Time Of Disease Progression Research Articles

Change in Liver Function in Durvalumab Plus Tremelimumab Treatment for Unresectable Hepatocellular Carcinoma.

Maintaining liver function throughout the treatment of hepatocellular carcinoma (HCC) is crucial, yet the impact of durvalumab plus tremelimumab (DT) treatment on liver function is not well understood. This multicenter study aimed to examine the changes in liver function during DT treatment. This nationwide multicenter study included 80 patients who received DT treatment for unresectable HCC. The primary outcome was changes in albumin-bilirubin (ALBI) scores at baseline, week 8, week 12, and at the time of progressive disease (PD). The median (interquartile range) ALBI scores at baseline, week 8, week 12, and the time of PD were -2.24 (-2.49 to -1.94), -2.13 (-2.51 to -1.86), -2.23 (-2.51 to - 1.77), and -2.06 (-2.53 to -1.72), respectively. No significant differences were observed at 8 weeks (p=0.06), at 12 weeks (p=0.4), and at PD (p=0.8) compared to baseline. Subgroup analyses were conducted for patients with an ALBI grade of 2 at baseline and for those who received DT treatment as a second-line or later treatment. No deterioration in liver function was observed at any time point in both analyses. DT treatment can maintain liver function throughout the treatment period. Maintaining liver function is crucial in managing HCC, and this is an advantage of using DT treatment as a first-line treatment for unresectable HCC.

Atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAFV600 mutation–positive melanoma with central nervous system (CNS) metastases (mets): Final results and exploratory biomarker analysis from the phase 2 TRICOTEL study.

9550 Background: Primary analysis results from the phase 2 TRICOTEL study showed intracranial activity with the triplet combination of A + C + V in pts with BRAFV600-mutated melanoma with CNS mets (1). Here, we report final analysis results and exploratory biomarker analyses for pts with BRAFV600-mutated melanoma in the triplet combination cohort from TRICOTEL. Methods: Eligible pts were aged ≥18 y and had melanoma, MRI-confirmed CNS mets ≥5 mm in ≥1 dimension, and no prior systemic treatment for metastatic disease. Pts received A (840 mg on days 1 and 15 of each 28-d cycle) + C (60 mg once daily for 21 d on, 7 d off) + V (720 mg twice daily) except in cycle 1, during which A was withheld. Tumor tissue and circulating tumor DNA (ctDNA) samples collected at baseline (cycle 1, day 1) and ctDNA at the time of progressive disease (PD) were profiled for mutations using next-generation sequencing. Tumor tissue was profiled using a pipeline programmed for MelArray, and ctDNA was measured based on the tissue genetic profile. Results: A total of65 pts were enrolled in the triplet combination cohort. At final analysis, median follow-up was 12.4 mo. Per independent review committee (IRC) assessment, intracranial ORR (confirmed by assessments ≥4 wk apart) was 38% (95% CI, 27–51) and median intracranial PFS was 5.1 mo (95% CI, 3.7–6.9) (Table). Median OS was 13.4 mo (95% CI, 10.7–16.9). No new safety signals were observed since primary analysis. Mutations were detected in baseline ctDNA samples of 60 pts (5 pts not reported) and showed high prevalence of NF1, NRAS, and GNAI2 mutations; relative to tumor tissue, 11 additional BRAF mutations were detected in ctDNA at baseline. Acquired mutations in AKT1 were detected in ctDNA at PD. Median OS shortened in pts with >2 versus ≤2 mutated MAPK pathway genes in ctDNA at baseline (9.1 vs 14.5 mo; hazard ratio, 2.0 [95% CI, 1.0–3.7]; p<0.05). In tumor tissue, baseline mutations in PIK3C2A and PLEKHG4 were enriched in nonresponders, while RAD51B mutations were enriched in responders. Conclusions: Combination A + C + V had clinical intracranial activity in pts with BRAFV600-mutated melanoma with CNS mets. Exploratory biomarker analyses in this small cohort demonstrate the presence of ctDNA in pts with melanoma and CNS mets and provide insight into mutations associated with response and resistance to the triplet combination. 1. Dummer R et al, Lancet Oncol 2023. Clinical trial information: NCT03625141 . [Table: see text]

Levels of circulating tumor DNA correlate with tumor volume in gastro-intestinal stromal tumors: an exploratory long-term follow-up study.

Patients with gastro-intestinal stromal tumors (GISTs) undergoing tyrosine kinase inhibitor therapy are monitored with regular computed tomography (CT) scans, exposing patients to cumulative radiation. This exploratory study aimed to evaluate circulating tumor DNA (ctDNA) testing to monitor treatment response and compare changes in ctDNA levels with RECIST 1.1 and total tumor volume measurements. Between 2014 and 2021, six patients with KIT proto-oncogene, receptor tyrosine kinase (KIT) exon-11-mutated GIST from whom long-term plasma samples were collected prospectively were included in the study. ctDNA levels of relevant plasma samples were determined using the KIT exon 11 digital droplet PCR drop-off assay. Tumor volume measurements were performed using a semi-automated approach. In total, 94 of 130 clinically relevant ctDNA samples were analyzed. Upon successful treatment response, ctDNA became undetectable in all patients. At progressive disease, ctDNA was detectable in five out of six patients. Higher levels of ctDNA correlated with larger tumor volumes. Undetectable ctDNA at the time of progressive disease on imaging was consistent with lower tumor volumes compared to those with detectable ctDNA. In summary, ctDNA levels seem to correlate with total tumor volume at the time of progressive disease. Our exploratory study shows promise for including ctDNA testing in treatment follow-up.

