deficient in AGO2 expression. Mechanistically, lack of PanIN to PDAC progression was due to oncogene-induced senescence (OIS) through activation of EGFR-wild type RASWT-phospho ERK signaling including reduced baseline autophagy in mice with AGO2 loss. Interestingly, in the KPC model simultaneous expression of oncogenic KRAS and loss of a p53 allele abrogates this phenotype, suggesting that p53 deficiency overcomes the OIS check by AGO2. However, in both mouse and human PDAC, AGO2 expression increased with disease progression and, interestingly, was predominant at the plasma membrane, where it co-localized with RAS. These in vivo analyses support a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR and WT RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical for PDAC progression. In the KRASG12D driven lung cancer mouse model, we see a similar requirement for AGO2 for diseases progression–but not for initiation–despite p53 loss indicating a context dependent requirement for AGO2. Given that AGO2 binds both the mutant and the WT forms of KRAS, we also investigated the role of RASWT-AGO2 interaction. Analysis using purified proteins showed that AGO2 competes with SOS1 to limit RASWT activation. AGO2 had no effect on the intrinsic GTPase activity of RAS or NF1-mediated GAP activity. In line with this data, AGO2 null mouse embryonic fibroblasts showed increased RAS activity and activation of MAPK/PI3K pathways. Further, using cell line models, we also showed that phosphorylation of AGO2Y393 by EGFR disrupted the interaction of RASWT with AGO2 at the membrane, but did not affect the interaction of mutant KRAS with AGO2. On the other hand, ARS-1620, a G12C-specific inhibitor, disrupted the KRASG12C-AGO2 interaction specifically in cells harboring this mutant, demonstrating that the oncogenic KRAS-AGO2 interaction can be pharmacologically targeted. Altogether, our findings reveal that the AGO2 interaction regulates RASWT and is essential for mutant KRAS driven oncogenesis. Citation Format: Sunita Shankar, Jean Ching-Yi Tien, Ronald F. Siebenaler, Seema Chugh, Vijaya L. Dommeti, Sylvia Zelenka-Wang, Jessica Waninger, Kristin M. Juckette, Xiao-Ming Wang, Sanjana Eyunni, Andrew Goodrum, Yuping Zhang, Ingrid J. Apel, Javed Siddiqui, Xuhong Cao, Jiaqi Shi, Sethuramsundaram Pitchiaya, Chandan Kumar-Sinha, Howard C. Crawford, Arul M. Chinnaiyan. AGO2 interaction limits wild type RAS activation yet essential for disease progression in oncogenic KRAS driven cancers [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 2577.

P-73 Clinical prognostic factors for overall survival and time to progression in RAS-wild type metastatic colorectal cancer treated with anti-EGFR monoclonal antibodies as third or subsequent-line therapy

Survival from metastatic colorectal cancer (mCRC) has improved with the use of anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies. However, one in four patients treated with it as a third or subsequent line therapy will not benefit. This study aims to identify prognostic factors for overall survival (OS) and time to progression (TTP) in Ras-wild type (RAS WT) colorectal cancer treated with anti-EGFR monoclonal antibodies as third or subsequent line therapy. This retrospective analysis included patients with RAS WT mCRC treated with cetuximab or panitumumab as third or subsequent line therapy between 2012 and 2017 at Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology. Multivariate Cox proportional regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for OS and TTP. A total of 162 patients were included in the study. Median age at diagnosis was 65 years, 87 (53,7%) patients were male. Median OS and TTP were 10.9 months and 4.1 months, respectively. Among 134 (83%) pts evaluable for response, there were 35 (26%) partial responses (PRs), 50 (37%) pts with SD and 49 (37%) pts with PD. No differences in OS and TTP were observed between cetuximab and panitumumab. A significantly worse prognosis in terms of OS was observed for patients with peritoneal metastasis (HRs = 2.54, p=0.01). There was also a trend towards worse overall survival in patients with lung metastasis (p= 0.07) and those with elevated serum alkaline phosphatase levels (p= 0.06). Factors associated with shorter TTP were lung metastasis (HRs = 1.63, p=0.02) and ECOG performance status (PS) greater than or equal to 2 (HRs = 2.58, p=0.002). A significantly better prognosis in terms of both OS and TTP was observed for patients with body mass index (BMI) above 25 kg/m2 [HRs = 0.5 (p=0.01) and 0.66 (p=0.049), respectively]. Taking into account the presence of visceral metastases, lung metastases, elevated serum ALKP and BMI<25, we constructed a new prognostic model by combining these prognostic variables in the following way: low-risk group (0 adverse factors); intermediate group (1-2 factors); high-risk group (3-4 factors). Median survival duration for low, intermediate, and high-risk groups were 15.4 months, 11.4 months, and 5.6 months, respectively. Patients from the low-risk group had significantly better survival than those in high-risk group (HR 0,41; CI 95% 0,232-0,711; p=0,002). Anti-EGFR antibodies are effective as the third or subsequent-line therapy in RAS WT mCRC patients. Patients with peritoneal metastasis showed worse prognosis in terms of OS, whereas lung metastasis and ECOG PS ≥2 were associated with shorter TTP. Our novel prognostic model was able to efficiently identify 3 groups of patients with significantly different OS outcomes.

