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Purpose:Complete and timely tissue genotyping is challenging, leading to significant numbers of patients with newly diagnosed metastatic non–small cell lung cancer (mNSCLC) being undergenotyped for all eight genomic biomarkers recommended by professional guidelines. We aimed to demonstrate noninferiority of comprehensive cell-free DNA (cfDNA) relative to physician discretion standard-of-care (SOC) tissue genotyping to identify guideline-recommended biomarkers in patients with mNSCLC.Patients and Methods:Prospectively enrolled patients with previously untreated mNSCLC undergoing physician discretion SOC tissue genotyping submitted a pretreatment blood sample for comprehensive cfDNA analysis (Guardant360).Results:Among 282 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 60 patients versus 77 cfDNA identified patients (21.3% vs. 27.3%; P < 0.0001 for noninferiority). In tissue-positive patients, the biomarker was identified alone (12/60) or concordant with cfDNA (48/60), an 80% cfDNA clinical sensitivity for any guideline-recommended biomarker. For FDA-approved targets (EGFR, ALK, ROS1, BRAF) concordance was >98.2% with 100% positive predictive value for cfDNA versus tissue (34/34 EGFR-, ALK-, or BRAF-positive patients). Utilizing cfDNA, in addition to tissue, increased detection by 48%, from 60 to 89 patients, including those with negative, not assessed, or insufficient tissue results. cfDNA median turnaround time was significantly faster than tissue (9 vs. 15 days; P < 0.0001). Guideline-complete genotyping was significantly more likely (268 vs. 51; P < 0.0001).Conclusions:In the largest cfDNA study in previously untreated mNSCLC, a validated comprehensive cfDNA test identifies guideline-recommended biomarkers at a rate at least as high as SOC tissue genotyping, with high tissue concordance, more rapidly and completely than tissue-based genotyping.See related commentary by Meador and Oxnard, p. 4583

Supplementary Table 1: Detailed assessment of each of the 282 patients. For each of the 282 patients, genomic testing outcome for each modality and each of the eight genomic biomarkers is outlined, as well as KRAS and tissue assessed PD-L1 expression. "-" denotes where mutations in these genes were not assessed. Supplementary Table 2: Comparison of tissue versus cfDNA results for biomarkers in newly diagnosed metastatic NSCLC. For EGFR, four patients had baseline EGFR tissue results that were "negative". Upon review, patients received targeted EGFR testing that did not assess for the mutation identified in cfDNA. Therefore, they were coded as "not assessed" in these expanded tables but were "negative" for the primary endpoint. Supplementary Table 3: Detailed results for patients with positive results. For all 221 patients with a guideline-recommended biomarker detected in cfDNA or tissue, KRAS detected in cfDNA or tissue, or PDL-1 over-expression on tissue Supplementary Table 4: Co-occurring guideline-recommended biomarker and PD-L1 overexpression. Supplementary Table 5: Tissue versus cfDNA analysis Supplementary Table 6: Sites and Principal Investigators for the NILE (Non-invasive versus Invasive Lung Evaluation)

