Prolonged PFS 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.

Exploring risk factors for endocrine-related immune-related adverse events: Insights from meta-analysis and Mendelian randomization.

This study utilized meta-analysis and Mendelian randomization (MR) to identify risk factors for endocrine-related immune-related adverse events (EirAEs) and to ascertain whether EirAEs confer better prognosis of immunotherapy. The meta-analysis identified several risk factors for EirAEs, including elevated baseline TSH (OR = 1.30, 95% CI 1.10-1.53), positive TgAb (OR = 14.23, p < .001), positive TPOAb (OR = 3.75, p < .001), prior thyroid-related medical history (OR = 4.19), increased BMI (OR = 1.11), combination immune checkpoint inhibitors (ICIs) therapy with targeted treatment (OR = 2.71, 95% CI 2.11-3.47), and dual ICI therapy (OR = 3.26, 95% CI 2.22-4.79). MR analysis further supported causalities between extreme BMI, hypothyroidism, and irAEs from a genetic perspective. In addition, cancer patients who experienced EirAEs exhibited significantly prolonged PFS (HR = 0.84, 95% CI 0.73-0.97) and OS (HR = 0.59, 95% CI 0.45-0.76) compared to those without. These findings provide valuable insights for clinical decision-making among healthcare professionals and offer direction for future research in this field.

Patterns of intersectional tumor volumes in T2-weighted MRI and [18F]FET PET in adult glioma: a prospective, observational study

Brain tumor volumes as assessed by magnetic resonance imaging (MRI) do not always spatially overlap with biological tumor volumes (BTV) measured by [18F]Fluoroethyltyrosine positron emission tomography ([18F]FET PET). We prospectively investigated volumetric patterns based on the extent of tumor volume overlap between the two modalities. Eighty-six patients with newly diagnosed glioma who had undergone MRI and [18F]FET PET between 2007 and 2009 were included in this prospective study and (re-)classified according to CNS WHO 2021 (Classification of Tumors of the Central Nervous System by the World Health Organization). Four different patterns of volume overlap were defined mathematically according to the extent of overlap between MRI-based T2 tumor volume (non-enhancing tumor volume, nCEV) and BTVs. Progression-free (PFS) and overall survival (OS) were determined. Seventy patients were diagnosed with isocitrate dehydrogenase wildtype (IDHwt) glioblastoma and 16 with IDH-mutant glioma, respectively. The most common pattern was characterized by a larger non-contrast-enhancing tumor volume (nCEV) that enclosed all or most of the BTV and was observed in 46 patients (54%) (pattern 1). This pattern was more frequent in IDH-mutant gliomas than in IDH-wildtype glioblastoma (81% versus 47%, p = 0.02). In multivariate analyses, pattern 1 was associated with prolonged PFS (HR 0.59; 95 CI 0.34-1.0; p = 0.05), but not OS (HR 0.66; 95 CI 0.4–1.08; p = 0.1). For OS, presence of an IDH mutation (p = 0.05) and lower age (p = 0.03) were associated with prolonged OS. The spatial relation between nCEV and BTV varies within and between glioma entities. Most frequently, a larger nCEV encases the BTV. Some patients show spatially dissociated nCEVs and BTVs. Not accounting for this phenomenon in surgery or radiotherapy planning might lead to undertreatment.

Time toxicity of lutetium-177 treatment in gastroenteropancreatic neuroendocrine tumours

Objectives: We aim to investigate the time toxicity of patients with gastroenteropancreatic-neuroendocrine tumours treated with lutetium-177 Dotatate in a single institution. Design: This is a retrospective cohort study. Methods: All patients with gastroenteropancreatic-neuroendocrine tumours treated with lutetium-177 Dotatate in the Alexander Fleming Institute were included. Our primary endpoint was to evaluate time toxicity, which accounted for every day that the patient had contact with any department of any healthcare institution. Results: Our cohort included 21 patients with metastatic disease, female sex 86%, and had a median age of 55 (IQR 44-63). The primary tumour site was small intestine in 47.6% of the cases. The median number of previous systemic treatments for advanced disease was 2 (IQR 2 - 3). The overall response rate was 19%, and 66.6% had disease clinical benefit. The median calculated 'time toxicity' was 11 days (IQR 8-18), representing 5.7% of the total treatment duration. The main contributors to time-toxicity included infusion days, blood draws, radiological scans, and hospitalizations (median 4 days for each). Conclusion: Lutetium-177 Dotatate treatment for gastroenteropancreatic-neuroendocrine tumours was associated with a low time toxicity, excellent tolerability, good response and a prolonged PFS, of which the median was not reached in the short follow-up we present. Newer treatments with different mechanisms of action provide longer survivals and widen the landscape of choices. Understanding new clinical endpoints is important for the transition into a more modern clinical practice, strengthening personalised and patient-oriented strategies.

Efficacy Analysis of PTCD + TACE vs PTCD + Apatinib in the Treatment of HCC with Obstructive Jaundice: A Retrospective Study.

