Longer PFS Research Articles

Prognostic role of serum cytokines level in non-small cell lung cancer patients with anti-PD-1 and chemotherapy combined treatment.

Chemotherapy combined with PD-1 inhibitor treatment has revolutionized the standard of care for patients with NSCLC. However, the benefit is not universal, highlighting the need for precise prediction factors. Given their relationship with the immune system and non-invasive nature, serum cytokines are potential candidates for predicting the clinical effects of chemoimmunotherapy. Our study aims to evaluate the association of serum cytokines with the prognosis of patients with NSCLC treated with chemoimmunotherapy. Levels of 10 serum cytokines were detected in 60 NSCLC patients receiving chemotherapy plus PD-1 inhibitor-based treatment. Of these, dynamic samples from 19 patients were collected at baseline and after two treatment cycles. Their association with patients' clinicopathological characteristics, PFS and OS was described and investigated using survival analysis, cox regression and time-dependent ROC analysis. Preliminary evaluation of changes in cytokine levels associated with treatment response was conducted. Patients with lower baseline levels of serum IL-6, IL-5, IL-8, TNF-α and IL-10 had longer PFS, while patients with higher levels of IL-4 had longer PFS. Patients with lower levels of serum IL-6, IL-8, IL-22, TNF-α and IL-10 had longer OS, while patients with higher levels of IL-4 had longer OS. Multivariate analysis suggested that higher IL-6 and IL-5 levels were associated with poorer PFS, and higher IL-6 levels were associated with dismal OS. Additionally, changes in serum cytokine levels could be associated with treatment response. Our study suggests that serum cytokines, specifically IL-6, IL-5, IL-8, TNF-α, IL-10, and IL-4, are potential prognostic factors for patients with NSCLC receiving chemotherapy plus PD-1 inhibitor treatment.

Retrospective study assessing the role of theandrogen receptor in clear cell renal cell cancer patients treated with VEGFR inhibitors in monotherapy.

Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading tothe question ofwhether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions. We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis. Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC. AR-overexpression and its association with other genes could favor a transcriptomic signature set to aidin identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.

Sintilimab combined with anlotinib and chemotherapy as second-line or later therapy in extensive-stage small cell lung cancer: a phase II clinical trial

Treatment options for patients with relapsed extensive-stage small cell lung cancer (ES-SCLC) remain scarce. This study aims to evaluate the efficacy and safety of combining anlotinib and sintilimab plus chemotherapy as a second line or later therapy for ES-SCLC patients. This is a phase II clinical trial (ChiCTR2100049390) conducting at Shandong Cancer Hospital. Patients with ES-SCLC and received at least one prior systemic treatment were enrolled. The trial design involved a combination therapy (sintilimab, anlotinib, and nab-paclitaxel) administered over six 21-day cycles, followed by maintenance sintilimab therapy. The primary endpoint was objective response rate (ORR). Circulating tumor DNA sequencing was employed for exploratory analysis. From July 2021 to April 2023, 25 eligible patients were enrolled. The confirmed ORR was 60% (95% CI: 38.7–78.9%) and the DCR was 76% (95% CI: 54.9–90.6%). The mPFS was 6.0 months (95% CI: 5.4–9.7), and the 6-month PFS rate was 49.2%. The mOS was 13.4 months (95% CI: 11.8-NR), with a 12-month survival rate of 62.2%. Treatment-related adverse events (TRAEs) of any grade occurred in 80% of patients, with the most common being fatigue (40%) and nausea (32%). TRAEs of Grade 3 or higher were reported in 12% of patients. ctDNA analysis indicated that low on-treatment blood tumor mutation burden was associated with longer PFS and OS and a potential role of KMT2D mutation in treatment resistance. This combination therapy shows promising efficacy and a manageable safety profile as a second-line or later treatment for ES-SCLC, with genomic insights providing potential biomarkers for treatment response.

The prognostic factors of clinical outcomes in non-small cell lung cancer patients receiving subsequent treatments after progression on initial immunotherapy.

