Biomarkers of Chinese advanced cancer patients based on real-world data: Actionable genomic alterations and tumor mutational burden.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14280-e14280
Author(s):  
HaiTao Wang ◽  
Huina Wang ◽  
Rongyun Guo ◽  
Mingwei Li ◽  
Yanrui Zhang ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Real World ◽  
Cell Cancer ◽  
Objective Response ◽  
Genetic Alterations ◽  
Cancer Type ◽  
Tumor Type ◽  
Mutational Burden ◽  
Esophagogastric Cancer ◽  
Tumor Mutational Burden

e14280 Background: Biomarkers would enrich patients(pts) with responsiveness to both targeted treatments and immunotherapy which have become a priority. However, molecular heterogeneous in actionable gene alterations and mutational loads need to be explored. In this study, based on a real world setting, Cancer Gene Panel (CGP） analysis was performed in a series samples of Chinese pts with advanced solid tumors, to delineate the landscape of actionable mutations and tumor mutational burden (TMB). Methods: 176 advanced pts were enrolled encompassing 19 common tumor types. All tissue samples were analyzed using next-generation sequencing with Acornmed panel including 808 genes. Results: The frequencies of genetic alterations among the most common driver genes were comparable to those reported by MSK-IMPACT (2018) ( TP53: 51.7% vs 44.8%; APC: 9.7% vs 9.8%; EGFR: 12.5% vs 7.7%; KRAS: 16.5% vs 13.6%; PIK3CA: 4.6% vs 12.0%; VHL: 4.0% vs 6.7%). 58.3% of pts with refractory solid tumors had at least one actionable mutation. Among those pts, 16.7% of them including CDK4, CDK6 or CDKN2A/B could benefit from palbociclib, and 32.1% of them including mTOR, PIK3CA, PTEN or STK11 could benefit from everolimus, and 61.9% of them including BRCA2, ARID1A, MSH1/2/6 or ATM could benefit from olaparib. Across all the specimens, the top 20% of TMB was 17.23 mutations/Mb, with a range of 0-48 mutations/Mb. The top 20% of TMB for each tumor type was 21.67(Bladder cancer), 17.23(Lung cancer), 16.45(Colorectal cancer), 11.04 (Renal cell cancer), 16.25 (Prostate cancer) , 19.70 (Hepatobiliary cancer), 14.78 (Esophagogastric cancer), 7.80 (Pancreatic cancer), 25.31 (undefined tumor) mutations/Mb respectively. Conclusions: This study indicates that most of pts with advanced refractory solid tumors have at least one actionable mutation, and matched therapies may confer clinical benefit. TMB fluctuated wildly across different cancer types, illustrating the unequal objective response rate of immunotherapy across various cancer type. Furthermore, CGP analysis in advanced pan-cancer pts can provide opportunities for targeted therapies and immunotherapy, especially in those with refractory cancer.

403 Early results from a phase 1 study to evaluate safety, pharmacokinetics, and efficacy of AMG 404, a programmed death-1 (PD-1) antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A428-A428
Author(s):  
Timothy Price ◽  
Sant Chawla ◽  
Gerald Falchook ◽  
Hans Prenen ◽  
Iwona Lugowska ◽  
...  
Keyword(s):  
Partial Response ◽  
Solid Tumors ◽  
Clear Cell ◽  
Phase 1 ◽  
Cell Cancer ◽  
Objective Response ◽  
Study Endpoint ◽  
Primary Study ◽  
Pharmacokinetic Parameters ◽  
Advanced Solid Tumors