The aim was to evaluate the safety and effectiveness of PTCD combined with TACE in the treatment of hepatocellular carcinoma with obstructive jaundice and to compare the efficacy of TACE in patients with different levels of bilirubin after PTCD. The clinical data of 141 patients with HCC complicated with obstructive jaundice were analyzed retrospectively. The patients underwent PTCD first. When the total bilirubin decreased, the patients received TACE or Apatinib treatment. They were divided into two groups: (1) PTCD+TACE group, N=68; (2) PTCD+Apatinib group, N=73. The PTCD+TACE group had higher ORR and DCR than the PTCD+Apatinib group (57.4% vs 12.3%, p < 0.001;80.9% vs 60.3%, p = 0.010). The mPFS of the PTCD+TACE group was longer than that of the PTCD+Apatinib group (7.1 months vs 3.8 months, p < 0.001). The mOS of the PTCD+TACE group was longer than that of the PTCD+Apatinib group(11.5 months vs 7.7 months, p < 0.001). In the subgroup analysis of the PTCD+TACE group, the results showed that the survival benefits of the groups with total bilirubin <2 times and 2-3 times were greater. In patients with HCC and obstructive jaundice, superselective TACE(lipiodol+epirubicin emulsion) significantly prolonged OS and PFS compared with Apatinib after using PTCD to reduce total bilirubin to <100umol/L. Patients whose total bilirubin dropped to ≤3 times of the upper limit of normal value after PTCD had longer OS and PFS than patients >3 times.

Unraveling the Predictive Value of the Novel Global Immune-Nutrition-Inflammation Index (GINI) on Survival Outcomes in Patients with Grade 4 Adult-Type Diffuse Gliomas.

This investigation evaluated the predictive and prognostic efficacy of the newly developed global immune-nutrition-inflammation index (GINI) in patients with grade 4 adult-type diffuse gliomas, comparing it with other established indices such as the systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and pan-immune-inflammation value (PIV). A retrospective cohort included 198 patients diagnosed with isocitrate dehydrogenase (IDH)-mutant gr4 (grade 4) astrocytoma and IDH-wt (wilde-type) glioblastoma (GBM) gr4 treated with surgical resection, radiotherapy, and temozolomide. Patients were stratified into two groups based on their GINI values: low GINI (<5815) and high GINI (≥5815). The primary endpoint was overall survival (OS). High GINI was significantly associated with older age, poor performance status, multifocal tumors, and higher SII, SIRI, and PIV values (p < 0.005). The GINI demonstrated strong correlations with SII (r = 0.694), SIRI (r = 0.516), and PIV (r = 0.657) (p < 0.001). Patients with high GINI exhibited poorer OS (5.0 vs. 17.0 months) and PFS (5.0 vs. 13.0 months) in comparison to those with low GINI. Kaplan-Meier survival analysis revealed significantly prolonged OS and PFS among patients with low GINI (p < 0.001). Multivariate analysis identified high GINI as an independent negative risk factor for both PFS and OS. GINI is a robust predictor of clinical outcomes in IDH-mutant gr4 astrocytoma and IDH-wt GBM gr4, highlighting the crucial impact of nutrition and cancer cachexia. It shows superior prognostic value relative to the SII, SIRI, and PIV.

Measurable residual disease (MRD) dynamics in multiple myeloma and the influence of clonal diversity analyzed by artificial intelligence

Minimal residual disease (MRD) assessment is a known surrogate marker for survival in multiple myeloma (MM). Here, we present a single institution’s experience assessing MRD by NGS of Ig genes and the long-term impact of depth of response as well as clonal diversity on the clinical outcome of a large population of MM patients; 482 MM patients at the University of California, San Francisco (UCSF) diagnosed from 2008 to 2020 were analyzed retrospectively. MRD assessment was performed by NGS. PFS curves were plotted by the Kaplan–Meier method. In the newly diagnosed group, 119 of 304, achieved MRD negativity at the level of 10−6 at least once. These patients had a prolonged PFS versus patients who were persistently MRD positive at different levels (p > 0.0001). In the relapsed disease group, 64 of 178 achieved MRD negativity at 10−6, and PFS was prolonged versus patients who remained MRD positive (p = 0.03). Three categories of MRD dynamics were defined by artificial intelligence: (A) patients with ≥3 consistently MRD negative samples, (B) patients with continuously declining but detectable clones, and (C) patients with either increasing or a stable number of clones. Groups A and B had a more prolonged PFS than group C (p < 10−7). Patients who were MRD positive and had not yet relapsed had a higher clonal diversity than those patients who were MRD positive and had relapsed. MRD dynamics can accurately predict disease evolution and drive clinical decision-making. Clonal Diversity could complement MRD assessment in the prediction of outcomes in MM.

Length of treatment after partial or complete remission in immunotherapy for metastatic melanoma: An EUMelaReg real world study.

