Lower Objective Response Rate Research Articles

Efficacy and safety of durvalumab plus tremelimumab for unresectable hepatocellular carcinoma in Thailand: A real-world multicenter observational study.

539 Background: Durvalumab plus tremelimumab (Durva/Treme) andatezolizumab plus bevacizumab are preferable first-line therapy for unresectable hepatocellular carcinoma (uHCC). This study aimed to evaluate the efficacy and safety of Durva/Treme in real world setting. Methods: Fifty patients with uHCC who enrolled in the expanded access program (EAP) for Durva/Treme as the first-line treatment from 12 centers in Thailand were included. Analysis was assessed for objective response rate (ORR), survival, and adverse events. We also compared data with the HIMALAYA study. Results: Median follow-up time was 9.8 months. There were 24 patients alive and 26 patients deceased. The median age was 62 years. Majority of the patients were male (80%). Hepatitis B, C and non-viral cause were identified in 44%, 30%, and 26%, respectively. Ninety-two percent of patients had Child-Pugh A, while 8% had Child-Pugh B(7). Macrovascular invasion was found in 24% of cases. The full data on efficacy and safety were summarized in table below. Conclusions: To date,this is the largest real-world data of Durva/Treme in the first-line treatment of uHCC. Our study demonstrated that Durva/Treme was effective but had lower ORR and higher liver toxicities than what reported in the HIMALAYA study. EAP (N=50) HIMALAYA (N=393) Response by RECIST1.1, n (%) CR PR SD PD Not evaluable 2(4)4(8)24(48)18(36)2(4) 12(3.1)67(17)157(39.9)157(39.9) - ORR (%) 12 20.1 DCR (%) 60 60.1 mPFS (range), mo 5.36(0.2-12.5) 3.78(3.7-5.3) mOS (range), mo NA 16.4 (14.2-19.6) Adverse events, n (%) A ny grade G rade > 3 A ny grade G rade > 3 Any AE Diarrhea Rash AST elevation ALT elevation Increase bilirubin Hypothyroidism Myocarditis Myositis 37(74) 3(6) 12(24) 23(46) 21(42) 8(16) 7(14) 1(2) 1(2) 12(24) 1(2) 0 6(12) 7(14) 4(8) 01(2) 1(2) 378(97.4)103(26.5) 87(22.4) 48(12.4) 36(9.3) 20(5.2) 47(12.1) -- 196(50.5)17(4.4) 6(1.5) 20(5.2) 10(2.6) 3(0.8) 02(0.5) 3(0.8)

Baseline (derived) neutrophil-lymphocyte ratio associated with survival in gastroesophageal junction or gastric cancer treated with ICIs

ObjectiveWe carried out the meta-analysis to determine the predictive value of baseline neutrophil to lymphocyte ratio (NLR) and derived neutrophil to lymphocyte ratio (dNLR) levels in patients with gastroesophageal junction or gastric cancer (GJGC) who underwent immune checkpoint inhibitor (ICI) treatment.MethodsEligible articles were obtained through PubMed, the Cochrane Library, EMBASE, and Google Scholar, until April 15, 2023. The clinical outcomes evaluated in this study encompassed overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR)ResultsA total of 24 articles with 2221 patients were included in this meta-analysis. The pooled results demonstrated that patients with high NLR levels had significantly poorer OS (HR: 1.860, 95% CI: 1.564-2.213, p < 0.001) and PFS (HR: 1.678, 95% CI: 1.354-2.079, p < 0.001), and lower ORR (OR: 0.754, 95% CI: 0.621-0.915, p = 0.004) and DCR (OR: 0.391, 95% CI: 0.262-0.582, p < 0.001). Besides, we also found that high dNLR levels were significantly associated with shorter OS (HR: 2.117, 95% CI: 1.590-2.820, p < 0.001) and PFS (HR: 1.803, 95% CI: 1.415-2.297, p < 0.001).ConclusionLow baseline (Derived) NLR has the potential to predict the good efficacy of ICIs and survival outcomes in patients with GJGC. (Derived) NLR could be useful in determining the optimal treatment strategies for these patients.

Phase II randomized study of dostarlimab alone or with bevacizumab versus non-platinum chemotherapy in recurrent gynecological clear cell carcinoma (DOVE/APGOT-OV7/ENGOT-ov80).

