Longer PFS Research Articles

The prognosis and risk factors for capecitabine maintenance treatment in metastatic breast cancer: a retrospective comparative cohort study.

BackgroundMaintenance treatment following efficient chemotherapy can improve the treatment outcomes of patients with metastatic breast cancer (MBC). However, there are no studies for identifying the prognostic factors for patients who could benefit from capecitabine maintenance. Therefore, this study aimed to investigate the prognosis and risk factors of capecitabine maintenance therapy and analysed the circulating tumour DNA (ctDNA) markers that may be related to the treatment response.MethodsThis study recruited 482 consecutive patients with MBC who achieved clinical benefit from capecitabine-based chemotherapy from 2011 to 2019. A total of 256 patients received subsequent capecitabine maintenance therapy. The baseline clinical factors included age at diagnosis, menopause, neoadjuvant therapy, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status and subtypes, prior treatment lines, and prior capecitabine-based treatment response. Treatment outcome (progression-free survival, PFS) was assessed by imaging tools according to RSCIST 1.1 standard during the first two treatment cycles and every 3 weeks thereafter. Univariate and multivariate Cox proportional hazards models were used to analysethe association between capecitabine maintenance treatment and prognosis.ResultsThe median PFS of patients receiving capecitabine maintenance treatment was 21.7 months [95% confidence interval (CI): 15.1–36.3 months]. Capecitabine maintenance showed similar effects as endocrine maintenance or anti-HER2 therapy in hormone receptor (HR)-positive or HER2-positive patients, with adjusted HR of 1.17 (95% CI: 0.81–1.71, P=0.40). In patients with triple-negative breast cancer (TNBC), capecitabine maintenance showed a marginal benefit in PFS. Compared to late-line (≥2) capecitabine maintenance, first-line capecitabine maintenance significantly prolonged median PFS. Compared to other HR/HER2 subtypes, patients with HR-positive and HER2-positive subtypes significantly benefited from capecitabine maintenance treatment. Analysis of ctDNA revealed that among patients receiving capecitabine maintenance, TP53 aberrations were concentrated in patients with short PFS.ConclusionsCapecitabine maintenance treatment is associated with longer PFS in patients with MBC, especially those receiving first-line capecitabine-based chemotherapy and those with HR positivity/HER2 positivity. TP53 aberrations may be responsible for the poor response to capecitabine maintenance treatment.

1478P Clearseq1-4 classifier in localized and metastatic clear-cell renal cell carcinoma (ccRCC)

The ccrcc1-4 transcriptomic subtypes that we have previously identified on fresh frozen ccRCC through unsupervised clustering, have prognostic value post-nephrectomy/metastasectomy and predictive value for 1L VEGFR-TKI. We aimed to develop a classifier for FFPE samples. RNA sequencing of tumoral FFPE tissue was performed in ccRCC patients. The classifier assigns subtypes through relative proportions of 8 gene signatures with strong discriminative value for the molecular subtypes (ccrcc3_upregulated, ccrcc3_downregulated, ccrcc2_upregulated, cell cycle, T effector, ccrcc1-4_upregulated, ccrcc4_upregulated, ccrcc1_upregulated). 214 tumors were classified. Sarcomatoid features and IMDC poor risk were enriched in ccrcc4 tumors. The favorable prognostic impact of the ccrcc2 subtype was validated after nephrectomy in localized setting, after cytoreductive nephrectomy (CN) and upon metastasectomy with curative intent (MWCI). The angiogenic ccrcc2 subtype was correlated with improved outcome on 1L VEGFR-TKI and the highly inflamed ccrcc4 subtype with improved outcome on 1L IO/IO. ccrcc2 tumors had the longest PFS on 1L VEGFR-TKI and the longest OS, as long as patients did not access to IO in later lines. In patients who could access IO in later line, OS was similar between subgroups, indicating that the ccrcc4 subtype has the largest OS benefit on IO therapy. On IO treatment in any line, ccrcc4 tumors had superior PFS. IO counteracted the poor prognosis of this subtype, resulting in OS outcomes comparable to those of less aggressive subtypes.Table: 1478Pnccrcc2ccrcc3ccrcc1ccrcc4pPrognostic impact post surgeryAfter nephrectomy in localized settingDFS110433019120.002After CNSTFS9263420.009Upon MWCIDFS6631211340.0006STFS732540160.007OS1165193320.01Impact on outcome on systemic therapyOn 1L VEGFR-TKIPFS145146940.003OS in patients without access to IO in later lines7423251150.002OS in patients with access to IO in later lines7139NR56790.21On 1L IO/IOPFS2011NA4470.04OS45NA23NR0.005On IO in any linePFS934130.048OS31300.37DFS: disease free survival. STFS: systemic therapy free survival. Open table in a new tab DFS: disease free survival. STFS: systemic therapy free survival. The Clearseq1-4 classifier allows reliable ccrcc molecular subtype determination on FFPE tissues and validates previous biomarker findings for both surgical and systemic treatment approaches.

LBA18 Final overall survival (OS) for abemaciclib plus trastuzumab +/- fulvestrant versus trastuzumab plus chemotherapy in patients with HR+, HER2+ advanced breast cancer (monarcHER): A randomized, open-label, phase II trial

Abemaciclib, an oral, selective CDK4 & 6 inhibitor, significantly improved PFS in HR+, HER2+ advanced breast cancer (ABC; locoregionally recurrent or metastatic) when combined with fulvestrant and trastuzumab, compared to trastuzumab plus chemotherapy in monarcHER (Tolaney 2020, Lancet Oncol.) Here, we report the OS results at the prespecified final analysis. monarcHER (NCT02675231) is a randomized, multicenter, open-label phase 2 trial. Randomization was 1:1:1 to arm A (abemaciclib 150mg PO BID, trastuzumab IV, fulvestrant 500mg IM), arm B (abemaciclib, trastuzumab), and arm C (trastuzumab, SOC chemotherapy). Stratification factors were number of prior systemic regimens for ABC and measurable disease. Exploratory biomarker analyses were also conducted, including evaluation of intrinsic subtypes by RNAseq. At the time of data cutoff (31 Mar 2022), of the 237 patients enrolled, 157 deaths had occurred across the treatment arms, 50 deaths (63%) arm A, 54 deaths (68%) arm B, and 53 deaths (67%) arm C. Median follow-up was 52.9 months. mOS was 30.3 months in arm A, 31.43 months in arm B and 22.7 months in arm C (A v C: HR 0.75 [95% CI 0.47, 1.21]; nominal 2-sided p-value 0.243; B v C: HR 0.73 [95% CI 0.46, 1.15]; nominal 2-sided p-value 0.177). In exploratory RNAseq analyses, luminal subtypes were associated with longer PFS (8.6 v 5.4 months [HR 0.54, 95% CI 0.38, 0.79]) and OS (31.7 v. 19.7 months [HR 0.68, 95% CI 0.46, 1]) compared to non-luminal. Updated PFS and safety findings were consistent with the primary analysis (data cutoff 8 Apr 2019). Abemaciclib plus trastuzumab ± fulvestrant numerically improved OS in women with HR+, HER2+ ABC compared to chemotherapy plus trastuzumab with a manageable safety profile.

