PFS Outcomes Research Articles

Efficacy and safety of immune checkpoint inhibitors for advanced or recurrent endometrial cancer: a systematic review and network meta-analysis.

Currently, several randomized controlled trials (RCTs) have been conducted to investigate the efficacy of combining immune checkpoint inhibitors (ICIs) with chemotherapy as a first-line treatment for advanced or recurrent endometrial cancer; however, the optimal treatment strategy remains undetermined. A comprehensive search of online databases was conducted to identify RCTs published until December 31, 2023. Network meta-analysis was performed to evaluate PFS, OS, TRAEs, irAEs, and the ranking of different treatment regimens. A total of 2702 patients from five RCTs (six reports) were included in the analysis. The combination therapy of ICIs significantly prolonged PFS (HR = 0.69, 95%CI 0.63-0.76, p < 0.0001) and OS (HR = 0.73, 95%CI 0.63-0.85, p < 0.0001) in the overall population. Among the different ICIs combinations evaluated, Durva-Olap-CP exhibited superior efficacy for both PFS and OS outcomes. In the pMMR population, both Durva-Olap-CP and Pembro-CP significantly reduced the risk of disease progression or death compared to Avelu-CP and Atezo-CP treatments; however, no significant differences were observed among various ICI combination therapies in patients with dMMR. In the dMMR population, Dostar-CP demonstrates a 42.2% probability of achieving first rank in terms of PFS, whereas in the pMMR population, Pembro-CP exhibits a 60% likelihood of securing the top position. Importantly, the toxicity associated with ICIs combination therapy was manageable and well-tolerated. The combination of ICIs and chemotherapy as first-line treatment for advanced or recurrent endometrial cancer has demonstrated superior survival outcomes compared to chemotherapy alone. Durva-Olap-CP exhibited the most favorable PFS and OS benefits in the overall population. In patients with dMMR, Dostar-CP showed the greatest improvement in PFS, while Pembro-CP demonstrated the most pronounced PFS benefit in patients with pMMR.

Assessment of Different Castration Resistance Definitions and Staging Modalities in Metastatic Castration-Resistant Prostate Cancer.

Background/Objectives: Progression to metastatic castration-resistant prostate cancer (mCRPC) is defined either biochemically, radiographically or both. Moreover, staging for mCRPC can be performed either conventionally or with molecular imaging such as prostate-specific membrane antigen computer tomography (PSMA-PET/CT). Methods: We relied on the Frankfurt Metastatic Cancer Database of the Prostate (FRAMCAP) database to compare progression-free (PFS) and overall survival (OS) outcomes regarding the cause of castration resistance and the staging modality used. Results: Overall, 35% progressed to mCRPC biochemically vs. 23% radiographically vs. 42% biochemically + radiographically. The PSA nadir in mHSPC (1.4 vs. 0.4 vs. 0.8 ng/mL) and PSA level at mCRPC progression (15 vs. 2 vs. 21 ng/mL, both p ≤ 0.01) were significantly higher for biochemical vs. radiographic vs. both progressed patients. In PFS and OS analyses, no significant differences were observed among all three compared groups. In the comparison of the staging used for progression to mCRPC, 67% received conventional vs. 33% PSMA-PET/CT, with higher metastatic burden in mHSPC and osseous lesions in mCRPC for conventionally staged patients (both p < 0.01). In PFS (15.3 vs. 10.1 months, hazard ratio [HR]: 0.75) and OS analyses (52.6 vs. 34.3 months, HR: 0.61, both p < 0.05), PSMA-PET/CT harbored better prognosis; however, this did not hold after multivariable adjustment. Similar results were observed for further analyses in second- and third-line mCRPC or patients with a PSA level of ≥2 ng/mL. Conclusions: The cause of progression to mCRPC seems not to influence cancer-control outcomes, despite important baseline tumor characteristic differences. The PSMA-PET/CT staging modality might be associated with better PFS and OS outcomes, possibly due to its more sensitive detection of progression or new metastatic lesions.

The Overexpressed MicroRNAs miRs-182, 155, 493, 454, and U6 snRNA and Underexpressed let-7c, miR-328, and miR-451a as Potential Biomarkers in Invasive Breast Cancer and Their Clinicopathological Significance.

Breast cancer comprises the leading cause of cancer-related death in women. MicroRNAs (miRNAs) have emerged as important factors with concern to carcinogenesis and have potential for use as biomarkers. This study provides a comprehensive evaluation of the microRNA expression in invasive breast carcinoma of no special type tissues compared with benign tissues via large-scale screening and the candidate-specific validation of 15 miRNAs and U6 snRNA applying qPCR and the examination of clinicopathological data. Of the six downregulated miRNAs, let-7c was identified as the most promising miRNA biomarker and its lower expression was linked with Ki-67 positivity, luminal B versus luminal A samples, multifocality, lymph node metastasis, and inferior PFS. Of the 9 upregulated sncRNAs, the data on U6 snRNA, miR-493 and miR-454 highlighted their potential oncogenic functions. An elevated U6 snRNA expression was associated with the tumor grade, Ki-67 positivity, luminal B versus A samples, lymph node metastasis, and worsened PFS (and OS) outcomes. An elevated miR-454 expression was detected in higher grades, Ki-67 positive and luminal B versus A samples. Higher miR-493 levels were noted for the tumor stage (and grade) and worse patient outcomes (PFS, OS). The data also suggested that miR-451a and miR-328 may have tumor suppressor roles, and miR-182 and miR-200c pro-oncogenic functions, while the remaining sncRNAs did not evince any significant associations. We showed particular microRNAs and U6 snRNA as differentially expressed between tumors and benign tissues and associated with clinicopathological parameters, thus potentially corresponding with important roles in breast carcinogenesis. Their importance should be further investigated and evaluated in follow-up studies to reveal their potential in clinical practice.

Impact of exposure on outcomes with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer.

