Significant Improvement In Overall Survival Research Articles

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial

ObjectiveTo evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy.DesignRandomised, double blind,...

Effect of PAWI-2 on pancreatic cancer stem cell tumors.

Worldwide, pancreatic cancer (PC) is a major health problem and almost 0.5million people were diagnosed with PC in 2020. In the United States, more than 64,000 adults will be diagnosed with PC in 2023. PC is highly resistant to currently available treatments and standard of care chemotherapies cause serious side effects. Most PC patients are resistant to clinical therapies. Combination therapy has showed superior efficacy over single-agent treatment. However, most therapy has failed to show a significant improvement in overall survival due to treatment-related toxicity. Developing efficacious clinically useful PC therapies remains a challenge. Herein, we show the efficacy of an innovative pathway modulator, p53-Activator Wnt Inhibitor-2 (PAWI-2) against tumors arising from human pancreatic cancer stem cells (i.e., hPCSCs, FGβ3 cells). PAWI-2 is a potent inhibitor of tumor growth. In the present study, we showed PAWI-2 potently inhibited growth of tumors from hPCSCs in orthopic xenograft models of both male and female mice. PAWI-2 worked in a non-toxic manner to inhibit tumors. Compared to vehicle-treated animals, PAWI-2 modulated molecular regulators of tumors. Anti-cancer results showed PAWI-2 in vivo efficacy could be correlated to in vitro potency to inhibit FGβ3 cells. PAWI-2 represents a safe, new approach to combat PC.

Can adjuvant immune checkpoint inhibitors improve the long-term outcomes of hepatocellular carcinoma with high-risk recurrent factors after liver resection? A meta-analysis and systematic review

BackgroundAdministering adjuvant therapy following liver resection is crucial for patients with hepatocellular carcinoma (HCC) exhibiting high-risk recurrence factors. Immune checkpoint inhibitors (ICIs) are effective against unresectable HCC; however, their effectiveness and safety for this specific patient group remain uncertain.MethodsWe conducted an extensive literature search across four scholarly databases to identify relevant studies. Our primary endpoints were overall survival (OS), recurrence-free survival (RFS), and adverse events (AEs). OS and RFS were quantified using hazard ratios (HRs), whereas the 1-, 2-, and 3-year OS and RFS rates were expressed as risk ratios (RRs). Additionally, the incidence of AEs was calculated.ResultsOur meta-analysis included 11 studies (N = 3,219 patients), comprising two randomized controlled trials (RCTs) and nine retrospective studies. Among these, eight studies reported HRs for OS, showing a statistically significant improvement in OS among patients receiving adjuvant ICIs (HR, 0.60; 95% confidence interval [CI], 0.45–0.80; p < 0.0001). All included studies reported HRs for RFS, indicating a favorable impact of adjuvant ICIs (HR, 0.62; 95% CI, 0.52–0.73; p < 0.0001). Moreover, aggregated data demonstrated improved 1- and 2-year OS and RFS rates with adjuvant ICIs. The incidence rate of AEs of any grade was 0.70 (95% CI, 0.49–0.91), with grade 3 or above AEs occurring at a rate of 0.12 (95% CI, 0.05–0.20).ConclusionAdjuvant ICI therapy can enhance both OS and RFS rates in patients with HCC exhibiting high-risk recurrence factors, with manageable AEs.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/#recordDetails PROSPERO, identifier CRD42023488250.

Comparison of Volumetric Modulated Arc Therapy (VMAT) and Conventional Intensity-Modulated Radiotherapy (IMRT) for Locally Advanced Head and Neck Squamous Cell Carcinoma: A Retrospective Cohort Study.

Purpose This study examines the outcomes of locally advanced head and neck squamous cell carcinoma (HNSCC) following the adoption of conventional intensity-modulated radiotherapy (cIMRT) and volumetric-modulated arc therapy (VMAT) over a decade. The region under study has higher comorbidities associated with increased HNSCC incidence and poorer prognosis. Materials and methods A 10-year retrospective review of electronic medical records included 296 patients with stage III, IVA, and IVB HNSCC (American Joint Committee on Cancer, Seventh edition). Survival outcomes were compared between VMAT and cIMRT using Kaplan-Meier survival curves and adjusted for relevant demographic factors using Cox's proportional hazards model. Analysis was performed using R software(R Foundation, Vienna, Austria). Results The median age of the cohort was 63 years, comprising of 80% males. The oropharynx was the most common primary tumor site. 264 (89%) received 50Gy or higher dose radiation by either cIMRT (22%) or VMAT (67%). At five years, locoregional control (LC) and overall survival (OS) rates were 79.5% and 56.7%, respectively. VMAT showed a significant improvement in five-year OS (63.4% versus 43.8% for cIMRT, p=0.0023)but no significant difference in five-year LC (81% VMAT versus 74.5% cIMRT, p=0.17). Grade 3-4 acute toxicity was observed in 22% of patients. Conclusions VMAT and cIMRT demonstrated excellent LC in locally advanced HNSCCdespite high comorbidity rates. Notably, VMAT was associated with significantly better OS compared to cIMRT. These outcomes surpass historical data, suggesting that VMAT technology may lead to improved patient outcomes. However, larger randomized controlled trials and dosimetric studies are needed to confirm these findings.