Research Progress in Alpha-fetoprotein-induced Immunosuppression of Liver Cancer.

Liver cancer is one of the most common malignant tumors, with limited treatment and 8.2% mortality. Liver cancer is the fourth leading cause of cancer-related deaths, which seriously endangers human life and health. Approximately 70% of liver cancer patients show increased serum Alpha- Fetoprotein (AFP) levels. AFP is the main diagnostic and prognostic indicator of liver cancer. AFP, a key marker of liver cancer, plays a crucial role in regulating the proliferation of tumor cells, apoptosis, and induction of cellular immune escape. High levels of AFP during embryonic development protect the embryos from maternal immune attack. AFP also promotes immune escape of liver cancer cells by inhibiting Tumor-Infiltrating Lymphocytes (TILs), Natural Killer cells (NK), Dendritic Cells (DC), and macrophages; thus, it is also used as a target antigen in immunotherapy for liver cancer. AFP is highly expressed in liver cancer cells. In addition to being used in the diagnosis of liver cancer, it has become a target of immunotherapy for liver cancer as a tumor-associated antigen. In immunotherapy, it was also confirmed that early AFP response was positively correlated with the efficacy of immunotherapy. Early AFP responders had longer PFS and OS than non-responders. At present, the methods of immunotherapy for liver cancer mainly include Adoptive Cell Transfer Therapy (ACT), tumor vaccine therapy, immune checkpoint inhibitors (ICIs) therapy, etc. A large number of studies have shown that AFP mainly plays a role in ACT and liver cancer vaccines. This review presents the research progress of AFP and immunosuppression of liver cancer.

A Real-World Multicentre Retrospective Study of Low-Dose Apatinib for Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer.

Simple SummaryThere are limited treatments for patients with HER2-negative breast cancer, especially for patients with metastatic breast cancer. This study aimed to observe the efficacy and safety of low-dose apatinib combined with chemotherapy in real-world clinical diagnosis and treatment of HER2-negative metastatic breast cancer. A total of 128 patients were treated with 250 mg apatinib, and we observed the median progression-free survival (PFS) and overall survival (OS) were 4.7 months and 15.3 months, respectively. This observation also indicated that the breast cancer susceptibility gene (BRCA) mutation predicted a better response to apatinib and that combination of immunotherapy or paclitaxel-platinum regimens might be an optimal treatment option. Importantly, a lower dose of apatinib showed mild side effects that improved the patients’ life quality.Treatment options for human epidermal growth factor receptor (HER2)-negative breast cancer patients are limited in comparison to the HER2-positive patients, particularly for metastatic breast cancer patients. Apatinib is a small-molecule tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor 2 (VEGFR-2). Here, we reported the apatinib-based therapy data in HER2-negative metastatic breast cancer. Apatinib was taken at a dose of 250 mg orally once per day and combined with standard chemotherapy regimens. The PFS and OS of 128 patients were 4.7 months and 15.3 months, respectively. The objective response rate (ORR) and the disease control rate (DCR) were 22.7% and 80.5%, respectively. Patients with breast cancer susceptibility gene (BRCA) mutations were found to have a longer PFS and OS. Moreover, combination immunotherapy or paclitaxel-platinum regimens shared an improved response to other regimens. Most of the adverse effects (hypertension, anaemia, and hand-foot syndrome) were grade 1 to 2. Metastatic breast cancer patients could benefit from apatinib therapy at a low dosage, and the adverse effects are mild in real-world clinical practice. Furthermore, BRCA may be a putative biomarker for apatinib in HER2-negative breast cancer. Immunotherapy or paclitaxel-platinum regimens may be recommended to combine with apatinib therapy.

B Cells in Tumor Microenvironment Associated With The Clinical Benefit to Programmed Cell Death Protein-1 Blockade Therapy in Patients With Advanced Esophageal Squamous Cell Carcinoma.

BackgroundB cells and B cell-related gene signatures in the tumor microenvironment (TME) are associated with the efficacy of anti-programmed cell death-1 (anti-PD-1) therapy in several cancer types, but not known for esophageal squamous cell carcinoma (ESCC).Patients and MethodsPatients with advanced ESCC receiving anti-PD-1/PD-L1-based therapy were retrospectively included. A targeted RNA profiling of 770 immune-related genes from archival ESCC tissues was performed. Differential immune-related pathways and the levels of infiltrating immune cells were estimated through Gene Set Enrichment Analysis and CIBERSORT, respectively. CD19 and CD138 expression were evaluated through immunohistochemistry (IHC). The markers evaluated were correlated with clinical benefit (CB; defined as either objective response or stable disease for ≥6 months) and survival.ResultsA total of 64 patients were enrolled. The transcriptome analysis based on 25 patients revealed that B cell signature was significantly increased in patients with CB (P <.05) and correlated with a longer PFS (P = .032) and OS (P = .013). Multiple genes representative of B cells, B cell functions, and plasma cells were upregulated in patients with CB. On further analysis of B cell subtypes in patients with CB, increase of naïve B cells (P = .057) and plasma cells (P <.01) was found but not memory B cells (P = .27). The CD19 expression in tumor stroma, detected by IHC, was higher in patients with CB (P = .033).ConclusionB cells in the TME were associated with CB in patients with advanced ESCC receiving anti-PD-1/PD-L1-based therapy.