Assessment of disease control rate and safety of sorafenib in targeted therapy for advanced liver cancer

ObjectiveThe clinical efficacy and safety of sorafenib in patients with advanced liver cancer (ALC) were evaluated based on transarterial chemoembolization (TACE).Methods92 patients with ALC admitted to our hospital from May 2020 to August 2022 were randomly rolled into a control (Ctrl) group and an observation (Obs) group, with 46 patients in each. Patients in the Ctrl group received TACE treatment, while those in the Obs group received sorafenib molecular targeted therapy (SMTT) on the basis of the treatment strategy in the Ctrl group (400 mg/dose, twice daily, followed by a 4-week follow-up observation). Clinical efficacy, disease control rate (DCR), survival time (ST), immune indicators (CD3+, CD4+, CD4+/CD8+), and adverse reactions (ARs) (including mild fatigue, liver pain, hand-foot syndrome (HFS), diarrhea, and fever) were compared for patients in different groups after different treatments.Resultsthe DCR in the Obs group (90%) was greatly higher to that in the Ctrl group (78%), showing an obvious difference (P < 0.05). The median ST in the Obs group was obviously longer and the median disease progression time (DPT) was shorter, exhibiting great differences with those in the Ctrl group (P < 0.05). Moreover, no great difference was observed in laboratory indicators between patients in various groups (P > 0.05). After treatment, the Obs group exhibited better levels in all indicators. Furthermore, the incidence of ARs in the Obs group was lower and exhibited a sharp difference with that in the Ctrl group (P < 0.05).ConclusionSMTT had demonstrated good efficacy in patients with ALC, improving the DCR, enhancing the immune response of the body, and reducing the incidence of ARs, thereby promoting the disease outcome. Therefore, it was a treatment method worthy of promotion and application.

EGFR-TKIs Combined with Allogeneic CD8+ NKT Cell Immunotherapy to Treat Patients with Advanced EGFR-Mutated Lung Cancer.

Background: To evaluate the efficacy and safety of allogenic CD8 + natural killer T (CD8+ NKT) immunotherapy combined with gefitinib in the treatment of advanced or metastatic EGFR mutant non-small cell lung cancer (NSCLC). Methods: This study is prospective. The NSCLC patients with exon 19 (Ex19del) or exon 21 L858R point mutations, and response to gefitinib treatment were enrolled into the trial to be randomly assigned into the gefitinib arm and the gefitinib/NKT arm. Allogenic CD8+ NKT cells were cultured in vitro and adaptive transferred into the patients via vein in the gefitinib/NKT arm. The primary endpoint was progression-free survival (PFS). Secondary endpoint analysis included time to disease progression (TTP), overall survival (OS), levels of serum tumour markers for carcinoembryonic antigen (CEA) and alanine aminotransferase (ALT) in the blood, the response rate and safety. From July 2017 to June 2021, 19 patients were randomly assigned to the gefitinib arm (n = 8) and the gefitinib/NKT arm (n = 11). Results: The estimated median survival PFS in the gefitinib/NKT arm was significantly longer than that of the gefitinib arm (12 months vs 7 months). Similar results were also observed for the median TTP. Moreover, the gefitinib/NKT arm had better CEA control than the gefitinib arm. Clinical grade 3 adverse reactions occurred in 64% and 39% of patients in the gefitinib/NKT arm and the gefitinib arm, respectively. The most common grade 3 adverse events in the gefitinib/NKT arm included abnormal liver function in 8 cases (73%) and diarrhoea in 1 case (9%), both of which resolved after drug intervention. Conclusion: The PFS of EGFR-mutated advanced NSCLC treated with allogenic CD8+ NKT cells combined with gefitinib was longer than that of gefitinib alone. No obvious serious adverse reactions occurred, and the patients compliance and survival status were good.

Extended Follow-up and Resistance Mutations in CLL Patients Treated with Acalabrutinib