9531 Background: A significant proportion of patients (pts) with non-resectable melanoma treated with immune checkpoint inhibitors (ICI) achieve durable remissions, but there is limited data on the optimal duration of ICI therapy in these pts. Therefore, the influence of the duration and maintenance of ICI therapy in pts with a partial (PR) or complete remission (CR) on further outcome was investigated. Methods: Primary objectives was the survival outcome after achieving PR or CR in non-resectable stage III/IV melanoma in relation to baseline prognostic variables and duration of maintenance treatment with ICIs in 1st line. This retrospective study evaluated melanoma cases from the EUMelaReg treatment registry, who achieved a best overall response (BOR) of PR or CR with either single agent anti-PD1 or combined anti-PD1/anti-CTLA4 in 1st line. Cases were stratified according to treatment duration after achieving a PR or CR: &lt; 6 months (M), 6-12 M, &gt; 12 M. To address immortal time bias, cases with early progression were cloned into all respectively compatible strata. These synthetical strata were further analyzed and compared by propensity score weighting, and robust confidence intervals were retrieved by bootstrapping techniques. Results: A total of 1,291 pts were included in the analysis. After cloning, 2,144 cases could be stratified to the synthetical arms of &lt;6 M (26.5%), 6-12 M (31.4%) or &gt;12 M (42.1%) treatment continuation after achieving PR or CR. Adjusted Kaplan-Meier estimates showed that treatment until progressive disease (PD) or &gt; 12 M after remission resulted in prolonged progression-free (PFS) and overall survival (OS) compared to the &lt; 6 M arm (hazard ratio (HR): 0.82 [95% confidence interval (CI): 0.6-0.9] and HR: 0.67 [95% CI: 0.5-0.9], respectively).This effect was more pronounced in PR (HR 0.66 for OS) than in (HR 0.84 for OS). Treatment for 6-12 M compared to &lt; 6 M also showed a trend towards prolonged PFS and OS (HR: 0.85 [95% CI: 0.7-1.1] and HR: 0.82 [95% CI: 0.6-1.1], respectively). Conclusions: This study showed PFS and OS benefit for pts continuing on treatment for &gt; 12 M or until progression after achieving PR or CR compared to pts treated for &lt; 6 M. [Table: see text]

Combined amphiregulin and epiregulin expression as a prognostic and predictive biomarker of panitumumab (Pmab), fluorouracil, and folinic acid (FU/FA) or FU/FA maintenance therapy following Pmab+FOLFOX induction in RAS wildtype metastatic colorectal cancer (mCRC): PANAMA trial (AIO-KRK-0212).

3528 Background: mRNA expression of amphiregulin ( AREG) and epiregulin ( EREG) as ligands of the epidermal growth factor receptor (EGFR) were associated with response to anti-EGFR directed antibodies in metastatic colorectal cancer (mCRC). Their role for maintenance treatment remained unclear yet and was investigated in the PanaMa trial (panitumumab (Pmab) and fluorouracil/folinic acid (FU/FA) vs. FU/FA alone after Pmab+FOLFOX induction therapy in RAS wild-type mCRC). Methods: Gene expression was measured after mRNA isolation in 196 of 248 patients of the full analysis set. The analysis was conducted using a customized Nanostring PanCancer Progression Panel. AREG and EREG mRNA expression was dichotomized by median. High combined expression was defined as mRNA expression of AREG and EREGequal or above the median. Median progression-free (PFS) and overall survival (OS) since start of maintenance were estimated by Kaplan-Meier-method and Cox-regression, using the log rank test. Objective response rates (ORR) of maintenance therapy were compared by Fisher’s exact test. Treatment interaction was tested by Cox regression. Results: In 196 patients with available mRNA expression data, high AREG, EREG and combined AREG / EREG expression were observed in 103 (52.6%), 97 (49.5%) and 84 (42.9%), respectively. Regardless of treatment, high combined AREG / EREG expression was associated with prolonged PFS (7.7 vs. 5.8 months, HR 0.69 (95% CI 0.51 – 0.93), P=0.016), OS (30.1 vs. 24.4 months, HR 0.58 (95% CI 0.41 – 0.82), P=0.002) and increased ORR of maintenance treatment (39.3% vs. 28.6%, P=0.13), compared to low expression. Tumors with high combined AREG / EREG expression were associated with numerical longer PFS, OS and higher ORR when treated with Pmab+FU/FA maintenance (Table). Significant interaction of combined AREG / EREG expression with treatment was observed in terms of PFS ( P=0.003) and OS ( P=0.016). Conclusions: Combined AREG and EREG mRNA expression was confirmed as prognostic biomarker for mCRC patients receiving maintenance treatment. Efficacy of maintenance treatment might potentially be higher for Pmab+FUFA maintenance in mCRC with high combined AREG / EREG expression in the PanaMa trial. [Table: see text]

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]

Abstract PO4-14-06: Impact of Serum HER2 Extracellular Domain in Metastatic Breast Cancer Patients Treated with Trastuzumab Deruxtecan (T-DXd)