P749: PROGNOSTIC SIGNIFICANCE OF SERIAL CIRCULATING TUMOR DNA STATUS POST TREATMENT IN MYELODYSPLASTIC SYNDROMES AND ACUTE MYELOID LEUKEMIA

Background: A major advance in our understanding of Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) biology has been the implementation of next generation sequencing (NGS) which influenced diagnostic, prognostic, and therapeutic decisions in myeloid malignancies. Circulating tumor DNA (ctDNA) sequencing, as as a novel and minimally invasive measure, was reported to exhibit excellent correlations with matched bone marrow NGS in MDS and AML. However, the clinical relevance of dynamic ctDNA monitor during active treatment is unknown. Aims: In this study, we assessed the role of ctDNA as a biomarker to monitor therapeutic response and clonal evolution in MDS and AML. Methods: Thirty-one MDS and AML patients who had both bone marrow NGS and ctDNA at baseline were included for concordance analysis. Twenty-seven patients who had at least two serial ctDNA assessment with at least one month interval were included for dynamic ctDNA analysis. Targeted deep sequencing was performed on bone marrow and ctDNA using a customized panel of 165 genes known to be recurrently mutated in MDS and acute myeloid leukemia. Results: Thirty out thirty-one patients were identified with ctDNA mutation at baseline. Diagnostic ctDNA and matched bone marrow DNA exhibited excellent correlations with variant allele frequencies (VAFs) (R2=0.721, p<0.001). For 27 patients who had ctDNA mutation in baseline and treated with HMA or chemotherapy, the average mutation VAFs at the end of treatment was lower in patients achieving a CR/CRi versus those with mCR, mLFS or SD (2.7% vs 24.1%, respectively, p<0.001). As expected, mutation VAFs from all patients with treatment failure did not decrease during treatment. (Figure 1). Similarly, the average decrease in mutation VAFs from pretreatment to end of treatment was greater in patients achieving a CR versus those who did not (87.7% vs 35.5%, respectively, p= 0.001). ctDNA negative post treatment was associated with longer PFS (median PFS not reached (NR) vs. 5.6 (95% CI 4.08-7.13) months; P=0.009)(Fig 2A) and OS (median OS NR vs. 12.0 (95% CI 9.08-15.0) months; P=0.023) (Fig 2B). Seven of ten MDS patients who transformed to AML were identified with lately acquired subclones harboring FLT3 or NF1, mutations involving in signaling pathway. Moreover, new subclones were detected 0.5 to 4 months prior to AML transformation in 4 cases, indicating that genetic progression can predate morphological progression. Image:Summary/Conclusion: ctDNA status post treatment was relevant to clinical response and was of prognostic significance for disease progress and relapse. Dynamic ctDNA changes revealed complex patterns of clonal structure of MDS and AML in response to treatment. ctDNA sequencing could be an attractive, prospective measure for disease monitoring.

P1245: CLINICAL IMPACT OF IMMUNOGLOBULIN HEAVY CHAIN REPERTOIRE IN MANTLE CELL LYMPHOMA: A STUDY FROM THE FONDAZIONE ITALIANA LINFOMI (FIL) PHASE III MCL0208 TRIAL.

Background: Mantle cell lymphoma (MCL) is characterized by a highly restricted immunoglobulin heavy chain (IGH) gene repertoire with stereotyped IGHV CDR3s, strongly implying a role for antigen-driven selection. Nonetheless, differently from chronic lymphocytic leukemia, where the prognostic role of IGH parameters is known since decades, published data are less consistent in MCL. Recently, LRPAP1 autoantibodies were detected in 13% of patients from the European MCL Network trials and were associated with superior outcome, while the autoreactivity of IGHV 4-34 antibodies is largely known. Aims: We aimed at characterizing the IGH VDJ repertoire and its putative clinical relevance in a large, prospective, trial of the Fondazione Italiana Linfomi (FIL) enrolling younger MCL patients. Methods: IGH clonal rearrangements detection was performed by Sanger sequencing on bone marrow or peripheral blood samples collected for minimal residual disease purposes in FIL MCL0208 trial (NCT02354313). This is a prospective, randomized phase III trial comparing lenalidomide maintenance vs observation after an intensive cytarabine containing chemo-immunotherapy followed by autologous transplantation in frontline <66 year-old MCL patients. IMGT/V-QUEST tool was used to annotate IGHV-D-J and mutational status (cut-off 98%) according to ERIC guidelines. Finally, these biological data were integrated with published clinical, pathological, and mutational data from the trial (current median follow-up 38 months). Results: A clonal IGH productive rearrangement was detected in 209/300 patients (70%), resulting in 159 (76%) unmutated (UM) and in 50 (24%) mutated (M) cases, as expected. Overall, VDJ usage included 29 IGHV families, with IGHV 3-21 (#45, 22%), 4-34 (#33, 16%), 3-7 (#15, 7%), 3-23 and 5-51 (#12 each, 6%), 4-39 and 4-59 (#10 each, 5%) as the most frequent groups, together representing the 66% of the analyzed series (Figure 1A). Interestingly, patients carrying IGHV 3-21 were often characterized by low Ki-67 index (Ki-67 <30%: 86% vs 64% of other cases, p<0.01) and low risk MIPI score (73% vs 43%, p=0.001), while no case of blastoid morphology was registered among the IGHV 4-34 patients (vs 89%, p<0.05). Moreover, by grouping together these two rearrangements, statistically significant associations were found with several biomarkers of favorable prognosis (low Ki-67, p<0.01; non-blastoid, p<0.05; absence of TP53 aberrations, p<0.05, or KMT2D mutations, p<0.05, and low-risk MIPI, p<0.0001). Accordingly, both IGHV 3-21 and 4-34 patients showed better long-term outcomes, with longer PFS and OS if compared with all the other cases, both singularly and when grouped together (3 years PFS: 75% vs 53%, p<0.05; 3 years OS: 91% vs 76%, p<0.01, Figure 1B, C). Finally, these results were independent from IGHV mutational status (p=0.09) and lenalidomide maintenance (p=0.46). Image:Summary/Conclusion: This is the first study assessing the clinical impact of VDJ IGH repertoire in a large prospective trial in MCL. As expected, 76% of patients resulted UM, with 3-21 and 4-34 representing more than one third of all the IGHV rearrangements. Notably, in our series, no significant correlation between mutational status and outcome was recorded. On the other hand, patients carrying either IGHV 3-21 or 4-34 rearrangements were characterized by favorable clinical and biological known prognosticators and were associated with both PFS and OS improvement, if compared to other patients. Deeper translational insights are needed to clarify the biological (autoreactive?) basis of this observation.