4503 Background: Enfortumab vedotin (EV) is approved in combination with pembrolizumab and as a monotherapy for locally advanced or metastatic urothelial cancer (la/mUC). EV, alone and in combination with pembrolizumab, has demonstrated an OS benefit and a generally manageable safety profile in patients (pts) with previously treated or untreated la/mUC. Dose modifications, including reductions and interruptions, are recommended to manage EV-related AEs. This analysis evaluates the association between EV plasma exposure, which is impacted by dose modifications, and safety and efficacy outcomes. Methods: Characterization of dose- and exposure-response for efficacy and exposure-response for safety outcomes included pts in EV-101 (EV monotherapy 0.75, 1.0, and 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle [3Q4W]), EV-201, and EV-301 (EV monotherapy 1.25 mg/kg 3Q4W). Time-averaged exposure up to an event of interest, Cavg, was computed using a population PK model. PK assessment included multiple samples in first 2 cycles, and pre-dose samples in subsequent cycles. Results: Dose modifications were common, including dose reductions to 1.0 mg/kg (EV-201 42.1%; EV-301 35.1%) and 0.75 mg/kg (EV-201 13.6%; EV-301 11.1%). EV showed consistent improvement in median PFS and OS vs chemotherapy across all exposure quartiles in EV-301 inclusive of dose modifications (Table). Greater initial EV exposure in the first 2 cycles was associated with a higher ORR and was consistent with dose-response (0.75 mg/kg 21.4% [sample size {n} = 14]; 1.0 mg/kg 18.5% [n = 27]; 1.25 mg/kg 40-51.1% across studies [n = 613]). Lower EV exposure was associated with lower risk of EV-related Grade ≥3 rash or skin reactions, Grade ≥2 peripheral neuropathy, and Grade ≥3 hyperglycemia (P&lt;0.0001 for all). Conclusions: EV improved PFS and OS outcomes vs chemotherapy in pts with la/mUC across all exposure quartiles. The starting dose of 1.25 mg/kg 3Q4W resulted in EV exposure that maximized likelihood of response. Recommended dose modifications are effective for managing EV-related AEs and should be used as clinically indicated. Clinical trial information: NCT02091999 , NCT03219333 , and NCT03474107 . [Table: see text]

Abstract 6389: An exosome-based liquid biopsy powered by machine learning predicts progression-free and overall survival before commencing first-line EGFR inhibitors for metastatic colorectal cancer: The EXONERATE Study

Abstract Introduction: We developed a liquid biopsy assay based on exosomal and cell-free microRNA (exo- and cf-miRNA, respectively) for patients with chemotherapy-naïve, metastatic, unresectable, RAS and BRAF wild-type colorectal cancer (mCRC), to predict progression-free (PFS) and overall survival (OS) before the commencement of first-line treatment with EGFR inhibitors (EXONERATE). Methods: Patients with mCRC were consecutively enrolled in two open-label, nationwide clinical trials and received first-line cetuximab or panitumumab. Cf- and exo-miRNA expression was quantified using RT-qPCR in plasma samples obtained before exposure to EGFR inhibitors. The prespecified primary endpoint was 12-month PFS, hierarchically tested in left-sided mCRC, right-sided mCRC, and the entire cohort. As secondary endpoints, the EXONERATE status was correlated with PFS and OS hazard ratios (HR). Results: After excluding those with RAS/BRAF mutations and unavailable samples, the complete analysis dataset comprised 120 patients (94 with left-sided and 26 with right-sided mCRC; 87 received cetuximab and 33 panitumumab). As expected, right-sided mCRC patients showed inferior PFS and OS outcomes (HR 1.80 [CI95% = 1.13 - 2.80] and 1.80 [CI95% = 1.00 - 3.27], respectively). Genome-wide small RNA sequencing on 20 patient samples identified 12 cf- and 14 exo-miRNA candidates, then narrowed to 8 and 9 based on best performance. We employed machine learning algorithms to develop two liquid biopsy assays, one based on cf- and the other on exo-miRNAs, predicting 12mPFS with AUC values of 0.84 and 0.81, respectively. These were then combined to establish the EXONERATE assay for left-sided mCRC (AUC = 0.89), successfully validated in right-sided mCRC patients (AUC= 0.84). Among left-sided mCRC patients, 35% were EXONERATE-high, exhibiting shorter median PFS (mPFS = 9.5 vs. 18.5 months, p&amp;lt;.001) and a higher mortality rate (HR 0.21 [CI95% = 0.10 - 0.42]). In the right-sided mCRC cohort, the EXONERATE-high panel robustly identified patients with shorter mPFS (8.6 vs. 23.7 months, p=.0042) and predicted 12mPFS with high accuracy (sensitivity 100%, NPV 81%, PPV 100%). Although in univariate analysis both the EXONERATE panel and sidedness showed associations with PFS and OS, in multivariate analysis only the EXONERATE panel could fully account for the differences in PFS and OS (HR 0.22 and HR 0.19, respectively). Hence, we employed the EXONERATE panel agnostically of tumor sidedness and observed that EXONERATE-high patients demonstrated poorer survival outcomes in mPFS (8.9 vs. 19.6 months, HR 0.27 [CI95% = 0.17 - 0.41]) and mOS (22.6 vs. &amp;gt;60 months, HR 0.18 [CI95% = 0.09 - 0.37]). Conclusion: The EXONERATE panel robustly predicted PFS and OS outcomes in both right- and left-sided mCRC patients before receiving either EGFR inhibitor. Citation Format: Xu Caiming, Alessandro Mannucci, Roy Souvick, Esposito Francis, Oliveres Helena, Alonso-Orduña Vicente, Escudero Pilar, Fernández-Martos Carlos, Salud Antonieta, Gallego Javier, Rodriguez Jose Ramon, Martín-Richard Marta M. Marta, Fernández-Plana Julen, Manzano Hermini, Aparicio Jorge, Feliu Jaime, Maurel Joan, Ajay Goel. An exosome-based liquid biopsy powered by machine learning predicts progression-free and overall survival before commencing first-line EGFR inhibitors for metastatic colorectal cancer: The EXONERATE Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6389.