BackgroundEnhancement of antitumor immunity through inhibition of the checkpoint PD-1 receptor has been effective in the treatment of many malignancies. AMG 404 is a monoclonal antibody (mAb) targeting PD-1. This phase 1, open-label, multicenter first-in-human study (NCT03853109) will evaluate the safety, tolerability, pharmacokinetics, and efficacy of AMG 404 monotherapy in adult patients with advanced solid tumors.MethodsThe primary study endpoint is dose-limiting toxicity (DLT) and safety; key secondary endpoints include pharmacokinetic parameters, objective response rate (assessed Q8W), duration of response, and progression-free survival. Key inclusion criteria include histologically or cytologically proven metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation for which standard therapies have been exhausted or not available. Prior anti-PD-(L)1 or other checkpoint inhibitors were not allowed. Five dose-finding cohorts, including 2 expansion cohorts, ranged from 3–20 patients each. AMG 404 was given until disease progression, intolerance, or consent withdrawal.ResultsAs of the data cutoff date of May 4, 2020, 62 patients received at least 1 dose of AMG 404 and were included in the safety and efficacy analysis sets. Fifty percent were men, 72% had ECOG 1 performance status, median age was 62 years (range: 28–83), and 42% had ≥3 lines of prior anticancer therapy. Median AMG 404 exposure was ~3 months (maximum: ~12 months). No DLTs were observed. Treatment-related adverse events (TRAEs) were reported for 29 patients (47%): those reported for ≥2 patients were fatigue (n=7); hypothyroidism (n=6); increased blood thyroid stimulating hormone and nausea (n=4 each); increased aspartate aminotransferase, decreased appetite, and pyrexia (n=3 each); and increased alanine aminotransferase, arthralgia, diarrhea, and increased weight (n=2 each). AEs leading to withdrawal of AMG 404 were reported for 3 patients (5%); all were serious and considered to be not related to AMG 404. Sixteen (26%) patients died on study; no deaths were considered related to AMG 404. Preliminary pharmacokinetic results were consistent with those of other therapeutic anti-PD-1 mAbs. Three patients had a confirmed partial response (pancreatic cancer, clear cell cancer, and pleomorphic sarcoma); an additional 4 patients had one scan with a partial response and are pending a confirmatory scan (clear cell renal carcinoma, undifferentiated nasopharyngeal carcinoma, sarcomatoid carcinoma of unknown primary, and colon cancer).ConclusionsAMG 404 is tolerable at the tested doses with no DLTs reported. All observed TRAEs are consistent with other anti-PD-1 therapies. Encouraging anti-tumor activity has been observed in heavily pretreated patients. The study is continuing enrollment into additional cohorts.Trial RegistrationNCT03853109Ethics ApprovalThe study was approved by the Ethics Board of each institution involved in this study and can be produced upon request.

Abstract LB012: Efficacy of atezolizumab in the treatment of solid tumors with high tumor mutational burden (TMB): A MyPathway study cohort

2021 ◽  
Author(s):  
John Hainsworth ◽  
Claire F. Friedman ◽  
Razelle Kurzrock ◽  
David R. Spigel ◽  
Howard Burris ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Study Cohort ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Immunotherapy in combination with PARP inhibition in advanced cervical cancer patients functionally competent or deficient for the Fanconi anemia repair pathway.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5597-TPS5597
Author(s):  
John Paul Diaz ◽  
Wenrui Duan ◽  
Eric Schroeder ◽  
Zuanel Diaz ◽  
Nicholas Lambrou ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Dna Repair ◽  
Programmed Cell Death ◽  
Phase Ii ◽  
Fanconi Anemia ◽  
Objective Response ◽  
Repair Pathway ◽  
Mutational Burden ◽  
Tumor Mutational Burden