The standard of care for non-small cell lung cancer (NSCLC) patients who encounter progression on initial immune checkpoint inhibitor (ICI) based treatment is uncertain. In the real world, there are various subsequent treatment options, but how to find the most suitable treatment for different patients is still unknown. The present study aimed to explore prognostic factors of subsequent treatment after progression (STAP) (defined as the next treatment after progression from the initial immunotherapy) of initial immunotherapy. In this retrospective cohort study, NSCLC patients received regimens after progression of initial immunotherapy at Beijing Chest Hospital, Capital Medical University, between March 2016 and May 2023 were retrieved. The major efficacy endpoint was progression-free survival 2 (PFS2), defined as the time from the initiation of next treatment after initial immunotherapy failure to disease progression or death from any cause. Subgroup analyses were conducted according to baseline characteristics, some subsequent regimens beyond progression, etc. for prognostic factors exploration. The Cox proportional hazards model was used for multivariate analysis. There were 176 patients enrolled. Median age was 64 years. There were 36 (20.5%) females, and 123 (69.9%) were smokers. Adenocarcinoma (99, 56.2%) was the major histological subtype. There were 95 (54.0%) patients with negative expression for programmed cell death ligand 1 (PD-L1). After progressive disease, 92 (52.3%) patients reused ICI-based treatment after progressive disease. Median PFS2 was 3.6 months [95% confidence interval (CI): 2.8-4.4]. Longer PFS2 was observed in patients with PD-L1 positive expression [hazard ratio (HR) =0.672, 95% CI: 0.477-0.947, P=0.023] or PFS ≥6 months in initial immunotherapy (HR =0.543, 95% CI: 0.358-0.824, P=0.004). Besides, patients switching to new ICI-based treatments without radiotherapy gained better PFS2 compared with patients receiving prior regimens (P=0.019). PD-L1 positive expression, and longer PFS in initial immunotherapy would be good prognostic factors for NSCLC patients undergoing STAP on first immunotherapy. Besides, compared with original regimen, changing ICI would prolong PFS2 for NSCLC patients reusing ICI.

The prognostic significance of circulating tumor cell enumeration and HER2 expression by a novel automated microfluidic system in metastatic breast cancer

BackgroundThe prognostic value of circulating tumor cells (CTCs) in metastatic breast cancer (MBC) has been extensively studied and verified by the CellSearch® system. Varieties of microfluidic systems have been developed to improve capture efficiency with the lack of standardization and automation. This study systematically verified the positive threshold for prognosis and its guidance value in anti-HER2 therapy based on a novel automated microfluidic system OmiCell®.MethodsCTCs isolation, enumeration and labeling were performed using the OmiCell® system. CTCs identification and reporting were performed using the DeepSight® scanning system.ResultsThe capture efficiency and specificity of OmiCell® system was 91.9% and 90%, respectively. Then, 65 MBC patients with known HER2 status of their metastatic tumors were enrolled. In the cohort, we detected ≥ 1 CTCs in 59 patients (90.8%, range: 1–55 CTCs, median = 6), < 8 CTCs in 45 (69.2%) and ≥ 8 CTCs in 20 (30.8%) patients at baseline. The patients with < 8 CTCs had longer PFS than ≥ 8 CTCs (median, 7 vs. 4.4 months, p = 0.028). CTC enumeration was found to be an independent prognostic factor in our cohort. Moreover, we found a weak concordance between tissue HER2 (tHER2) status and the corresponding CTCs (k = 0.16, p = 0.266). The patients with tHER2 positive and cHER2 negative had better PFS compared with patients with both tHER2 and cHER2 positive (median, 8.2 vs. 3.3 months, p = 0.022).ConclusionsThis clinical study shows the prognosis value of a new threshold of CTC number and meanwhile the guidance value of cHER2 status in anti-HER2 therapy.

Transcriptome-based classification to predict FOLFIRINOX response in a real-world metastatic pancreatic cancer cohort

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at metastatic stage and typically treated with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Few patients benefit from this treatment. Molecular subtypes are prognostic in particularly resectable PDAC and might predict treatment response. This study aims to correlate molecular subtypes in metastatic PDAC with FOLFIRINOX responses using real-world data, providing assistance in counselling patients. We collected 131 RNA-sequenced metastatic biopsies and applied a network-based meta-analysis using published PDAC classifiers. Subsequent survival analysis was performed using the most suitable classifier. For validation, we developed an immunohistochemistry (IHC) classifier using GATA6 and keratin-17 (KRT17), and applied it to 86 formalin-fixed paraffin-embedded samples of advanced PDAC. Lastly, GATA6 knockdown models were generated in PDAC organoids and cell lines. We showed that the PurIST classifier was the most suitable classifier. With this classifier, classical tumors had longer PFS and OS than basal-like tumors (PFS: 216 vs. 78 days, p = 0.0002; OS: 251 vs. 195 days, p = 0.049). The validation cohort showed a similar trend. Importantly, IHC GATA6low patients had significantly shorter survival with FOLFIRINOX (323 vs. 746 days, p = 0.006), but no difference in non-treated patients (61 vs. 54 days, p = 0.925). This suggests that GATA6 H-score predicts therapy response. GATA6 knockdown models did not lead to increased FOLFIRINOX responsiveness. These data suggest a predictive role for subtyping (transcriptomic and GATA6 IHC), though no direct causal relationship was found between GATA6 expression and chemoresistance. GATA6 immunohistochemistry should be seamlessly added to current diagnostics and integrated into upcoming clinical trials.