Abstract 5594: Exploring genetic determinants: A comprehensive analysis of SERPINB family variants and prognosis in Jordanian glioblastoma multiforme patients

Abstract Background: Glioblastoma multiforme (GBM) is a major concern with high fatality rate. In Jordan, the incidence of GBM has notably increased, emphasizing the urgency for population-specific research. Serpins are serine proteinase inhibitors, with several Serpins being overexpressed in cancer cells however the exact mechanism by which they affect GBM progression remains unclear. Thus, we aim to analyze the single-nucleotide polymorphism (SNP) of SERPINB11 and its association with GBM survival. Methods: A cohort of 63 GBM patients recruited from King Abdullah University Hospital (KAUH) in Jordan, underwent genomic DNA extraction, polymorphism analysis, and overall survival (OS) assessments. The Serpin B family were validated using The Cancer Genome Atlas (TCGA-GBM) cohort of 160 patients. We constructed a risk-score using the principal component analysis for the following Serpin genes: Serpinb3, Serpinb5, Serpinb6, Serpinb11, and Serpinb12, and patients were grouped into high- vs. low-risk based on median cutoff. Univariable Cox models were used to study the survival outcomes, differential expression analysis between the high- and low-risk groups was carried out to identify the differentially expressed genes (DEGs), gene ontology (GO and tumor microenvironment analyses were carried out. Results: In our primary cohort, we identified a significant association between rs4940595 (SERPINB11) SNP and survival, with the G/T- genotype showing worse prognosis compared to the G/G-T/T genotype in the over dominant model (HR: 2.75, 95% CI: 1.29-5.88, p-value=0.009). In the TCGA validation-cohort, alterations in the SERPINB3gene showed significantly worse OS (Median: 9.53 vs. 14.3, p-value=0.044) compared to the no alteration group. Univariable Cox showed worse PFS outcomes with higher SERPINB5 (HR: 1.67, 95% CI: 1.15-2.43, p-value=0.007) and SERPINB6 expression (HR: 1.44, 95% CI: 1.06-1.96, p-value=0.021). A Serpin B 5-gene risk score was constructed revealing significant association with IDH mutation status and a trend towards worse PFS in the high-risk group. Upregulated DEGs showed GO enrichment in cytokine regulation and production, positive regulation of leukocyte activation and MAPK cascade. While the downregulated DEGs were enriched in forebrain development, and negative regulation of neuron differentiation. The high-risk group showed a significantly higher infiltration of M2 macrophages and activated mast cells. Conclusion: Our findings showed a significant role of the Serpin B family with GBM survival in the Jordanian population. Molecular analyses showed potential mechanisms underlying these associations. Our exploration of SERPINB family and associated SNPs provides valuable insights into the molecular landscape of GBM, paving the way for potential targeted interventions and personalized treatment strategies. Citation Format: Sohaib Al-Khatib, Mohammad Nitham Almajali, Ayah Al-Bzour, Joud Al-Ramadneh, Laila Sa'd, Noor Othman. Exploring genetic determinants: A comprehensive analysis of SERPINB family variants and prognosis in Jordanian glioblastoma multiforme patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5594.

The diagnostic and prognostic value of exosomal microRNAs in lung cancer: a systematic review.

Studies have shown that many exosomal microRNAs (miRNAs) can be used as non-invasive biomarkers of lung cancer, but their diagnostic and prognostic values need to be further clarified. We conducted a systematic literature search in Web of Science, PubMed, and ScienceDirect databases, obtained relevant articles and extracted data, and used statistical methods and statistical software to comprehensively evaluate the diagnostic and prognostic value of exosomal miRNAs in lung cancer. PROSPERO CRD42023447398. In terms of diagnosis, two exosomal miRNAs (miR-486-5p and miR-451a) were reported with the highest frequency in lung cancer patients, both of which had good diagnostic value. Compared with the control group, the pooled sensitivities of miR-486-5p and miR-451a were 0.80 (95% CI: 0.73-0.86) and 0.76 (95% CI: 0.60-0.87), specificities: 0.93 (95% CI: 0.63-0.99) and 0.85 (95% CI: 0.72-0.92), and AUCs: 0.85 (95% CI: 0.81-0.88) and 0.88 (95% CI: 0.84-0.90), for the respective miRNAs. For prognosis, in lung cancer patients with abnormally expressed exosomal miRNAs, miR-1290 was associated with PFS outcome; miR-382, miR-1246, miR-23b-3p, miR-21-5p, and miR-10b-5p were associated with OS outcome; miR-21 and miR-4257 were associated with DFS outcome; miR-125a-3p and miR-625-5p were associated with PFS and OS outcomes; miR-216b and miR-451a were associated with OS and DFS outcomes. Exosomal miRNAs are valuable biomarkers in lung cancer patients. Exosomal miR-486-5p and miR-451a can be used as new diagnostic biomarkers for lung cancer. Dysregulated exosomal miRNAs could serve as indicators of survival outcomes in lung cancer patients.

Exploring Genetic Determinants: A Comprehensive Analysis of Serpin B Family SNPs and Prognosis in Glioblastoma Multiforme Patients.

