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Baseline clinico-pathological characteristics from patients included versus not included in the ctDNA analysis

Study protocol

Calculation of the neoadjuvant rectal (NAR) score.

Kaplan-Meier estimates of disease-free survival and overall survival according to paired CEA and ctDNA baseline and pre-surgery A. Disease-free survival according to baseline ctDNA and baseline CEA B. Overall survival according to baseline ctDNA and baseline CEA C. Disease-free survival according to pre-surgery ctDNA and pre-surgery CEA D. Overall survival according to pre-surgery ctDNA and pre-surgery CEA pos: positive; neg: negative

Kaplan-Meier estimates of disease-free survival and overall survival according to pCR and NAR score in the sub-study cohort A. Disease-free survival according to pCR B. Overall survival according pCR C. Disease-free survival according to NAR score D. Overall survival according NAR score

Genomic sequencing is necessary for first-line advanced non-small cell lung cancer (aNSCLC) treatment decision-making. Tissue next generation sequencing (NGS) is standard but tissue quantity, quality, and time-to-results remains problematic. Here, we compare upfront cell-free-DNA (cfDNA) NGS clinical utility against routine tissue testing in patients with aNSCLC.cfDNA-NGS was performed in consecutive, newly identified aNSCLC patients between December 2019-October 2021 alongside routine tissue genotyping. Variants were interpreted using AMP/ASCO/CAP guidelines. The primary endpoint was tier-1 variants detected on cfDNA-NGS. cfDNA-NGS results were compared to tissue results.Of 311 patients, 282 (91%) had an informative cfDNA-NGS test; 118 (38%) patients had a tier-1 variant identified by cfDNA-NGS. Of 243 patients with paired tissue-cfDNA tests, 122 (50%) tissue tests were informative; 85 (35%) tissue tests identified a tier-1 variant. cfDNA-NGS detected 39 additional tier-1 variants compared to tissue alone, increasing the tier-1 detection rate by 46% (from 85 to 124). The sensitivity of cfDNA-NGS relative to tissue was 75% (25% tissue tier-1 variants were not detected on cfDNA-NGS); 33% of cfDNA tier-1 variants were not identified on tissue tests. Median time from request-to-report was shorter for cfDNA-NGS versus tissue (8 versus 22 days; p 0.0001). A total of 245 (79%) patients received first-line systemic-therapy: 49 (20%) with cfDNA-NGS results alone. Median time from sampling-to-commencement of first-line treatment was shorter for cfDNA-NGS blood draw versus first tissue biopsy (16 versus 35 days; p 0.0001).cfDNA-NGS increased the tier-1 variant detection rate with high concordance with tissue, and halves time-to-treatment. 'Plasma-first' upfront cfDNA-NGS use should be considered routinely for aNSCLC.

Purpose Treatment guidelines for advanced non–small-cell lung cancer (aNSCLC) recommend broad molecular profiling for targeted therapy selection. This study prospectively assessed comprehensive next-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) compared with standard-of-care (SOC) tissue-based testing to identify guideline-recommended alterations in aNSCLC. PATIENTS AND METHODS Patients with treatment-naïve aNSCLC were tested using a well-validated NGS cfDNA panel, and results were compared with SOC tissue testing. The primary objective was noninferiority of cfDNA vs. tissue analysis for the detection of two guideline-recommended biomarkers ( EGFR and ALK) and an additional six actionable biomarkers. Secondary analyses included tissue versus cfDNA biomarker discovery, overall response rate (ORR), progression-free survival (PFS) to targeted therapy, and positive predictive value (PPV) of cfDNA. RESULTS The primary objective was met with cfDNA identifying actionable mutations in 46 patients versus 48 by tissue ( P < .05). In total, 0/186 patients were genotyped for all eight biomarkers with tissue, compared with 90.8% using cfDNA. Targetable alterations or KRAS were identified in 80.7% when cfDNA was used first versus 57.1% when tissue was used first. PPV for cfDNA-detected EGFR was 100.0% (25/25). ORR and PFS in patients receiving targeted therapy based on tissue or cfDNA were similar to those previously reported. Conclusion This prospective study confirms a previous report that comprehensive cfDNA testing is noninferior to SOC tissue testing in detecting aNSCLC-recommended biomarkers. Furthermore, cfDNA-based first-line therapy produced outcomes similar to tissue-based testing, demonstrating the clinical utility of comprehensive cfDNA genotyping as the initial genotyping modality in patients with treatment-naïve aNSCLC when tissue is insufficient or when all actionable biomarkers cannot be rapidly assessed.