TPS5597 Background: Immunotherapy has improved outcomes for patients with recurrent or metastatic cervical cancer whose tumors express PD-L1. Pembrolizumab (PEM), a monoclonal antibody that binds to programmed cell death 1 (PD 1) receptor, inhibits interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). It is approved for the treatment of recurrent or metastatic cervical cancer. Despite promising results, new strategies are being developed to improve immunotherapy responses. This includes DNA-damaging agents that have the potential to enhance the response to immunotherapy by promoting neo-antigen release, increasing tumor mutational burden, and enhancing PD-L1 expression. Poly-ADP-ribose polymerase (PARP) inhibitors, such as olaparib, have shown synergy with immunotherapy in preclinical and early clinical studies. PARP-based therapy is based on the inhibition of single-strand DNA repair, leading to DNA damage and increased tumor mutational burden. As a result, the tumor becomes a more attractive target for immunotherapy. Based on this, we are investigating the interplay between homologous recombination (HR) repair deficiency, another mechanism of DNA repair, and solid tumor response to ICI. Our approach uses an all-inclusive functional immunofluorescence assay of the Fanconi Anemia triple-staining immunofluorescence (FATSI) we developed and can be performed in paraffin-embedded tumors. Methods: This is a phase II open-label single center trial evaluating the role of PEM and olaparib in patients with metastatic cervical cancer who have progressed on first-line standard of care chemotherapy. FATSI will be performed in all patients. We hypothesize that FATSI negative tumors will be associated with improved responses. Other eligibility criteria include measurable disease by imaging, 18 years of age or older, and no previous exposure to ICI or PARP inhibitor. The primary objective is to evaluate the immune-related objective response rate (iORR) achieved in patients with FA Repair Pathway functionally competent and functionally deficient tumors. Secondary objectives include 20-week progression free survival and overall survival. Other exploratory objectives include evaluation of the mutation load and markers of neo-antigenicity, T cell receptor clonotype analyses (before and after treatment), and alterations in HR repair genes. We will utilize a two-stage phase II design to detect an iORR ≥ 20% in the whole population tested vs. the null hypothesis that the true iORR ≤5%, represents a response by chance alone or other infrequent unknown mechanisms. An interim analysis requires at least 2 of the first 20 evaluable patients enrolled have an objective response. If this occurs, we will accrue 28 additional patients to total 48. Enrollment is ongoing and two patients are currently on treatment. Clinical trial information: NCT04483544.

A phase 2 study of defactinib (VS-6063) in patients with NF2 altered tumors: Results from NCI-match (EAY131) subprotocol U.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3087-3087
Author(s):  
David Michael Jackman ◽  
Opeyemi Jegede ◽  
Marjorie Glass Zauderer ◽  
Edith P. Mitchell ◽  
James Zwiebel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Stable Disease ◽  
Objective Response ◽  
Genomic Analysis ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Outcome Analysis ◽  
Clinical Activity ◽  
Match Trial ◽  
Best Response

3087 Background: The NCI-MATCH trial assigns patients (pts) with solid tumors, lymphomas, or multiple myeloma to targeted therapies based on genetic alterations identified in tumor biopsies. Neurofibromatosis 2 (NF2)-inactivated tumors demonstrate increased sensitivity to FAK inhibition in preclinical models. Arm U evaluated the FAK inhibitor defactinib in pts with NF2 altered tumors. Methods: Patients found to harbor an inactivating NF2 mutation on NGS were assigned to the ARM U substudy MATCH. Defactinib 400 mg was given by mouth twice daily until progression or intolerable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included toxicity, progression-free survival (PFS), and 6-month PFS. Results: Of 5,548 cases with sufficient tissue for genomic analysis, 51 pts were found to have NF2 alterations (< 1% of the total analyzed). While NF2 alterations are known to occur more commonly in meningiomas and mesotheliomas, alterations were also detected in an array of other tumor types, including renal cell carcinomas and ovarian cancers. Thirty-five pts were ultimately enrolled; 33 patients were started on therapy, with 2 of those determined to be ineligible for outcome analysis. All pts had received at least one prior therapy, with 52% (16/31) having received 3 or more prior lines of therapy. Median follow-up was 35.9 months. ORR [90% CI] was 3% (1/31, [0.16, 14.86]), with the one partial response in a pt with choroid meningioma. Of the twelve pts whose best response was stable disease (39%, 12/31), 8 demonstrated some degree of tumor shrinkage (Table) with a disease control rate of 42% (13/31). Median PFS was 1.9 months for the 31 eligible pts who received study treatment, with median PFS of 9.3 months for the 9 patients who had a best response of stable disease or better. Six pts achieved a PFS of greater than 5.5 months. Among all treated pts (n=33), the most common treatment-related toxicities were fatigue (36%), nausea (33%), and hyperbilirubinemia (27%). There were no grade 4 or 5 toxicities; 27% of pts had grade 3 toxicities. No correlation could be made between clinical outcomes and tumor histology or specific NF2 genotype. Conclusions: Defactinib monotherapy had limited clinical activity in this cohort of previously treated patients with solid tumors exhibiting NF2 loss. Clinical trial information: NCT04439331. [Table: see text]