Abstract 5762: Genomic correlates of response to immune checkpoint blockade in Epstein-Barr virus-associated pulmonary lymphoepithelioma-like carcinoma

Abstract Introduction: Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and distinct subtype of non-small cell lung cancer (NSCLC). The use of immune checkpoint inhibitors (ICIs) for advanced PLELC and tumor genomic features underlying varied treatment responses remains poorly investigated. Methods: The study involved 33 PLELC patients with clinically annotated outcomes to ICIs. Targeted sequencing covering 520 cancer related genes were performed in 22 patients to identify single nucleotide variations (SNVs), copy number variations (CNVs), tumor mutation burden (TMB) and microsatellite instability. Mutation profiles of PLELC were compared with other NSCLC subtypes including lung adenocarcinoma (LUAD) and squamous cell lung carcinoma (LUSC) as well as EBV (Epstein-Barr virus) positive nasopharyngeal carcinoma (NPC) in public databases. Associations between PLELC mutation profiles and treatment responses to ICIs were analyzed. An external dataset of ICI-treated melanoma was used in further analysis of B2M. Results: The objective response rate (ORR), disease control rate (DCR), durable clinical benefit (DCB) rate, and median PFS was 18.2%, 60.6%, 45.5%, and 4.5 months respectively. Genetic alterations were frequently identified in B2M (9 of 22, 41%), CDKN1B (7 of 22, 32%), TP53 (6 of 22, 27%), SGK1 (5 of 22, 23%), NFKBIA (4 of 22, 18%) and TNFAIP3 (4 of 22, 18%). CNVs were comprehensively presented in PLELC while SVNs were less common. In our study, 8 of 9 tumors with B2M mutations and all tumors with CDKN1B, SGK1, TNFAIP3 mutations harbored copy number amplifications. Mutation profiles of PLELC were largely different from those of LUAD and LUSC but were similar to NPC. The median TMB was 2.99 mutations/Mb. All tumors were microsatellite stable (MSS). Patients with higher TMB showed improved DCR (p=0.029), PFS (p=0.056) and overall survival (p=0.038) than those with lower TMB. Patients with lower baseline plasma EBV DNA level also had longer PFS (p&amp;lt;0.001). The presence of B2M amplifications was significant associated with higher TMB level (p=0.022). The PFS of 7 patients with high TMB and amplified B2M were significantly longer than that of other patients (p=0.046). In the external dataset, higher expression of B2M was associated with better ICI responses for melanoma (p&amp;lt;0.05). Pathways involving anti-tumor immune responses such as NK cell-mediated cytotoxicity, antigen processing and presentation were correlated with high B2M expression while Wnt, TGF-beta and MAPK pathways that define poor response to ICI were correlated with low B2M expression. Conclusion: Our study observed comprehensive CNVs in PLELC patients which is a unique molecular feature compared with other NSCLC subtypes and EBV-positive NPC. Higher TMB level and amplifications of B2M in PLELC patients may be used as potential biomarkers to indicate better treatment responses to ICIs. Citation Format: Li-na He, Xuanye Zhang, Xinze Lv, Yuxi Zhou, Min Li, Ting Hou, Wenjie Sun, Li Zhang, ShaoDong Hong. Genomic correlates of response to immune checkpoint blockade in Epstein-Barr virus-associated pulmonary lymphoepithelioma-like carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5762.

Correlative results from NCI protocol 10250: A phase II study of temozolomide and olaparib for the treatment of advanced uterine leiomyosarcoma.

11509 Background: uLMS is an aggressive sarcoma subtype of smooth muscle origin. Chemotherapy provides limited benefit for advanced disease. 18-25% of uLMS harbor deleterious alterations in homologous recombination (HR) DNA repair genes. uLMS exhibits high levels of replicative stress. These findings prompted a phase 2 study of O+T in pretreated uLMS where O+T demonstrated activity: ORR 27%, mPFS 6.9 mos (Ingham M. et. al. ASCO 2021: #11506) Methods: NCI protocol #10250 is a single-arm, multicenter, phase 2 trial evaluating O+T in advanced uLMS pts with progression on ≥1 prior line. Pre-treatment (Pre) and on-treatment (On) biopsies were collected from 22 pts. In prespecified analysis, we evaluated for a relationship between clinical outcomes and HR gene alterations by whole exome sequencing (WES), SLFN11/MGMT expression by RNAseq, and RAD51 foci formation (functional assay). HRD scores were calculated from WES using scarHRD. Gene expression was evaluated using a Spearman rank-order correlation analysis to identify genes associated with PFS (p &lt; 0.01) and overexpressed in sensitive (S: PFS &gt; 240d) or resistant (R: PFS &lt; 240d) pts. Gene set enrichment analysis (GSEA) was performed (q = FDR-adjusted p value). Pts with available results: WES/RNAseq (16), Pre HRD score (13), Pre RAD51 foci (12). Results: 31% (5/16) pts had a mutation (Mut) or homozygous deletion (Hd) in the HR panel: ATRX Mut (2), ATR Mut, PALB2 Hd, RAD51B Hd. Pts with PALB2 and RAD51B Hd had longest PFS on study. Recurrent alterations also occurred in TP53 (56%) and RB1 (19%). Median HRD score in Pre samples was 51 (range 36-66) and 10/13 had HRD scores ≥ 42. Pre and On SLFN11 and MGMT RNA expression were not correlated with ORR/PFS. 6/13 Pre samples were HR-deficient by the RAD51 foci assay. Of pts with PFS ≥ 200d, 4/6 were HR-deficient. In Pre samples, 81 genes were overexpressed in S pts and 73 in R pts. In On samples, 146 genes were overexpressed in S pts and 127 in R pts. In On samples, GSEA identified the epithelial-mesenchymal transition enriched in S pts (q = 3.38e-7) and cell cycle pathways (E2F targets, G2M checkpoint) in R pts (q = 7.43e-4). Only 2 genes, CXCL10 and PCDH15, were differentially expressed between paired Pre and On samples (both increased in On). Gene expression signatures for replicative stress showed borderline association with worse PFS. Conclusions: Most uLMS tumors exhibit HR defects as measured by HRD scores. A subset of pts with greater benefit from O+T were identified by WES for HR genes and the RAD51 assay. There was no correlation between SLFN11 and MGMT expression and outcomes. GSEA identified pathways differentially expressed in S and R pts in On samples. O+T induced CXCL10 which has been associated with T-cell trafficking to tumors. A randomized phase 3 trial of O+T versus investigator’s choice is planned. These results provide insight into which pts may benefit most from this novel drug combination. Clinical trial information: NCT03880019.

Dostarlimab in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC): The GARNET study.