Treatment pattern among patients with relapsed/refractory multiple myeloma (RRMM) who had received pomalidomide-based regimens in Taiwan

ABSTRACT Background/purpose The treatment landscape of relapsed/refractory multiple myeloma (RRMM) is rapidly evolving in Taiwan. The present study aimed to assess the treatment patterns among RRMM patients in Taiwan. Methods This retrospective, chart review-based, non-interventional study collected data on RRMM patients (≥20 years old) receiving pomalidomide-based treatment between January 2017 and December 2020 across five sites in Taiwan. Results Median age of the study population was 65.6 years. Approximately 75% patients received a doublet regimen and 25% were on a triplet regimen. Disease progression was the most common cause for switching to pomalidomide-based treatments in doublet (71.2%) and triplet (58.3%) groups. Patients in doublet and triplet groups (>80%) received 4 mg pomalidomide as a starting dose. Overall response rate (ORR: 31.5% and 45.8%) and median progression-free survival (PFS: 4.7 and 6.8 months) were reported in the doublet and triplet regimen. Doublet regimen was discontinued mainly due to disease progression or death (78.1%); however, triplet regimen patients mainly terminated their treatment due to reimbursement limitations (29.2%). Healthcare resource utilization (HRU) was comparable between doublet and triplet groups. Conclusion In Taiwan, half of RRMM patients received pomalidomide-based triplet regimens. Triplet regimens showed a trend towards better outcomes with longer PFS and higher response rates compared to doublets. Notably, the duration of triplet use is influenced by reimbursement limitations. This study provides insight into RRMM treatment patterns in Taiwan and the findings suggest that triplet regimens may be a better alternative than doublet regimens.

Monitoring changing patterns in HER2 addiction by liquid biopsy in advanced breast cancer patients

BackgroundDuring targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D.MethodsaHER2 and sHER2 were assessed by digital PCR and ELISA before and after standard-of-care treatment of advanced HER2-positive breast cancer patients (n=37) with the antibody-drug conjugate (ADC) Trastuzumab-emtansine (T-DM1).ResultsAs expected, aHER2 was invariably suppressed by T-DM1, but this loss was surprisingly mirrored by sHER2 gain, sometimes of considerable entity, in most (30/37; 81%) patients. This unorthodox split in HER2 oncogenic dosage was supported by reciprocal aHER2/sHER2 kinetics in two representative cases, and an immunohistochemistry-high status despite copy-number-neutrality in 4/5 available post-T-DM1 tumor re-biopsies from sHER2-gain patients. Moreover, sHER2 was preferentially released by dying breast cancer cell lines treated in vitro by T-DM1. Finally, sHER2 gain was associated with a longer PFS than sHER2 loss (mean PFS 282 vs 133 days, 95% CI [210-354] vs [56-209], log-rank test p=0.047), particularly when cases (n=11) developing circulating HER2-bypass alterations during T-DM1 treatment were excluded (mean PFS 349 vs 139 days, 95% CI [255-444] vs [45-232], log-rank test p=0.009).ConclusionsHER2 gain is adaptively selected in tumor tissues and recapitulated in blood by sHER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies, but favorable to the host during treatment with a strongly cytotoxic ADC such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2. Whichever the interpretation, HER2-2D might help to tailor/prioritize anti-HER2 treatments, particularly ADCs active on aHER2-low/sHER2-low tumors.Trial registrationNCT05735392 retrospectively registered on January 31, 2023 https://www.clinicaltrials.gov/search?term=NCT05735392

Primary Tumor Characteristics as Biomarkers of Immunotherapy Response in Advanced Melanoma: A Retrospective Cohort Study.

Identifying patients likely to benefit from immune checkpoint inhibitor (ICI) treatment remains a crucial goal for melanoma. The objective of this study is to assess the association between primary tumor features and immunotherapy response and survival in advanced melanoma patients. In this single-center retrospective cohort study, disease characteristics, response to immunotherapy, PFS, and OS were assessed among melanoma patients (excluding mucosal and uveal primaries) treated with ICI. Among 447 patients, 300 (67.1%) received anti-PD-1 monotherapy and 147 (32.9%) received ipilimumab/nivolumab. A total of 338 (75.6%) had cutaneous melanoma, 29 (6.5%) had acral melanoma, and 80 (17.9%) had melanoma of unknown primary. Ulceration and stage at initial presentation were associated with inferior outcomes on univariate analysis. However, on multivariate analysis, this result was not observed, but cutaneous melanoma and each of its subtypes (superficial spreading, nodular, other, unknown) were positively associated with response, longer PFS, and longer OS. Metastatic stage (M1c, M1d) at presentation (OR = 1.8, p < 0.05) and BRAFV600E mutation status (OR = 1.6, p < 0.001) were associated with shorter PFS. This study is limited by its retrospective and single-center design. Cutaneous melanoma and its subtypes were significantly associated with response, PFS, and OS compared with acral or unknown primary melanoma.