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Neuregulin-1 (encoded by NRG1) serves as a ligand for ERBB3 and can lead to dysregulated cellular proliferation in cases of NRG1 fusions. The reported incidence of NRG1 fusions in solid tumors is ~0.1-0.3% with enrichment in invasive mucinous adenocarcinoma of the lung and KRAS wildtype pancreatic adenocarcinoma. However, the real-world incidence of NRG1 fusions across diverse tumor types continues to evolve with the clinical implementation of comprehensive next-generation sequencing (NGS) methods including RNA based NGS. The true diversity and prognostic significance of specific NRG1 fusion partners has yet to be elucidated. We report on NRG1 fusions from a large clinico-genomic database of patients (pts) in community-based oncology settings where NGS is ordered as standard clinical practice. We conducted a retrospective, records-based analysis of pts across Sarah Cannon’s network of over 299 partner community-based oncology clinics to identify pts with NRG1 fusions detected by commercial NGS testing ordered as a part of standard of care from 1/1/2017 - 7/7/2022. NRG1 fusions were reported in 0.05% (19 of 40,857) of pts with commercial NGS test results across a range of tumor types including lung (59%; n=11/19), pancreas (11%; n=2), breast (5%; n=1), colorectal (5%), esophageal (5%), endometrial (5%), soft tissue liposarcoma (5%), and carcinoma of unknown primary (5%). NGS identifying an NRG1 fusion was performed in 5 (26%) pts with early stage disease while 11 (58%) pts had NGS testing after initial diagnosis of or progression to advanced/metastatic disease. A majority of pts harboring NRG1 fusions were female (68%; n=13). NRG1 fusions were detected by DNA (58%; n=11) and RNA based (42%; n=8) NGS from liquid (5%; n=1) and tissue biopsies (95%; n=18). A total of 11 different fusion partners were reported. CD74 was the most prevalent fusion partner and was primarily detected by DNA NGS including in one pt from liquid biopsy. Five novel, as yet to be described, fusion partners (CDK13, IL1RL2, FUT10, PPP2R2A, PIM3) were detected - 3 by RNA sequencing and 2 by DNA sequencing of NRG1 (versus sequencing of the fusion partner). TP53 (42%; n=8), CDKN2A (32%; n=6), and MTAP (16%; n=3) were the most frequently co-altered genes. Other notable co-altered genes included mutations in PIK3CA (11%; n=2), BRAF (5%; n=1), EGFR (5%), ALK (5%), and NRAS (5%). Immune biomarkers were largely negative, with 16% (n=3) PD-L1 positive, 0% MSI-high, and 5% (n=1) TMB-high cases. These data highlight the importance of comprehensive molecular profiling for pts with solid tumors, as NRG1 fusions occur across tumor types and stage of disease. Appropriate test selection is paramount as novel NRG1 fusions are more robustly detected by RNA over DNA NGS and are more routinely detected in tissue over liquid biopsies. Clinical trials investigating therapies to target NRG1 fusions are ongoing [CRESTONE (NCT04383210); eNRGy (NCT02912949)]. Citation Format: Emma G. Sturgill, Jaya Srivastava, Jessica Correia, Cooper Schumacher, Daniel Luckett, Cesar A. Perez, Judy S. Wang, Stephen G. Divers, Babar Bashir, Jennifer Johnson, Valerie M. Jansen, Andrew J. McKenzie, David R. Spigel. Identification of NRG1 fusions in patients with solid tumors: analysis from a real-world community oncology network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 921.

738 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a devastating diagnosis with an overall 5-year survival rate of ~10%. Therapies targeting KRAS G12D, a prevalent molecular driver of PDAC, represent an active area of investigation with many agents currently in clinical development. This study characterizes the real-world clinico-genomic landscape of patients with KRAS G12D-mutated PDAC to inform ongoing therapeutic development and clinical trial design. Methods: We conducted a retrospective, records-based analysis of 2,805 patients with PDAC from across 299 community-based oncology clinics. All patients had broad-panel next generation sequencing (NGS) from commercial vendors performed as standard of care. Patients were stratified into KRASWT (26%), KRASG12D (31%), and KRASnon-G12D (43%) cohorts according to NGS results and assessed for co-mutations, overall survival, and time to chemotherapy failure. Results: The KRASG12D and KRASnon-G12D cohorts exhibited similar mutational landscapes with frequent alterations in TP53, CDKN2A, and SMAD4 ( > 20% frequency occurrence) and infrequent actionable co-mutations (i.e. ATM, MTAP, BRCA1/2, PIK3CA, and MYC; < 5% frequency occurrence). KRASG12D exhibited significantly decreased overall survival compared to KRASWT (m (95% CI); 32.4 months (27.6-37.6 months) [ KRASWT], 20.1 months (17.0-22.7 months) [ KRASG12D], 21.7 months (20.0-25.0 months) [ KRASnon-G12D]; Cox model p-value < 0.001) as well as significantly shortened time to chemotherapy failure compared to both KRASnon-G12D and KRASWT (m (95% CI); 10.8 months (9.6-11.6 months) [ KRASWT], 7.8 months (7.3-8.7 months) [ KRASG12D], 9.8 months (8.8-11.1 months) [ KRASnon-G12D]; Cox model p-value < 0.01). Within the KRASG12D cohort, no co-mutations were significantly associated with overall survival. Conclusions: This study demonstrates the acute need for KRAS G12D-targeted agents in the clinic, as patients with KRAS G12D-driven PDAC experience particularly poor patient outcomes and lack alternative molecular targets.