5509 Background: Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the U.S. as a monotherapy in patients (pts) with dMMR AR EC that has progressed on or after treatment with a platinum-containing regimen or dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options; and in the E.U. as a monotherapy in pts with dMMR/MSI-H AR EC that has progressed on or after treatment with a platinum-containing regimen. Here, we report on efficacy and safety in the 2 expansion cohorts of the GARNET trial that enrolled pts with EC. Methods: GARNET is a multicenter, open-label, single-arm phase 1 study. Pts were assigned to cohort A1 (dMMR/MSI-H EC) or cohort A2 (MMRp/MSS EC) based on local assessment. Pts received 500 mg of dostarlimab IV Q3W for 4 cycles, then 1,000 mg Q6W until disease progression, discontinuation, or withdrawal. The primary endpoints are ORR and DOR by blinded independent central review using RECIST v1.1. Results: For this third interim analysis, 153 dMMR/MSI-H and 161 MMRp/MSS pts were enrolled and dosed. Of these, 143 dMMR/MSI-H and 156 MMRp/MSS pts had measurable disease at baseline and ≥ 6 mo of follow-up and were included in the efficacy-evaluable population. ORRs were 45.5% (dMMR/MSI-H) and 15.4% (MMRp/MSS; Table). Median (m) DORs were not reached (NR; dMMR/MSI-H) and 19.4 mo (MMRp/MSS). Probability of PFS at 6, 9, and 12 mo was 49.5%, 48.0%, and 46.4% in dMMR/MSI-H EC and 35.8%, 31.3%, and 29.4% in MMRp/MSS EC, respectively. mOS was NR (dMMR/MSI-H) and 16.9 mo (MMRp/MSS). Overall, 27 pts (8.6%) discontinued treatment because of a treatment-related adverse event (TRAE; 13 dMMR/MSI-H, 14 MMRp/MSS). The majority of TRAEs were grade 1 or 2. The most common any-grade TRAEs were fatigue (56; 17.8%), diarrhea (46; 14.6%), and nausea (43; 13.7%). No deaths were attributed to dostarlimab in the EC cohorts. Hypothyroidism (12; 8%) was the most common any-grade immune-related TRAE. Conclusions: Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H and MMRp/MSS AR EC. dMMR/MSI-H was associated with better outcomes: a higher response rate and longer PFS and OS. Safety was consistent with other PD-1 antibodies. Clinical trial information: NCT02715284. [Table: see text]

ZFHX4 mutation as a novel predictive biomarker for immune checkpoint blockade in non-small cell lung cancer.

e20535 Background: ZFHX4 mutation as a novel predictive biomarker for immune checkpoint blockade in non-small cell lung cancer. Methods: 165 NSCLC patients treated with ICIs from independent public cohorts(Rizvi2015; Hellmann2018; Miao 2018) were included to assess immunotherapeutic predictive performance of ZFHX4 mutation. The genomic, mRNA profile and its corresponding survival data were retrieved from The Cancer Genome Atlas (TCGA) database for prognostic analysis. Results: In public cohorts 43 (26.06%) NSCLC patients harbored ZFHX4 mutations. Longer PFS was detected in NSCLC patients with ZFHX4 mutation (ZFHX4-mut) compared with those with wildtype ZFHX4 (ZFHX4-wt) (median PFS 22.1 months vs 4.2 months, HR 0.37; 95% CI 0.22 to 0.61; p &lt; 0.001). Higher ORR and DCR were also observed in patients with ZFHX4-mut compared with ZFHX4-wt (ORR: 62.8% vs 21.3%, p＜0.001; DCR: 86.0% vs 60.7%, p＜0.001, respectively). In the multivariable Cox proportional hazards regression model adjusted by PD- L1 expression and tumor mutational burden (TMB) and other confounding factors, ZFHX4-mut remained an independent predictor (HR 0.43; 95% CI 0.22 to 0.83; p = 0.01). ZFHX4-mut was associated with significantly higher TMB compared to ZFHX4-wt (P＜0.001). According to ZFHX4 status and TMB level, we stratified patients into four subgroups: ZFHX4mut-TMB high, ZFHX4mut-TMB low, ZFHX4wt-TMB high, and ZFHX4wt-TMB low. As expected, ZFHX4mut-TMB high patients achieved the longest PFS 23 months (HR 0.21 95% CI 0.10 to 0.43; p &lt; 0.01) among all groups. The combination of ZFHX4 mutation and TMB-H had a better predictive effect. Conclusions: Our results suggested that ZFHX4 mutation might be a potential predictor for ICIs therapy in NSCLC. Prospective studies to further understand the mechanism are warranted.

Early circulating tumor DNA (ctDNA) kinetics using a tumor-naïve assay as a predictive biomarker in early-phase immunotherapy (IO) clinical trials.

2546 Background: ctDNA kinetics with tumor-informed assays can predict treatment outcome in patients (pts) treated with anti-PD1 IO ( Bratman et al, Nature Cancer 2020). We evaluated whether early ctDNA kinetics with a tumor-naïve assay were associated with clinical outcomes in advanced solid tumor patients treated on early phase IO trials. Methods: Advanced solid tumor pts treated with investigational IO agents at the Princess Margaret Phase I program were enrolled. Baseline (B) and pre-cycle 2 (C2) (3-4 weeks after first dose) plasma samples were prospectively collected via an institutional liquid biopsy program (LIBERATE, NCT03702309). ctDNA was assessed using the tumor-naïve 425-gene Geneseeq Prime panel in a clinical laboratory. Mutations in each gene detected in ctDNA were measured as Variant Allele Fraction (VAF). Mean VAF from all mutations was calculated. Radiological response was measured per RECIST criteria and correlated using ROC curves. Hyperprogression (HPD) was defined using VHIO criteria ( Matos et al, CCR 2020). Survival outcomes were estimated using the Kaplan Meier method. Results: From 12/2017 to 3/2020, 162 plasma samples from 81 pts with 25 different tumor types were collected. Pts were treated within 25 different IO phase I/II trials, 72% of which involved a PD-1/PD-L1 inhibitor. Median age was 58y (range 21 – 79), 54% female, 76% ECOG1. Sarcoma and colorectal (11%, each) followed by breast (8%) and melanoma (7%) were the most frequent tumors. Median follow up was 10.3 months (m) (1.8-46.9). CR 4% (n = 3), PR 6% (n = 5), HPD 11% (n = 9). Clinical benefit (CB) rate (CR+PR+SD &gt; 6 months) was 20% (n = 16). ctDNA was detected in 122/162 samples (75.3%) (60 at B, 62 at C2). The most frequent mutations were TP53 (32%), PI3KCA (12%), PKHD1 (11%), and KRAS (9%). Mean VAF at B below median was not associated with OS (HR = 0.68 95%CI 0.4-1.16; p = 0.16) or PFS (HR = 0.93 95%CI 0.56-1.54; p = 0.77). Mean VAF change (difference between mean VAF at B and at C2) was associated with response (AUC = 0.99) and CB (AUC = 0.86). A decrease in mean VAF from B to C2 was seen in 24 pts (37.5%) and was associated with longer PFS (median PFS 2.7 vs 1.8 m; HR: 0.43, 95%CI 0.24-0.77; p &lt; 0.01) and OS (median OS 10.8 vs 9.1 m; HR: 0.54; 95%CI 0.3-0.96; p = 0.03) compared to an increase in mean VAF. These differences were more marked if there was &gt; 50% decrease in mean VAF from B to C2 (n = 11, 17%) compared to decrease &lt; 50% or increase: median PFS 3.6 vs 1.8 m (HR: 0.29, 95%CI 0.13-0.62; p &lt; 0.01) and median OS not reached vs 9.6 m (HR: 0.23, 95%CI 0.09-0.6; p &lt; 0.01). No differences in mean VAF change were seen between HPD and PD pts. Conclusions: In a pan-cancer solid tumor early phase trial IO cohort, a decrease in ctDNA within 4 weeks of treatment was associated with increased CB, OS and PFS. HPD pts did not show greater increases in ctDNA. Tumor-naïve ctDNA assays may be useful to identify early treatment benefit in phase I/II trials with IO.