LGG-12. INTEGRATED CLINICAL AND MOLECULAR CHARACTERIZATION OF 200 DISSEMINATED PEDIATRIC LOW-GRADE GLIOMAS

Abstract Pediatric low-grade gliomas (PLGG) have excellent outcomes overall but are a major clinical challenge when disseminated. Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a recognised entity both clinically and pathologically, however many disseminated LGG (DLGG) fall outside this diagnosis. To better understand the clinical and molecular features of DLGG as well as risk factors for dissemination, we assembled an international consortium of 30 sites, contributing over 200 patients with clinical annotation, along with genomic and methylation profiling. DLGG have worse progression-free (PFS) and overall survival (OS) than PLGG overall (p&amp;lt;0.0001). Seventy (35%) presented with a localized mass and secondary dissemination, including some with initial gross-total resection. The most common growth pattern observed (n=77, 40%) is a dominant suprasellar/optic pathway tumor with leptomeningeal drop-metastases involving the brainstem and spinal cord. Only 27 (14%) patients had diffuse tumors (without an identifiable dominant mass), and these had significantly worse OS (p=0.03). The most common pathologic diagnosis was pilocytic/pilomyxoid astrocytoma (n=92; 53%). DLGNT comprised a minority of cases (n=23, 14%), with a trend (p=0.056) towards worse survival compared to other diagnoses. The most frequent molecular alteration was BRAF fusion (78/151 with molecular testing; 52%), followed by FGFR mutations or fusions (18/151; 12%). BRAF V600E was underrepresented (14/151; 9%). 1p deletion was rare (17 patients) but highly associated with DLGNT. Methylation classification (n=70) was highly concordant with histologic diagnoses rather than clinical behavior. Importantly, patients who received upfront targeted therapies (TT; BRAF and/or MEK inhibition, n=9) had better PFS compared to those receiving chemotherapy (n=146, p=0.05). Furthermore, patients who were treated sequentially with chemo then TT had longer PFS on TT (p=0.011). This study presents the largest cohort of DLGG to date, expanding our understanding of the clinical, pathologic, and molecular features of this disease and supports the use of upfront targeted therapy.

The prognostic and predictive value of homologous recombination deficiency status in patients with advanced stage epithelial ovarian carcinoma after first-line platinum-based chemotherapy.

Homologous recombination (HR) comprises series of interrelated pathways that repair double-stranded DNA breaks and inter-strand crosslinks. It provides support for DNA replication to recover stalled or broken replication forks. Compared with homologous recombination proficiency (HRP), cancers with homologous recombination deficiency (HRD) are more likely to undergo cell death when treated with DNA-damaging agents, such as platinum agents, and have better disease control. Patients diagnosed with stage III/IV ovarian cancer, early stages with recurrence, who received adjuvant chemotherapy after debulking surgery, and who also had known HR status were eligible. Forty-four patients were included, with 21 in the HRD group (including 8 with germline mutations) and 23 in the HRP group. The HRD group was composed predominantly of serous carcinoma (95.2%), while mucinous (n=3) and clear cell (n=1) cases were all found in the HRP group. Stage III/IV disease was 66.7% and 91.3% in HRD and HRP groups, respectively (p=0.064). Patients who were optimally debulked to no residual disease was 90.0% and 72.7% (p=0.243), respectively. Late line use of PARP inhibitors was 33.3% and 17.4% (p=0.303). Median PFS was 22.5 months (95% CI, 18.5 - 66.6) and 21.5 months (95% CI, 18.3-39.5) (p=0.49) in HRD and HRP respectively. Median platinum free interval (PFI) was 15.8 months (95% CI 12.4-60.4) and 15.9 months (95% CI 8.3-34.1) (p=0.24), respectively. Median OS was 88.2 months (95% CI 71.2-NA) and 49.7 months (95% CI 35.1-NA) (p=0.21). The PFS of the patients with germline BRCA mutations (n=5) was 54.3 months (95% CI 23.1-NA) and 21.5 months (95% CI 18.3-39.5) in the HRP group (p=0.095); the PFI difference was 47.7 months (95% CI 17.6-NA) in the BRCA mutation group, and 15.9 months (95% CI 12.4-60.4) in HRP, showing statistical significance (p=0.039); while the median OS was NA and 49.7 months (95% CI 35.1-NA) respectively (p=0.051). When adding two additional patients with somatic BRCA mutations to the germline BRCA mutation carriers, the median OS is NA (95% CI 73, NA) versus 49.7 months (95% CI 35.1, NA) for HRP (p=0.045). HRD status was not associated with longer PFS or PFI in advanced ovarian cancer who received first line adjuvant platinum-based chemotherapy. Its role as a prognostic marker for overall survival is suggested, particularly in the subgroup with germline and somatic BRCA mutations.