Background: Covalent Bruton tyrosine kinase inhibitor (cBTKi) is a standard treatment for chronic lymphocytic leukemia (CLL). Understanding of acquired resistance to cBTKi therapy has largely come from data on patients (pts) treated with the first-in-class cBTKi ibrutinib. Mutations in BTK C481 and to a lesser extent PLCG2 are frequently detected in ibrutinib-treated pts at the time of progressive disease (PD). In contrast, much less is known about genetic mechanisms of drug resistance in pts treated with next generation cBTKi acalabrutinib and zanubrutinib. A recent study identified 3 pts with BTK C481 mutations and no pts with PLCG2 mutations among 8 acalabrutinib-treated pts with progressive disease (PD) (Black, et al. Blood 2022). A second study found a kinase-dead BTK L528W mutation in 7/13 zanubrutinib-treated pts (Blombery, et al. Blood Adv 2022). Although cBTKi share the same mechanism of action by binding to BTK C481, the latter report discloses differences in clonal selection and underscores the need for further investigation in pts treated with next generation cBTKi. In a phase 2 study of acalabrutinib in pts with treatment naïve (TN) CLL or small lymphocytic lymphoma (SLL) with 17p deletion, or TP53 or NOTCH1 mutation, or relapsed/refractory (R/R) CLL/SLL regardless of cytogenetics or somatic mutations (Sun, et al. Blood 2020), we sought to understand clonal evolution during treatment. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from 48 pts at baseline, after 6 months, then annually on treatment until PD. Current analysis includes 14 PD pts [excluding 3 Richter transformation (RT) pts] comprising 10 R/R and 4 TN CLL pts. Additionally, paired baseline and PD bone marrow (BM) from 6 pts and lymph node (LN) samples from 2 pts were included. Targeted next-generation sequencing of ~700 recurrently mutated genes in hematological malignancies (Collins, et al. Leuk Lymphoma. 2021) was performed using DNA isolated from CD19 + enriched cryopreserved PBMCs and BM aspirates, as well as fresh-frozen core LN biopsies. Filtered variants in putative CLL driver genes (Knisbacher, et al. Nat Genet. 2022) with variant allele frequencies (VAF) ≥1% for BTK and PLCG2, ≥5% for variants with known oncological significance, and ≥7.5% for all other variants were included in downstream analysis. Results: After a median follow-up of 6.5 years (IQR 2.9-6.3), 23/48 (48%) pts developed PD (20 CLL, 3 RT). PD occurred in 17/32 (53%) R/R pts and 6/16 (38%) TN pts. Median progression-free survival was reached at 6.0 years. Best response was complete remission in 2/20 (10%) pts and partial remission in 18/20 (90%) pts with CLL PD. IGHV was unmutated in all but one PD patient. At baseline, 34 CLL driver genes were mutated in 41/45 pts (91%; excluding 3 RT pts) with most mutations in NOTCH1, TP53, ATM, SF3B1, BIRC3, and NFKBIE. During acalabrutinib treatment but before PD, 14/45 pts (31%; 8 R/R and 6 TN) acquired mutations in 11 driver genes, most commonly in BRAF (n=4), CREBBP (n=4), and KMT2D (n=2). At the time of PD, 11/14 pts (79%) had newly acquired mutations in 4 genes, predominantly BTK (n=6) and PLCG2 (n=4). BTK C481 mutations (VAF 2-42%) were detected in 6/14 (43%; 4 R/R and 2 TN) pts and T474I mutation (VAF 4-46%) in 3/14 (21%; 1 R/R and 2 TN) pts. Paired BM samples in 2 pts and LN samples in 2 pts showed the same BTK mutations as PBMCs with similar VAFs. PLCG2 mutations (VAF 1-8%) were found in 4/14 (29%; 2 R/R and 2 TN) pts. BTK C481 co-occurred with BTK T474I in 3 pts, but on different sequencing reads suggesting independent subclones, and with a PLCG2 mutation in 1 pt. There have been no pts with BTK L528 mutations. In conclusion, mutations in BTK and PLCG2 are the predominant resistance mechanism to acalabrutinib. Among BTK mutations, C481 was the most common. All T474I mutations co-occurred with C481.

Predictive significance of circulating tumor DNA against patients with T790M-positive EGFR-mutant NSCLC receiving osimertinib

Circulating tumor DNA (ctDNA) provides molecular information on tumor heterogeneity. The prognostic usefulness of ctDNA after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are limited. Therefore, the present study evaluated ctDNA during osimertinib administration as a second-line or more setting to identify the relationship between EGFR mutation levels and outcomes in patients with advanced non-small cell lung cancer (NSCLC). Forty patients with EGFR T790M-positive NSCLC receiving osimertinib after prior EGFR-TKI treatment were registered. Plasma samples were collected at osimertinib pretreatment, after 1 month of treatment, and at the time of progressive disease (PD). ctDNA analysis was performed by digital polymerase chain reaction. The detection rate of copy numbers of exon 19 deletion, L858R, and T790M in plasma samples was significantly lower 1 month after osimertinib than at pretreatment, and significantly higher at PD than at 1 month, whereas that of C797S was significantly higher at PD than at 1 month. No statistically significant difference was observed in the copy numbers of exon 19 deletion, L858R, T790M, and C797S between complete response or partial response and stable disease or PD. The detection of T790M at PD after osimertinib initiation was a significant independent prognostic factor for predicting shorter prognosis, and the presence of major EGFR mutations at pretreatment and PD was closely linked to worse survival after osimertinib initiation. Molecular testing based on ctDNA is helpful for predicting outcomes of osimertinib treatment in T790M-positive NSCLC after previous EGFR-TKI treatment.

The China Monoclonal Gammopathy Screening Project in First-Degree Relatives of Patients with Multiple Myeloma (CHAPERONE) –a Multicenter Screening Study