Investigating the various predictive values of POLE/POLD1 mutations for response to immune checkpoint inhibitors (ICIs) in different solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2606-2606
Author(s):  
Yanling Niu ◽  
Tonghui Ma ◽  
Yanling Niu ◽  
Tao Li
Keyword(s):  
T Cells ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Cancer Center ◽  
Cancer Type ◽  
Cancer Dataset ◽  
Predictive Values ◽  
Esophagogastric Cancer ◽  
Cancer Types

2606 Background: Both POLE and POLD1 encode the catalytic subunit of polymerase enzyme complexes involved in DNA replication and repair. The mutations of POLE and POLD1 have been shown to be oncogenic and lead to DNA repair defects and elevated tumor mutation burden (TMB). And patients with POLE/POLD1 mutations are more likely to benefit from ICIs therapy. Previous studies have shown that TMB has divergent predictive value for response to ICIs therapy in different cancer types. We hypothesized that the associations between POLE/POLD1 mutations and ICIs efficacy are also varied in different solid tumors. Therefore, we explored the prediction values of POLE/POLD1 mutations in some cancer types. Methods: The ICIs treatment cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was selected to analyze the association of POLE/POLD1 mutations with ICIs efficacy. TCGA cohort was enrolled for characterizing tumor infiltrating lymphocytes (TILs) with CIBERSORT. The patients were classified into two groups: POLE/POLD1 mutations (Mut) and wildtype (WT). Overall survival (OS) after ICIs therapy was estimated with Kaplan-Meier method. Results: In MSKCC pan-cancer dataset, patients with POLE/ POLD1 mutations had significantly longer median OS after ICIs therapy (34.00 vs 19.00 months, P = 0.0143), indicating that POLE/POLD1 mutations were associated with better immunotherapy outcomes. Then we analyzed the predictive roles in each cancer type. Notably, we found the associations of POLE/POLD1 mutations with longer median OS in NSCLC (Undefined vs 12.00 months, P = 0.05) and esophagogastric cancer (27.00 vs 15.00 months, P = 0.05). However, the associations between POLE/POLD1 mutations and ICIs efficacy were not observed in bladder cancer, melanoma, glioma, head and neck cancer, renal cell carcinoma, and colorectal cancer. Furthermore, our data showed that the median TMB was significantly higher in the Mut group for NSCLC (20.2 vs 6.9 muts/Mb, P < 0.0001) and esophagogastric cancer (21.4 vs 5.6 muts/Mb, P < 0.0001). In TCGA esophagogastric cancer cohort, POLE/POLD1 mutations were correlated with decreased naive B cells (P = 0.0306) and increased activated memory CD4+ T cells (P = 0.0224). In TCGA NSCLC cohort, POLE/POLD1 mutations were correlated with elevated gamma delta T cells (P = 0.0219). These data suggested that POLE/POLD1 mutations were also involved in the infiltration of some immune cells. Conclusions: Although POLE/POLD1 mutations were associated with better ICIs efficacy for all the enrolled patients, the prolonged OS was only found in the Mut group for NSCLC and esophagogastric. These data suggested that POLE/POLD1 mutations may be a useful predictor for ICIs efficacy in these two types of cancer. Moreover, POLE/POLD1 mutations were correlated with the level of TILs in NSCLC and esophagogastric. The finding was consistent with the efficacy of immunotherapy.

Clinical relevance of clonal hematopoiesis in metastatic gastrointestinal malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16082-e16082
Author(s):  
Bill Diplas ◽  
Ryan Ptashkin ◽  
Andrea Cercek ◽  
Rona Yaeger ◽  
Kelly L Bolton ◽  
...  
Keyword(s):  
Overall Survival ◽  
Genetic Alterations ◽  
Smoking History ◽  
High Status ◽  
Tumor Type ◽  
Gastrointestinal Malignancies ◽  
Clonal Hematopoiesis ◽  
Multivariate Survival ◽  
Esophagogastric Cancer ◽  
The Impact