Recurrent gynecological clear cell carcinoma (rGCCC) has a low objective response rate (ORR) to chemotherapy. Previous preclinical and clinical data suggest a potential synergy between immune checkpoint inhibitors and bevacizumab in rGCCC. Dostarlimab, a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1), combined with the anti-angiogenic bevacizumab, presents a novel therapeutic approach. This study will investigate the efficacy of dostarlimab +/- bevacizumab in rGCCC. DOVE is a global, multicenter, international, open-label, randomized phase 2 study of dostarlimab +/- bevacizumab with standard chemotherapy in rGCCC. We will enroll 198 patients with rGCCC and assign them to one of three groups in a 1:1:1 ratio: arm A (dostarlimab monotherapy), B (dostarlimab + bevacizumab), and C (investigator's choice of chemotherapy [weekly paclitaxel, pegylated liposomal doxorubicin, doxorubicin, or gemcitabine]). Patients with disease progression in arm A or C will be allowed to cross over to arm B. Stratification factors include prior bevacizumab use, prior lines of therapy (1 vs. >1), and primary site (ovarian vs. non-ovarian). Key inclusion criteria are histologically proven recurrent or persistent clear cell carcinoma of the ovary, endometrium, cervix, vagina, or vulva; up to five prior lines of therapy; disease progression within 12 months after platinum-based chemotherapy; and measurable disease. Key exclusion criteria are prior treatment with an anti-PD-1, anti-programmed death-ligand 1, or anti-programmed death-ligand 2 agent. The primary endpoint is progression-free survival determined by investigators. Secondary endpoints are ORR, disease control rate, clinical benefit rate, progression-free survival 2, overall survival, and toxicity. Exploratory objectives include immune biomarkers. ClinicalTrials.gov Identifier: NCT06023862.

Evaluation of First-Line Endocrine Therapy for HR+/HER2- Metastatic Breast Cancer: Efficacy, Tolerance and Prescribing Practices. A Prospective and Observational study

Introduction: Endocrine therapy is commonly employed for MBC (Metastatic Breast Cancer) patients due to its efficacy in modulating hormone receptors and its generally favorable side effect profile. This study aims to evaluate the effectiveness and tolerability of first-line endocrine therapy in HR+(Hormone receptor)/HER2-( Human epithelial growth factor receptor) metastatic breast cancer patients, to investigate differences among various endocrine therapies, and examine changes in prescribing practices influenced by evolving clinical guidelines. Methods: We conducted a multicenter, observational, prospective study involving 100 women aged over 18 years with de novo HR+, HER2- MBC. Data were collected between 2020 and 2023. The primary objective was to assess the ORR (Objective Response Rate) at 6 months under first-line endocrine therapy. Secondary objectives included evaluating the influence of types of endocrine therapy on the ORR, the evolution of the response at 2 years, clinical efficacy, and tolerability. Results: At 6 months, the ORR was 38%, with 3 complete responses (CR). No significant difference in ORR was observed between aromatase inhibitors and Faslodex (p=0.439). The clinical benefit rate was 80%. 84% of patients reporting mild to moderate adverse effects. Discussion: A first-line endocrine therapy for HR+/HER2- MBC offers substantial clinical benefit rate with an 80%, and manageable side effects. Despite a lower ORR, the therapy effectively controls disease progression and preserves quality of life. The results support the continued use of endocrine therapy while emphasizing the importance of managing adverse effects. Initial hesitations among practitioners were due to concerns about its efficacy. Conclusion: Endocrine therapy provides significant clinical benefits and maintains patient quality of life.

Efficacy and safety of first-line immunotherapy-containing regimens compared with chemotherapy for advanced or metastatic urothelial carcinoma: a network meta-analysis of randomized controlled trials.

To assess the efficacy and safety of first-line immunotherapy-containing regimens compared with chemotherapy for advanced or metastatic urothelial carcinoma (UC). A comprehensive search was performed in four databases (Pubmed, Embase, Web of Science, and the Cochrane Library) to identify randomized controlled trials (RCTs) assessing the efficacy of first-line immunotherapy-containing regimens for advanced or metastatic UC. The search encompassed the time span from the inception of the databases to April 23, 2024. A network meta-analysis (NMA) was conducted to assess the rates of progression-free survival (PFS), overall survival (OS), complete response (CR), objective response rate (ORR), and grade ≥ 3 adverse events (AEs). We conducted a comprehensive analysis of five randomized controlled trials (RCTs) that included a total of 4749 patients. Nine different treatment regimens included in the study were ranked statistically and intuitively using NMA. The top five effective regimens, ranked by OS, were EV + Pembro (1.000), Nivol + Chemo (0.724), Atezo + Chemo (0.610), Durva + Treme (0.558), and Pembro + Chemo (0.530). The top five effective regimens, ranked by PFS, were EV + Pembro (0.999), Nivol + Chemo (0.640), Pembro + Chemo (0.484), Atezo + Chemo (0.373) and Chemo (0.003). The top five effective regimens, ranked by CR, were EV + Pembro (0.969), Nivol + Chemo (0.803), Atezo + Chemo (0.772), Pembro + Chemo (0.472), Durva + Treme (0.449). The top five effective regimens, ranked by ORR, were EV + Pembro (0.995), Nivol + Chemo (0.852), Pembro + Chemo (0.761), Atezo + Chemo (0.623), and Chemo (0.519). Our results indicated that EV + Pembro as first-line therapy resulted in considerably improved efficacy and safety compared to chemotherapy for advanced or metastatic UC. ICI plus chemotherapy as first-line treatment resulted in a longer PFS, a greater ORR, but no longer OS compared to chemotherapy alone, as well as higher toxicity. ICI alone as first-line therapy provided similar OS and lower toxicity compared to chemotherapy, but lower ORR. https://www.crd.york.ac.uk/prospero, identifier CRD42024538546.