Homogeneity of pathological response (PR) and histopathological growth pattern (HGP) in resected colorectal liver metastases (CRLM) are associated with favorable survival outcome after surgery.

3596 Background: Surgical resection of CRLM aims to maximize patient survival. However, recurrence rates remain high post-surgery. We previously reported the prognostic relevance of tumor regression grading (TRG) and HGP of resected CRLM. Several studies reported the association of tumoral heterogeneity with anti-cancer drug resistance and prognosis. This study aims to explore tumoral heterogeneity for TRG and HGP in patients resected for CRLM and its prognostic implication. Methods: Tumor homogeneity for PR and HGP was evaluated in 2 independent cohorts. Cohort 1 included 57 patients (159 CRLMs) resected after chemotherapy/bevacizumab (prospective BEV-ONCO trial). Cohort 2 included 221 patients (582 CRLMs) operated after preoperative treatment or not. TRG (1 to 5 according complete to no response), HGP (desmoplastic, pushing, replacement or mixed) were evaluated for each CRLM. Max-TRG (higher TRG among all the CRLM) was used to define PR. Homogenous TRG (TRG-h) and HGP (HGP-h) was defined when all CRLMs had the same TRG or HGP pattern. HGP homogeneous desmoplastic (HGP-hd) was defined when all CRLM had a desmoplastic HGP. TRG-h, HGP-h and HGP-hd were combined into a homogeneity score (H-score: 0 to 3, 1 point given for each parameter and summed-up). Overall survival (OS for both cohorts), progression-free survival (PFS for cohort 1) and time to relapse (TTR for cohort 2) were estimated using the Kaplan–Meier method and compared by log-rank tests. Cox proportional hazard models were used for univariate and multivariate analyses. Results: Patient and disease characteristics were comparable in both cohorts excepted for preoperative treatment. In cohort 1, TRG-h and HGP-h were significantly associated with a longer PFS (HR = 0.21; 95CI:0.10-0.43, p &lt; 0.001; HR = 0.27; 95CI = 0.14-0.54, p &lt; 0.001) and better OS (HR = 0.23; 95CI = 0.07-0.70, p = 0.010; HR = 0.32; 95CI = 0.10-0.93, p = 0.037). Interestingly, the same significant results were observed in cohort 2 for TTR (TRG-h: HR = 0.60; 95CI = 0.43-0.85, p = 0.004; HGP-h: HR = 0.68; 95CI = 0.49-0.94, p = 0.017) and OS (TRG-h: HR = 0.51;95CI = 0.33-0.80, p = 0.003; HGP-h: HR = 0.63; 95CI = 0.41-0.97, p = 0.034). HGP-h reported a significant association with TRG-h, a Max-TRG &lt; = 3, the absence of HGP replacement and mixed, a desmoplastic pattern, and the absence of sinusoidal obstruction syndrome in both cohorts. H-score was significantly associated with TTR (score 1-2: HR = 0.57; 95CI = 0.38-0.85, p = 0.004; score 3: HR = 0.4; 95CI = 0.24-0.64, p &lt; 0.001) and OS (score 3: HR = 0.31; 95CI = 0.15-0.64, p &lt; 0.001) in univariate analysis and with OS (HR = 0.74; 95CI = 0.59-0.94, p = 0.011) in multivariate analysis (cohort 2). Conclusions: TRG-h and HGP-h are strongly associated with patient’s survival. H-score could be an easy morphological and prognostic score to assess. Validation studies are needed.

Prognostic value of early bone marrow MRD status in CAR-T therapy for myeloma.

8022 Background: Bone marrow (BM) assessment of minimal residual disease (MRD) is being considered as a surrogate endpoint in clinical trials and is prognostic for survival in multiple myeloma (MM). Timing of BM assessment is variable across Chimeric Antigen Receptor T cell (CART) therapy trials and differs from standard of care practice. BM myeloma cell clearance can be detected by month 1 post CART, even before serum immunofixation becomes negative. BM is still hypocellular at month 1, thus prognostic value of MRD negative (MRDneg) at this timepoint is unclear. We examined impact of Day 30 MRD status in patients (pts) who received CART at Mayo Clinic. Methods: Medical records were reviewed retrospectively for MM pts who received CART between 8/2016 and 6/2021. PFS and OS were plotted by Kaplan-Meier method. Results: Sixty MM pts received CART and had BM biopsy at month 1. Median age was 62 yrs, 53% were male, and 78% were BM MRDneg by flow cytometry. Baseline demographics were similar between MRDneg and MRD+ (Table). Overall, 85% (40/47) who were month 1 BM MRDneg had i/u FLC&lt;normal. Patients who achieved CR/sCR had higher rates of BM MRDneg (100% vs 61%, p&lt;0.001) and i/u FLC&lt; normal (89% vs 58%, p&lt;0.001). At month 1, 24/60 (40%) pts had hypocellular BM. Serial BM samples at month 3 (n=35), 6 (n=28) and 12 (n=23) showed MRDneg rate of 93% (25/27), 56% (9/16) 58% (7/12), respectively.. Rate of hypocellularity was 54% (19/35), 32% (9/28) and 30% (7/23), respectively. Among the MRDneg/hypocellular pts at month 1, hypocellular BM was seen in 8/11 (73%) pts at month 3 and 2/4 (50%) pts at month 6 and 12. Compared to MRD+, pts who had BM MRDneg at months1 had longer PFS (Table). PFS was not statistically significantly different between pts who had BM MRDneg and were either hypocellular or not. MRDneg pts with i/u FLC&lt;normal at months1 had better median PFS compared to those who did not. (MRD+:2.9 months (1.2-NR). MRDneg/FLC&gt;normal: 4.9 months (2.3-NR). vs MRDneg/FLC&lt;normal:17.9 months (11.8-NR), p&lt;0.0001). Conclusions: Hypocellular BM is common in the 3 months post CART. Regardless of BM cellularity, BM MRDneg at month 1 correlates with deep response and prolonged PFS. Majority of BM MRDneg pts at month 1 also had FLC&lt;normal. BM MRDneg status and FLC normalization were associated with longer survival. Our data support the continued evaluation of BM early post CART infusion as a prognostic tool. [Table: see text]