FOLFOXIRI/bevacizumab (bev) versus doublets/bev as initial therapy of unresectable liver-only, right-sided and/or RAS or BRAF mutated (mut) metastatic colorectal cancer (mCRC): An individual patient data-based pooled analysis of randomized trials.

e15563 Background: FOLFOXIRI/bev was associated with longer PFS and OS versus doublets/bev independently of the presence of liver-limited disease or not, and the secondary resection of metastatic lesions. Recently, in the CAIRO-5 study patients with liver-limited right-sided and/or RAS or BRAF mutated mCRC experienced no OS difference, but higher ORR, R0 resection rate, and longer PFS with the triplet/bev when compared with doublets/bev. Here we aim at providing an estimation of the efficacy and activity of FOLFOXIRI/bev over doublets/bev in patients with unresectable liver-only, right-sided and/or RAS or BRAF mut mCRC. Methods: We selected pts with liver-only, right-sided and/or RAS or BRAF mut mCRC, and treated with first-line doublets/bev or FOLFOXIRI/bev in four phase II or III randomized controlled trials (RCTs): TRIBE (NCT00719797), TRIBE2 (NCT02339116), CHARTA (NCT01321957), and STEAM (NCT01765582). Patients included in these RCTs were deemed initially unresectable according to a multidisciplinary evaluation and were not selected based on the potential conversion to resectability. We compared FOLFOXIRI/bev with doublets/bev in terms of PFS, OS, ORR, and R0 resection. Results: A total of 300 pts were eligible. The median age was 61 years and most of them had an ECOG performance status of 0 (83%) and synchronous metastases (91%). One hundred and thirty (43%) and 170 (57%) pts received doublets/bev and FOLFOXIRI/bev, respectively. Baseline characteristics were homogeneous between the two treatment groups. Pts receiving FOLFOXIRI/bev showed longer PFS (12.3 vs 10.3 months [mos] HR:0.75, p = 0.019) and a statistically not significant trend for better OS (29.1 vs 23.2 mos, HR:0.85, p = 0.253), than those treated with doublets/bev. FOLFOXIRI/bev was also associated with higher ORR (64% vs 53%, OR:1.54, p = 0.076) and no differences in R0 resection rate (27% vs 24%, OR:1.15, p = 0.696) was reported. No significant interaction was found between treatment effect and the achievement of R0 resection in terms of both PFS (Pinteraction:0.81) and OS (Pinteraction:0.53). Conclusions: As compared to doublets/bev, upfront FOLFOXIRI/bev provides a meaningful advantage to pts with initially unresectable, liver-only, right-sided and/or RAS or BRAF mut mCRC, in terms of activity and efficacy, thus corroborating the choice of this regimen as upfront treatment for these pts, regardless of the opportunity to achieve the R0 secondary resection of their liver metastatic lesions.

Comprehensive analysis of predictive factors for efficacy in concurrent chemo-radiotherapy for locally advanced non-small cell lung cancer, utilizing individual patient data from the Japan lung cancer society integrated clinical trial database: Is there room for further improvement?

8043 Background: The standard treatment for unresectable, locally advanced NSCLC is concurrent chemoradiotherapy followed by durvalumab. While the effectiveness of chemoradiotherapy is pivotal, the exploration into predictive factors of the efficacy is notably limited. Methods: The Japanese Lung Cancer Society (JLCS) integrated eight randomized Phase II/III trials (JCOG9812, JCOG0301, NJLCG0601, OLCSG0007, SPECTRA, TORG1018, WJOG5008L, WJTOG0105) concerning chemoradiotherapy for locally advanced NSCLC, constructing the JLCS Integrated Clinical Trial Database (JIDB), with individual data of 1288 patients. This study analyzed 1162 patients who underwent concurrent chemoradiotherapy, focusing on factors impacting PFS. A logistic regression with the least absolute shrinkage and selection operator (LASSO) analyses for 3-yr PFS were performed, and the five most related factors were further evaluated using the Kaplan-Meier method and log-rank tests. The impact of pneumonitis and esophagitis on PFS was also explored. Results: Age [median (Q1;Q3)]; 64 (57;71), male/female; 961/201, Ad/Sq/Oth; 580/446/134, PS 0/1/2; 562/578/5, stage IIIA/IIIB; 468/694, T factor 4/3/2/1/0; 436/158/341/156/3, N factor 3/2/1/0; 300/692/44/62, PS 0/1/2; 562/578/5, primary site; upper, middle/lower lobe; 599/161, BMI; 21.8 (19.7;24.0), weight loss (≥5% within 6m) yes/no; 135/644, LDH (IU/l); 203 (175;276), CRP (mg/dl); 0.70 (0.20;2.60), irradiated dose (Gy); 60 (60;60), combined regimen; platinum/taxane 303, CDDP/mitomycin/vindesine; 254, CDDP/5-FU-based; 196, CDDP/vinorelbine 87, CDDP/pemetrexed 50, others 272. The median PFS in all patients was 9.72m (95% CI; 9.33 – 10.38), with 3-yr, 5-yr, and 10-yr PFS rates of 19.7, 14.3, 10.1%. LASSO logistic regression identified Sq, lower lobe primary, age, pack-years, and weight loss as the top negative influencers. The PFS curve was significantly shorter in patients with lower lobe primary (median of 8.15 vs. 9.46m, p = 0.023) and weight loss (median of 7.29 vs. 9.72m, p &lt; 0.0001). Pneumonitis occurred in 50.9% (grade≥3 in 6.7%) and esophagitis in 41.9% (grade≥3 in 3.9%). Grade≥2 pneumonitis shortened PFS (8.2 vs. 10.2m, p = 0.00015), while, unexpectedly, grade≥1 esophagitis was associated with longer PFS (12.9 vs. 8.6m, p &lt; 0.0001). Conclusions: The efficacy of concurrent chemoradiotherapy varies significantly based on the primary site. Weight loss is a significant predictor of efficacy, as is in metastatic disease. The impact of pneumonitis and esophagitis suggest that modifying lung and esophageal irradiation might enhance treatment efficacy. Further research in this area is still certainly warranted.