Abstract Background: Trastuzumab deruxtecan (T-DXd) is a standard of care as 2nd line and after prior chemotherapy for HER2 positive and low metastatic breast cancer (MBC), respectively, based on Destiny Breast03 and 04 results. However, biopsies over time during treatment have shown that HER2 expression is variable. The predictive factors of trastuzumab deruxtecan (T-DXd) for MBC with HER2 positive and low are unclear. The HER2 extracellular domain (HER2-ECD) has been confirmed as a prognosis marker and predictive marker of treatment for HER2-positive MBC. Especially, HER2-ECD is considered a promising biomarker in cases where HER2 expression in metastases is unconfirmed. We hypothesized that HER2-ECD could serve as a biomarker for T-DXd. Patients and methods: A retrospective study of consecutively treated patients in a single center between 2019-2023 with HER2-low and HER2-positive MBC was performed using chart review. HER2 status was diagnosed according to 2020 ASCO-CAP guidelines. HER2-ECD high was defined as &amp;gt;15.0 ng/ml. HER2-ECD was collected prior to T-DXd treatment. We compared overall response (ORR), progression-free survival (OFS), overall survival (OS), and disease control rate (DCR) at HER2-ECD high and low groups. Cox regression analyses were performed to assess the ORR. We used the Kaplan-Meier method to estimate the PFS and OS and the log-rank test to compare each treatment group. Results: A total of 41 MBC patients were included in this study. Patients with HER-positive and HER2-low were 34 and 7, respectively. Among HER2 positive (n=34), HER2-ECD high and low are 14 (41%) and 20 (59%) patients, respectively. Among HER2 low (n=7), HER2-ECD high and low are 3 (43%) and 4 (57%) patients, respectively. Twenty-six patients received T-DM1 prior to T-DXd treatment for MBC with HER2 positive, but no patients received CPT-11 before T-DXd for MBC with HER2 positive and low. The ORR of T-DXd was 89% and 52% in the HER2-ECD high and low groups, respectively (p&amp;lt; 0.001). All 6 cases with CR were HER2-ECD high. Among HER2 low group (n=7), ORR of T-DXd was 67% (2/3) and 25% (1/4) in HER2-ECD high and low groups, respectively. The median PFS in the HER2-ECD high group showed longer than the HER2-ECD low group, 21.8 vs. 8.0 months (HR 0.31; 95%CI, 0.13-0.78, p=0.012). Although there were no significant differences in OS, HER2 ECD high group tended to show longer OS (HR 0.23; 95%CI, 0.04-1.16, p=0.07). The DCR was 100% in the HER2 ECD high group and 87% in the low group. Conclusion: T-DXd showed significantly better response and prolonged PFS in the group with high HER2-ECD. HER2-ECD has the potential to become a biomarker for T-DXd. Further study is warranted to assess the HER2-ECD as a biomarker, especially for HER2 low MBC patients treated with T-DXd. Table. Association between the response and the HER2 status or HER2-ECD status Citation Format: Kazuki Nozawa, Maho Kusudo, Nari Kureyama, Akira Nakakami, Rie Komaki, Yuka Endo, Ayumi Kataoka, Haruru Kotani, Akiyo Yoshimura, Masaya Hattori, Masataka Sawaki, Hiroji Iwata. Impact of Serum HER2 Extracellular Domain in Metastatic Breast Cancer Patients Treated with Trastuzumab Deruxtecan (T-DXd) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-14-06.

Antitumor immunity and prognosis value elicited by FAT3 and LRP1B co-mutation in endometrial cancer

Objective: FAT3 and LRP1B are two tumor suppressor genes with high mutation frequency in multiple cancer types, we sought to investigate the prognostic and immunological significance of these two genes in EC.Methods: Based on a cohort of 502 EC samples, we conducted a comprehensive analysis of its multidimensional data types including genomic, transcriptomic, and clinical information, the potential impact of FAT3 and LRP1B co-mutation on antitumor immune response and prognosis were systematically discussed.Results: We observed that FAT3 and LRP1B co-mutation was not only defined a dataset with prominently increased TMB, decreased tumor aneuploidy, and specially enriched in MSI-H subtype, but also manifested increased expression of immune-related markers, especially exclusive upregulation of PD-L1 levels and higher PD-L1+/CD8A+ proportion. Further analysis focused on lymphocyte infiltration and pathway enrichment explored the immune cell composition of the microenvironment and underlying molecular mechanisms affecting tumor development. Furthermore, EC patients with FAT3 and LRP1B co-mutation possessed significantly prolonged PFS and OS, and the co-mutation status was proved to be an independent prognostic factor. And a nomogram with high predictive performance was constructed by incorporating co-mutation with clinical features. More strikingly, the prognosis of MSI-H patients in EC with co-mutation was significantly improved, and their survival reached a level consistent with the POLE subtype.Conclusions: In endometrial cancer, co-mutation of FAT3 and LRP1B not only leads to activation of the immune state, but also represents a subgroup with an improved prognosis, particularly in the MSI-H subtype.

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...

Abstract CT034: Results from phase 3 KEYLYNK-008: Pembrolizumab (pembro) with and without maintenance olaparib (ola) after first-line (1L) pembro plus chemotherapy (chemo) for metastatic squamous non-small-cell lung cancer (sqNSCLC)