Background and Significance: Multiple myeloma (MM) evolves from the precursor state monoclonal gammopathy of undetermined significance (MGUS). According to previous reports, the incidence of MM and its precancerous state MGUS was lower in Asian populations than in Western populations. However, with the aging of the population, we found that the incidence of MM in China has been on the rise in recent years, and the medical burden has continued to increase. Therefore, early recognition of MM and its precursor condition is even more critical. Our previous research has confirmed that monoclonal gammopathy (M-protein) screening and close follow-up of MGUS can increase the early diagnosis rate of MM and improve the prognosis of MM patients[1]. M-protein screening in healthy people at high risk for MM is a rational strategy. The risk of MM in the first-degree relatives of myeloma patients is 2-4 times that of the general population, constituting a high-risk group for MM. Although the screening of M-protein in high-risk populations has been explored in the US (the PROMISE study), little was known about the incidence, clinical features, and prognosis of MGUS in high-risk groups in China. Here, we describe the first prospective screening project to assess the potential benefits of M-protein screening and the prevalence and outcomes of MGUS in first-degree relatives of patients with multiple myeloma in the China population (NCT05965115). Study Design and Methods: The CHAPERONE study is a prospective, multicenter screening study for MGUS in first-degree relatives of MM patients, including a risk-stratified follow-up strategy(Figure). Clinical trial registry number: NCT05965115, actively recruiting. This study aims to assess the clinical significance of screening for monoclonal gammopathy in first-degree relatives of patients with multiple myeloma in China. The primary objective is to determine the prevalence and incidence rate of MGUS, the time to disease progression (TTP), and its influencing factors in first-degree relatives of MM patients in China. The secondary and exploratory study objective is to explore the clinical/genomic features, survival, and quality of life of the screened MGUS cases. The expected screening size is 10,000 healthy persons. To be eligible, participants must be over 18, with one or more first-degree relatives (including parents, children, and biological siblings) having multiple myeloma diagnosed by the International Myeloma Working Group (IMWG) Myeloma Diagnostic Criteria. Participants with a known diagnosis of plasma cell diseases, such as MGUS, smoldering myeloma (SMM), or MM, will be excluded. All eligible participants will receive M-protein screening by serum electrophoresis. Individuals with detected M-protein will undergo further diagnostic tests, including peripheral blood tests (immunofixation electrophoresis, serum free light chain, immunoglobulin quantification, blood routine, liver and kidney function, and blood calcium level) and X-ray bone assays. Patients with suspecting MM features will undergo further bone marrow surveys to ascertain the diagnosis. Patients with MGUS will be carefully assessed and stratified by the risk of progression to MM according to the IMWG MGUS consensus. Low-risk MGUS will be followed-up annually, while intermediate/high-risk MGUS will be biannual. Participants who progress to MM will be offered early treatment. Conclusions and Future Directions: One path to making MM a preventable cancer is better understanding its precursor condition (MGUS). This trial is positioned to provide epidemiology, clinical, and potential mechanistic data on MGUS at a high-risk group in China population that has yet to be thoroughly studied. Reference: [1] Li J, Wang Y, Liu P. The impact on early diagnosis and survival outcome of M-protein screening-driven diagnostic approach to multiple myeloma in China: a cohort study[J]. J Cancer, 2019, 10(20): 4807-4813.

P09.06.B GAIT CHARACTERISTICS OF PROGRESSIVE DISEASE IN HIGH GRADE GLIOMA: THE BRAINWEAR STUDY

Abstract BACKGROUND Walking is a useful measure of overall health and walking speed has well-documented predictive value for health-related outcomes such as mortality, quality of life, physical and cognitive functional decline in older people. Wearable technology-based gait analysis is emerging as a powerful tool to detect early disease and monitor progression in areas such as Parkinson’s disease. We present an exploratory analysis of gait characteristics at the time of progressive disease from patients with high grade glioma (HGG) participating in the BrainWear Study which evaluates the use of free-living accelerometers in patients with brain tumours. MATERIAL AND METHODS All agreed to wear a wrist-worn Axivity AX3 triaxial accelerometer changed at 14-day intervals. Raw accelerometer data was processed using the UKBiobank OxWearables stepcount model v2.1.2 for Python and inclusion of high-quality wear time selected as ≥72 hours of data in a 7-day data collection and data in each 1-hour period of a 24-hour cycle over multiple days. 12 gait measures were characterised including total daily steps, cadence, cadence peak and minutes walking per day. We analysed variation in gait measures by patient demographics and MRI result. Wilcoxin-signed rank test was used to compare participant gait measures at timepoints of stable disease (SD) or progressive disease (PD). Mixed-effects models were used to evaluate longitudinal changes in gait measures. RESULTS 17 HGG patients (6 female; 11 male) provided 4654 days of accelerometer data across 49 MRI Head scan RESULTS , 32 labelled as PD and 17 as SD. Median age was 62 years (32-79) and mean study participation 273 days (41-550). 8 patients provided accelerometer data at timepoints of both PD and SD allowing for paired analysis. There were no differences in 12 gait measures between age (&amp;lt;60 and &amp;gt;60 years) and gender. In the 6 weeks surrounding an MRI scan, patients with PD walked on average 1856 steps less per day than those with SD, and spent 22 minutes less walking (p=0.0403). Peak 1-minute cadence was 77 steps/min in patients with SD versus 67 steps/min with PD. CONCLUSION The complexity of HGG treatment, recovery and survivorship creates a need for novel monitoring approaches. Wearable accelerometry is feasible and acceptable and evaluating gait measures captures objective evidence of significant differences in patients with PD versus SD. Physical activity measures can guide clinicians in optimising quality of life and may act as an alert system prior to events such as disease progression.