4152 Background: Despite huge efforts patients (pts) with advanced PDAC, still have a dismal long-term prognosis. The lack of available good-quality tissue samples for next generation sequencing (NGS) prevents from finding actionable alterations that could guide personalized treatments. Circulating tumor DNA (ctDNA) provides a non-invasive method for obtaining molecular information with therapeutic potential. Here, we present prospective data of ctDNA sequencing in pts with PDAC. Methods: We collected a single blood sample from advanced PDAC pts at any line of treatment (Tx) and at least 10 days apart from their last therapy. The samples were analyzed by Guardant360 plasma-based NGS, a standardized assay which covers microsatellite instability [MSI] evaluation and analysis of all four types of somatic alterations in 74 genes. Alterations were reported either as pathogenic or non-pathogenic. We classified each gene alteration according to the different OncoKB therapeutic levels of evidence [LE]. Additionally, we gathered the dates of both blood collection and molecular report. In case the molecular report showed no tumor-related alterations, it was interpreted as either absence of detectable mutations or low ctDNA levels, which would translate low disease burden or pts responding to therapy. Demographic and clinical data have been accessed from the medical records. Results: From 08/2019 to 09/2021 we collected blood samples from 94 PDAC pts. 56% of them were male and 53% were >65 years old. At the time of sample collection, nearly all pts were metastatic (98%). Regarding previous lines of Tx, 57% pts were Tx naïve; 10% were receiving active systemic Tx and 33% had experienced disease progression. Molecular reports were available in an average of 9.1 days. A total of 243 gene alterations were detected, having 94% of pts at least 1 genomic alteration, which was pathogenic in 69% of the cases (see Table). There were no pathogenic alterations ranked as OncoKB LE 1-2 ( MSI or NTRK). Seventy alterations (30%) were ranked as OncoKB LE 3A and 4 ( ARID1A, BRAC2, CDKN2A, KRAS). Three of these pts were treated with PARP inhibitors due to the presence of BRCA2 mutations. No ctDNA was detected in 15 pts (16%), despite being the sample collected >10 days from receiving their last Tx. Of these, 11 had low tumor burden (only peritoneal or lung metastases) and 4 had documented response to the Tx by the time the samples were collected. Conclusions: Real-time and prospective genomic profiling of pts with advanced PDAC using ctDNA is feasible and conveniently fast, which would allow its role in identifying and developing therapeutic targets for approved Tx or clinical trial treatments. [Table: see text]

10569 Background: Preliminary data has highlighted inherited predisposition to lung cancer (LC) related to certain pathogenic germline variant (PGV) in cancer predisposing genes, including patients (pts) with tumors harboring somatic driver oncogene alterations (alt); however, the frequency of PGV in LC is unknown. Liquid biopsy assays may be able to identify incidental PGV (iPGV) in pts with solid tumors at scale. Here, we report the prevalence of iPGV in genes predisposing to cancer in pts with advanced non-small cell LC (aNSCLC) relative to driver alt status. Methods: Genomic results were retrospectively queried from 31126 pts with aNSCLC who had Guardant360 testing as part of routine clinical care from 10/2020-12/2021. iPGVs were defined as being non-synonymous, non-VUS alt in selected genes known to increase lifetime cancer risk (Table) with variant allele frequency (VAF) >30% and pathogenicity defined by a proprietary bioinformatics pipeline. Clinical factors such as age, gender, histology, and diagnosis status (new/progressing) were extracted from test requisition forms. The driver group included guideline-recommended and emerging somatic mutations (m) in EGFR/KRAS/BRAF/MET/HER2, fusions (f) in ALK/ROS1/RET/NTRK1-3 and amplifications (a) in HER2/MET. Results: Out of 31126, 720 (2.3%) of pts had predicted iPGV, of whom 54% were female, with a median age of 64 (22-100); most pts were newly diagnosed (66%). Among them, 92% of pts had iPGVs identified in the homologous recombination and repair (HRR) pathway, 3% in mismatch repair (MMR) pathway and 5% EGFR iPGVs. A total of 335 (47%) pts with iPGVs had somatic driver alt (Table): 20% of pts with iPGV had KRASm (n=144/720; 67 G12C), 12% EGFRm (n=87; 28 ex19del, 35 ex21(L858R)), 2.5% BRAFm (n=18), 2.5% METm ex14 skip (n=18), 0.1% HER2m (n=1), 0.8% ALKf (n=6), 0.1% ROS1f (n=1), 0.1% RETf (n=1), 0.1% HER2a (n=1), and 0.4% METa (n=3). ATM iPGVs were enriched in pts with driver alt. (45% driver vs 27% non-driver, p