Abstract Introduction: 1L pembro + chemo significantly improved OS vs chemo for metastatic sqNSCLC in the KEYNOTE-407 study. Poly(ADP-ribose) polymerase inhibitors (PARPi) can upregulate PD-L1 expression and promote immune-mediated response, which may increase the efficacy of anti‒PD-(L)1‒based therapies. The randomized, double-blind (and in-house blinding), phase 3 KEYLYNK-008 study (NCT03976362) evaluated addition of ola (PARPi) as maintenance therapy for metastatic sqNSCLC with SD or CR/PR after 1L pembro + chemo. Methods: Eligible patients (pts) aged ≥18 y had previously untreated stage IV NSCLC, confirmed squamous histology, measurable disease per RECIST v1.1, and ECOG PS 0-1. Pts with CR, PR, or SD after 4 cycles of Q3W induction therapy with pembro 200 mg, carboplatin AUC 6, and paclitaxel 200 mg/m2 or nab-paclitaxel 100 mg/m2 were randomized 1:1 to ola 300 mg BID or placebo (pbo), both given with ≤31 cycles of pembro 200 mg Q3W. Randomization was stratified by ECOG PS (0 vs 1), PD-L1 TPS (&amp;lt;50% vs ≥50%), and response to induction treatment (CR/PR vs SD). Primary endpoints were PFS (RECIST v1.1 by BICR) and OS. Final PFS testing occurred at interim analysis (IA) 2 (data cutoff, Feb 23, 2023); other endpoints were assessed at IA3 (data cutoff, Sep 21, 2023). Efficacy boundaries based on actual observed events were 1-sided P = 0.003202 for PFS (IA2) and P = 0.014647 for OS (IA3). Results: Of 851 pts who received induction treatment, 591 were randomized to pembro + ola (n = 296) or pembro + pbo (n = 295). Median PFS (95% CI) was 8.3 (6.7-9.7) mo for pembro + ola and 5.4 (4.1-5.6) mo for pembro + pbo (HR 0.77; 95% CI 0.63-0.93; P = 0.0040). 24-mo PFS rates (95% CI) were 27.5% (21.9%-33.4%) and 21.1% (16.1%-26.5%), respectively. Median follow-up to IA3 was 33.4 (19.0-46.8) mo. Median (95% CI) OS was 19.1 (15.9-22.2) mo for pembro + ola and 18.6 (16.0-21.6) mo for pembro + pbo (HR 1.01; 95% CI 0.83-1.24; P = 0.5481). 24-mo OS rates (95% CI) were 40.9% (35.1%-46.5%) vs 41.2% (35.4%-46.8%). ORR (95% CI) was 25.0% (20.2%-30.3%) for pembro + ola vs 15.3% (11.3%-19.9%) for pembro + pbo. Median DOR (range) was 21.0 (2.1 to 42.8+) mo vs 26.0 (1.2+ to 39.6+) mo. 225/294 pts (76.5%; grade 3-5, 29.6%) had treatment-related AEs in the pembro + ola arm and 190/292 (65.1%; grade 3-5, 12.7%) in pembro + pbo arm. 2 pts (pneumonitis, multiple organ dysfunction syndrome) in the pembro + ola arm and 1 (thrombocytopenia) in the pembro + pbo arm died due to treatment-related AEs. Conclusions: In KEYLYNK-008, the addition of ola to pembro as maintenance therapy after 1L pembro + chemo for metastatic sqNSCLC numerically prolonged PFS vs pembro + pbo, but neither PFS nor OS met the prespecified statistical significance boundary. No new safety signals were identified. The study has been discontinued per the recommendation of an independent data monitoring committee. Citation Format: Maximilian Hochmair, Michael Schenker, Manuel Cobo Dols, Tae Min Kim, Sang-We Kim, Ozgur Ozyilkan, Maria Smagina, Leonova Viktoriya, Terufumi Kato, Alexander Fedenko, Flavia De Angelis, Achim Rittmeyer, Jhanelle E. Gray, Alastair Greystoke, Qinlei Huang, Bin Zhao, Humberto Lara-Guerra, Ernest Nadal. Results from phase 3 KEYLYNK-008: Pembrolizumab (pembro) with and without maintenance olaparib (ola) after first-line (1L) pembro plus chemotherapy (chemo) for metastatic squamous non-small-cell lung cancer (sqNSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT034.

Effect of Clinical Complete Remission Following Neoadjuvant Pembrolizumab or Chemotherapy in Bladder-Preservation Strategy in Patients with Muscle-Invasive Bladder Cancer Declining Definitive Local Therapy.

This study aimed to evaluate the outcomes and identify the predictive factors of a bladder-preservation approach incorporating maximal transurethral resection of bladder tumor (TURBT) coupled with either pembrolizumab or chemotherapy for patients diagnosed with muscle-invasive bladder cancer (MIBC) who opted against definitive local therapy. We conducted a retrospective analysis on 53 MIBC (cT2-T3N0M0) patients who initially planned for neoadjuvant pembrolizumab or chemotherapy after maximal TURBT but later declined radical cystectomy and radiotherapy. Post-therapy clinical restaging and conservative bladder-preservation measures were employed. Clinical complete remission was defined as negative findings on cystoscopy with biopsy confirming the absence of malignancy if performed, negative urine cytology, and unremarkable cross-sectional imaging (either CT scan or MRI) following neoadjuvant therapy. Twenty-three patients received pembrolizumab, while thirty received chemotherapy. Our findings revealed that twenty-three (43.4%) patients achieved clinical complete response after neoadjuvant therapy. The complete remission rate was marginally higher in pembrolizumab group in comparison to chemotherapy group (52.1% vs. 36.7%, p = 0.26). After a median follow-up of 37.6 months, patients in the pembrolizumab group demonstrated a longer PFS (median, not reached vs. 20.2 months, p = 0.078) and OS (median, not reached vs. 26.8 months, p = 0.027) relative to those in chemotherapy group. Those achieving clinical complete remission post-neoadjuvant therapy also exhibited prolonged PFS (median, not reached vs. 10.2 months, p < 0.001) and OS (median, not reached vs. 24.4 months, p = 0.004). In the multivariate analysis, clinical complete remission subsequent to neoadjuvant therapy was independently associated with superior PFS and OS. In conclusion, bladder preservation emerges as a viable therapeutic strategy for a carefully selected cohort of MIBC patients without definitive local therapy, especially those achieving clinical complete remission following neoadjuvant treatment. For patients unfit for chemotherapy, pembrolizumab offers a promising alternative treatment option.

CEACAM6 and IFITM3 as potential biomarkers for pelareorep in pancreatic adenocarcinoma (PDAC).