Lung adenocarcinomas with mucinous histology: clinical, genomic, and immune microenvironment characterization and outcomes to immunotherapy-based treatments and KRASG12C inhibitors

Approximately 10% of lung adenocarcinomas (LUADs) have mucinous histology (LUADMuc), which is associated with a light/absent smoking history and a high prevalence of KRAS mutations. We sought to characterize LUADMuc by comparing it with LUAD without mucinous histology (LUADnon-muc) and determine the relative benefit of current treatments. Patients with LUAD from five institutions and The Cancer Genome Atlas Pan-Cancer Atlas classified as LUADMuc or LUADnon-muc were included. Clinicopathologic, genomic, immunophenotypic, transcriptional features, and treatment outcomes were compared between LUADMuc and LUADnon-muc. Of 4082 patients with LUAD, 9.9% had LUADMuc. Compared with LUADnon-muc, patients with LUADMuc had a lighter smoking history (median 15 versus 20 pack-years; P= 0.008), lower programmed death-ligand 1 (PD-L1) tumor proportion score (median 0% versus 5%, P < 0.0001), and lower tumor mutation burden (median 6.8 versus 8.5 mutations/megabase, P < 0.0001). Mutations in KRAS, NKX2-1 [thyroid transcription factor 1 (TTF-1)], STK11, SMARCA4, GNAS, and ALK rearrangements were enriched in LUADMuc, while TP53, EGFR, BRAF, and MET mutations were enriched in LUADnon-muc. At stage IV diagnosis, LUADMuc was more likely to have contralateral lung metastasis (55.2% versus 36.9%, P < 0.0001) and less likely to have brain metastases (23.3% versus 41.9%, P < 0.0001). Compared with LUADnon-muc, LUADMuc cases showed lower intratumor CD8+, PD-1+, CD8+PD-1+, and FOXP3+ cells. Among metastatic cases receiving immune checkpoint inhibitors, compared with LUADnon-muc (n= 1511), LUADMuc (n= 112) had a lower objective response rate (ORR 8.4% versus 25.9%, P < 0.0001), and shorter median progression-free survival (mPFS 2.6 versus 3.9 months, P < 0.0001) and overall survival (mOS 9.9 versus 17.2 months, P < 0.0001). Similarly, patients with LUADMuc had worse outcomes to chemoimmunotherapy. LUADMuc (n= 18) and LUADnon-muc (n= 150) had similar ORR (16.7% versus 34.9%, P= 0.12) and mPFS (4.6 versus 5.6 months, P= 0.17) to treatment with KRASG12C inhibitors, but LUADMuc had shorter mOS (6.8 versus 10.8 months, P= 0.018). LUADMuc represents a distinct LUAD subpopulation with unique clinicopathologic, genomic, immunophenotypic, and transcriptional features, achieving worse outcomes to standard immunotherapy-based treatments.

Antiangiogenic therapy combined with immune checkpoint blockade in urothelial cancer: Systematic review and meta-analysis

Background Antiangiogenic therapy had been tested in urothelial cancer (UC) without reaching the clinic. Objective We provide a systematic review and meta-analysis of trials to assess efficacy of immune checkpoint inhibitors (ICI) combined with antiangiogenic agents in UC. Methods Following PRISMA guidelines, we searched for trials with at least one arm of patients with UC treated with ICI plus antiangiogenics. Data were analyzed with the “meta” package from R using a one-staged frequentist meta-analysis. Results After screening 13,708 titles and abstracts, 9 studies were selected for analysis with 14 identified cohorts comprising 621 patients: 448 were ICI-naïve (ICI-N) and 173 were ICI-exposed (ICI-E). The estimated objective response rate (ORR) in all patients was 27% (21–35). In the ICI-N group, ORR was 34% (28–41). Conversely, the ICI-E group had a lower ORR of 16% (9–28). This difference was mainly driven by a higher partial response rate of 27% (23–31) in ICI-N group compared to 13% (8–20) in the ICI-E group. Disease control rate was 72% (66–77) ICI-N group vs. 71% (64–78) in ICI-E group. Median overall survival ranged from 6.4 to 24.9 months in the ICI-N group, and 8.2 to 10.4 months in ICI-E group. Median progression free survival ranged from 1.9 to 10.1 months and from 3 to 3.9 months in both groups, respectively. Conclusion ORR with ICI plus antiangiogenics was lower after prior ICI exposure, with substantial variability estimates among included trials, either due to differences among antiangiogenic agents used or trial-related factors. Future exploration of ICI combined with antiangiogenics in UC, especially in ICI-refractory setting, will benefit from better patient selection.