Randomized Phase III Trial Comparing Epirubicin/ Doxorubicin Plus Docetaxel and Epirubicin/ Doxorubicin Plus Paclitaxel as First Line Treatment in Women with Advanced Breast Cancer

This study aimed to examine the efficacy of docetaxel plus epirubicin against docetaxel plus capecitabine as first-line therapy for women with advanced breast cancer (ABC). Patients with ABC who had not been treated in the past were split into two groups: those who received docetaxel and epirubicin (DE) on day 1 and those who received docetaxel and capecitabine (DC) on day 1 and twice daily on days 1-14 of each 21-day cycle. Prior neoadjuvant treatment with anthracyclines was permitted if it had been finished more than a year prior to enrolment. The study's major aim was to evaluate the difference in time to disease progression (TTP). Median TTP for DE was 10.6 months and for DC it was 11.0 months (P = 0.7), with each arm treating 170 women. Using the RECIST criterion, we found that the rates of complete responses were higher in DC (61%) than in DE (11%), and that the rates of partial responses were lower in DC (40%) than in DE (45%) (P = 0.8). Grade 3-4 neutropenia was more common with DE than DC (57% vs. 46%, P = 0.07), as were febrile neutropenia (11% vs. 8%, P = 0.4), hand-foot syndrome (0% vs. 4%, P = 0.02), grade 2-3 anemia (20% vs. 7%, P = 0.001), and asthenia (12% vs. 6%, P = 0.09).

Circulating Tumor DNA Dynamics and Treatment Outcome of Regorafenib in Metastatic Colorectal Cancer.

Circulating tumor DNA (ctDNA) is emerging as a valuable non-invasive tool to identify tumor heterogeneity and tumor burden. This study investigated ctDNA dynamics in metastatic colorectal cancer patients treated with regorafenib. In this prospective biomarker study, plasma cell-free DNA (cfDNA) samples obtained at baseline, at the first response evaluation after 2 cycles of treatment, and at the time of progressive disease were sequenced using a targeted next-generation sequencing platform which included 106 genes. A total of 285 blood samples from 110 patients were analyzed. Higher baseline cfDNA concentration was associated with worse progression-free survival (PFS) and overall survival (OS). After 2 cycles of treatment, variant allele frequency (VAF) in the majority of ctDNA mutations decreased with a mean relative change of -31.6%. Decreases in the VAF of TP53, APC, TCF7L2, and ROS1 after 2 cycles of regorafenib were associated with longer PFS. We used the sum of VAF at each time point as a surrogate for the overall ctDNA burden. A reduction in sum (VAF) of ≥ 50% after 2 cycles was associated with longer PFS (6.1 vs. 2.7 months, p=0.002), OS (11.3 vs. 5.9 months, p=0.001), and higher disease control rate (86.3% vs. 51.1%, p < 0.001). VAF of the majority of the ctDNA mutations increased at the time of disease progression, and VAF of BRAF increased markedly. Reduction in ctDNA burden as estimated by sum (VAF) could be used to predict treatment outcome of regorafenib.

Therapies in Refractory Metastatic Renal Cell Carcinoma

As the therapeutic landscape for metastatic clear cell renal cell carcinoma (mccRCC) expands to include vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) and immunotherapies, new challenges are in place for evaluating and treating refractory disease. Assessing and managing refractory disease has several elements: (1) the mechanism(s) of front-line treatment, (2) timing of progressive disease, (3) rapidity and sites of progressing disease, (4) use of adjuvant therapy, and (5) incorporation of surgical and radiation techniques. These variables all have distinct impact on the biology of refractory or resistant mccRCC. A better understanding of the essential mechanisms of both primary and secondary immunotherapy resistance will inform biomarker development and therapeutic strategies in the refractory setting. This paper addresses the current understanding of treatment sequencing in refractory mccRCC, focusing on treatment options with prospective clinical trial data, considers refractory mccRCC after adjuvant immunotherapy, and incorporates radiation or surgical resection for oligoprogressive disease.

Lanreotide Depot to Treat Gastroenteropancreatic Neuroendocrine Tumors in a US Community Oncology Setting: A Prospective, Observational Study.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can result in symptoms such as diarrhea, flushing, abdominal pain, and fatigue and are often associated with a significant disease burden and poor prognosis. This non-interventional, prospective, observational study evaluated the real-world safety and effectiveness of lanreotide depot, a somatostatin analog (SSA) used to treat GEP-NETs, in a community setting. In this prospective, non-interventional study (NCT02730104), adult patients with locally advanced (inoperable), metastatic GEP-NETs treated with lanreotide depot were evaluated by their physician every 6 months from enrollment for 24months. Clinically defined time to disease progression (TTDP) and overall survival (OS) were estimated for the total population and by primary tumor type (gastrointestinal [GI], pancreatic, unknown origin), and an exploratory analysis determined the rate of progression-free survival (PFS) at 12 and 24months. Patient satisfaction was evaluated via the Treatment Satisfaction Questionnaire for Medication (TSQM-9), and safety information was recorded. Of 99 patients, the 24-month PFS rate was 73.7% (95% confidence interval [CI] 63.1-81.7) and 24-month OS rate was 84.2% (95% CI 74.0-90.7). Median TTDP was not reached because few patients experienced disease progression during the study period. The majority of responding patients expressed satisfaction with treatment on each domain of the TSQM-9. Treatment-related adverse events (AEs) occurred in 19.2% of patients, while no serious AEs (SAEs) were related to the study drug. Lanreotide depot is an effective and well-tolerated treatment for GEP-NETs in the real-world community setting. ClinicalTrials.gov identifier, NCT02730104.