Postoperative radiotherapy versus surgery alone in pN1 oral cavity cancer patients: A meta-analysis.

The aim of this meta-analysis is to evaluate the potential benefits of postoperative radiotherapy (PORT) in patients with pN1 oral cavity squamous cell carcinoma. A literature search through major databases was conducted until January 2023. The adjusted hazard ratio (aHR) or risk ratio (RR) with 95% confidence intervals (CIs) of different survival outcomes were extracted and pooled. Ten studies published between 2005 and 2022, with a pooled patient population of 2888, were included in this meta-analysis. Due to differences in study design and reported outcomes, the studies were categorized into distinct groups. In pN1 patients without extranodal extension (ENE), PORT was associated with a significant improvement in overall survival (OS) (aHR 0.76, 95% CI: 0.61-0.94). In pN1 patients without ENE and positive margins, PORT improved OS (aHR 0.71, 95% CI: 0.56-0.89) and was associated with a lower regional recurrence rate (RR 0.35, 95% CI: 0.15-0.83). However, in pN1 patients without ENE, positive margins, perineural invasion, and lymphovascular invasion, there were no significant differences observed between the PORT and observation groups in either 5-year OS (RR 0.48, 95% CI: 0.07-3.41) or 5-year disease-free survival (RR 0.37, 95% CI: 0.07-2.06). The current study demonstrated that PORT has the potential to improve OS in pN1 disease. However, the decision of whether to administer PORT still hinges on diverse clinical scenarios, and additional research is necessary to furnish a more conclusive resolution. 2.

Postoperative radiotherapy does not improve survival in patients with Masaoka-Koga stage IIB thymomas: A propensity score matching study based on the SEER database.

This study, based on a population, explored the prognostic value of postoperative radiotherapy (PORT) for Masaoka-Koga IIB stage thymomas. Patients diagnosed with thymoma from 2004 to 2017 in the Surveillance, Epidemiology, and End Results (SEER) database were included in the retrospective study. Through propensity score matching, the baseline characteristics of the patients were successfully matched to mitigate the selection bias of PORT. Survival rates and survival curves were compared between the PORT and non-PORT groups, with potential confounding factors addressed using a multivariate Cox regression model. In this study, 785 cases of IIB stage thymoma were included from the SEER database, and 303 patients were successfully matched between PORT and non-PORT groups through propensity score matching, with no significant differences in baseline characteristics. In the PORT and non-PORT groups, 10-year overall survival rates were 65.2% versus 59.6%, and cancer-specific survival rates were 87.0% vs. 84.4%, PORT did not yield statistically significant improvements in overall survival (P = .275) or cancer-specific survival (P = .336) for stage IIB thymomas. Based on the SEER database, the results of our study indicated that PORT does not confer a significant survival benefit for IIB stage thymomas.

Squamous cell carcinoma of the colon: evaluation of treatment modalities and survival

BackgroundSquamous cell carcinoma of the colon (CSCC) is a rare subtype of colon cancer. This study aimed to evaluate treatment strategies and overall survival (OS). MethodsUsing the Surveillance, Epidemiology, and End Results program database from 2008 to 2019, patients aged 18 years with CSCC were identified. Treatment strategies and OS were summarized using the Kaplan-Meier analysis and the log-rank test. Adjusted Cox proportional hazards regression model ratios were calculated to evaluate the effect of confounding variables. ResultsAfter exclusions, 153 patients met the inclusion criteria. The most common treatment modalities included surgery alone (52.1%), surgery and adjuvant chemotherapy (12.9%), and no treatment (26.4%). Kaplan-Meier analysis revealed that patients who underwent surgery and adjuvant chemotherapy had significant improvements in OS (log-rank P = .002). Cox regression analysis revealed tumor grade (hazard ratio [HR], 2.12; 95% CI, 1.17–3.86) and receipt of chemotherapy (HR, 2.66; 95% CI, 1.23–5.76) as the only factors associated with improvements in OS. ConclusionPatients who underwent surgery in combination with chemotherapy had better OS than those who underwent surgery alone. Tumor grade and receipt of chemotherapy were independently associated with OS.