Serpins are serine proteinase inhibitors, with several serpins being overexpressed in cancer cells. Thus, we aim to analyze the single-nucleotide polymorphism (SNP) of Serpinb11 and its association with GBM survival. A cohort of 63 GBM patients recruited from King Abdullah University Hospital in Jordan underwent polymorphism analysis and overall survival (OS) assessments. The Cancer Genome Atlas (GBM) cohort was useful for validation. We constructed a risk score using the principal component analysis for the following Serpin genes: Serpinb3, Serpinb5, Serpinb6, Serpinb11, and Serpinb12, and patients were grouped into high- vs. low-risk groups based on the median cutoff. Univariable Cox models were used to study the survival outcomes. We identified a significant association between rs4940595 and survival. In the TCGA cohort, Serpinb3 alterations showed worse OS. Univariable Cox showed worse PFS outcomes with higher SERPINB5 and SERPINB6 expression. A Serpin B 5-gene risk score showed a trend towards worse PFS in the high-risk group. Upregulated DEGs showed GO enrichment in cytokine regulation and production, positive regulation of leukocyte activation, and the MAPK cascade. The high-risk group showed a significantly higher infiltration of M2 macrophages and activated mast cells. Our findings showed a significant role of the Serpin B family in GBM survival in the Jordanian population.

Cyclophosphamide maintenance to extend combination chemotherapy-free interval in metastatic pancreatic ductal adenocarcinoma.

Administering chemotherapy until progression to metastatic pancreatic ductal adenocarcinoma (PDAC) patients lacks of supporting evidence and causes cumulative toxicity. We explored the role of cyclophosphamide as maintenance therapy. PDAC germline BRCA1-2 wild-type patients who were progression-free after ≥6 months of any regimen and line of chemotherapy and received maintenance cyclophosphamide (mCTX) (50mg/day), were included in the analysis. 42 patients were included in the analysis. Thirty-nine patients had progression of disease. Median PFS was 3.5 (range 1.0-31+) months. PFS rates at 6 and 12 months were 26.2% and 11.9%. At a median follow-up of 20.0 months (range 12.1-31.0 months), 20 patients died and 22 are alive. Median OS was 20.0 months (range 2.2-31.0+). OS at 6 and 12 months was 97.6% (95%CI: 93.4-100), and 73.8% (95% CI: 61.1-86.5), respectively. Only 2 patients receiving mCTX had Grade 3 toxicity. mCTX therapy yielded promising PFS and OS outcome in PDAC patients who were progression-free after induction chemotherapy, with unremarkable toxicity. Accordingly, this approach warrants further investigation.

Enhanced therapeutic outcomes with atezolizumab-bevacizumab and SIRT combination compared to SIRT alone in unresectable HCC: A promising approach for improved survival

BackgroundIntegrating immunotherapy with locoregional therapies marks a significant milestone in the realm of hepatocellular carcinoma (HCC) treatment . This study aimed to assess the impact of addition of Atezolizumab-Bevacizumab (AtezoBev) on the outcome patients treated with SIRT. MethodsWe conducted a study that included all Child-Pugh A HCC treated with SIRT since 2017. We examined the effects of the addition of 3 infusions of AtezoBev before the SIRT procedure and after SIRT on patients outcome (AtezoBev-SIRT group). Time-to-event data were analyzed using Kaplan-Meier with the log-rank test. ResultsThirty five HCC patients treated with SIRT were included, of whom 23 % also received AtezoBev infusions. The two groups were similar in terms of liver function and HCC parameters. The median OS was not reached for patients who received AtezoBev in combination with SIRT and 14 months for patients only treated by SIRT. The median PFS was higher in the group treated by SIRT and AtezoBev vs SIRT alone (11.3 months vs 5.8 months). In the global cohort, 8 patients presented a downstaging (23 %), 4 underwent liver surgery (1 in the AtezoBev-SIRT group) and 4 liver transplantation (1 in the AtezoBev-SIRT group) ConclusionsThe administration of AtezoBev, both before and after SIRT, is associated with enhanced OS and PFS outcomes compared to SIRT alone for unresectable HCC.

High pre-chemoradiotherapy pan-immune-inflammation value levels predict worse outcomes in patients with stage IIIB/C non-small-cell lung cancer

Background and objectivesWe explored the prognostic usefulness of the pan-immune-inflammation value (PIV) in patients with stage IIIB/C non-small-cell lung cancer (NSCLC) who underwent concurrent chemoradiotherapy (CCRT).Methods and patientsFor all patients, the PIV was calculated using platelet (P), monocyte (M), neutrophil (N), and lymphocyte (L) measures obtained on the first day of CCRT: PIV = P × M × N ÷ L. Using receiver operating characteristic (ROC) curve analysis, we searched for the existence of an ideal cutoff that may partition patients into two groups with unique progression-free- (PFS) and overall survival (OS) results. The primary endpoint of this retrospective cohort research was to determine whether there were any significant relationships between pretreatment PIV measures and post-CCRT OS outcomes.ResultsThe present research included a total of 807 stage IIIB/C NSCLC patients. According to ROC curve analysis, the ideal PIV cutoff was 516 [area under the curve (AUC): 67.7%; sensitivity: 66.4%; specificity: 66.1%], which divided the whole cohort into two: low PIV (L-PIV: PIV < 516; N = 436) and high PIV (H-PIV: PIV ≥ 516; N = 371). The comparisons between the PIV groups indicated that either the median PFS (9.2 vs. 13.4 months; P < 0.001) or OS (16.7 vs. 32.7 months; P < 0.001) durations in the H-PIV group were substantially inferior to their L-PIV counterpart. Apart from the H-PIV (P < 0.001), the N3 nodal stage (P = 0.006), IIIC disease stage (P < 0.001), and receiving only one cycle of concurrent chemotherapy (P = 0.005) were also determined to be significant predictors of poor PFS (P < 0.05, for each) and OS (P < 0.05, for each) outcomes in univariate analysis. The multivariate analysis findings revealed that all four variables had independent negative impacts on PFS (P < 0.05, for each) and OS (P < 0.05, for each).ConclusionsThe findings of this hypothesis-generating retrospective analysis claimed that the novel PIV was an independent and steadfast predictor of PFS and OS in stage IIIB/C NSCLC patients.

Efficacy of Treatment for Metastatic Hormone-Sensitive Prostate Cancer: An Umbrella Review of Systematic Reviews and Meta-Analyses.