First-line panitumumab plus capecitabine for the treatment of older patients with wild-type RAS metastatic colorectal cancer. The phase II, PANEL study

BackgroundDespite the high morbidity and mortality of metastatic colorectal cancer (mCRC) in older patients, they have been underrepresented in clinical trials and their optimal treatment is yet to be determined. This open-label phase II study evaluated the benefits of panitumumab and capecitabine as a first-line chemotherapy regimen in older patients with wild-type [WT] RAS mCRC. Patients and MethodsPatients (≥70 years; ECOG≤2) received 3-week cycles of panitumumab (9 mg/kg on day 1) plus capecitabine (850 mg/m2 twice daily on days 1–14) until disease progression or unacceptable toxicity. Response was evaluated every 9 weeks according to RECIST_1.1. Outcome measures were: objective response rate (ORR), duration of response (DoR), time to response (TTR), progression (TTP) and treatment failure (TTF), progression-free survival (PFS), overall survival (OS), and safety. ResultsTwenty-seven patients (11 women; median age: 78 years; ECOG: 0 [26%], 1 [67%], 2 [7%]) were evaluated. Median follow-up was 17.7 months. Confirmed ORR (95%CI) was 44.4% (25.7–63.2), with 25.9% of patients achieving at least stable disease. Median (95%CI) DoR was 8.7 (5.5–10.4) months, and median TTR was 2.2 (1.9–2.8) months. Median TTP was 9.6 (4.8–11.5) months, with a median TTF of 5.2 (2.8–7.2) months. The median PFS was 7.5 (4.4–10.4) months, and the median OS was 23.7 (7.4–27.5) months. Seventeen (63%) patients reported panitumumab and/or capecitabine-related adverse events grade 3–4, with skin toxicity (18.5%) being the most common. Two (7.4%) deaths were treatment-related. ConclusionThis study suggests that panitumumab plus capecitabine is a safe and effective regimen in older patients with WT RAS mCRC.

Regorafinib outcomes from the population-based South Australian mCRC registry (SAmCRCR).

e19344 Background: Regorafinib has been shown to improve survival over BSC alone in large randomized trials. The median survival in the CORRECT study was 6.4 months and 12 month survival 24.3%. In Australia regulators have limited the use of regorafenib and patients are required to self-fund. Understanding the potential benefit of regorafenib in a real world non trial setting would be informative for consumers when considering self funding. Methods: The SAmCRCR collects all mCRC patients prospectively. The Registry was analysed for patients who had received regorafinib between February 2006 and December 2018. Survival was analysed using Kaplan Meier method. Results: Only 53 patients have received regorafenib therapy since February 2006. The median age was 66 (range 34-82). 66% were male, 66% had stage IV at diagnosis, 53% had liver only, 13% liver and lung and 6% lung only involvement. 75% were left sided. K/RAS was available in 35/53 patients, 49% WT. BRAF in 8/53, 25% MT. MSI measured in 14, and MSI-H 21%. Prior lines of treatment received: one 4%, two 9%, three 23%, four 26%, &gt; four 37%. Prior biological use: bevacizumab 72%, anti-EGFR 100% (for RAS WT). Median survival from diagnosis was 3.3 years (95% CI 2.8-3.8 years). From start of regorafinib median survival was 7.1 months (95% CI 4.8-9.4 months) and12 month survival 28%. Conclusions: The outcome for those patients who do access regorafinib is in keeping with that reported from large randomized trials and thus clinicians can quote these outcomes when discussing access to regorafinib in the community.