Efficacy of the combination of lenvatinib with pembrolizumab in patients with advanced renal cell carcinoma

Objective: to re-evaluate the efficacy and safety of lenvatinib with pembrolizumab in unselected Russian renal cell carcinoma (RCC) patients, included in the phase IV study, in a median follow-up extended to 17.1 months. The primary end point was progression-free survival (PFS), secondary end points were overall survival (OS), objective response rate (ORR) and duration of response (DOR), disease control rate (DCR) and its duration, as well as safety.Materials and methods. The study included medical data of 165 patients with verified advanced RCC who received lenvatinib with pembrolizumab in 36 centers of the Russian Federation from 05.02.2018 to 25.07.2024. The median age was 60 (20–76) years, the male to female ratio was 2.3:1. The majority of patients had Karnofsky performance status ³80 % (74.6 %), clear cell RCC (93.3 %) without sarcomatoid differentiation (93.3 %), metachronous metastases (50.9 %) localized in &gt;1 organ (75.2 %), were nephrectomized (63.0 %) and did not receive antitumor therapy (91.0 %). At the time of lenvatinib with pembrolizumab therapy start 40 patients (24.2 %) were classified into International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable prognostic group, 92 (55.8 %) in the intermediate prognostic group, and 33 (20.0 %) in the poor prognostic group. The median follow-up was 17.1 (1.5–72.9) months.Results. The median PFS achieved 24.0 (18.7–29.3) months, 17-month PFS 60.5 %. The median OS was 48.9 (18.5– 79.2) months, 17-month OS – 76.1 %. Objective response was registered in 46.0 % of patients including 2.4 % complete responders; the DCR was 92.1 %. The median DOR was 16.6 (2.1–72.9) months, duration of disease control –14.3 (2.1–72.9) months. Confirmed dynamics of change in the sum of tumor foci diameters was recorded in 152 patients, while the median change was –25 % (from –100 % to +29 %). Any decrease in the sum of tumor foci diameters occurred in 69.1 % of cases. The incidence of any adverse events (AE) was 78.2 %, severe AE – 24.2 %, and serious AE – 9.7 %. Immune-mediated AEs developed in 17.0 % of cases and AE grades 3–4 in 6.7 % of cases. Mortality from AEs was 1.2 %.Conclusion. Compared with the registration study, in real-world clinical practice in patients with advanced RCC the lenvatinib with pembrolizumab provides a lower ORR with comparable PFS and OS rates and demonstrates a satisfactory safety profile.

Chronotherapy in head and neck cancer: A systematic review and meta-analysis.

Optimizing the timing of radiotherapy and chemotherapy tailored to the body's biological clock (i.e., chronotherapy) might improve treatment efficacy and reduce side effects. This systematic review evaluated the effect of chrono-radiotherapy and chrono-chemotherapy on treatment efficacy, toxicity and adverse events in head and neck cancer (HNC) patients from prospective and retrospective studies published between the date of database inception until March 2024. The primary outcome measures for chrono-radiotherapy were treatment efficacy and incidence of grade ≥3 oral mucositis, and the main outcome measures for chrono-chemotherapy were objective response rate (ORR) and overall toxicity and adverse events. Of 7349 records identified, 22 studies with 3366 patients were included (chrono-radiotherapy = 9 and chrono-chemotherapy = 13). HNC patients who underwent chrono-radiotherapy had 31% less risk of developing severe oral mucositis (grade ≥3) compared to evening radiotherapy (risk ratio: 0.69, 95% CI: 0.53-0.90, p < 0.05). Further, HNC patients who underwent chrono-chemotherapy using platinum-based and antimetabolite agents had 73% less risk of lower ORR compared to nontime-stipulated chemotherapy (risk ratio: 0.27, 95% CI: 0.09-0.84, p < 0.05). In addition, HNC patients who underwent chrono-chemotherapy had 41% less risk of lower overall toxicity and adverse events in comparison to nontime-stipulated chemotherapy (risk ratio: 0.59, 95% CI: 0.47-0.72, p < 0.05). In conclusion, chrono-chemotherapy studies showed evidence of improved treatment efficacy, while in chrono-radiotherapy it was maintained. Chrono-radiotherapy and chrono-chemotherapy studies provide evidence of reduced toxicity and adverse events. However, optimized circadian-based multicentric clinical studies are needed to support chrono-radiotherapy and chrono-chemotherapy in managing HNC.

The pharmacogenomic and immune landscape of snoRNAs in human cancers

Small nucleolar RNAs (snoRNAs) are a class of non-coding RNAs primarily known for their role in the chemical modification of other RNAs. Recent studies suggested that snoRNAs may play a broader role in anti-cancer treatments such as targeted therapies and immunotherapies. Despite these insights, the comprehensive landscape of snoRNA associations with drug response and immunotherapy outcomes remains unexplored. In this study, we identified 79,448 and 75,185 associations between snoRNAs and drug response using data from VAEN and CancerRxTissue, respectively. Additionally, we discovered 29,199 associations between snoRNAs and immune checkpoint genes and 47,194 associations between snoRNAs and immune cell infiltrations. Sixteen snoRNAs were significantly correlated with immunotherapy objective response rate (ORR), and 92 snoRNAs showed significantly differential expression between cancers with high and low ORR. Furthermore, we identified 17 snoRNAs with significantly differential expression between cancer types with high and low immune-related adverse event (irAE) reporting odds ratio (ROR). Several snoRNAs, such as SNORD92, and SNORD83B, may represent promising biomarkers or therapeutic targets that needs further investigation. To facilitate further research, we developed a user-friendly portal, Pharmacogenomic and Immune Landscape of SnoRNA (PISNO, https://hanlaboratory.com/PISNO/), enabling researchers to visualize, browse, and download multi-dimensional data. This study highlights the potential of snoRNAs as biomarkers or therapeutic targets, paving the way for more effective and personalized anti-cancer treatments.