This umbrella review focused on evaluating the efficacy and adverse events of the metastatic hormone-sensitive prostate cancer patients receiving any treatment regimens, including ADT alone or combination treatments. This study conducted an umbrella review following the PRISMA 2020 checklist, aiming to summarize the available studies to evaluate the efficacy of medical treatments for metastatic hormone-sensitive prostate cancer. A literature search was performed to identify systematic reviews and meta-analyses (SRMAs) that included only randomized controlled trials (RCTs) up to September 2023. This study summarized their findings, evaluated overlapping data (i.e., the same RCTs were included in >one SRMA), tested for excessive significance (i.e., observed number of statistically significant studies > expected number by chance) and assessed the quality of the studies. A total of 4191 studies were identified, but only 27 were included. Among those 27 studies, 12 were network meta-analyses and 15 were direct meta-analyses. Most studies showed no statistically significant difference in overall mortality among GnRH agonists, antagonists and bilateral orchiectomy. Combination treatment is more beneficial than ADT alone in both OS and PFS outcomes with more adverse events. Nevertheless, there is no OS advantage of any combination regimen over the others. Combination treatments demonstrated clear benefits in OS and PFS over ADT alone with more AEs. Further studies are needed to compare among combination treatments.

Predictors of Relapse after Definitive Treatment of Solitary Plasmacytoma: A Systematic Review

Introduction Solitary plasmacytoma refers to a rare form of mature B-cell malignancy that can present either extraosseous i.e., solitary extramedullary plasmacytoma (SEP), or the more common type, intraosseous i.e., solitary bone plasmacytoma (SBP). According to the National Comprehensive Care Network, the primary treatment of solitary plasmacytoma is radiotherapy with 40-50 Gy to the involved field +/- surgery (if the patient is unstable or has symptoms indicative of neurological compression), or chemotherapy (if the patient has bulky disease defined as ≥5 cm or unresponsive to radiotherapy). This systematic review aimed to assess relapse predictors of solitary plasmacytoma following definitive treatment. Methods A systematic review was conducted in adherence to the PRISMA guidelines with a pre-specified study protocol registered on PROSPERO (CRD42023432422). A literature search was performed utilizing Medline, ScienceDirect, Google Scholar, Cochrane, and Clinicaltrials.gov, on April 15, 2023. The MeSH terms “plasmacytoma”, “recurrence”, “relapse”, “prognosis”, and “treatment” were used. The inclusion criteria were defined as retrospective, randomized, or non-randomized controlled studies published in English that include patients with solitary plasmacytomas of any site, who received radiotherapy, chemotherapy, and/or surgery, and have outcomes of overall survival, progression-free/relapsed-free survival (PFS/RFS), and time to progression to multiple myeloma. Results After meeting the inclusion criteria, twenty-seven studies were included. Among 1412 patients,1034 (73%) SBP, 427 (30%) SEP, and 844 (60%) males were studied. Most articles were published in the USA (15%), followed by Italy (11%) and France (11%). Several overlapping predictors of relapse were observed (Table 1), with younger age (age &amp;lt;60) and tumor size &amp;lt;5 cm the most common significant better prognostic factors; mentioned in 10 (37%) and 7 (26%) studies, respectively. Interestingly, SBP tumor type was associated with worse prognosis in 3 (11%) studies, while SEP tumor type had mixed prognostic association; worse prognostic association in 4 (15%), and better in 3 (11%) studies. Less common negative prognostic indicators included immunoparesis at diagnosis, occult marrow disease, positive serum M protein, persistent M spike, positive serum B2 microglobulin, positive Bence Jones protein, and positive urinary monoclonal light chains. Radiotherapy exhibited a better prognosis alone, with surgery, and with chemotherapy. In addition, a higher radiation dose (&amp;gt;40 Gy) was associated with better prognosis, supported by another study that showed a worse prognosis with a lower radiation dose (&amp;lt;50 Gy). Four studies did not demonstrate a statistically significant prognostic factor. Conclusion Tumor size and age appear to be the most common significant prognostic indicators for solitary plasmacytoma when indexed to outcomes of OS, PFS, MMFS, and median time to MM progression. Several other prognostic indicators have been reported but require further research to ascertain their strength of association and possibly direct future screening and management.

Distinct Circulating Genomic Features of Classical Hodgkin Lymphoma of Older Adults