Combined PD-1 inhibition (Pembrolizumab) and CCR5 inhibition (Maraviroc) for the treatment of refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC): First results of the PICCASSO phase I trial.

3010 Background: Checkpoint inhibition using PD-1/PD-L1 inhibitors does not show clinically relevant activity in MSS/pMMR (Mismatch Repair Proficient) colorectal cancer. Previous work showed that inhibition of CCR5 (C-C chemokine receptor type 5) leads to a macrophage re-polarization towards M1 macrophages within the tumor microenvironment which directly affects immune cell infiltrates. The current phase I trial explores a combined modification of the innate immune system (by CCR 5 blockade) and the adaptive immune system (by PD-1 inhibition) in the treatment of MSS CRC. Methods: 20 patients with metastatic MSS/pMMR colorectal cancer with failure of fluoropyrimidines, oxaliplatin, irinotecan, VEGF antibodies and EGFR antibodies (in ras WT patients) received pembrolizumab 200 mg q21d and maraviroc 300 mg bid cont. for 8 cycles, followed by pembrolizumab monotherapy for a maximum of 24 additional cycles. Imaging was performed every nine weeks (RECIST and irRECIST criteria). Primary endpoint was the feasibility rate (rate of patients receiving the protocol treatment during the core treatment without special event: treatment-related Grade ≥ 3 immune-related abnormalities, treatment-related Grade ≥ 4 AEs or any toxicity-related premature withdrawal of treatment). Secondary endpoints included safety/toxicity, ORR, PFS and OS. Results: 20 patients were enrolled. The median number of applied cycles was 3.5 for pembrolizumab and 3.5 for maraviroc. Two patients completed the core treatment period with pembrolizumab and started maintenance treatment. The feasibility rate was 94.7% (90% CI 77.4 to 99.7%), with one patient experiencing a special event. Except this grade 4 event (hyperglycemia) no ≥ 3 treatment-related toxicities were observed. According to irRECIST criteria one patient showed a partial response and one a stable disease as best response, resulting in an irDCR of 10.5%. Median PFS according to irRECIST was 2 months (CI 95%, 2 to 3), median OS 9 months (CI 95%, 6 to 20). Conclusions: Therapy with pembrolizumab and maraviroc was feasible and showed a beneficial toxicity pattern. Clinical activity in MSS CRC patients was limited, however prolonged disease stabilizations were observed in single patients and overall survival was higher than expected in this heavily pretreated population. Clinical trial information: NCT03274804 .

Abstract A21: Loss of Argonaute 2 leads to oncogene-induced senescence in mutant RAS-driven cancer