684 Background: Pelareorep (P) is a proprietary formulation of live, replication-competent, naturally occurring Reovirus Type 3 Dearing strain. We previously performed a phase II trial of P with carboplatin (C) and paclitaxel (Pxl) vs C and Pxl alone in metastatic PDAC (NCT01280058). Although P did not improve progression-free survival compared to C and Pxl alone, some exceptional durable responses were seen in the P arm. Low levels of carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) mRNA expression were associated with prolonged PFS in P-treated pts (p=0.05) and there was a 3.3 times higher fold change in Interferon-inducible transmembrane protein 3 (IFITM3) expression in the pts doing poorly versus responders (nominal p&lt;0.05) in P arm. Here we investigate mechanisms of resistance to P infection mediated through CEACAM6 and IFITM3 in a panel of pancreatic ductal adenocarcinoma cell lines. Methods: Prior studies noted CEACAM6 and IFITM3 may restrict cell entry of certain enveloped viruses. CEACAM6 and IFITM3 protein levels were measured in PDAC cell lines using Western blot. Flow cytometry was used to assess P infectivity. We have generated multiple knockdowns of CEACAM6 and IFITM3 in PDAC cell lines to determine changes in P infectivity and other inflammatory signalling pathways. Live cell imaging was used to assess cell viability. Results: Basal expression of CEACAM6 was measured in a panel of 4 PDAC cells (PANC10.5, HPAFII, BxPC3, CFPAC1). Panc10.05 had low basal expression nor could expression be induced by 24hr P infection. All other cell lines showed moderate to high basal expression that was inducible. P infectivity at 24hrs was significantly higher in Panc10.05 cells compared to high CEACAM6 expressing cell lines. There was varying basal expression of IFITM3, however all cell lines showed IFITM3 induction when exposed to P. Of the 3 cell lines that also expressed high levels of CEACAM6 (HPAFII, CFPAC1, BxPC3), low basal expression of IFITM3 was strongly associated with increased sensitivity to P infection and decreased viability at 72hrs, which could be induced by knockdown of IFITM3 in high expressing cell lines. Neither C or Pxl altered levels of CEACAM6 or IFITM3 in any of the four cell lines. Conclusions: High CEACAM6 and IFITM3 play a role in P viral infectivity across multiple pancreatic cell lines, confirming results obtained in translational datasets. Further analysis is ongoing to elucidate mechanism and identify pathways to alter expression of CEACAM6 and IFITM3 and enhance P infectivity in future trials.

Phase 2 study of cabozantinib (Cabo) and pembrolizumab (Pembro) in metastatic gastric/gastroesophageal adenocarcinoma (mGEA) resistant or refractory to immune checkpoint inhibitors (ICI).

315 Background: Most mGEA patients (pt) progress on therapy including ICI, with about 5% progression-free at 6 mo (PFS-6) with single agent ICI in later lines of therapy. Alternative therapeutic approaches are needed. Cabo is a multi-tyrosine kinase inhibitor thought to enhance the immunomodulatory effects of ICI. This study reports on safety and efficacy of the combination of Cabo+Pembro in mGEA resistant or refractory to ICI. Methods: Investigator-initiated, single‐arm, single institution, phase 2 study in pts with mGEA after ≥1L of fluoropyrimidine and platinum-containing regimens. Pts with a PD-L1 CPS score ≥10% had also progressed on ICI. Cabo dose was 40mg p.o. daily on days 1 through 21 of a 21‐day cycle, with Pembro 200 mg i.v. on day 1. The primary endpoint was PFS-6, with H0=5%, Ha≥20%, requiring n=27 evaluable pts and n≥4 pts with PFS-6 to reject H0 in favor of Ha. Results: 27 pts were enrolled. Median age 58 years (24-87), female (n=14), ECOG 0/1= 13/14, GC/GEJ= 16/11, Non-Hispanic White/Hispanic/Asian= 12/8/7. The primary endpoint was met with n=6 pts having PFS&gt;6mo. After a median follow-up of 31.4mo (range 3.3-42.5), PFS-6 is 22.2% (95% CI 9.0-39.0). The median PFS and OS are 2.3mo (95% CI 1.7-4.1) and 5.5mo (3.1-14.0), respectively. The most common mutations were TP53 (78.3%) and CDH1/PIK3CA/CTNNB1 (17.4% each). In exploratory analyses, 5/7 (71.4%) pts in the top quartile for PFS had alterations in the cMET-PI3K-AKT pathway. The most common any grade (G) treatment related adverse events (TRAE) were diarrhea (25.9%), fatigue (18.5%), hypertension and muscle cramps (14.8% each). G3-4 TRAE were seen in n=3 pts (Hypertension, Thromboembolic event, esophageal perforation; each n=1). No G5 were observed. Conclusions: The addition of Cabo to Pembro shows clinical benefit in ICI resistant or refractory mGEA with an observed PFS-6 of 22.2%. The regimen appears tolerable with no new safety signals. An exploratory association of alterations in the cMET-PI3K-AKT pathway with prolonged PFS needs to be confirmed in a larger cohort. Clinical trial information: NCT04164979 .

First-line serplulimab plus HLX04 and XELOX versus placebo plus bevacizumab and XELOX in metastatic colorectal cancer: A phase 2/3 study.