Introduction: Despite significant progress in curing younger patients with classical Hodgkin lymphoma (cHL), older patients continue to have substantially inferior outcomes. The bimodal distribution of age at cHL diagnosis has suggested distinct underlying pathogenesis in older adults. For example, among older patients where EBV+ disease is more prevalent, EBV+ status is associated with worse outcomes, unlike younger patients where it confers more favorable prognosis (Keegan, JCO 2005). The reasons for this disparity remain enigmatic. To address these challenges, we used circulating tumor DNA (ctDNA) profiling, enabling noninvasive genotyping, risk stratification, and classification into distinct molecular subtypes (Spina, Blood 2018; Alig, ASH 2022). We leveraged several non-invasive techniques to systematically characterize the genomic peculiarities of elderly cHL patients distinguishing them from younger counterparts, with special attention to EBV status. Methods: We comprehensively profiled newly diagnosed cHL patients from 3 prospective clinical trials: LYSA-PVAB (NCT02414568) for subjects ≥60 years (Ghesquières, ASH 2019), AHL2011 (NCT01358747) for patients aged 16-59 years with advanced cHL, and BIO-LYMPH (NCT04417803) for patients ≥18 years. We used age ≥60 as a threshold for stratification of older versus younger patients, a common cutoff in clinical trials. We identified somatic single nucleotide variants using CAPP-Seq (Newman et al, Nature Biotech 2016); and analyzed copy number alterations with CANARy (Chabon, Nature 2020). Patients were categorized into high vs low pretreatment ctDNA levels using a predefined threshold (2.5 log hGE/mL; Kurtz, JCO 2018). We determined EBV status using EBER and/or LMP1 staining of FFPE tumor tissue or plasma EBV levels (&amp;gt;32 copies/mL) by VirCAPP-Seq (Garofalo, ASH 2022). Results: A total of 215 newly diagnosed cHL patients were evaluable, with a median age of 51 years, and 35% being older (≥60 years). In this cohort, 82% had advanced stage disease, 68% had high IPS (≥3), and 57% had extra nodal involvement. At 4-year follow-up, OS and PFS were 84% and 74%, respectively. At presentation, older patients (≥60y) had more advanced stage (93% vs 73%, p&amp;lt;0.001), higher IPS (78% vs 61%, p&amp;lt;0.001), and greater EBV+ prevalence (63% vs 36%, p&amp;lt;0.001). Older patients also experienced significantly more relapses (39% vs 17%, p&amp;lt;0.001). and mortality (29% vs 6%, p&amp;lt;0.001). The median pre-treatment ctDNA level was 982 hGE/mL, but not significantly different in older vs younger patients (p=0.28). Higher ctDNA levels were positively associated with risk-associated features including B symptoms (p=0.01), IPS (p&amp;lt;0.001), bulky disease (p=0.04), extra nodal disease (p=0.02) and correlated with TMTV (R=0.47, p&amp;lt;.001). Older patients had significantly fewer somatic mutations than younger counterparts (Median 107 vs 192 SNVs within targeted genomic regions, p&amp;lt;0.001; Fig. 1A top); among older patients, EBV+ cases had even fewer mutations than EBV- counterparts (Median 83 vs 142 SNVs, p=0.05). Older cHL cases harbored significantly more BCL2 mutations and recurrent copy number anomalies, but had significantly fewer mutations in STAT6, ITPKB, B2M, GNA13, PAX5 and XPO1 among others(all p&amp;lt;0.05 Fig. 1A bottom). The H2 genomic subtype prevalence, characterized by genomic instability as well as mutations in TP53, KMT2D, and BCL2 (Alig et al, ICML 2023), was higher among older patients (56%) than younger patients (21%) (p=0.01). Older H2 cHL showed no significant difference in EBV+ status compared to H1 counterparts (p=0.9). In older patients, multivariate Cox regression (including EBV status, ctDNA, and IPS) identified EBV+ status (HR=2.2, p=0.02) as an independent predictor of worse PFS and DFS outcomes (HR=2.5, p=0.02 and HR=2.7, p=0.04). When older cHL patients were stratified by baseline ctDNA level and EBV status, high-risk cases (EBV+ and ctDNA High) had particularly poor outcomes in terms of both PFS and DFS ( Fig. 1B). Conclusion: Older cHL patients exhibit unique genomic characteristics compared to younger counterparts, including more prevalent H2 tumor genetic subtype and EBV positivity. Identifying of a high-risk subgroup of older cHL underscores the importance of ctDNA levels and EBV status. We envision future trials of personalized biomarker driven treatment strategies could therapeutically target this risk, including by PD1 blockade.

Comparison of the Efficacy in Clinical Trials Versus Effectiveness in the Real-World of Treatments for Multiple Myeloma: A Population-Based Cohort Study

Introduction: Improvements in outcomes of patients with multiple myeloma (MM) depend on the use of regimens approved based on results from large phase III randomized controlled trials (RCTs) demonstrating their efficacy. However, many real-world (RW) patients would not have met the stringent RCTs inclusion criteria. Therefore, the effectiveness of these drugs in the RW setting is unknown. Understanding this efficacy-effectiveness gap is important to contextualize the expected outcomes in the current RW setting. Therefore, we conducted a retrospective population-based study to compare the efficacy versus effectiveness of registration RCTs with RW patients using standard of care (SoC) MM regimens for the primary outcomes of 1) progression free survival [PFS]; 2) overall survival [OS] and 3) serious adverse events (AEs). Methods: RW data was obtained from the Institute for Clinical Evaluative Sciences, an administrative database capturing all health records in the publicly funded health care system in Ontario, Canada. Adult patients treated between Jan 2007 to Dec 2020 with SoC regimens were included. Only regimens with corresponding registrational phase III RCTs which led to the public reimbursement in Ontario were included (lenalidomide/dex [Rd] and bortezomib/Rd [VRd] for newly diagnosed transplant ineligible patients, and relapsed MM (RRMM) regimens included carfilzomib/Rd [KRd], carfilzomib/dex [Kd], daratumumab/Rd [DRd], daratumumab/bortezomib/dex [DVd], pomalidomide/dex [Pd]). In the RW cohort, PFS was defined as the time from initiation of index regimen to death, initiation of subsequent MM treatment, or last follow-up, and patients remaining on the index regimen as last follow up were censored. Kaplan-Meier curves from pivotal phase 3 RCTs were manually digitized to provide individual patient-level estimates of PFS and OS. Meta-analyses were performed to compare the gap of PFS and OS outcomes of RW versus RCT patients, and effect estimates were summarized using hazard ratios (HR). The frequency of serious AE data was abstracted from published RCTs. Given that serious AEs in RCTs would have resulted in hospitalization, hospital admission during treatment with the index regimen was used as a surrogate for serious AEs in the RW cohort. Differences in RW and RCT safety outcomes were reported descriptively. Results &amp; Discussion: A total of 3951 RW MM patients, treated with 7 standard of care MM regimens, were included. Baseline characteristics of patients in the RW and RCT cohorts are shown in table 1. Overall, patients in the RW cohort were older than in the RCTs. For relapsed regimens, there was a longer time between MM diagnosis and start of the regimen in the real-world versus RCT. With regards to the efficacy-effectiveness gap, MM patients treated in routine practise in the RW had a worse PFS despite overestimated of RW PFS compared to highly selected RCT patients for 6 of the 7 MM regimens evaluated, with a pooled HR of 1.44 (95% CI 1.34-1.54) in the meta-analysis (Figure 1A). Similarly, RW patients had a worse OS compared to RCT patients treated with 6 of the 7 regimens, with a pooled HR of 1.75 (95% ci 1.63-1.88) in the meta-analysis (Figure 1B). RRMM patients in the RW had higher rates of prior lenalidomide exposure compared to RCT patients. The only regimen which showed a trend towards performing better in the RW as compared to RCTs was Pd. The reason for this is likely multifactorial but perhaps patients included in the MM-003 RCT may have had more refractory MM (given the higher prior immunomodulatory drug exposure and longer time from diagnosis to treatment among Pd RCT patient) compared to RW patients in this study. With regards to safety, the percentage of patients with inpatient hospitalization during treatment in the real-world cohort and reported serious AEs in RCT were comparable (VRD 57% vs not reported [NR]; Rd 64% vs NR; Kd 57% vs 59%; KRd 53% vs 60%; DVd 36% vs NR; DRd 46% vs 49%; Pd 59% vs 61%). Conclusion: This is one the largest population-level studies highlighting the significant efficacy-effectiveness gap between registrational RCTs and RW usage of these regimens, with RW patients experiencing 44% worse PFS and 75% worse OS compared to RCT patients. Our data emphasize the importance of ongoing evaluation of RW data to contextualize effectiveness and toxicity of selected regimens in the clinic, and better inform both clinicians and patients for shared treatment decision making.