Abstract The RAS gene family is among the most commonly mutated genes within cancer, but little progress has been made in successfully targeting RAS mutations. Targeting binding partners of mutated RAS, however, presents a promising alternative therapeutic strategy. With the goal of uncovering novel interactors of RAS, we recently identified Argonaute 2 (AGO2) of the RNA-induced silencing complex (RISC) as a novel partner of the Switch II domain of KRAS. In order to assess the role of AGO2 in KRAS-G12D driven disease, we developed a mouse model of pancreatic cancer with conditional loss of AGO2. While AGO2 knockout did not prevent development of early precursor pancreatic intraepithelial (PanIN) lesions, loss of AGO2 prevented progression to late-stage PanINs, pancreactic ductal adenocarcinoma (PDAC), and metastatic disease. AGO2 null lesions displayed increased activation of the EGFR-RAS signaling axis during PanIN development. This signaling resulted in an increase in WT RAS-GTP activation, pEGFR-Y1068, and pERK levels leading to the development of oncogene-induced senescence in these PanIN lesions. Furthermore, we observed that EGFR-mediated phosphorylation of AGO2-Y393 disrupted the interaction between WT RAS and AGO2. This regulation by EGFR, however, was blocked in cells expressing mutant KRAS. These results suggested that the interaction of mutant RAS and AGO2 was vital to tumor development. To better assess the role of AGO2 loss in mutant RAS driven cancer, we performed AGO2 knockdown in multiple cell lines expressing mutations in either NRAS or HRAS isoforms. In each cell line, AGO2 directly interacted with KRAS, NRAS, and KRAS. In addition to suppressing growth in mutant RAS-driven cells (T24: HRAS-G12V, SK-MEL-2: NRAS-Q61H), loss of AGO2 produced marked increases in beta-galactosidase and p16 expression, as well as a decrease in cyclin D1, suggesting development of oncogene-induced senescence. Interestingly, upon AGO2 loss, cells displayed induction of pEGFR and pERK similar to what was observed in our pancreatic mouse model, and despite decreased expression of mutant RAS, WT RAS-GTP loading upon AGO2 loss was strongly induced. Together these results suggest a unique EGFR-AGO2-RAS signaling axis that requires AGO2-RAS interaction to prevent induction of oncogene-induced senescence in mutant RAS-driven cancers. Citation Format: Ronald F. Siebenaler, Sunita Shankar, Jean C. Tien, Vijaya L. Dommeti, Sylvia Zelenka-Wang, Jessica Waninger, Malay Mody, Seema Chugh, Chandan Kumar-Sinha, Arul M. Chinnaiyan. Loss of Argonaute 2 leads to oncogene-induced senescence in mutant RAS-driven cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A21.

Abstract B43: A systems biology approach to elucidate the mechanism of EGFR inhibitor sensitivity in mutant KRAS-driven colorectal cancer

Abstract Standard protocol to treat colorectal cancer (CRC) includes surgery, chemotherapy and radiotherapy as first-line treatment options. When applicable, targeting agents such as anti-EGFR therapies (i.e., cetuximab and panitumumab) have become important long-term neoadjuvant therapies that increase survival in some patients. In recent years it has become common practice to sequence patients and their tumor specimens’ DNA. This recent push in genomic medicine has led to the identification that 30-40% of CRC patient harbor an activating KRAS mutation. These mutations are thought to be an early driver in the cancer’s progression. KRAS is also considered to be the key player in conferring resistance to the anti-EGFR treatments cetuximab and panitumumab. That Ras mutations confer resistance to EGFR inhibitors is intuitive. In recent years, clinical guidelines have extended the list of contraindicated genotypes to many mutations in both the KRAS and NRAS genes. In contrast with the current guidelines for managing CRC with EGFR inhibitors, it has been shown that patients harboring a KRAS G13D mutation are sensitive to cetuximab. This has been reproducibly shown in both in vitro and in vivo model systems and is supported by retrospective analysis of initial clinical trial data. The current mutant-RAS restrictive guidelines are supported by a method that relied upon the grouping of all common Ras mutations as “equal,” which potentially washes out less common yet sensitive mutations. Whether KRAS G13D mutations are sensitive to cetuximab has remained a controversial topic for many years due to the lack of understanding of a mechanism, as it is counterintuitive to the current understanding of EGFR signaling cascade. We here identify a novel mechanism by which G13D RAS mutant is sensitive to EGFR inhibition by a nonintuitive process of reliance upon WT RAS molecules. We utilized a computational model of RAS signaling previously developed by our laboratory to explore mutant Ras signaling and thereby investigated the controversial response of KRAS G13D to anti-EGFR agents. Our computational studies of the historically reported biochemical processes that regulate Ras signals reveal a nonintuitive, mutant-specific dependency of wild-type RAS activation on EGFR. The model also reveals this dependency is determined by the interaction strength between a KRAS mutant and tumor suppressor neurofibromin. Our prospective experiments confirm this mechanism that arises from the systems-level regulation of Ras pathway signaling. Overall, our work demonstrates how systems approaches enable mechanism-based inference in genomic medicine. Citation Format: Thomas McFall, Jolene Diedrich, Stacy L. Littlechild, Laura Sisk-Hackworth, James Moresco, Meron Mengistu1, Andrey Shaw, Ed Stites. A systems biology approach to elucidate the mechanism of EGFR inhibitor sensitivity in mutant KRAS-driven colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B43.