The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2− disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities., Circulating tumour DNA can provide useful information on disease burden. Here, the authors analysed circulating tumour DNA from 800 patients from a breast cancer clinical trial and investigate the subclonal nature of the disease, and identify DNA mutations associated with resistance and poor survival.

Background: Early changes in circulating tumour DNA (ctDNA) levels may identify which patients respond to therapy earlier than imaging, with ctDNA levels falling rapidly in patients who respond to therapy. The plasmaMATCH trial assessed the utility of ctDNA testing with an error-corrected 73-gene targeted panel (Guardant360, Guardant Health) to allocate patients to four mutation matched therapy cohorts. ESR1-extended fulvestrant (A), HER2-neratinib +/- fulvestrant (B), AKT1-capivasertib + fulvestrant (C), AKT basket-capivasertib (D). Here, we report paired baseline and early on treatment ctDNA analysis from plasmaMATCH, to establish the optimal criteria for predicting progression free survival (PFS). Methods: In plasmaMATCH treatment cohorts, plasma samples were collected for ctDNA analysis pre-treatment at cycle 1-day 1 (C1D1) and cycle 2-day 1 (C2D1) timepoints, and sequenced with the Guardant 360 assay. Patients were included if they had a minimum of 14 days of treatment in the first cycle. Multiple different methods were investigated to integrate variant allele fractions (VAF) of mutations identified at each timepoint to estimate the level of ctDNA, including maximum VAF, mean VAF and weighted mean VAF, and weighted mean VAF of clonal mutations at C1D1. Variants with a VAF Table 1ctDNA dynamics categoryMedian PFS months (95%CI)6-month PFSORRUndetectable (N=11) CDR=018.2 (10.2-NA)91%9/11 (82%)Suppressed (N=14) CDR 05.4 (4.6-NA)48%6/14 (43%)High (N=52) CDR >=0.1322.4 (2.0-3.7)8%4/52 (8%) Citation Format: Javier Pascual, Rosalind J Cutts, Belinda Kingston, Sarah Hrebien, Lucy S Kilburn, Sarah Kernaghan, Laura Moretti, Katie Wilkinson, Andrew M Wardley, Iain R Macpherson, Richard D Baird, Rebecca Roylance, Michael Hubank, Giselle Walsh, Iris Faull, Kimberly C Banks, Richard B Lanman, Isaac Garcia-Murillas, Judith M Bliss, Alistair Ring, Nicholas C Turner. Assessment of early ctDNA dynamics to predict efficacy of targeted therapies in metastatic breast cancer: Results from plasmaMATCH trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-02.

Purpose: Total neoadjuvant treatment (TNT) is a valid strategy for patients with high-risk locally advanced rectal cancer (LARC). Biomarkers of response to TNT are an unmet clinical need. We aimed to determine the value of circulating tumor DNA (ctDNA) to predict tumor response, recurrence, and survival in patients with LARC treated with TNT. Experimental Design: The GEMCAD 1402 was a phase II randomized, multicentric clinical trial that randomized 180 patients with LARC to modified schedule of fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) +/− aflibercept, followed by chemoradiation and surgery. Plasma samples were collected at baseline and after TNT within 48 hours before surgery (presurgery). An ultrasensitive assay that integrates genomic and epigenomic cancer signatures was used to assess ctDNA status. ctDNA results were correlated with variables of local tumor response in the surgery sample, local/systemic recurrence, and survival. Results: A total of 144 paired plasma samples from 72 patients were included. ctDNA was detectable in 83% of patients at baseline and in 15% following TNT (presurgery). No association was found between ctDNA status and pathologic response. Detectable presurgery ctDNA was significantly associated with systemic recurrence, shorter disease-free survival (HR, 4; P = 0.033), and shorter overall survival (HR, 23; P < 0.0001). Conclusions: In patients with LARC treated with TNT, presurgery ctDNA detected minimal metastatic disease identifying patients at high risk of distant recurrence and death. This study sets the basis for prospective clinical trials that use liquid biopsy to personalize the therapeutic approach following TNT.