Comparison of second-line treatments in metastatic renal cell carcinoma patients: A single-center experience.

Renal cell carcinoma is the 10th most common type of cancer, accounting for 3.7% of all cancers. Our study examines patients with metastatic renal cell carcinoma who received Axitinib or Nivolumab as second-line treatment. This study was designed as a retrospective analysis. Patients who received Axitinib or Nivolumab as second-line treatment for metastatic renal cell carcinoma at the Istanbul University Oncology Institute Medical Oncology outpatient clinic were included in the study. A total of 81 patients were included in the study, with a median follow-up period of 18.5 months (2-260 months). Of these patients, 29 (35.8%) received Axitinib as second-line treatment, while 52 (64.2%) received Nivolumab. The median duration of second-line treatment was 14 months (6-52) for Axitinib and 13.5 months (3-77) for Nivolumab. In our study, Nivolumab was found to have statistically better PFS and OS outcomes than Axitinib in male patients, patients diagnosed with metastatic disease, those with a favorable or intermediate International Metastatic Renal Cell Carcinoma Database Consortium risk score, patients diagnosed with metastatic disease or who developed metastasis within 12 months of diagnosis, those who developed metastasis ≥ 24 months after diagnosis, and patients with metastasis in a single organ. Both drugs are recommended as monotherapy for second-line and later treatments in the current NCCN guidelines for kidney cancers. Although there is no study in the literature showing that axitinib is more effective than nivolumab, nivolumab was found to be much more effective than axitinib in our study. Prospective studies with higher number of patients are needed on this subject.

The use of machine learning models to predict PFS and OS outcomes from waterfall plots in randomized clinical trials (MAP-OUTCOMES).

107 Background: Depth of tumor response (DepOR) of individual patients, as visualized by waterfall plots, is an emerging short-term endpoint that may represent a surrogate for survival-based outcomes such as PFS and OS. We hypothesize that the configuration of waterfall plots in randomized trials may predict PFS/OS outcomes. Methods: A literature-based search was performed for all phase II/III randomized clinical trials published in MEDLINE from 2010 to 2022 testing molecularly targeted agents (MTA) or immunotherapy (IO). Articles reporting at least 1 waterfall plot for each treatment arm depicting maximum DepOR of target lesions with corresponding PFS/OS Kaplan-Meier plots were included. Studies are defined as positive or negative based on the achievement of a priori stated primary endpoint. Trial data collected included sample size per arm, cancer type, mechanisms of action of drug(s) tested, line of treatment, etc. Images of waterfall plots were manually extracted from publications and then processed through a semi-automatic extraction process using WebPlotDigitizer and Tesseract to produce tabular representations. Logistic regression with L2 regularization was used for modeling; hyperparameter tuning was accomplished with five-fold cross-validation on a training set compromising 80% of the data. Results: A total of 111 studies were identified: 65 (59%) phase III and 46 (41%) phase II, mean sample size per arm 317 (19-1581). Most frequent cancer type was gastrointestinal 24 (22%). MTA, IO and combinations were tested in 113 (51%), 35(16%) and 11 (5%) studies respectively. Chemotherapy and other treatment regimens were used in 63 (28%) trials. PFS was the primary endpoint in 62 (56%); 80 (75%) studies were positive. Of the 111 studies only 83 (75%) were retained for machine learning analysis, the remainder were excluded due to atypical formatting such as superimposed waterfall plots. Performance of the model was assessed on a test set which comprised 20% of the original dataset. Table below shows the classification metrics from modelling. Both PPV and NPV were ≥80%. Conclusions: MAP-OUTCOMES evaluated pan-cancer randomized studies with diverse therapeutic anticancer agents. It is a computational tool with the potential to predict survival-based outcomes from waterfall plots and may help with decisions regarding follow-on randomized studies. Further validation is ongoing. [Table: see text]

First-line systemic treatment for hepatocellular carcinoma: A systematic review and network meta-analysis

The rapid development of novel therapeutic options for advanced hepatocellular carcinoma (aHCC) has generated some uncertainty about the rational choice of the systemic upfront treatment. So far, a variety of therapeutic strategies have been investigated, including the combination of immunecheckpoint inhibitors and anti-VEGF. To identify the treatment that should be preferred as front-line approach, we compared the efficacy and toxicity of a variety of therapeutic strategies. With this aim, we performed a systematic review and a meta-analysis of randomized clinical trials. OS, PFS, ORR and tolerability outcomes were considered, and for each outcome the treatment ranking was evaluated by the surface under the cumulative rankings (SUCRAs). Combination of Camrelizumab + Rivoceranib scored the best in OS, followed by Sintilimab + Bevacizumab, whereas Lenvatinib + Pembrolizumab showed higher probability to be the best treatment in PFS and Sintilimab + Bevacizumab performed best in ORR. Finally, Durvalumab is the most tolerated treatment.