SO-36 An immune-related gene expression profile predicts the efficacy of adding atezolizumab to first-line FOLFOXIRI/bevacizumab in metastatic colorectal cancer: A translational analysis of the phase II randomized AtezoTRIBE study

The AtezoTRIBE study demonstrated that the addition of atezolizumab to first-line FOLFOXIRI/bevacizumab prolongs PFS of mCRC patients, but a clinically modest benefit was observed among patients with proficient mismatch repair (pMMR) tumours. Therefore, identifying a pMMR subgroup able to achieve benefit from immune-checkpoint inhibitors (ICIs) is a crucial challenge of translational research. We investigated the predictive role of an immune-related gene expression signature (IO score), which reflects the presence of infiltrating inflammatory cells versus a differentiated stromal microenvironment. AtezoTRIBE was a phase II comparative trial in which mCRC patients, unselected for MMR status, were randomized 1:2 to receive first-line FOLFOXIRI/bevacizumab (control arm) or FOLFOXIRI/bevacizumab/atezolizumab (experimental arm). RNA was obtained from FFPE blocks of pre-treatment tumour specimens from 142 (65%) out of 218 enrolled patients. RT-qPCR was performed using DetermaIO™, to assess mRNA expression of a 27-gene targeted panel. In each sample the IO score was calculated according to the established pan-cancer IO algorithm. The predefined IO cut-point (0.09) was applied to dichotomize tumours as IO + or IO -. To identify patients deriving maximal benefit from the experimental arm, an exploratory analysis was conducted to find an optimized IO score cut-point (IO OPT), by using a method based on maximizing the log-rank statistics for comparing the two groups. The identified IO OPT cut-point was then adopted to dichotomize tumours as IO OPT+ or IO OPT-. IO score was successfully determined in 122 (86%) cases. Thirty-three (27%) tumours were IO +. No differences between IO + and IO - tumours were observed in terms of baseline clinical and molecular features and clinical outcome (mPFS: 14.4 vs 13.6 mos; HR:0.84 [95%CI:0.53-1.33], p=0.468). An interaction between IO status and treatment effect was reported (p for interaction=0.066), with higher PFS benefit from the experimental arm among patients with IO + (HR:0.39 [95%CI:0.15-1.02]) than IO - tumours (HR:0.83 [95%CI:0.50-1.35]). In the pMMR tumours (n=110), a similar trend was observed (IO + tumours [n=30]: HR for PFS 0.47 [95%CI:0.18-1.25]; IO - tumours [n=80]: HR for PFS 0.93 [95%CI:0.56-1.55]) (p for interaction=0.139). In the overall population (n=122), the computed IO OPT cut-point was 0.277. Sixteen (13%) tumours were IO OPT+. When compared with IO OPT- ones, IO OPT+ tumours were more frequently TMB-high (p=0.007), had longer PFS (mPFS: 14.8 vs 13.3 mos; HR:0.50 [95%CI:0.28-0.87], p=0.053) and derived significantly higher PFS benefit from the experimental treatment (HR in IO OPT+ 0.10 [95%CI:0.02-0.52] vs HR in IO OPT- 0.85 [95%CI:0.54-1.33], p for interaction=0.004). Similar results were observed in the pMMR subgroup (n=110), where the computed IO OPT cut-point was 0.304 and twelve tumours (11%) were classified as IO OPT+. The investigated IO score signature using the predefined cut-point may help to predict benefit from the addition of atezolizumab to first-line FOLFOXIRI/bevacizumab in mCRC, even within pMMR tumours. The exploratory IO OPT cut-points should further be validated in independent mCRC cohorts.

Real-world outcomes of immunotherapy regimens in first line non small cell lung cancer in lebanese patients.

e18741 Background: Immunotherapy provides improved treatment efficacy and survival in NSCLC patients. This is well established from clinical trials. However, the effectiveness of immunotherapy in real world practice is not well assessed. We aimed to characterize real-world outcomes for patients with NSCLC treated with 1L I-O in Lebanon. Methods: Patients aged ≥18 years with confirmed metastatic NSCLC who received either 1L I-O monotherapy or single-agent I-O combined with chemotherapy on or after January 1, 2014. Primary objectives were to examine overall survival (OS) and real-world progression-free survival. Multivariable analysis were made on correlation of different factors and survival. Results: among 135 patients, Median age at diagnosis was 68 years Most patients received chemotherapy alone as first line(54%), 18.3 % received immunotherapy and 27.8% received the combination treatment of chemotherapy and immunotherapy. Median PFS 1 was 7.7, 14, 11.1 months for chemotherapy, immunotherapy and chemo-immunotherapy respectively (p = 0.062). Median OS was 22.9 months (CI 95%, 17.7-28.1) with no significant correlation with treatment type (p = 0.85) multivariate analysis showed that having PDL levels between 1 and 49 (HRa = 0.15) and ≥50 (HRa = 0.12) compared to &lt; 1 were significantly associated with longer PFS period, whereas having squamous (HRa = 3.45) and other (HRa = 27.36) type of cancer compared to adenocarcinoma was significantly associated with shorter PFS period. (HRa = 3.28) was significantly associated with lower overall survival period (p = 0.10).Concerning adverse effects, rash was the most frequent (14%) followed by pneumonitis (12.2%). Conclusions: In real world practice, IO was well tolerated in lebanese patients. Patients with high (≥50) and intermediate (between 1 and 49) tumor programmed death ligand 1 (PD-L1) expression demonstrated longer median OS vs those with low expression. We hypothesize that bone metastasis impairs immunotherapy efficacy.

Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced gastric cancer.