e16082 Background: Clonal hematopoiesis (CH) represents non-random clonal selection of bone marrow-derived cells marked by somatic mutations in certain genes. The presence of CH is associated with development of atherosclerosis and leukemia, and accelerated by toxic exposures (chemotherapy, radiation, smoking) and aging (Jaiswal et al. NEJM 2017; Abelson et al. Nature 2018). The impact of these genetic alterations on cellular function is unknown, especially in the broader context of immunity and in response to cancer therapy. To determine the contribution of CH to therapeutic response and hematologic toxicity in cancer patients, we examined the outcomes of patients treated with cytotoxic and immunotherapy in relationship to CH status. Methods: We evaluated patients with metastatic colorectal cancer (CRC) or esophagogastric cancer (EGC). DNA extracted from whole blood and tumor tissue were sequenced in tandem as part of the MSK-IMPACT hybridization capture-based sequencing assay. CH was defined as any mutation with a VAF of at least 2%, present in at least 10 reads, with at least 2:1 blood:tumor reads, or 1.5:1 blood:lymph node that was not found in gnomAD with a frequency > 0.005. Additional filtering and putative driver definitions (CH-PD) were described by Bolton et al. Nature Genetics 2020. Multivariate survival analyses were performed using a Cox Proportional Hazard model correcting for CH, CH-PD, prior smoking, prior chemotherapy, prior radiation, MSI status, and age at cancer diagnosis. Results: 654 patients with EGC (n = 348) and CRC (n = 306) who began treatment between 2006 and 2020 were included in the analysis. CH was present in 34.5% and 24.4% of each group, and 17.2% and 12.9% harbored CH-PD, respectively. CH and CH-PD were both associated with older age and smoking history, and CH was also associated with prior radiation and MSI-high status (p < 0.05). Patients with CH or CH-PD receiving first-line (1L) therapy for CRC or EGC demonstrated no difference in mPFS after multivariate analysis, though 1L EGC patients with CH-PD had inferior mOS (p = 9e-5). There was no difference in pre-1L WBC, ANC, or ALC, nor in G-CSF or PEG-G-CSF doses administered during 1L therapy between patients with CH or CH-PD versus those without. Similarly, presence of CH or CH-PD had no impact on mPFS or mOS in patients receiving immune checkpoint blockade (ICB) without concurrent chemotherapy after multivariate survival analysis. Conclusions: We confirmed that the mere presence of CH is not prognostic for overall survival, but that EGC patients with CH-PD mutations have inferior overall survival, which is consistent with previous findings. Presence of CH or CH-PD was not associated with differences in baseline leukocyte counts nor need for G-CSF support, nor did it impact PFS in either tumor type, suggesting limited utility of CH in solid tumor clinical decision-making.

scholarly journals The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 666 ◽  
Author(s):  
Evangelos Koustas ◽  
Panagiotis Sarantis ◽  
Athanasios G. Papavassiliou ◽  
Michalis V. Karamouzis
Keyword(s):  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanisms ◽  
Epigenetic Alterations ◽  
Primary Resistance ◽  
Cellular Processes ◽  
Mutational Burden ◽  
Number Of Patients ◽  
Tumor Mutational Burden

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors.

scholarly journals Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 445 ◽  
Author(s):  
David Vossen ◽  
Caroline Verhagen ◽  
Martijn van der Heijden ◽  
Paul Essers ◽  
Harry Bartelink ◽  
...  
Keyword(s):  
Patient Outcome ◽  
Head And Neck ◽  
Genetic Alterations ◽  
Hypopharyngeal Carcinoma ◽  
Advanced Stage ◽  
Biopsy Material ◽  
Tumor Biopsy ◽  
Mutational Burden ◽  
Hpv Status ◽  
Tumor Mutational Burden

About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were associated with progression free survival (PFS) in advanced stage HNSCC patients who were uniformly treated with definitive platinum-based chemoradiotherapy. To this end, we performed targeted DNA sequencing on frozen pre-treatment tumor biopsy material from 77 patients with advanced stage oro- and hypopharyngeal carcinoma. This provided somatic point mutation and copy number aberration data of 556 genes. The most frequently mutated genes, TP53 (62%), CCND1 (51%), CDKN2A (30%) and PIK3CA (21%), were not associated with PFS. However, co-occurring CCND1 and CDKN2A mutations were associated with short PFS (HR 2.24, p = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, p = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, p = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring CCND1 and CDKN2A mutations are associated with chemoradiotherapy outcomes in advanced stage oro- and hypopharyngeal HNSCC patients, thereby highlighting their prognostic potential. Given their poor prognosis association and link to biological targets, they may also identify patients for novel targeted therapies and immunotherapies.

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