Co-delivery of SN38 and MEF2D-siRNA via tLyp-1-modified liposomes reverses PD-L1 expression induced by STING activation in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) exhibits an immunosuppressive tumor microenvironment, leading to a low objective response rate when immune checkpoint inhibitors (ICIs) are utilized. The cGAS-STING pathway demonstrates a powerful immune stimulatory effect, nevertheless, activation of this pathway triggers an upregulation of PD-L1, which inhibits the anti-tumor function of immune cells. The present study discovered that knockdown of MEF2D by a siRNA in H22 cells decreases the expression of PD-L1. Subsequently, tLyp-1-modified liposomes were developed for the delivery of SN38 and MEF2D-siRNA. The outcomes indicated that the modification of tLyp-1 could enhance the uptake of liposomes by tumor cells. tLip/siMEF2D/SN38 liposomes can effectively knockdown the expression of MEF2D in HCC cells and reduce the expression of PD-L1 in vitro and in vivo, thereby enhancing proliferation inhibition and apoptosis induction, and effectively suppressing the growth of tumors. SN38 treatment elevated the expression of p-TBK1 and p-IRF3 in tumor tissue, signifying the activation of the cGAS-STING pathway and facilitating the maturation of dendritic cells in vitro and in vivo. At the same time, the co-delivery of MEF2D-siRNA reduced the expression of PD-L1, thereby decreasing the quantity of M2 macrophages and myeloid-derived suppressor cells (MDSCs) in tumors, increasing the number of CD4+ T cells within the tumor, and strengthening the anti-tumor immune efficacy. In conclusion, our results suggest that tLyP-1 modified, SN38- and MEF2D siRNA-loaded liposomes have the potential for the treatment of HCC and optimize the immunotherapy of HCC via STING activation.

Prognostic significance of bone metastasis and clinical value of bone radiotherapy in metastatic non-small cell lung cancer receiving PD-1/PD-L1 inhibitors: results from a multicenter, prospective, observational study.

Bone metastasis (BoM) is a prevalent occurrence in patients with non-small cell lung cancer (NSCLC), significantly impacting prognosis and diminishing both survival rates and patients' quality of life. More and more studies have demonstrated that immunotherapy can improve the prognosis of NSCLC patients with bone metastases. Previous investigations pertaining to BoM in NSCLC have generally suffered from small sample sizes, absence of propensity score matching (PSM) to equate baseline characteristics, and an omission of the examination of patterns of treatment failure. This study aims to evaluate the prognostic significance of BoM and potential clinical value of bone radiation in metastatic NSCLC patients receiving immunotherapy. Metastatic NSCLC patients receiving programmed cell death protein 1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors from three academic centers were enrolled in a prospective, observational trial (https://clinicaltrials.gov/study/NCT04766515) and those with measurable disease and adequate follow-up were retrospectively reviewed. Propensity score matched (PSM) patients with and without BoM were included in this study. Treatment efficacy, pattern of failure and clinical value of bone radiotherapy were extensively evaluated. A total of 544 out of 1,451 immunotherapy-treated NSCLC patients were included after PSM, including 272 with BoM and 272 without. Patients with baseline BoM had a median progression-free survival (PFS) of 7.8 months [95% confidence interval (CI): 7.0-8.7], lower than those without it (9.5 months; 95% CI: 8.9-10.0) (P<0.001). Patients with baseline BoM had a median overall survival (OS) of 14.5 months (95% CI: 12.6-16.4), lower than those without 27.6 months (95% CI: 25.1-30.1) (P<0.001). Patients with BoM also had lower objective response rate than those without it (11.1% vs. 15.8%, P<0.001). Initial disease progression in the bone was more common in those with BoM (56.5%) compared to those without it (31.7%) (P<0.001). Meanwhile, among patients with BoM, no significant difference of PFS was found between those receiving bone radiation or not, possibly due to a dominant use of palliative radiotherapy. Baseline BoM correlated with worse prognosis and palliative bone radiation did not improve PFS in metastatic NSCLC patients receiving PD-1/PD-L1 inhibitors.

Cabozantinib plus ipilimumab/nivolumab in patients with previously treated advanced differentiated thyroid cancer.

This investigator-initiated phase II trial aimed to evaluate the efficacy of cabozantinib in combination with nivolumab and ipilimumab (CaboNivoIpi) in previously treated patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) (NCT03914300). Eligible patients with RAI-refractory DTC who progressed on 1 prior line of VEGFR-targeted therapy received a 2-week run-in of cabozantinib monotherapy followed by CaboNivoIpi for 4 cycles (cycle length = 6 weeks), followed by cabozantinib plus nivolumab (cycle length = 4 weeks) until disease progression. The primary endpoint was objective response rate (ORR) within the first 6 months of treatment. A Simon optimal 2-stage design allowed for an interim analysis after accrual of 10 evaluable patients. At least 5 responses were needed to proceed to stage 2. Among 11 patients enrolled, the median age was 69 years. Prior VEGFR-targeted therapies included lenvatinib, pazopanib, and sorafenib plus everolimus. Median follow-up was 7.9 months. Among 10 evaluable patients, ORR within the first 6 months of treatment was 10% (1 partial response). Median progression-free survival was 9 months [95% CI: 3.0, not reached] and median overall survival was 19.2 months [(95% CI: 4.6, not reached]. Grade 3/4 treatment-related adverse events (AEs) were noted in 55% (6/11) and grade 5 AEs in 18% (2/11) of patients. The most common treatment-related AE was hypertension. The study did not reach its prespecified efficacy threshold. CaboNivoIpi had low ORRs and a high rate of grade ≥3 treatment-related AEs. NCT03914300.