4045 Background: Alterations in DNA damage response (DDR) and repair are associated with genomic instability and increased somatic tumor mutational burden, and modulating DNA repair using specific inhibitors is a promising strategy to boost the efficacy of cancer immunotherapy. Ceralasertib is an oral inhibitor of the serine/threonine protein kinase Ataxia Telangiectasia and Rad3 Related (ATR), which is crucial to the cell’s response to replication stress. Methods: This phase 2 trial was designed to evaluate the efficacy and safety of ceralasertib in combination with durvalumab in patients with advanced gastric cancer (AGC). The study drug regimen was ceralasertib 240 mg BD days 15 to 28 in a 28-day cycle in combination with durvalumab at 1500 mg day 1 every 4 weeks. The primary end point was overall response rate (ORR) by RECIST (v1.1). Exploratory biomarker analysis was performed using fresh tumor biopsies in all enrolled patients. Results: 31 patients (median no. of prior lines, 2; range, 2-5) were enrolled between Jul 2019 and Mar 2020. All enrolled patients had confirmed microsatellite stable tumors, 5 patients were EBV positive, and 24 patients were PD-L1 positive (CPS≥1). Two patients had received prior anti-PD-1 treatment. At the time of data cut-off (Dec 2020), 30 patients were evaluable for response: 7 partial responses (one patient with prior anti-PD-1 treatment), 11 stable disease, and 12 disease progression were observed. The ORR was 22.6%, DCR 58.1 %, median PFS 3.0 months (95% confidence interval (CI), 2.1-3.9), median duration of response 5.7 months (95% CI, 4.9-6.5), and median OS was 6.7 months (95% CI, 3.8-9.6). A subgroup of patients (n = 11) who with loss of ATM expression and/or high proportion of mutational signature attributable to homologous repair deficiency (sig. HRD) demonstrated significantly longer PFS than those (n = 12) who had intact ATM and low sig. HRD (5.60 vs 1.65 months, hazard ratio 0.13, 95% CI 0.045-0.39, long-rank P &lt; 0.001). The most common adverse events of any grade were fatigue (n = 22, 71.0%), nausea (n = 20, 64.5%) and anorexia (n = 19, 61.3%), and the most common adverse events of grade 3 or more were anemia and thrombocytopenia (n = 11, 35.5% each). Conclusions: Ceralasertib in combination with durvalumab demonstrated promising anti-tumor activity with durable responses in refractory AGC. Clinical trial information: NCT03780608.

Negative hyperselection for mutations associated with anti-EGFR antibody resistance in RAS wildtype metastatic colorectal cancer (mCRC): Evaluation of the PANAMA trial (AIO-KRK-0212, maintenance therapy with 5-FU, folinic acid (FU/FA) with or without panitumumab).

3536 Background: We evaluated the prognostic and predictive impact of DNA mutations related to anti-EGFR antibody resistance in patients of the PANAMA trial, which compared Panitumumab (Pmab) and FU/FA versus FU/FA maintenance therapy after Pmab-FOLFOX induction therapy in RAS wild-type (wt) mCRC. Methods: Next generation panel sequencing was conducted on 201 of 248 tumors obtained prior to study inclusion from the full analysis set using the Cancer Hotspot Panel v2 on an Illumina MiSeq system. Hyperselection covered mutations of the following genes: KRAS, NRAS, BRAF, HER2, PTEN, AKT1, PIK3CA. Median progression-free (PFS) and overall survival (OS) since start of maintenance were estimated by Kaplan-Meier and Cox-regression (log rank test). Objective response rates (ORR) of maintenance therapy were compared by Chi-square-test. Results: From 201 tumors, 41 (20.4 %) carried at least one mutation: KRAS: 7 (3.5%), BRAF: 23 (11.4%), PTEN: 4 (2.0%), AKT1: 2 (1.0%), PIK3CA: 12 (6.0%), with 6 tumors harboring co-occuring mutations. No mutations were found in NRAS and HER2. Negative hyperselection (wt for all genes) was associated with (numerically) favourable prognosis in terms of PFS (HR 0.79 (95% CI 0.55 – 1.12), p=0.184), OS (HR 0.61 (95% CI 0.40 – 0.95), p=0.028) and ORR (39.4% vs. 29.3%, p=0.279). The benefit of adding Pmab to FU/FA during maintenance was limited to the hyperselection wt subgroup, with significantly longer PFS (9.9 vs. 6.0 months, 0.64 (95% CI 0,46 – 0.90), p = 0.011), numerically longer OS and significantly higher ORR (49.4% vs 26.6%, p=0.009) compared to FU/FA (Table). Conclusions: Mutations related to resistance concerning anti-EGFR antibodies were detected in 41 of 201 (20.4%) of analysed tumors and associated with a worse prognosis compared to hyperselected wt tumors. Negative hyperselection may aid in the identification of patients with relevant benefit from maintenance therapy including Pmab. [Table: see text]

Landscape of DNA damage response gene mutations in microsatellite-stable colorectal carcinoma.

e15558 Background: Colorectal carcinoma (CRC) is one of the most frequent and lethal cancers in the world. Important therapeutic progress of immune checkpoint inhibitors (ICIs) is limited to molecular niche of CRC with microsatellite-stable(MSS). The identification of genomic alterations in the DNA damage response (DDR) pathway have been recognized as pathogenic factors in hereditary cancer predisposition. Few studies showed the effects of ICIs on DDR pathway in patients with MSS CRC. Some reports suggested that DDR could reshape tumor immune microenvironment by regulating tissue repair and local immune response. Here we evaluated the molecular roles of DDR pathway and the immune microenvironment in efficacy of immunotherapy in MSS CRC. Methods: A total of 67 patients with MSS CRC were enrolled into the study. All samples were collected and detected by using NGS with a 1021 gene panel which containing 56 DDR genes (Supplementary table 1). Furthermore, comprehensive bioinformatics analysis were performed by the TCGA and MSK data. We defined pathway alteration as at least one gene in DDR pathway mutated. Results: In our results, three DDR pathway alteration showed poor prognosis (P = 0.0167) compared with DDR wild type in TCGA data (Figure 1A). The MSK data demonstrated that three DDR pathway alteration were associated with a better prognosis in MSS CRC patients through ICIs therapy (P = 0.0416, P = 0.00627, respectively, Figure 1B). The clinical data suggested the patient with DDR pathway alteration had longer OS (354.7 ± 134.0 days, PR) than the others with DDR wild type (247.1± 258.4 days, PD/SD) after PD-1-targeted therapies (P = 1.587e-08). Moreover, the patient with DDR pathway alteration showed significant longer PFS (312.3 ± 179.2 days, PR) compared with DDR wild type (163.3 ± 157.7 days, PD/SD) through immune therapies (P = 4.249e-10). Moreover, significant results of immune infiltrate deconvolution revealed resting memory CD4+ T cells were the most prevalent population between DDR pathway alteration and DDR wild type using CIBERSORT analysis (P = 0.0295, Figure 1C). The activated memory CD4+ T cells in DDR pathway alteration were lower than DDR wild type (P = 0.00858, Figure 1C-D) in patients with MSS CRC. The effects of DDR pathway alteration on immune microenvironment was also necessary for effective PD-1-targeted therapy in future study. Our results suggest that two or more DDR pathways and CD4 + T cells may serve as immunotherapy markers for advanced MSS colorectal cancer. Conclusions: Mutations in DDR pathway may serve as a biomarker for PD-1-targeted therapy through memory CD4+ T cells for MSS CRC patients, which warrants further studies.