Purpose:Complete and timely tissue genotyping is challenging, leading to significant numbers of patients with newly diagnosed metastatic non–small cell lung cancer (mNSCLC) being undergenotyped for all eight genomic biomarkers recommended by professional guidelines. We aimed to demonstrate noninferiority of comprehensive cell-free DNA (cfDNA) relative to physician discretion standard-of-care (SOC) tissue genotyping to identify guideline-recommended biomarkers in patients with mNSCLC.Patients and Methods:Prospectively enrolled patients with previously untreated mNSCLC undergoing physician discretion SOC tissue genotyping submitted a pretreatment blood sample for comprehensive cfDNA analysis (Guardant360).Results:Among 282 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 60 patients versus 77 cfDNA identified patients (21.3% vs. 27.3%; P < 0.0001 for noninferiority). In tissue-positive patients, the biomarker was identified alone (12/60) or concordant with cfDNA (48/60), an 80% cfDNA clinical sensitivity for any guideline-recommended biomarker. For FDA-approved targets (EGFR, ALK, ROS1, BRAF) concordance was >98.2% with 100% positive predictive value for cfDNA versus tissue (34/34 EGFR-, ALK-, or BRAF-positive patients). Utilizing cfDNA, in addition to tissue, increased detection by 48%, from 60 to 89 patients, including those with negative, not assessed, or insufficient tissue results. cfDNA median turnaround time was significantly faster than tissue (9 vs. 15 days; P < 0.0001). Guideline-complete genotyping was significantly more likely (268 vs. 51; P < 0.0001).Conclusions:In the largest cfDNA study in previously untreated mNSCLC, a validated comprehensive cfDNA test identifies guideline-recommended biomarkers at a rate at least as high as SOC tissue genotyping, with high tissue concordance, more rapidly and completely than tissue-based genotyping.See related commentary by Meador and Oxnard, p. 4583

Background Somatic genomic testing is recommended by numerous expert guidelines to inform targeted therapy treatment for patients with advanced nonsquamous non-small cell lung cancer (aNSCLC). The NILE study was a prospective observational study that demonstrated noninferiority of cell-free circulating tumor DNA (cfDNA)-based tumor genotyping compared to tissue-based genotyping to find targetable genomic alterations in patients with newly diagnosed nonsquamous aNSCLC. As the cohort has matured, clinical outcomes data can now be analyzed. Methods This prospective, multicenter North American study enrolled patients with previously untreated nonsquamous aNSCLC who had standard of care (SOC) tissue genotyping performed and concurrent comprehensive cfDNA analysis (Guardant360). Patients with targetable genomic alterations, as defined by NCCN guidelines, who were treated with physician's choice of therapy had objective response rates, disease control rate, and time to treatment collected and compared to published outcomes. Results Among 282 patients, 89 (31.6%) had an actionable biomarker, as defined by NCCN, detected by tissue (21.3%) and/or cfDNA (27.3%) analysis. Sixty-one (68.5%) of these were treated with an FDA-approved targeted therapy guided by somatic genotyping results (EGFR, ALK, ROS1). Thirty-three patients were eligible for clinical response evaluation and demonstrated an objective response rate of 58% and disease control rate of 94%. Twenty-five (76%) and 17 (52%) achieved a durable response > 6 months and 12 months, respectively. The time to treatment (TtT) was significantly faster for cfDNA-informed biomarker detection as compared to tissue genotyping (18 vs. 31 days, respectively; P = .0008). Conclusions cfDNA detects guideline-recommended biomarkers at a rate similar to tissue genotyping, and therapeutic outcomes based on plasma-based comprehensive genomic profiling are comparable to published targeted therapy outcomes with tissue profiling, even in community-based centers.

9027 Background: Somatic genomic testing is recommended by numerous expert guidelines to inform targeted therapy treatment for patients with advanced lung adenocarcinoma (aLUAD). The NILE study was a prospective observational study that demonstrated non-inferiority of cell-free circulating tumor DNA (cfDNA)-based tumor genotyping compared to tissue-based genotyping to find targetable genomic alterations in patients with newly diagnosed aLUAD. As the cohort has matured, clinical outcomes data can now be reported. Methods: This prospective, multicenter North American study (NCT03615443) enrolled patients with previously untreated aLUAD who had standard of care (SOC) tissue genotyping performed and concurrent comprehensive cfDNA analysis using the commercially available Guardant360 assay (Guardant Health, Redwood City, CA). After 12 months of study enrollment, objective response rates, disease control rate, and time to treatment data were collected for patients with targetable genomic alterations, as defined by NCCN guidelines, who were treated with physician’s choice of therapy. Results: Among 282 patients on the study, 89 (31.6%) had an actionable biomarker detected by tissue (21.3%) and/or cfDNA (27.3%) analysis. Sixty-one (68.5%) of these patients were treated with an FDA-approved targeted therapy guided by somatic genotyping results ( EGFR, ALK, ROS1). Thirty-three patients were eligible for clinical response evaluation and demonstrated an objective response rate of 58% and disease control rate of 94%. Twenty-five (76%) achieved a durable response > 6 months; 17 (52%) achieved a durable response > 12 months. Patients responded to targeted therapy regardless of the variant allele frequency of the target alteration. The time to treatment (TtT) was significantly faster for cfDNA-informed biomarker detection as compared to tissue genotyping (median 18 vs 31 days, respectively; p = 0.0008). Conclusions: This is the first prospective community-based study to find that cfDNA detects guideline-recommended biomarkers at a rate similar to tissue genotyping, and therapeutic outcomes based on plasma-based comprehensive genomic profiling are comparable to published tissue-based targeted therapy clinical outcomes. The NILE study complements and confirms findings in the prospective FLAURA and SLLIP studies, which exclusively enrolled at academic sites. Clinical trial information: NCT03615443.