Immunotherapy and PD-L1 Tumor Expression in Moroccan Non-Small Cell Lung Cancer Patients with Various Metastasis.

The question of whether tumor expression of PD-L1 and the presence of distant metastasis could influence the efficacy of immunotherapy represents a major challenge and needs to be further elucidated. The aim of this study is to evaluate the predictive significance of tumor expression of PD-L1 as well as the number and site of metastasis in non-small cell lung cancer (NSCLC) among Moroccan patients treated with immunotherapy. Between January 2019 and February 2023, we recruited Moroccan patients with metastatic NSCLC. All were treated with immunotherapy, either as monotherapy or in combination with chemotherapy. Immunohistochemistry was used to assess PD-L1 (clone 22C3) and ALK (clone D5F3) status. EGFR status was established by qPCR. Tumor PD-L1 expression was classified into 2 levels: TPS <1% (negative expression) and TPS ≥1% (positive expression). Statistical analysis was performed using SPSS Statistics V.21 software. The median age of patients (N=40) was 67 years (39- 92 years) and the sex ratio was 9. Disease dissemination revealed that 22.5% (N=9) of patients had a metastatic burden ≥ 3 (MB≥3). As for the sites of metastasis, the results showed that 20% (N=8), 10% (N=4), 42.5% (N=17), 22.5% (N=9), 27.5% (N=11), 45% (N=18) and 27.5% (N=11) of patients had developed lymph node, liver, bone, brain, pleural, contralateral lung and adrenal metastasis respectively. Positive PD-L1 expression was significantly associated with shorter overall survival (OS = 17.19 vs. 28.85 months, p=0.01). High metastatic burden (MB ≥ 3) was associated with lower objective response rate (ORR), shorter progression-free survival (PFS), and reduced OS, respectively (ORR = 0 vs. 58.06%, p=0.002; PFS = 10.23 vs. 25.27 months, p=0.001; and OS = 11.60 vs. 27.91 months, p=0.003). Only the presence of osseous metastasis was significantly associated with lower ORR, shorter PFS, and OS compared to other metastatic locations (ORR = 5.88 vs. 73.9%, p=0.000; PFS = 10.72 vs. 31.33 months, p=0.000; and OS = 11.39 vs. 36.17 months, p=0.000). Finally, the presence of hepatic metastasis was significantly associated with shorter PFS (10.75 months) compared to those without hepatic metastasis (22.53 months) (p=0.046). Finally, the results of the multivariate analysis revealed that the presence of bone metastasis was strongly correlated with a significant decrease in progression-free survival (p=0.001) as well as overall survival (p=0.002). Our results suggest that tumor expression of PD-L1 and metastatic burden should play a significant role in predicting the response to immunotherapy. Furthermore, it is important to note that the presence of osseous and hepatic metastasis could negatively influence the clinical outcomes of immunotherapy.

Evaluating Safety and Clinical Activity of Front-line Treatment with Cadonilimab plus Chemotherapy in Advanced/Metastatic Nonsmall Cell Lung Cancer Harboring STK11 Genetic Aberration: A Protocol of Phase II Study

Cadonilimab is a first-in-class bispecific PD-1/CTLA-4 antibody. Serine/threonine kinase (STK11) mutation was shown to be related to low PD-L1 expression and objective response rate (ORR) in nonsmall cell lung cancer (NSCLC), resulting in poor progression-free survival (PFS) and overall survival (OS). Herein, we hypothesized that combining cadonilimab with chemotherapy could enhance antitumor immunity and extend survival in these patients. Consequently, we designed this study to explore the clinical activity and safety of cadonilimab combined with chemotherapy in patients with advanced/metastatic NSCLC harboring STK11 alteration. This single-center, open-label, single-arm phase II trial is conducted at the first affiliated hospital of Guangzhou Medical University. Treatment-naïve advanced/metastatic NSCLC patients harboring STK11 mutation will be enrolled in this study. Eligible patients will receive either cadonilimab (10mg/kg on Day 1) plus pemetrexed (500 mg/m2) and carboplatin (AUC = 5) for nonsquamous NSCLC or abraxane (100 mg/m2) and carboplatin (AUC = 5) for squamous NSCLC for 4 cycles, followed by maintenance therapy (cadonilimab plus pemetrexed or abraxane). The treatment will be discontinued when disease progression, intolerability to cadonilimab, and/or chemotherapy occurs. Measurable lesions were assessed according to the Response Evaluation Criteria in Solid Tumors (1.1). The main endpoint is ORR and safety. Subordinate endpoints include PFS, disease control rate, and duration of response. The study commenced enrolment in September 2023, with preliminary findings regarding the primary endpoint anticipated by January 2025.