A 16 year-retrospective study of refractory meningiomas: Prognostic factors and systemic treatments.

2085 Background: Meningiomas are the most common brain tumors, with no established standard systemic treatment for refractory cases after surgical and radiotherapeutic interventions. This study aims to identify prognostic factors for overall survival in refractory meningioma and document patient evolution with systemic treatments. Methods: In a retrospective study, we identified patients with meningioma initially followed at CHUM university hospital between 2006 and 2022. Patients with progression after first-line treatment and over 6 months of follow-up were included. The population was divided into two: group 1 received surgery and/or radiotherapy for progression, and group 2 received additional systemic treatments. Survival analysis with Kaplan-Meier curves and group comparisons (Log-Rank, Fisher's Exact Tests) were conducted. Results: A total of750 patients with meningioma were identified. 99 (13%) progressed after first-line treatment. Among them, 70 (9%) were categorized in group 1 and 29 (4%), in group 2. The median follow-up time from diagnosis was 7.5 years. The overall 10-year survival rate was higher in group 1 compared to group 2 (88% vs 62%). Prognostic factors affecting survival were identified as the following: disease progression after second-line treatment, age ≥ 65 years, and grade 2 or 3. When comparing PFS-1 after first-line treatment, they were similar between group 1 and group 2 (mPFS-1: 2.63 vs 3.49 years; p = 0.421). However, PFS-2 after second-line treatment was significantly shorter in group 2 (mPFS-2 : 12.6 vs 2.3 years ; p &lt; 0.001). Age of ≥ 65 years (10-year survival: 57% vs 89%; p &lt; 0.001) and higher grades (10 year survival: 90% grade 1 vs 58% - grade 2 vs 75% - grade 3; p = 0.027) were associated with lower survival rates. The number of lesions (unique or multiple) and localization (supra or infratentorial) of tumors had no significant impact on survival (p=0.257; p = 0.482). Regarding systemic treatments, 7 patients (25%) received Bevacizumab. It was the treatment associated with the longest PFS (mPFS = 22.5 months) when compared to Hydroxyurea (n=18 [62%], mPFS = 4 months), Somatostatin (n = 5 [17%], mPFS = 8 months), a combination of Hydroxyurea and Somatostatin (n=7 [24%], mPFS = 8 months) and Sunitinib (n=3 [10%], mPFS = 14 months). For patients discontinuing systemic treatment, median survival was 5 months. Systemic treatments were well-tolerated. Among moderate to severe side effects (grade ≥ 2), we documented bradycardia (Somatostatin, n=1), elevated liver enzymes (Sunitinib, n=1), anemia and neutropenia (Hydroxyurea, n=3) and proteinuria (Bevacizumab, n=1). Conclusions: Prognostic factors for survival in meningioma include age ≥ 65 years, grades 2 and 3, and the occurrence of a second progression. Our study highlights Bevacizumab in systemic treatment strategies which was well tolerated in our patients.

Results and exploratory biomarker analyses of a phase II study CHANGEABLE: Combination of HX008 and niraparib in germ-line-mutated metastatic breast cancer.