Next-generation sequencing of cell-free circulating solid tumor DNA addresses two challenges in contemporary cancer care. First this method of massively parallel and deep sequencing enables assessment of a comprehensive panel of genomic targets from a single sample, and second, it obviates the need for repeat invasive tissue biopsies. Digital SequencingTM is a novel method for high-quality sequencing of circulating tumor DNA simultaneously across a comprehensive panel of over 50 cancer-related genes with a simple blood test. Here we report the analytic and clinical validation of the gene panel. Analytic sensitivity down to 0.1% mutant allele fraction is demonstrated via serial dilution studies of known samples. Near-perfect analytic specificity (> 99.9999%) enables complete coverage of many genes without the false positives typically seen with traditional sequencing assays at mutant allele frequencies or fractions below 5%. We compared digital sequencing of plasma-derived cell-free DNA to tissue-based sequencing on 165 consecutive matched samples from five outside centers in patients with stage III-IV solid tumor cancers. Clinical sensitivity of plasma-derived NGS was 85.0%, comparable to 80.7% sensitivity for tissue. The assay success rate on 1,000 consecutive samples in clinical practice was 99.8%. Digital sequencing of plasma-derived DNA is indicated in advanced cancer patients to prevent repeated invasive biopsies when the initial biopsy is inadequate, unobtainable for genomic testing, or uninformative, or when the patient’s cancer has progressed despite treatment. Its clinical utility is derived from reduction in the costs, complications and delays associated with invasive tissue biopsies for genomic testing.

8568 Background: Chemotherapy (chemo) has significant clinical utility, however consequent damage to hematopoietic stem and progenitor cells (HSPCs) and the immune system may limit activity. If chemo-mediated anti-tumor activity was maximized, while minimizing myelosuppression and immunosuppression, patient outcomes would be improved. Trilaciclib (T) is an intravenous CDK4/6 inhibitor in development to reduce myelosuppression and preserve immune system function during chemo. HSPCs are dependent on CDK4/6 for proliferation. Preclinical data demonstrated that transient T-induced G1 cell cycle arrest renders HSPCs resistant to chemo cytotoxicity, allowing faster hematopoietic recovery, preservation of long-term function, and enhancement of anti-tumor immunity and activity. Methods: Objectives of this ongoing multicenter Phase 1b/2a study are to assess dose limiting toxicities (DLTs), safety, tolerability, hematological profile, PK, and anti-tumor activity of T administered prior to EP. Phase 1b was open-label, dose-finding, and the ongoing Phase 2a is randomized (1:1), double-blind. Eligible pts had confirmed diagnosis of ES-SCLC, adequate organ function, ECOG PS 0-2, no prior chemo, and no symptomatic brain metastases. Results: 19 pts were enrolled in the Phase 1b: 10 pts received T 200 mg/m2 + EP and 9 pts received T 240 mg/m2 + EP. T + EP was well tolerated. 2 pts at T 200 mg/m2 and 1 pt at T 240 mg/m2 experienced asymptomatic DLTs in cycle 1. 2 pts (1 at each dose) had an ANC < 1500 on cycle 2 day 1, delaying the start of cycle 2, and 1 pt at the T 200 mg/m2dose had grade 4 thrombocytopenia. There were no cases of febrile neutropenia or bleeding. PK analysis showed no drug interactions between T and EP. 17/19 pts were evaluable: 1 pt had CR, 14 had PR (confirmed ORR = 88%); 1 pt had SD (clinical benefit rate = 94%). Conclusions: In the Phase 1b part of the study, T + EP was well tolerated. Early activity results are promising with a confirmed objective response rate of 88%. This novel approach allowing the administration of chemotherapy while preserving HSPC and immune system function could potentially improve treatment outcomes for SCLC pts. Clinical trial information: NCT02499770.