Abstract PO3-06-14: Phase I/II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer

Abstract Background: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer (TNBC). This trial evaluated the efficacy of pembrolizumab in combination with binimetinib, a MEK inhibitor. Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were enrolled. Treatment includes a 2-week run-in with binimetinib followed by pembrolizumab. There were 2 dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL -1. A standard 3+3 design was used in Phase I, and Simon’s two-stage Optimal design was used in Phase II. PD-L1 22C3 was performed in archival samples with CPS ≥ 10 considered as positive (PD-L1+). Tumor-infiltrating lymphocytes (TILs) were quantified into 0, 1, 2, and 3+. Circulating tumor cells (CTC) and circulating cancer-associated macrophage-like cells (CAML) were isolated using CellSieve microfilters and immunofluorescently labeled with PD-L1 and p-ERK. Wilcoxon rank sum test, Chi-square test, Cox regression model, and Spearman correlation were used for analysis. Results: 22 patients were enrolled with a median age of 58 years old. Dose-limiting toxicity (DLT) was observed in 2 out of 4 patients in DL 0, with grade 3 ALT abnormality, flank pain, and nausea. In the next 6 patients in DL -1, there was 1 DLT with grade 3 AST/ALT abnormality. There were 17 patients treated with DL -1 and were evaluable for response. The objective response rate (ORR) was 29.41% (95% CI: 10.31-55.9) with 1 complete response (CR) and 4 partial responses (PR). The clinical benefit rate (CBR ≥ 24 weeks) was 35.29% (95% CI: 14.21-61.67). ORR in patients without liver metastases was 55.56% (95% CI: 21.20 - 86.30) and CBR was 66.67% (95% CI: 29.93-92.51). No response was observed in all 5 patients with liver metastases. There were 40.9% of patients with PD-L1 CPS ≥ 10. ORR in patients with PD-L1+ was 80%. However, 11.1% of patients with PD-L1 negative tumors also had an objective response and 44.4% of patients had clinical benefit ≥ 24 weeks. PD-L1 expression in archival tissue was associated with ORR (p 0.032) but not CBR (p 0.198), progression-free survival (PFS, p 0.373), and overall survival (p 0.348). TILs in archival tissue were also not associated with CBR (p 0.155) and PFS (p 0.157). One patient with TILs 0 had a stable disease ≥ 24 weeks and 2 patients TILs 1+ also had an objective response. We further evaluated blood-based biomarkers with CTC and CAML. Baseline PD-L1 in CAML (p 0.04) and decline in CAML size (p 0.02) after 1 cycle was significantly associated with CBR. However, baseline CTC count, CAML count (p 0.64), CAML size (p 0.46), p-ERK in CAML (p 0.23), and changes in CTC count, CAML count (p 0.83), p-ERK (p 0.07), and PD-L1 (p 0.08) in CAML were not significantly associated with responses. Using Cox regression analysis, a reduction in CAML count (p 0.02), CAML size (p 0.01), and PD-L1 in CAML (p 0.03) were associated with significant improvement in overall survival but not the reduction in p-ERK (p 0.6). However, PD-L1 expression in CAML is not associated with PD-L1 expression in archival tissue (Spearman correlation 0.13). Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Consistent with the preclinical data that MEKi can restore T cell function, promising activity was observed even in patients with low TILs and PD-L1 negative, particularly in patients without liver metastases. PD-L1 expression in peripheral blood CAML rather than archival tumor tissue may serve as a better biomarker to predict the clinical benefit of this combination. Early reductions in CAML count and size, were also significantly associated with responses. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination. Citation Format: Saranya Chumsri, Joseph Larson, Daniel Adams, Kathleen Tenner, Cha-Mei Tang, Morgan Weidner, Amanda Arnold, Dana Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, Edith Perez, Keith Knutson. Phase I/II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer [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 PO3-06-14.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer (TOPAZ-1): patient-reported outcomes from a randomised, double-blind, placebo-controlled, phase 3 trial

In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1. In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration-ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration-and adjusted mean change from baseline in patient-reported outcomes. Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI -0·71 to 3·16) in the durvalumab group and 0·35 (-1·63 to 2·32) in the placebo group. The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer. AstraZeneca.

Efficacy and safety of novel immune checkpoint inhibitor-based combinations versus chemotherapy as first-line treatment for patients with extensive-stage small cell lung cancer: A network meta-analysis.