124 Background: Immunotherapy significantly improved survival in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC). However, whether the addition of immunotherapy to the current standard-of-care treatments can improve efficacy in pMMR/MSS mCRC, the predominant type of mCRC, is unclear. This study aimed to compare the efficacy of serplulimab, a novel PD-1 inhibitor, plus HLX04, a bevacizumab biosimilar, and XELOX versus placebo plus bevacizumab and XELOX as first-line treatment for mCRC. Methods: This was a randomized, double-blind, multicenter phase 2/3 study; current report will focus on the phase 2 part. Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomized 1:1 to receive serplulimab (300 mg, Q3W IV) plus HLX04 (7.5 mg/kg, Q3W IV) and XELOX (group A) or placebo plus bevacizumab and XELOX (group B). Randomization was stratified by PD-L1 expression level (CPS &lt;1 vs. 1≤ CPS &lt;50 vs. CPS ≥50), ECOG PS score (0 vs. 1), and primary tumor site (left- vs. right-sided). The primary endpoint was IRRC-assessed PFS per RECIST 1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, biomarker explorations, and quality-of-life assessments. Results: Between July 16, 2021 and January 20, 2022, 114 patients were enrolled and randomly assigned to group A (n=57) and group B (n=57). 83 (72.8%) patients were male. All patients had stage IV CRC, and 90 out of the 94 (95.7%) with available MSI status were MSS. Current report will focus on efficacy and safety findings in the modified intention-to-treat population, which included only patients who received study treatment (group A, n=55; group B, n=57). As of June 1, 2023 (data cutoff), median follow-up duration was 17.7 months. IRRC-assessed median PFS was longer in group A than in group B (17.2 vs. 10.7 months; stratified HR 0.60, 95% CI 0.31–1.14). Median OS was not reached in either group (stratified HR 0.77, 95% CI 0.41–1.45). 36 (65.5%) patients in group A and 32 (56.1%) in group B had grade ≥3 treatment-related adverse events (AEs), most commonly neutrophil count decreased (21.8% vs. 10.5%) and platelet count decreased (16.4% vs. 10.5%). Grade ≥3 immune-related AEs were reported for 5 (9.1%) patients in group A and 1 (1.8%) in group B. Treatment-related deaths occurred in 4 (7.3%) patients in group A and 3 (5.3%) in group B. Conclusions: Serplulimab plus HLX04 and XELOX prolonged PFS compared to placebo plus bevacizumab and XELOX. Improvements in other efficacy endpoints were also observed with a manageable safety profile in patients with mCRC. Serplulimab plus HLX04 and XELOX is a promising first-line treatment option for mCRC patients that warrants further investigation. Clinical trial information: NCT04547166 .

Daratumumab-Based Regimens Versus Cybord in Newly Diagnosed Patients with AL Amyloidosis and IIIb Cardiac Stage: A Matched Case-Control Study

Background: Improving the outcomes of light chain (AL) amyloidosis patients and advanced heart involvement, IIIb Mayo cardiac stage, is an unmet need. The standard front-line treatment has been cyclophosphamide-bortezomib-dexamethasone (CyBorD) until the approval of daratumumab with CyBorD (Dara-CyBorD) in 2021, which significantly improved the rate of hematologic response (HR) as reported by the ANDROMEDA trial. However, stage IIIb patients were excluded from the study and the best upfront treatment strategy in these patients remains to be clarified. For this reason, daratumumab was not licensed for use in stage IIIb patients in many countries. Preliminary data of the ongoing EMN22 phase II multicenter study (NCT04131309), that specifically addresses this issue using daratumumab monotherapy, are promising. Chakraboty et al. reported that Dara-CyBorD is effective in inducing profound hematologic response, at least a very good partial response (VGPR), in treatment-naïve patients with IIIb AL amyloidosis. Similar results were reported by Theodorakakou et al. using different daratumumab combinations. Finally, in a study conducted by Oubari et al. daratumumab-based regimens were associated with better clinical outcomes compared to others treatments. However, all available data on daratumumab in stage IIIb patients derive from uncontrolled studies or lacked a matched or stratified control group. We designed the present retrospective case-control study to assess the efficacy of daratumumab-based therapies versus CyBorD regimens as upfront treatment for newly diagnosed AL amyloidosis with IIIb cardiac stage. Methods:the whole study population comprises 62 matched newly diagnosed patients with IIIb stage AL amyloidosis evaluated in our center between 2012 and 2022. The daratumumab cohort is composed of all the 31 consecutive subjects treated with daratumumab-based regimens between 2021 and 2022. Thirteen patients (41%) received daratumumab in combination with bortezomib [11 (35%) associated with melphalan and dexamethasone; 2 (6%) Dara-CyBorD], 11 (35%) with lenalidomide and 7 (22%) were treated with daratumumab monotherapy. They were matched with 31 controls selected from a total of 71 subjects treated with CyBorD. Patients and controls were matched for age, estimated glomerular filtration rate, N-terminal pro-brain natriuretic peptide, free light chain and bone marrow plasma cell. Hematologic response was assessed according to the International Society of Amyloidosis criteria. The analysis of response was by intent-to-treat: patients who died before response evalutation were considered non responders . PFS is defined as the time from diagnosis to any one of the following events, whichever comes first: death, starting a second line of therapy, organ or hematologic progression as per consensus guidelines. Results:Patients' characteristics are listed in Table 1. Median follow-up of living patients was 20.5 months (95% CI: 14.3 - 55.9 months). Median OS was 4.6 months (95% CI: 3 - 6.3 months), and patients of the daratumumab cohort had a significantly prolonged OS (6.7 vs 4 months; p=0.032, Fig. 1). No differences in early mortality rate, within 3 months from diagnosis, were observed between the two cohorts (32% vs 35%, p=0.796). At three months, the overall HR rate to daratumumab was 50% [complete response (CR) 12%, VGPR 29%, partial response (PR) 9%] as compared with 21% (CR 6%, VGPR 9%, PR 6%) of the control group, p=0.021. A higher proportion of ≥VGPR was observed in the daratumumab cohort (41% vs 16%; p=0.029). Cardiac response rate was significantly more frequent in patients treated with daratumumab [8 (25%), 3 cardiac VGPR and 5 cardiac PR] compared to controls [1 (3%) cardiac PR], p=0.014. A significantly prolonged PFS was observed in patients receiving daratumumab compared to CyBorD (5 vs 2.4 months; p=0.017). Conclusions: This matched case-control study shows that even in stage IIIb patients the addition of daratumumab to CyBorD results in higher rates of deep hematologic response. This is associated with higher cardiac response rates and prolonged OS and PFS. Although the outcome of stage IIIb patients remains dismal, Dara-CyBorD was able to improve response rate and survival in these severely compromised subjects. Taken together these observations encourage the use of daratumumab combinations also in stage IIIb patients with AL amyloidosis.