Background: A high level of reading skill and comprehension is necessary to understand and complete most consent forms that are required for participation in clinical research studies. This study was conducted to test the hypothesis that a simplified consent form would be less intimidating and more easily understood by individuals with low-to-marginal reading skills. Methods: During July 1996, 183 adults (53 patients with cancer or another medical condition and 130 apparently healthy participants) were tested for reading ability and then asked to read either the standard Southwestern Oncology Group (SWOG) consent form (16th grade level) or a simplified form (7th grade level) developed at Louisiana State University Medical Center-Shreveport (LSU). Participants were interviewed to assess their attitudes toward and comprehension of the form read. Then they were given the alternate consent form and asked which one they preferred and why. Results: Overall, participants preferred the LSU form (62%; 95% confidence interval [CI] = 54.8%-69.2%) over the SWOG form (38%; 95% CI = 30.8%-45.2%) (P = .0033). Nearly all participants thought that the LSU form was easier to read (97%; 95% CI = 93.1%99.9%) than the SWOG form (75%; 95% CI = 65.1%-85.7%) (P

Background: Chemotherapy-induced toxicity to the bone marrow and immune system is a significant acute and long-term issue of cancer therapy. G1T28 is a highly potent and selective CDK4/6 inhibitor (CDK4/6i) in development to reduce chemotherapy-induced myelosuppression and preserve immune system function in patients (pts) with CDK4/6-independent cancers such as SCLC. Hematopoietic stem and progenitor cells (HSPC) are dependent upon CDK4/6 for proliferation, and preclinical models demonstrated that transient G1T28-induced G1 cell cycle arrest renders them resistant to chemotherapy cytotoxicity, allowing faster hematopoietic recovery, preservation of long-term function, and enhancement of chemotherapy anti-tumor activity. Methods: Objectives of this ongoing multicenter Phase 1b/2a study are to assess the dose limiting toxicities (DLTs), safety and tolerability, hematological profile, PK, and anti-tumor activity of G1T28 in combination with etoposide and carboplatin (EP; NCT02499770). Part 1 is open-label, dose-finding, in up to 24 pts, and Part 2 is randomized (1:1), double-blind, in 70 pts. Eligible pts had histologically or cytologically confirmed diagnosis of ES-SCLC, adequate organ function, ECOG performance status (PS) 0-2, no prior chemotherapy, and no symptomatic brain metastases. G1T28 200 mg/m2 (derived from Phase 1a healthy volunteer study [G1T28-1-01] and expected to maintain HSPC G1 arrest beyond EP exposure) was administered IV prior to EP on days 1-3 every 21-days. Results: The first cohort enrolled 6 pts: median age 72 years; 5 females, 1 male; 2, 3, and 1 with ECOG PS of 0, 1, and 2, respectively. G1T28 + EP was well tolerated. Two asymptomatic DLTs occurred in cycle 1 in two pts: absolute neutrophil count (ANC) < 1,500 prior to cycle 2 day 1 (ANC = 1,200), and grade 4 thrombocytopenia (24,000 platelets). No febrile neutropenia occurred. All pts had a tumor response. Two had disappearance of all target lesions after 4 cycles, one with a confirmed complete response (CR) at cycle 6 and one with a confirmed partial response (PR) after cycle 4 (non-target lesions still present). Three pts had robust confirmed PRs after cycle 4 and one pt had a robust PR after cycle 2. G1T28 AUC was slightly lower than expected; etoposide and carboplatin PK were consistent with historical data. Conclusions: G1T28, a novel CDK4/6i, is being investigated in combination with EP for pts with ES-SCLC. In the first 6 pts, the combination was well tolerated, without any episodes of febrile neutropenia. Early efficacy results are promising with all 6 enrolled pts responding to therapy (CR or PR). This novel approach allowing the administration of chemotherapy with preservation of hematopoietic function and cellular immunity could improve treatment outcomes of pts with CDK4/6-independent tumors. Enrollment is ongoing and updated data will be presented. Citation Format: Caio Max S. Rocha Lima, Patrick J. Roberts, Victor M. Priego, Stephen G. Divers, Melanie Thomas, Ralph Boccia, R. Timothy Webb, Katie Stabler, Karenann M. Makhuli, Rajesh Malik, Raid Aljumaily. G1T28, a cyclin dependent kinase 4/6 inhibitor, in combination with etoposide and carboplatin for extensive stage small cell lung cancer (ES-SCLC): preliminary results. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT151.

11028 Background: Mutational testing has become standard of care in melanoma, lung, and colorectal cancers. The advent of Next Generation Sequencing (NGS) and increasing availability of new targete...