Abstract 1729: Single-cell transcriptome profiling of multiple myeloma bone marrow samples suggests that disease progression interplays with tumor and tumor microenvironment in The MMRF CoMMpass Study

Abstract Multiple Myeloma (MM) is a hematologic malignancy marked by uncontrolled clonal expansion of plasma cells. Previous research has examined single-cell transcriptome profiles of Monoclonal gammopathy of undetermined significance (MGUS) and MM tumor microenvironment (TME) and found that natural killer (NK) cell abundance is elevated in the early stages and correlated with altered chemokine receptor expression. This study suggested the critical role of immune cells on myeloma progression from asymptomatic MGUS to symptomatic MM. Up to date, however, there are no published studies comprehensively comparing tumor and immune populations differences between MM NON-progressors (NPs) and FAST-progressors (FPs) and investigating how clonal plasma cells affect disease progression in a large cohort. Therefore, understanding how tumor and immune cells influence disease progression within symptomatic MM is of great interest.Here, we subjected CD138-negative Bone Marrow Mononuclear cells (BMMC) samples from 418 MM patients to scRNA-seq. From MMRF CoMMpass study (NCT01454297), we also have whole exome sequencing (WES) and bulk RNA-seq from CD138-positive fraction of BMMC samples. Based on time to progressive disease (TTPD), we classified patients into 2 categories. Patients with TTPD less than 18 months were classified as FAST-progressors (FPs), whereas patients with TTPD more than 5 years were classified as NON-progressors (NPs). By analyzing patient genomic alterations and its association with progression, we found that there was a significant association of slow MM progression with t(11;14) (p = 0.048), consistent with previous study. In our preliminary analysis, we profiled 83 CD138-sorted MM bone marrow samples using scRNA-seq. Interestingly, we found plasma cells from samples with the same genetic alterations tend to cluster together, highlighting the important role of genetic drivers in transcriptome profiles of plasma cells. Moreover, integrated analysis of bone marrow samples from 83 MM patients and 4 healthy donors revealed an atypical naïve-B cell subset with enrichment of cells from fast-progressors and partial expression of MS4A1. Differentially expressed genes for this naïve-B cell subset includes KLF9, BCL2L11, JOSD1, and IRS2, etc. Overall, as part of MMRF immune profiling research, this study will help to interrogate how genetic alterations and disease progression interplay MM tumor and TME and provide a sufficiently broad and valuable dataset for systematically characterizing MM at single-cell resolution. Hopefully, this study could identify novel targets for MM immunotherapies, and ultimately identify patients with high risk of fast progression for early intervention in the clinic. Citation Format: Lijun Yao, Tianjiao Wang, Kazuhiro Sato, Reyka Jayasinghe, I-Ling Chiang, Darwin D'souza, William Pilcher, Edgar Gonzalez-Kozlova, Yered Pita-Juarez, Taxiarchis Kourelis, Deon Bryant Doxie, Beena Thomas, Brian Lee, Swati Sharma Bhasin, Upadhyaya Bhaskar, Mark Fiala, Julie Fortier, Travis Dawson, John Leech, Shaji Kumar, Hearn Cho, Seunghee Kim-Schulze, Bee Raj, Stephen Oh, the MMRF Immune Profiling Research Team, John Dipersio, Ravi Vij, Adeeb Rahman, Ionnis Vlachos, Shaadi Mehr, Mark Hamilton, Daniel Auclair, Surendra Dasari, David Avigan, Madhav Dhodapkar, Sacha Gnjatic, Manoj Bhasin, Li Ding. Single-cell transcriptome profiling of multiple myeloma bone marrow samples suggests that disease progression interplays with tumor and tumor microenvironment in The MMRF CoMMpass Study [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 1729.

Mechanisms of action and acquired resistance to atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancer (mTNBC).

1078 Background: In the IMpassion130 study (NCT02425891) first-line atezolizumab plus nab-paclitaxel (A+nP) provided clinical benefit compared with placebo plus nP (P+nP) in patients with mTNBC whose tumors were PD-L1+ (Schmid NEJM 2018). However, in many patients, disease that was initially controlled eventually progressed. The mechanism of action of A+nP and nP in the mTNBC tumor microenvironment (TME) and the biological changes associated with tumor progression with these therapies remain largely unknown. The goal of the current study was to evaluate biological changes in the TME induced by atezolizumab and nP early on treatment (OT) and at the time of progressive disease (PD) in IMpassion130. Methods: Paired tumor biopsies from IMpassion130 collected pre-treatment at baseline (BL), after 4 weeks OT, and at clinical PD were evaluated histologically for PD-L1 expression, CD8 content, stromal tumor infiltrating lymphocytes and immune phenotypes. RNA sequencing was also used to evaluate TNBC molecular subtypes and gene expression (hallmark gene sets, and immune cell and stromal gene signatures). Matched tumor pair samples from BL and PD were further analyzed by next-generation sequencing for genomic changes using the FoundationOne gene panel. Wilcoxon, Fisher, and McNemar’s tests were used for statistical analysis. Results: OT A+nP (n = 24 pairs), but not P+nP (n = 18 pairs) increased PD-L1 in both tumor-infiltrating immune cells and tumor cells, and increased frequency of immune-inflamed tumors. RNA-based signatures for A+nP showed an increase in lymphocytes (T-, B-, and NK cell), as well as IFN-α and IFN-γ responses, driven mainly by responders. While P+nP increased RNA-based stromal signatures (cancer-associated fibroblasts, pericytes, and angiogenesis) and epithelial mesenchymal transition, these changes were not observed with A+nP. OT A+nP and P+nP both reduced cell proliferation but only A+nP reduced metabolic pathways. At PD there was a significant reduction of RNA-based immune and stromal signatures in both A+nP (n = 59) and P+nP (n = 55) arms. Cell proliferation and DNA repair signatures were increased with A+nP but not P+nP. Evaluation of genomic changes suggested that both A+nP and P+nP increased tumor mutational burden (TMB), but only A+nP increased genomic scarring. At PD, the tumor immune phenotypes changed at PD with no directionality, while TNBC subtypes remained stable. Conclusions: A+nP boosted tumor immune inflammation and decreased tumor cell proliferation and metabolism in mTNBC patients, particularly in responders. Addition of atezolizumab prevented early stromal recruitment induced by nP. While decreased immune and stromal components and increased TMB were observed with both nP and A+nP, A+nP tumor escape was characterized by increased cell proliferation and DNA scarring. Clinical trial information: NCT02425891.