Molecular Determinants of Response to Mosunetuzumab Plus CHOP in Patients with Previously Untreated (1L) Diffuse Large B Cell Lymphoma (DLBCL)

Co-lead authors: Habib Hamidi and Patrick Kimes Background: Standard induction therapy cures ~60% of patients (pts) with DLBCL; however, most remaining non-responders die from lymphoma, highlighting a need for improved first-line treatments. Biomarkers that can reliably assess the efficacy of new treatments are lacking in clinical practice. Mosunetuzumab (Mosun) is a CD20xCD3 T cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. In a Phase Ib/II trial (NCT03677141), Mosun combined with CHOP chemotherapy (M-CHOP) induced high response rates in pts with 1L DLBCL (ORR 87.5%, CR 85%; Phillips et al. ASH 2020). Here, we sought to identify biomarkers associated with M-CHOP response. Methods: Pts with 1L DLBCL receiving M-CHOP (six cycles) in NCT03677141 and with available biomarker data were included. Bulk RNASeq data from pre-treatment tumor biopsies were analyzed using gene set variation for tumor intrinsic pathways and xCell cell-type enrichment for immune and stromal cell types. High or low expression of each gene signature was determined by median cut-off. Cox regression examined associations between gene signatures and PFS. To assess specificity to M-CHOP, gene signatures were examined in pre-treatment biopsies from pts treated with rituximab + CHOP chemotherapy (R-CHOP) in GOYA (NCT01287741; Sehn et al. J Hematol Oncol 2020). Peripheral blood biomarkers were evaluated by whole blood flow cytometry and plasma cytokines by ELISA. Circulating tumor (ct) DNA levels were measured at baseline and on treatment using the AVENIO NHL CAPP-Seq assay (Stokowski et al. ASH 2022). Results: In M-CHOP-treated pts (n=33), gene expression analysis revealed two types of signatures associated with PFS: tumor immune microenvironment signature (TIMS) and tumor intrinsic proliferation signature (TIPS; Figure). High TIMS expression (e.g., CD4+ T cells) was associated with significantly longer PFS than low expression. Conversely, pts with high TIPS expression (e.g., MYC targets, DNA repair) had shorter PFS than those with low expression. These biological associations were specific to M-CHOP and were not observed in R-CHOP-treated pts. Consistent with the tumor-gene expression analysis, immune profiling of peripheral blood suggested that in pts treated with M-CHOP, a higher T cell baseline count was associated with a trend for prolonged PFS compared with pts with a lower baseline count. A higher count of circulating suppressive T cells was also associated with shortened PFS. Early on-treatment pharmacodynamic (PD) changes were observed following the first Mosun dose, including: induction of TNFα and IL-6, transient margination of CD4+ and CD8+ T cells, and activation of CD4+ and CD8+ T cells. The magnitude of the PD effects were similar to observations with Mosun monotherapy in pts with relapsed or refractory DLBCL (Hernandez et al. ASH 2019), confirming that Mosun maintains its immune activation effect when combined with CHOP in pts with 1L DLBCL. High baseline ctDNA levels were associated with high IPI score (n=32, Wilcoxon rank-sum p=0.007), ABC/non-GCB DLBCL subtype (n=30, p=0.033), and high lactate dehydrogenase (n=32, p=0.004). Pts with baseline ctDNA levels &amp;lt; median had a modest trend for improved PFS compared with pts &amp;gt; median (unadjusted hazard ratio [HR]=0.57 [95% CI 0.16, 1.75]; IPI-adjusted HR=0.72 [95% CI 0.16, 3.20]). The proportion of pts with undetectable ctDNA increased with each M-CHOP cycle (C) (C2 day [D]1, 25% [8/32]; C3D1, 69% [20/29]; C5D1, 88% [22/25]). Pts with undetectable ctDNA at any on-treatment time point (C2D1, C3D1, C5D1) had superior PFS compared with pts with detectable ctDNA (unadjusted HR=0.12 [95% CI 0.03, 0.52]; IPI adjusted HR=0.14 [95% CI 0.03, 0.61]). Conclusions: Consistent with the Mosun mode of action, pts with high expression of TIMS and those with high levels of circulating T cells had improved PFS versus pts with low expression. In contrast, there was no association between immune cell signatures and PFS in pts treated with R-CHOP, suggesting that the different mode of action of rituximab versus Mosun may influence this. Future studies are warranted to confirm the potential clinical utility of immune cell signatures as biomarkers associated with CD20xCD3 bispecifics' activity.