BRAF V600 mutations have been found in 1&ndash, 2% of non-small-cell lung cancer (NSCLC) patients, with Food and Drug Administration (FDA) approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50&ndash, 80% of BRAF mutations in lung cancer are non-V600, and can be class II, with intermediate to high kinase activity and RAS independence, or class III, with impaired kinase activity, upstream signaling dependence, and consequently, sensitivity to receptor tyrosine kinase (RTK) inhibitors. Plasma cell-free DNA (cfDNA) of 185 newly diagnosed advanced lung adenocarcinoma patients (Spanish Lung Liquid versus Invasive Biopsy Program, SLLIP, NCT03248089) was examined for BRAF and other alterations with a targeted cfDNA next-generation sequencing (NGS) assay (Guardant360&reg, Guardant Health Inc., CA, USA), and results were correlated with patient outcome. Cell viability with single or combined RAF, MEK, and SHP2 inhibitors was assessed in cell lines with BRAF class I, II, and III mutations. Out of 185 patients, 22 had BRAF alterations (12%) of which seven patients harbored amplifications (32%) and 17 had BRAF mutations (77%). Of the BRAF mutations, four out of 22 (18%) were V600E and 18/22 (82%) were non-V600. In vitro results confirmed sensitivity of class III and resistance of class I and II BRAF mutations, and BRAF wild type cells to SHP2 inhibition. Concomitant MEK or RAF and SHP2 inhibition showed synergistic effects, especially in the class III BRAF-mutant cell line. Our study indicates that the class of the BRAF mutation may have clinical implications and therefore should be defined in the clinical practice and used to guide therapeutic decisions.

[Objectives] Resistance to tyrosine-kinase inhibitors (TKIs) is a clinical challenge in patients with oncogene-driven non-small-cell lung cancers (NSCLC). We have analyzed the utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) to impact the clinical care of patients with TKI resistance., [Materials and methods] We conducted a multi-institutional prospective study including consecutive EGFR, ALK, or ROS1-altered NSCLC patients with TKI resistance from 12 Spanish institutions. Post-progression ctDNA NGS was performed by Guardant Health (Guardant360 assay)., [Results] We included 53 patients separated in 3 cohorts: 31 EGFR-mutant NSCLCs with first/second-generation TKI resistance (cohort 1), 15 EGFR T790M + NSCLCs with osimertinib resistance (cohort 2), and 7 ALK/ROS1-rearranged NSCLCs with crizotinib and/or next-generation TKI resistance (cohort 3). Besides Guardant360, 22 patients from cohort 1 (71%) underwent post-progression tumor biopsies and/or alternative plasma-based genotyping. In the entire study population, 34 patients (64%) had reliable evidence of tumor-DNA shed for resistance assessment, and 24 patients (45%) had actionable alterations. Target-independent pathogenic alterations were frequently detected, particularly at osimertinib resistance. Eleven patients (20%) received subsequent molecular-guided therapies indicated by plasma NGS alone (n = 9, 17%), or plasma NGS and tissue sequencing (n = 2, 4%), deriving the expected clinical benefit. Of these, 9 had EGFR T790 M mutation and received osimertinib, 1 had ALK G1202R mutation and received lorlatinib, and 1 had ROS1 G2032R mutation and received cabozantinib. Two additional cases from cohort 1 (6%) had undetectable EGFR T790 M by Guardant360 but were T790M + by tissue and BEAMing digital PCR respectively, and also received osimertinib., [Conclusion] NGS of ctDNA detects actionable alterations in a large proportion of oncogene-driven NSCLC patients with TKI resistance, and can be used to guide subsequent treatments as a complement or alternative to tissue or PCR-based plasma genotyping in the real-world clinical setting., J. Zugazagoitia was funded by Instituto de Salud Carlos III (Rio Hortega, CM15/00196). E. Jantus-Lewintre and C. Camps were funded by CIBERONC (CB16/12/00350). P Garrido was funded by ISCIII: PIE15/00050, and CIBERONC (C16/12/00442). L. Paz-Ares was funded by ISCIII: PI1401964, PIE15/00076, RTICC (R12/0036/0028), CIBERONC (C16/12/00442), and CAM (B2017/BMP-3884), co-funded by FEDER from Regional Development European Funds (European Union). M: Provencio was funded by ISCIII: PIE 1400/64, PI16/01818 and European Union Funds: H2020-sc1-2016-2017.