1084 Background: The combination of poly (ADP-ribose) polymerase inhibitors and immune-checkpoint inhibitors demonstrated synergistic antitumor activity in preclinical studies. Here we report the efficacy, safety, and biomarker analyses of the combination of niraparib and PD-1 inhibitor HX008 in metastatic breast cancer (MBC) patients with germline DDR gene mutations in a phase II trial (CHANGEABLE). Methods: Eligible patients had histologically confirmed MBC with at least one measurable disease and germline pathogenic/suspected pathogenic mutations in DDR genes. Patients were enrolled into two cohorts: the main cohort (HER2-negative MBC patients with gBRCA1/2, gPALB2, gCHEK2) and the exploration cohort (MBC patients with gDDR gene mutations and brain metastases). Simon's Two-Stage design was used for recruiting patients in the main cohort. Patients with HER2-negative MBC received niraparib 200 mg qd combined with HX008 200 mg q3w, while HER2-positive patients received additional anti-HER2 TKI pyrotinib 400mg qd if having brain metastases, until disease progression. The primary endpoint was ORR. NGS of tissue and ctDNA were performed for exploratory biomarker analyses. Results: As of January 12, 2024, 37 patients were enrolled. In the main cohort with gBRCA1/2 mutations (n = 28), ORR was 78.6% (22/28), with 3 patients having complete response. DCR was 96.4% (27/28). Median PFS was 7.3 months (95%CI 4.2 to 10.4). According to Simon's Two-Stage design, since two patients with gCHEK2 mutations in the first stage had only stable disease, the recruitment was terminated. One patient with gPALB2 mutation had stable disease and the remaining one is in the screening process. In the patients having brain metastases (exploration cohort), ORR was 40% (2/5) and DCR was 80% (4/5). The most common treatment-related adverse events of grade 3 or higher were anemia (13 [35.1%]), thrombocytopenia (4 [10.8%]), and neutropenia (3 [8.1%]). No treatment-related deaths were reported. In the biomarker analysis, NGS of 700 genes was performed on 24 patients with gBRCA1/2 mutations in the main cohort. No significant difference was found in ORR or PFS between gBRCA1 and gBRCA2 mutations. Somatic mutations in XPO1 (16 patients (73%), 15/18 PR+CR, 1/4 SD+PD) showed significant correlation with response. Somatic TP53 mutations are significantly correlated with shorter PFS, while ASXL1 mutations are significantly correlated with longer PFS. Four somatic mutations (AR_c.1418_1420del, AR_c.231_239dup, 2 DUSP22 mutations) showed a consistent trend of decreasing in PD samples, while NF1_c.3198-4dup showed a consistent trend of increasing in PD samples. Conclusions: The combination of niraparib and HX008 demonstrated promising clinical benefits with a tolerable safety profile in MBC patients with germline BRCA1/2 mutations, even in patients with brain metastases. Clinical trial information: NCT04508803 .

Evaluating CR as a surrogate endpoint for PFS in R/R chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): A meta-analysis of randomized controlled trials (RCT).

7046 Background: CLL/SLL is the most common leukemia in adults. Achieving a CR by International Workshop on CLL 2018 criteria indicates complete eradication of CLL/SLL in all disease compartments. Patients with R/R CLL/SLL who achieved CR tend to have delayed disease progression/death compared with patients who did not achieve CR. This is the first report to evaluate CR as a surrogate endpoint for PFS in R/R CLL/SLL using aggregate RCT data. Methods: A systematic literature review (SLR) identified published RCTs in R/R CLL/SLL from inception to 10/2023, reporting nonzero CR rates (CRR) and PFS. Association between treatment effects on CR and PFS across RCTs was estimated using a weighted linear model (WLM) in the primary analysis, and Daniels and Hughes (D&amp;H) and Riley bivariate random-effects meta-analysis (BRMA) in sensitivity analyses. Strength of association was assessed based on surrogacy criteria described by D&amp;H. Predictive performance of models was evaluated using leave-one-out cross-validation. Results: The SLR identified 13 RCTs with a total of 4388 patients with R/R CLL/SLL treated with a variety of therapies, including but not limited to BTKi, BCL2i, PI3Ki, CAR T cell therapy, anti-CD20 mAb, and chemotherapy. Across the evidence base, CRR ranged from 0.48% to 38.10% and median PFS was between 1 and 35.9 months (excluding unreached medians). Across RCTs, contrasting treatment and control arms, higher odds of CR resulted in lower hazards of disease progression/death (CRR improvement translated to PFS benefit). D&amp;H surrogacy criteria were met for WLM: 1) a near-zero, statistically nonsignificant intercept, indicating that no treatment effect on CRR implies no effect on PFS; 2) a negative, statistically significant slope, suggesting that improved CRR correlates with longer PFS; and 3) a near-zero conditional variance, meaning that PFS HR variation was primarily explained by CR odds ratio. During cross-validation, treatment effects on CR were predictive of PFS benefits, as the 95% predictive interval of PFS HR contained the observed HR in all RCTs for WLM. Results were largely consistent across all 3 models(Table). Conclusions: Improved CRR corresponds to prolonged PFS across RCTs and treatment comparisons. The results support CRR as an important treatment goal for R/R CLL/SLL and a valid surrogate endpoint. Consistent results and predictive performance across different models indicate the robustness of the results. [Table: see text]

Efficacy and safety of PD-1/PD-L1 inhibitors in elderly patients with advanced non-small cell lung cancer.