A randomized phase 2 study of continuous or intermittent dosing schedule of imatinib re-challenge in patients with tyrosine kinase inhibitor-refractory gastrointestinal stromal tumors.

11538 Background: Resumption of imatinib is one of the available therapeutic options for patients with gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs). Intermittent dosing of imatinib was suggested to delay outgrow of the imatinib-resistant clones in a preclinical study. Methods: A randomized phase 2 study was performed to evaluate the efficacy and safety of continuous or intermittent schedule of imatinib in GIST patients whose disease had progressed to at least imatinib and sunitinib. Patients were randomly assigned (1:1) to the intermittent dosing group that received 400mg daily imatinib based on a 1 week-on and 1 week-off schedule or the continuous dosing group that received imatinib 400mg daily without drug holiday. Disease control rate (DCR) rate at 12 weeks was the primary endpoint. Plasma samples were collected for circulating tumor DNA analysis at baseline, at 3 months of continuous or intermittent imatinib treatment and at the time of progressive disease. Results: Fifty patients received at least one dose of imatinib and were included in the full analysis set. Most patients (n = 46) had received prior regorafenib. DCR rate at 12 weeks was 34.8% and 43.5% in the continuous and intermittent groups, respectively. Median progression-free survival was 1.68 months and 1.57 months in the continuous and intermittent groups, respectively. The frequency of any grade anorexia, dysphagia, diarrhea, decreased neutrophil was lower in the intermittent group, whereas that of abdominal pain was higher in the intermittent group. Two patients in the continuous imatinib group underwent dose modification, and there was no patient who discontinued the study treatment because of adverse events related to study treatment. Conclusions: We confirmed that imatinib re-challenge was effective in TKI-refractory GIST patients. Intermittent dosing schedule may also be a clinically feasible treatment option for imatinib resumption in TKI-refractory GIST patients. Clinical trial information: NCT02712112.

Immunogenicity and disease control induced by a multineoantigen vaccine (ADXS-503) in patients with metastatic non–small cell lung cancer who have progressed on pembrolizumab.

9042 Background: The administration of a lung cancer-specific immunotherapy with 22 tumor-associated antigens (ADXS-503, A503), has been evaluated as an add-on therapy for patients (pts) with metastatic non-small-cell lung cancer (NSCLC) who have progressed on pembrolizumab (pembro) as last therapy [Haigentz M et al. ASCO 2021]. The present study explores the immunogenicity and potential reversal of immune resistance with A503 when added-on to pembro at the time of progressive disease (PD). Methods: A phase 2 study of A503 + pembro is being conducted in pts with metastatic squamous or non-squamous NSCLC. In Part B of the study, A503 was added-on to pembro within 12 weeks after the first scan showing disease progression following pembro therapy (per RECIST criteria v1.1). Both A503 (1x108 CFU) and pembro (200 mg) were infused by IV every 3 weeks until disease progression or dose-limiting toxicity. Immunogenicity assays included serum cytokine and chemokine levels; flow cytometry; and in-vitro stimulation FluoroSpot assay with 4 different antigen-pools represented in A503 [i.e., hot spot mutations, heteroclitic/wild-type tumor-associated antigens and other antigens not included in the A503 construct (antigen spreading)]. Results: A total of 14 pts have been treated in Part B, of which 13 are clinically evaluable and up to 11 have immune assessments. Combination therapy was well tolerated with transient increased secretion of cytokines for several hours after infusion of A503 consistent with the expected immune activation and transient ‘flu-like’ syndrome. The objective response rate (16%) and disease control rate (46%) were encouraging with 2 partial responses (PR), 4 stable diseases (SD) and 7 pts with PD. Pts with disease control, in particular, generated CD8+ T cells reactive to neoantigens in 1 or more of the 4 antigen pools tested in FluoroSpot. Also, activation of NK cells and of cytotoxic- and memory-CD8+ T cells was mainly observed in pts with PR or SD, but not in those with PD, as shown in the table. Conclusions: Adding A503 to pembro after PD appears to induce innate and adaptive immune responses that may restore or enhance sensitivity to checkpoint inhibitors in pts with clinical benefit. Clinical trial information: NCT03847519. [Table: see text]

Abstract P2-08-04: Progressive metastatic breast cancer with no detectable circulating tumor DNA: Evaluating limitations of this highly sensitive tool