The Current State of Systemic Therapy of Metastatic Uveal Melanoma.

Uveal melanoma (UM) is genetically a distinct tumor compared to cutaneous melanoma (CM), and due to its low mutational burden, it is far less perceptible to the immune system. Thus, treatments that have revolutionized the treatment of CM remain widely inefficient in metastatic UM or only demonstrate effectiveness in a small subpopulation of patients. To this end, the therapeutic benefit of immune checkpoint blockade is very limited and may come at the expense of severe immune-related adverse events that could potentially affect all organ systems. Notably, tebentafusp, an entirely novel class of anti-cancer drugs, has received official authorization for the treatment of metastatic UM. It is the first agent that demonstrated a survival advantage in a randomized controlled trial of metastatic UM patients. Despite the survival benefit and approval, the restriction of tebentafusp to HLA-A*02:01-positive patients and the low objective response rate indicate the persistent need for additional therapies. Thus, liver-directed therapies are commonly used for tumor control of hepatic metastases and represent a central pillar of the daily management of liver-dominant disease. Further, promising data from targeted therapies independent of MEK-inhibitors, such as the combination of darovasertib and crizotinib, raise hope for additional options in metastatic UM in the future. This narrative review provides a timely and comprehensive overview of the current treatment landscape for metastatic UM.

Temozolomide and nivolumab in patients with refractory metastatic melanoma (MM).

e21521 Background: Immune checkpoint inhibitors (ICI) are the standard treatment for patients (pts) with MM. However, only a subset of pts respond to ICIs. Temozolomide (TEM) is used in refractory settings but with low objective response rates and no clear overall survival benefit. The efficacy of combined ICI + TEM is not well described. Methods: This was a single center, retrospective study of pts with MM who received treatment with nivolumab (NIVO) and TEM or TEM alone between 11/6/2013 and 11/6/2023. Demographic information, disease characteristics, LDH, treatment, toxicity, objective response, and outcomes were collected. Results: 34 patients were included. 16 were treated with NIVO + TEM and 18 were treated with TEM alone. In the NIVO + TEM group, 81% were male (n = 13) with median age of 59.5 years (range 20-79), and in the TEM group, 56% were male with median age 61 (range 35-81). For NIVO + TEM, 31% had partial response (PR; n = 5), 6% had stable disease (SD, n = 1), and 63% had progressive disease (PD; n = 10). For TEM, 11% had PR (n = 2), 22% had SD (n = 4), and 67% had PD (n = 12) (p = 0.37). For NIVO + TEM, 2 PRs were durable, ongoing at 442 and 741 days; 3 PRs were transient (85-179 days); 1 pt had durable SD ongoing at 201 days. For TEM, PR durations were 173 and 504 days, and SD durations between 213-435 days. Five pts with PD treated with NIVO + TEM had mixed responses (31%) compared with 1 pt treated with TEM (6%). Median progression free survival (PFS) was 80 days (range 11-748) for NIVO + TEM and 55.5 days (7-415) for TEM (p = 0.31). Median overall survival (OS) was 160 days (43-363) for NIVO + TEM and 118 days (7-1938) for TEM (p = 0.15). There were 26 adverse events (AEs) for NIVO + TEM (27% grade 1, 42% grade 2, 19% grade 3, and 12% grade 4; thrombocytopenia and pneumonitis), and 25 AEs for TEM (40% grade 1, 40% grade 2, 12% grade 3, and 8% grade 4; thrombocytopenia) [p = 0.64]. Conclusions: NIVO + TEM occasionally produced durable responses, although outcome metrics were not clearly superior to TEM alone in this small study. Further studies should quantify the benefit of ICI + chemotherapy regimens in refractory MM. [Table: see text]

Analysis of proteomics based on LC-MS detection on the efficacy of immunocombined therapy for hepatocellular carcinoma.

e14549 Background: Combined immunotherapy has become the preferred treatment for HCC. However, it faces challenges: possible serious adverse reactions, the low objective response rate, and the median overall survival is about 20 months, which is far from meeting the clinical treatment needs. There is still a lack of effective predictive biomarkers in clinical practice to screen the dominant population of combined immunotherapy. The purpose of this study is to use LC-MS to screen and identify differential metabolites between patients with different efficacy to help screen the dominant population of clinical immunotherapy. Methods: 38 HCC patients were included who were treated in the Tumor Center of the First Hospital of Jilin University from June 2020 to March 2022 and received combined immunotherapy. Sample collection and follow· -up, and collect basic clinical data. The enrolled patients underwent enhanced CT examination every 3 treatment cycles, and the efficacy of the patients was evaluated according to the solid tumor efficacy evaluation standard 1.1 (RECIST V1.1). The serum of patients before treatment was detected by LC-MS, and the difference of mass spectrometry data between patients with different curative effects was compared, and the differential metabolites were explored by proteomics analysis. Results: The best of response was partial response in 7 patients (22.6 %), stable disease in 6 patients, and progressive disease in 18 patients (58.1 %). Based on LC-MS proteomics analysis, differential metabolites between patients with different therapeutic effects were screened and identified, namely Q9Y275, Q56UQ5, P13611, and P30530 (P &lt; 0.05). The relative abundance of Q9Y275, Q56UQ5, P13611 and P30530 in the disease control rate group was higher than that in the PD group. Conclusions: Based on LC-MS proteomics analysis, four types of differential metabolites between different populations of PLC patients receiving combined immunotherapy were screened and identified, namely Q9Y275, Q56UQ5, P13611 and P30530.