This study aimed to investigate the efficacy and safety of PD-1/PD-L1 inhibitors in treatment of elderly patients with advanced non-small cell lung cancer (NSCLC). Patients with advanced NSCLC ≥70 years old who received PD-1/PD-L1 inhibitors in our hospital were retrospectively analyzed. According to age, the patient were stratified as follows: 70-75 years old, 76-80 years old, and >80 years old. Kaplan-Meier method was used for survival analysis, and univariate and multivariate Cox proportional hazards regression models were used to analyze the correlation between different clinical characteristics and survival. A total of 58 elderly patients with advanced non-small cell cancer were enrolled in this study. Patients aged 70-75, 76-80, and >80 years old were 32, 19, and 7, respectively. For the all, median OS was 17.0months, and PFS was 7.0months. PFS and OS did not differ according to age (P = 0.396, 0.054, respectively). Univariate analysis showed that PS of 0-1, stage III, first-line therapy and irAEs were associated with longer PFS, and PS of 0-1, stage III, and first-line therapy were associated with longer OS. Multivariate analysis showed that patients with stage III had longer PFS. PFS and OS of patients with PS ≥ 2 were significantly shorter than those of patients with PS of 0-1. In the present real-world retrospective cohort, PD-1/PD-L1 inhibitors are effective and well tolerated in elderly patients with advanced NSCLC. Immunotherapy should be actively used as early as possible in older patients advanced NSCLC.

Treatment patterns, clinical outcomes and gene mutation characteristics of hepatitis B virus-associated mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an uncommon and incurable B-cell lymphoma subtype that has an aggressive course. Hepatitis B virus (HBV) infection has been associated with an increased risk for B-cell lymphomas, and is characterized by distinct clinical and genetic features. Here, we showed that 9.5% of MCL Chinese patients were hepatitis B surface antigen positive (HBsAg+). Compared to HBsAg-negative (HBsAg-) patients, HBsAg+ MCL patients had a greater incidence of elevated lactate dehydrogenase (LDH), but no difference was observed in the other clinical characteristics, including sex, age, ECOG ps, Ann Arbor stage, MIPI, extranodal involvement and Ki-67. The HD-AraC (high-dose cytarabine) regimen was the main first-line induction regimen for younger HBsAg+ patients, and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) were used for elderly patients. HBsAg seropositivity was associated with a significantly shorter PFS than HBsAg seronegativity when patients were treated with rituximab or CHOP-based regimens. Compared with CHOP, the HD-AraC regimen was associated with longer PFS in HBsAg+ patients. Treatment with a Bruton tyrosine kinase inhibitor (BTKi) alone can also cause HBV reactivation. Among the 74 patients who underwent targeted deep sequencing (TDS), the nonsynonymous mutation load of HBsAg+ MCL patients was greater than that of HBsAg- MCL patients. HDAC1, TRAF5, FGFR4, SMAD2, JAK3, SMC1A, ZAP70, BLM, CDK12, PLCG2, SMO, TP63, NF1, PTPR, EPHA2, RPTOR and FIP1L1 were significantly enriched in HBsAg+ MCL patients.

Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer

BackgroundCombining immune checkpoint inhibitors (ICIs) with chemotherapy has become a standard treatment for patients with non-small cell lung cancer (NSCLC) lacking driver gene mutations. Reliable biomarkers are essential for predicting...

The impact of EGFR T790M mutation status following the development of Osimertinib resistance on the efficacy of Osimertinib in non-small cell lung cancer: A meta-analysis.

Previous studies have suggested that loss of the EGFR T790M gene mutation may contribute to the development of resistance to Osimertinib in non-small cell lung cancer (NSCLC). This study aims to assess the relationship between the clinical effectiveness of Osimertinib in NSCLC patients and the T790M mutation status following resistance to Osimertinib and examine differences between plasma and tissue tests and between Asian and non-Asian groups. The PubMed, Web of Science, Cochrane, and EMBASE databases were comprehensively searched for studies on the association between T790M mutation status and the efficacy of Osimertinib between January 2014 and November 2023. Meta-analysis was carried out using Review Manager 5.4 software. After evaluating 2727 articles, a total of 14 studies were included in the final analysis. Positive correlations between EGFR T790M mutation status after Osimertinib resistance and longer PFS (HR: 0.44, 95% CI: 0.30-0.66), longer OS (HR: 0.3, 95% CI: 0.10-0.86), longer TTD (HR: 0.69, 95% CI: 0.45-1.07), and improved clinical outcomes including PFS and TTD subgroups (HR: 0.58, 95% CI: 0.47-0.73) were observed. Subgroup analysis revealed that, compared with the blood tests, the results of the T790M mutation tests by the tissue are more significant (HR: 0.24, 95% CI: 0.11-0.52 for tissue tests; HR: 0.47, 95% CI: 0.22-1.00 for plasma tests), and the PFS of Osimertinib were similar for Asian and non-Asian patients (HR: 0.46, 95% CI: 0.31-0.68 for Asians; HR: 0.12, 95% CI: 0.01-1.27 for non-Asians). Persistence of the T790M gene mutation after the development of Osimertinib resistance is associated with higher therapeutic benefits of Osimertinib in NSCLC patients. The results of tissue detection are more significant than those of plasma detection.