15 Background: Accurate genotyping is mandatory for the management of mCRC pts. Tissue-based testing is still the SoC; however, is not available for all pts. and may be exhausted by serial testing, resulting in incomplete genotyping. We aimed to establish the validity of comprehensive non-invasive ctDNA testing in 1L mCRC pts for whom SoC tissue genotyping was available. Methods: 1L mCRC pts were tested with a comprehensive ctDNA test (Guardant360), a RAS ctDNA test (OncoBeam), and SoC tissue testing at the time of diagnosis. The primary endpoint was NCCN guideline biomarker discovery rate ( KRAS, NRAS, and BRAF mutations, ERBB2 amplification, and microsatellite instability). Results: In 91 evaluable pts, the biomarker discovery rate was 54.9% (50/91) for SoC tissue testing, 59.3% (54/91) for comprehensive ctDNA testing ( p= 0.0318 for non-inferiority vs. SoC), and 42.9% (39/91) for RAS ctDNA testing (inferiority not rejected vs. SoC). Both comprehensive and RAS ctDNA testing showed high positive agreement (85%, 44/52, and 86%, 31/36) and negative agreement (96%, 268/279, and 93%, 93/100) relative to SoC tissue testing at the gene level. Expanding genotyping beyond KRAS codon 12/13 mutations increased biomarker discovery rate by 56% for tissue testing (50/91 vs. 32/91, McNemar’s p< 0.0001) and by 64% for comprehensive ctDNA (54/91 vs. 33/91, McNemar’s p< 0.0001). Turnaround time was significantly shorter for comprehensive ctDNA testing vs. SoC tissue testing (mean 11.7 days vs. 23.0 days, paired T-test p= 0.0002). On retrospective analysis, 92% of biomarker-positive pts would have been identified at 2 weeks using the comprehensive ctDNA test for initial genotyping with reflex to tissue for biomarker-negative pts, whereas initial use of SoC tissue testing would have identified only 85% of positive pts at 4 weeks (Fisher’s exact p< 0.0001). Conclusions: As previously reported for lung cancer, comprehensive ctDNA testing in 1L mCRC identifies at least as many biomarker-positive pts as SoC tissue genotyping with high concordance to tissue and in half the turnaround time.