A phase II multicenter study of enfortumab vedotin with or without pembrolizumab in rare genitourinary tumors (E-VIRTUE).

TPS4628 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting nectin-4 with a monomethyl auristatin E (MMAE) payload, a potent microtubule inhibitor. It is standard of care (SOC) in metastatic urothelial carcinoma in combination with pembrolizumab in untreated patients and as monotherapy in post-chemotherapy, post-immune checkpoint blockade (ICB) patients. Nectin-4 expression has been retrospectively observed in 66.7-100% of urinary tract adenocarcinoma, 70-100% of urinary tract squamous cell carcinoma (SCC) (Case et al., 2022; Hoffman-Censits et al., 2021) and 36% of testicular germ cell tumors (GCTs) (The Human Protein Atlas). Metastatic urinary tract adenocarcinoma and SCC, and treatment refractory GCTs do not have an established SOC. Given the known nectin-4 expression, we hypothesize that EV with or without pembrolizumab will be active in these rare GU tumors. Methods: E-VIRTUE is an open-label, non-randomized, Phase 2 multicenter study. Eligible patients must have locally advanced or metastatic urinary tract pure adenocarcinoma, urinary tract pure SCC or refractory GCTs and have measurable disease by RECIST 1.1. Patients may have received any number of lines of prior systemic therapy except EV or other MMAE-based ADCs, and GCT patients must be refractory to all curative SOC treatments. Each histology will have an ICB-naïve and post anti-PD-1/PD-L1 ICB cohort: ICB-naïve patients will be given EV 1.25 mg/kg (maximum 125 mg) on Days 1 and 8 and pembrolizumab 200 mg on Day 1 of 21-day cycles, and post ICB patients will be given EV 1.25 mg/kg (maximum 125 mg) on Days 1, 8 and 15 of 28-day cycles. EV will be given for up to 5 years and pembrolizumab will be given for up to 2 years, or until progressive disease (PD) or unacceptable toxicity. Patients who stop pembrolizumab after achieving a complete response may resume it for 1 year after developing PD. The primary objective is to evaluate the objective response rate (ORR) in all cohorts. Secondary objectives include safety, progression-free survival (PFS) and overall survival (OS). The initial 6 cohorts will each be evaluated with exploratory intent. With 10 patients in each cohort, an exact binomial test with a 10% one-sided significance level will have 85.3% power to detect the difference between a very low (5%) ORR and a higher (30%) ORR. If there are ≥2/10 objective responses in any cohort, activity will be demonstrated. Additional histologies may be added after nectin-4 data emerges to justify their inclusion. Exploratory objectives include estimating the level of nectin-4 expression for each histology, performing DNA and RNA sequencing of tumor and blood samples, and observing changes in levels of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) with treatment and disease status. Clinical trial registration NCT06041503. Clinical trial information: NCT06041503 .

A three-arm randomized phase II study of dostarlimab alone or with bevacizumab versus nonplatinum chemotherapy in recurrent gynecological clear cell carcinoma: DOVE (APGOT-OV7/ENGOT-ov80 study).

TPS5627 Background: Recurrent gynecological clear cell carcinoma (rGCCC) is known for low objective response rates to chemotherapy. Prior preclinical and clinical data suggests potential synergy of immune checkpoint inhibitor adding bev in rGCCC. Dostarlimab, a humanized monoclonal antibody targeting PD-1, combined with the anti-angiogenic bevacizumab, presents a novel therapeutic approach. The aim of the present study is to investigate the efficacy of dostarlimab +/- bevacizumab in rGCCC. Methods: DOVE is a global, multicenter, international, open-label, randomized phase 2 study of dostarlimab +/- bevacizumab with standard chemotherapy in patients with rGCCC. It enrolls 198 patients with rGCCC, assigning them to one of three groups in a 1:1:1 ratio: Group A (dostarlimab monotherapy), Group B (dostarlimab + bevacizumab), Group C: investigator’s choice chemotherapy. Patients with PD on Group A or Group C were allowed to crossover to Group B. Stratification factors are prior bevacizumab use, prior lines of therapy (1 vs. &gt;1), and primary site (ovarian vs. non-ovarian). Key inclusion criteria are histologically proven confirmed recurrent or persistent clear cell carcinoma of the ovary, endometrium, cervix, vagina and vulva, up to 5 prior lines of therapies, disease progression within 12 months after platinum-based chemotherapy, and measurable disease. Key exclusion criteria are prior treatment with an anti PD-1, anti PD-L1, or anti PD-L2 agent. The primary endpoint is progression-free survival by investigator. The secondary endpoints include ORR, DCB, DCR, PFS2, OS, and toxicity. Exploratory objectives include immune biomarker. The study, commencing in Jan 2024, is registered with Clinicaltrials.gov (NCT06023862). Clinical trial information: NCT06023862 .