Analysis of phase III clinical trials in metastatic NSCLC to assess the correlation between QoL results and survival outcomes

BackgroundIn addition to improving survival outcomes, new oncology treatments should lead to amelioration of patients’ quality of life (QoL). Herein, we examined whether QoL results correlated with PFS and OS outcomes in phase III randomized controlled trials (RCTs) investigating new systemic treatments in metastatic non-small cell lung cancer (NSCLC).MethodsThe systematic search of PubMed was conducted in October 2022. We identified 81 RCTs testing novel drugs in metastatic NSCLC and published in the English language in a PubMed-indexed journal between 2012 and 2021. Only trials reporting QoL results and at least one survival outcome between OS and PFS were selected. For each RCT, we assessed whether global QoL was “superior,” “inferior,” or with “non-statistically significant difference” in the experimental arm compared to the control arm.ResultsExperimental treatments led to superior QoL in 30 (37.0%) RCTs and inferior QoL in 3 (3.7%) RCTs. In the remaining 48 (59.3%) RCTs, a statistically significant difference between the experimental and control arms was not found. Of note, we found a statistically significant association between QoL and PFS improvements (X2 = 3.93, p = 0.0473). In more detail, this association was not significant in trials testing immunotherapy or chemotherapy. On the contrary, in RCTs testing target therapies, QoL results positively correlated with PFS outcomes (p = 0.0196). This association was even stronger in the 32 trials testing EGFR or ALK inhibitors (p = 0.0077). On the other hand, QoL results did not positively correlate with OS outcomes (X2 = 0.81, p = 0.368). Furthermore, we found that experimental treatments led to superior QoL in 27/57 (47.4%) trials with positive results and in 3/24 (12.5%) RCTs with negative results (p = 0.0028). Finally, we analyzed how QoL data were described in publications of RCTs in which QoL outcomes were not improved (n = 51). We found that a favorable description of QoL results was associated with sponsorship by industries (p = 0.0232).ConclusionsOur study reveals a positive association of QoL results with PFS outcomes in RCTs testing novel treatments in metastatic NSCLC. This association is particularly evident for target therapies. These findings further emphasize the relevance of an accurate assessment of QoL in RCTs in NSCLC.

Trop-2 mRNA expression and association with clinical outcomes with sacituzumab govitecan (SG) in patients with HR+/HER2– metastatic breast cancer (mBC): Biomarker results from the phase 3 TROPiCS-02 study.

1082 Background: SG is a Trop-2–directed antibody-drug conjugate approved in multiple countries for patients with metastatic triple-negative breast cancer who received at least 1 prior systemic therapy and in the US for patients with pretreated HR+/HER2– mBC. In the TROPiCS-02 study, SG significantly improved progression-free survival (PFS; median, 5.5 vs 4.0 mo; HR, 0.66 [95% CI, 0.53-0.83]; P=0.0003) and overall survival (OS; median, 14.4 vs 11.2 mo; HR, 0.79 [95% CI, 0.53-0.83]; P=0.020) over treatment of physician’s choice (TPC) in patients with pretreated, endocrine-resistant HR+/HER2– mBC. In TROPiCS-02 post hoc analyses, SG improved OS regardless of Trop-2 expression by immunohistochemistry (IHC; Rugo HS, et al. SABCS 2022), but association using more sensitive assays are lacking. Here, we examine efficacy outcomes for SG versus TPC by Trop-2 gene ( TACSTD2) mRNA expression and the correlation of TACSTD2 expression with other genes. Methods: Patients with HR+/HER2– mBC who received ≥1 prior taxane, endocrine therapy and a CDK4/6 inhibitor, and 2-4 prior chemotherapy regimens for mBC were randomized 1:1 to SG or TPC. The primary endpoint was PFS by central review per RECIST v1.1. RNA was isolated from archival tumor tissue samples using AllPrep DNA/RNA kits and libraries prepared with TruSeq RNA Exome Prep Kit. Sequencing was via NovaSeq (2x150bp). Gene expression quantitation was performed using Salmon. TACSTD2 expression was defined as high or low via median cut. Results: In the mRNA analytical cohort (N=197), 49% had TACSTD2 high expression (SG, n=51; TPC, n=46), and 51% had TACSTD2 low expression (SG, n=47; TPC, n=53). Baseline characteristics were generally consistent between TACSTD2 expression subsets and the intention-to-treat population. A positive concordance between TACSTD2expression and Trop-2 IHC (H-score) was observed (categorical concordance 71%; Cohen’s kappa = 0.41). TACSTD2 expression was similar across HER2 IHC0 and HER2-Low subgroups (log2 transcripts per million [TPM] of 3.36 [IQR, 2.76-4.22] and log2TPM of 3.44 [IQR, 2.59-4.22], respectively). SG showed a numerically higher median PFS ( TACSTD2 high, 7.3 vs 5.6 mo; TACSTD2 low, 5.6 vs 2.8 mo) versus TPC regardless of TACSTD2 expression. Similarly, for OS, outcomes favored SG over TPC regardless of TACSTD2 expression. Conclusions: This mRNA-based biomarker analysis demonstrated that SG improves PFS and OS outcomes in patients with pretreated, endocrine-resistant HR+/HER2– mBC regardless of Trop-2 mRNA expression. There was no correlation between Trop-2 mRNA expression and HER2 status. Trop-2 mRNA expression was not predictive of benefit with SG. Additional studies are needed to determine whether Trop-2 mRNA expression has a prognostic role in mBC. Clinical trial information: NCT03901339 .