Background: In advanced NSCLC pts, current guidelines recommend broad molecular profiling for the following genes EGFR, ALK, ROS1, RET, MET, ERBB2, BRAF and KRAS. Tissue may be used for genomic testing in newly diagnosed advanced NSCLC but comprehensive plasma-based genotyping is less invasive and may provide a quicker and more complete assessment. The present study was conducted to prospectively assess performance of cfDNA compared to standard of care (SOC) tissue-based genomic testing to identify guideline recommended alterations in NSCLC pts. Methods: In this prospective, multicenter study, blood samples from treatment-naïve stage IIIB-IV NSCLC pts were tested using the Guardant360 next-generation sequencing (NGS) cfDNA panel and compared with SOC tissue testing. The primary objective was to demonstrate the non-inferiority of cfDNA vs tissue analysis for the detection of guideline-recommended biomarkers (not including KRAS) in NSCLC (NI margin = 10%). The rate of incomplete tissue genotyping was defined as the proportion of pts who were biomarker negative in tissue but incompletely genotyped for all 8 guideline-referenced biomarkers. Exploratory analyses included estimation of positive predictive value (PPV) of cfDNA against tissue genotyping and the biomarker discovery rate in tissue testing alone vs tissue plus cfDNA testing. Results: 199 metastatic NSCLC pts were enrolled between August 2016-June 2017, and 185 were included in this interim analysis. The primary objective of non-inferiority was met, with 47 actionable mutations identified by cfDNA vs. 48 by tissue (p Conclusions: This prospective, multi-center study demonstrates that a comprehensive and highly sensitive cfDNA NGS assay is non-inferior to SOC tissue testing in the detection of guideline-recommended actionable genomic alterations in NSCLC. Moreover, the addition of cfDNA to testing algorithms at the time of diagnosis markedly improved the biomarker detection rate in tissue negative/non-assessable pts. The PPV of the cfDNA assay utilized was high, supporting the use of cfDNA in treatment selection. These results demonstrate the clinical utility of comprehensive cfDNA genotyping to identify all guideline-recommended biomarkers in newly diagnosed advanced NSCLC pts. Citation Format: Ramon Palmero, Alvaro Taus, Santiago Viteri, Margarita Majem, Enric Carcereny, Javier Garde, Enriqueta Felip, Lourdes Gomez, Andrea Malfettone, Miguel Sampayo, Noemí López, Rebecca Nagy, Matthew Jackson, Iris Faull, Daniel Dix, Niki Karachaliou, Rafael Rosell. Use of comprehensive cell-free circuating tumor DNA (cfDNA) analysis to identify genomic biomarkers in newly diagnosed advanced non-small cell lung cancer (NSCLC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 449.

9055 Background: KRAS m in LUAC p are recalcitrant to therapy. In mice models and p, STK11 m confer poor prognosis. Patients with KRAS, or KRAS with TP53 m, benefit from immunotherapy (IO). We used a cell free DNA (cfDNA) sequencing platform to sub-group 53 LUAC p with KRAS m from the Spanish Lung Liquid versus Invasive biopsy Program (SLLIP, NCT03248089), according to the coexistence of TP53 and STK11 m. We evaluated the treatment outcome in the KRAS subgroups and we explored the mutational evolution at 2 weeks (w), and at the end of the study (EOS). Methods: SLLIP was a multi-center observational study in patients with treatment-naïve metastatic LUAC. Genotyping, with a clinically validated cfDNA assay (Guardant360) was performed at 3 time points: before start of treatment, at 2 w, and upon progression or at 12 months (mo). Oncoprints were constructed based on mutation status and variant allele frequency (VAF). Results: 53 p with KRAS alterations were included. 36 male; median age 59; 46 current/ex-smokers; 64% received 1st line platinum-based chemotherapy (CT), 4% platinum-based CT+IO, 8% platinum-based CT plus bevacizumab, and 24% other or no therapy. 13 p had only KRAS m (K-only group), 25 p had KRAS + TP53 m (KP group), and 15 p had KRAS + STK11 with or without TP53 m (KS group). Median progression-free survival was 3.5 mo for all 53 p, 4.8 mo for the K-only group, 4.4 mo for the KP group, and only 2.6 mo for the KS group (p = 0.05 for KS versus K-only). The average VAF for K-only, KP, and KS groups at EOS were 6.4%, 9.7%, and 46%, respectively. When looking at p with cfDNA analysis at the three time points, the following were observed: In the K-only group, 25% lost KRAS m at 2 w and 50% at EOS. 50% and 75% gained TP53 m, at 2 w and EOS, respectively. None gained STK11 at the 2 time points. In the KP group, 40% lost KRAS m at 2 w but all had KRAS m at EOS. 20% and 10% lost TP53 m, at 2 w and EOS, respectively. 10% gained STK11 m at the 2 time points. In the KS group, 33% lost KRAS m at the 2 time points. All and 33% lost STK11 m at 2 w and EOS, respectively. 66% gained TP53 at the 2 time points. Conclusions: Subgroups of KRAS m traced in cfDNA confirm dismal prognosis to 1st line therapies. These findings prompt us to tailor IO for K-only or KP subgroups. For p with STK11 m, restoration of the STK11 function is warranted. Clinical trial information: NCT03248089.

e24044Background: Genomic profiling of cell-free ctDNA is a non-invasive method to guide personalised medicine. We assessed the utility of ctDNA in routine clinical practice where tumor Bx were imp...

9101Background: Approximately 20 % of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. In this study, we have anal...