Abstract Background: Circulating tumor DNA (ctDNA) is being evaluated as a tool to monitor disease and guide therapy escalation and de-escalation in advanced breast cancer. The patient, disease, and treatment characteristics that influence whether tumor DNA is isolated and sequenced from the bloodstream are not well understood. We aimed to describe patient and disease characteristics of cases with undetectable ctDNA levels despite progressive metastatic breast cancer (MBC). Methods: We retrospectively identified patients (pts) with MBC who had ctDNA evaluation by the Guardant 360 assay (Redwood City, CA) as part of their routine care from 2015-2020. We correlated the ctDNA assay with the disease status at collection. We identified the patient cohort with no detectable ctDNA despite evaluation at the time of progressive disease but prior to the initiation of a new therapy (ND ctDNA/PD) and compared the clinical, pathologic, and molecular features of this group to those with detected ctDNA. Differences were tested by two proportion z-tests. Results: Of 1151 ctDNA samples collected among 473 pts with MBC, 87 (7.5%) samples had no detectable (ND) ctDNA. 54 of 87 samples with ND ctDNA were collected at a time of stable or responding disease or after a new line of therapy was started, leaving only 33 ctDNA evaluations (2.8%) among 30 pts with ND ctDNA despite collection at the time of PD prior to new therapy. Among this group there were 14 pts (47%) with HR+ HER-, 11 pts (37%) with HER2+, and 5 pts (17%) with TN MBC. This compared to 254 pts (60%) with HR+ HER2-, 82 pts (19%) with HER2+, and 85 pts (20%) with TN MBC and detectable ctDNA. HER2-positive MBC was more common in the ND ctDNA/PD group than detectable ctDNA group (p-0.02). In the ND ctDNA/PD group, the median time from MBC diagnosis to ctDNA evaluation was 7 months and pts had received a median of 0.5 prior lines of therapy for MBC. Four pts (13%) had lobular breast cancer, 24 pts (80%) had recurrent disease, 14 pts (47%) had visceral metastases, and 12 pts (40%) had oligometastatic disease. Sites of metastases at the time of ND ctDNA/PD were bone n=16 (53%), lung n=7 (23%), liver n=6 (20%), lymph node n=11 (37%), skin and soft tissue n=5 (17%), and CNS n=5 (17%). When compared to those with detectable ctDNA these differences in characteristics were not statistically significant, although numerically pts with ND ctDNA had more CNS disease (17% vs 10%) and less liver disease (20% vs 32%). At the time of ND ctDNA, the site of progression was bone n=14 (47%), CNS n=5 (17%), lymph node n=9 (30%), lung n=7 (23%), and liver n=5 (17%). There was a single site of progression in 20 pts (67%). 16 of 30 pts had repeat ctDNA analysis of which 9 pts had subsequent detectable ctDNA with a median VAF of 0.3%, a median of 1 alteration per sample, and oncogenic or likely oncogenic alterations in TP53 in 3 pts and BRCA1, CCNE1, CDH1, and PIK3CA in 1 pt each. Seven had tissue NGS, all of which showed multiple oncogenic alterations. The remaining 22 pts with ND ctDNA but no PD were responding to therapy based on imaging or had already started a new therapy since the last progression. This group also had a high proportion of HER2+ MBC (n=7, 32%) and low proportion with visceral disease (n=6, 27%) Conclusions: Although ctDNA is a highly sensitive tool to detect active MBC (&amp;lt;3% of samples had ND ctDNA), its sensitivity may be less in some clinical scenarios, including HER2+ MBC, when there are limited sites of progression, or when there is isolated CNS progression. Citation Format: Ami N Shah, Lorenzo Gerratana, Shruti Chandra, Dhruvika Mukhija, Neelima Katam, Anthony K Kang, Andrew A Davis, Millen Srivastava, Saya Jacob, Paolo D'Amico, Qiang Zhang, Carolina Reduzzi, Michael Gurley, Firas Wehbe, William J Gradishar, Amir Behdad, Massimo Cristofanilli. Progressive metastatic breast cancer with no detectable circulating tumor DNA: Evaluating limitations of this highly sensitive tool [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-04.

Comparison of Two Blood-Based Genotyping Tests to Investigate the KRAS G12C Mutation in Patients with Non-Small-Cell Lung Cancer at Failure of First-Line Treatments.

Although molecular profiling at diagnosis has traditionally relied on direct sampling of neoplastic tissue, cancer clonal evolution represents a critical obstacle to use primary tissue biopsies to guide clinical decision-making at the time of progressive disease. Liquid biopsies might offer enormous advantages over tissue biopsies, tracking in real-time temporal-based tumor dynamics following each line of treatment. Here, we compared two liquid biopsy assays, specifically real-time polymerase chain reaction and next-generation sequencing, to track the KRAS G12C mutation at onset of progression from previous lines of therapy. The KRAS G12C mutation was acquired at the time of progressive disease in 24% of patients. Furthermore, all patients with KRAS G12C mutation-positive tissue became negative in ctDNA at progressive disease. The presence of other somatic mutations in all these samples confirmed the tumor origin of the circulating DNA. This pilot study suggests that in the assessment of the plasma KRAS G12C mutation as a druggable target, real-time PCR assay Idylla might be a suitable approach to better match patients to interventional biomarker-targeted therapies.

Novel Mechanisms of Acalabrutinib Resistance in Patients with Chronic Lymphocytic Leukemia By Whole Genome Methylome Sequencing

Novel Mechanisms of Acalabrutinib Resistance in Patients with Chronic Lymphocytic Leukemia By Whole Genome Methylome Sequencing