Patients with extensive-stage small cell lung cancer (ES-SCLC) have an exceptionally poor prognosis and immune checkpoint inhibitors (ICIs) combined with etoposide-platinum is recommended as standard first-line therapy. However, which combination pattern is the best still remains unknown. This network meta-analysis was performed to compare the efficacy and safety of currently available patterns including an antiangiogenic agent containing regimen and probed into the most appropriate therapy for patients. Hazard ratios (HRs) and odds ratios (ORs) were generated using R software. The outcomes of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events of grade 3 or higher (grade ≥ 3 adverse events [AEs]) were analyzed. A total of 10 randomized controlled trials (RCTs) involving 5544 patients were included for analysis. Drug combination patterns included adebrelimab, atezolizumab, durvalumab, durvalumab plus tremelimumab, ipilimumab, pembrolizumab, serplulimab, benmelstobart plus anlotinib, tislelizumab, tiragolumab plus atezolizumab and toripalimab in combination with chemotherapy. The novel antiangiogenic agent containing regimen benmelstobart + anlotinib + chemotherapy showed the highest possibility to present the best PFS and OS versus chemotherapy. Compared with ICI plus chemotherapy, it also achieved significantly better PFS and presented a tendency of OS benefit. As for safety and toxicity, patients treated with benmelstobart + anlotinib + chemotherapy and durvalumab + tremelimumab + chemotherapy suffered a higher likelihood of more grade ≥ 3 AEs without unexpected AEs. PD-1/PD-L1 inhibitors-based combinations are associated with significant improvement in both PFS and OS for treatment-naïve ES-SCLC patients. Benmelstobart plus anlotinib with chemotherapy (CT) yielded better survival benefit versus CT alone or other ICIs + CT with caution for more adverse effects along with the addition of an antiangiogenic agent.

Ischemia-free liver transplantation improves the prognosis of recipients using functionally marginal liver grafts.

The shortage of donor liver hinders the development of liver transplantation. This study aimed to clarify the poor outcomes of functionally marginal liver grafts (FMLs) and provide evidence for the improvement of ischemia-free liver transplantation (IFLT) after FML transplantation. Propensity score matching was used to control for confounding factors. The outcomes of the control group and FML group were compared to demonstrate the negative impact of FMLs on liver transplantation patients. We compared the clinical improvements of the different surgical types. To elucidate the underlying mechanism, we conducted bioinformatic analysis based on transcriptome and single-cell profiles. FMLs had a significantly greater hazard ratio (HR: 1.969, P=0.018) than did other marginal livers. A worse 90-day survival (Mortality: 12.3% vs. 5.0%, P=0.007) was observed in patients who underwent FML transplantation. Patients who received FMLs had a significant improvement in overall survival after IFLT (Mortality: 10.4% vs 31.3%, P=0.006). Pyroptosis and inflammation were inhibited in patients who underwent IFLT. The infiltration of natural killer cells was lower in liver grafts from these patients. Bulk transcriptome profiles revealed a positive relationship between IL-32 and Caspase 1 (R=0.73, P=0.01) and between IL-32 and Gasdermin D (R=0.84, P=0.0012). FML is a more important negative prognostic parameter than other marginal liver parameters. IFLT might ameliorate liver injury in FMLs by inhibiting the infiltration of NK cells, consequently leading to the abortion of IL-32, which drives pyroptosis in monocytes and macrophages.

Network meta-analysis of pembrolizumab as monotherapy and in combination with chemotherapy for first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma

Pembrolizumab monotherapy or in combination with chemotherapy is approved as first-line treatment in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) based on improved overall survival (OS) versus EXTREME regimen in the KEYNOTE-048 trial. The clinical outcomes of pembrolizumab were compared with other recommended first-line treatments in R/M HNSCC in this study through a Bayesian network meta-analysis. A systematic literature review was conducted in July 2022, from which six trials that matched the KEYNOTE-048 patient eligibility criteria were included in the network. The OS and progression-free survival (PFS) outcomes were compared in the approved pembrolizumab indication (i.e., total population for pembrolizumab in combination with chemotherapy and combined positive score [CPS] ≥ 1 population for pembrolizumab monotherapy). A significant OS improvement was observed for pembrolizumab in combination with chemotherapy and pembrolizumab monotherapy versus EXTREME regimen (hazard ratio, 95% credible interval: 0.72, 0.60-0.86; 0.73, 0.60-0.88), platinum+5- FU (0.58, 0.43-0.76; 0.58, 0.44-0.78), and platinum+paclitaxel (0.53, 0.35-0.79; 0.53, 0.35-0.81), respectively. A non-significant numeric trend in OS improvement was observed versus the TPEx regimen. PFS was comparable with most first-line treatments and was improved versus platinum+5-FU (0.48, 0.36-0.64; 0.59, 0.45-0.79). Additional analyses in higher CPS subgroups also showed consistent results. Overall, our study results showed an improvement in OS outcomes versus alternative first-line treatments, consistent with the findings of the KEYNOTE-048 trial. These data support using pembrolizumab as a suitable firstline treatment option in R/M HNSCC.

XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6–18.0) for the immunotherapy group compared with 9.9 months (8.0–11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40–0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3–32.8) for the control group (HR, 0.57 [95% CI, 0.33–0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

Early Incorporation to Palliative Care (EPC) in Patients With Advanced Non-Small Cell Lung Cancer: The PACO Randomized Clinical Trial.

Patients with non-small cell lung cancer (NSCLC) experience a considerable disease burden, evident in symptomatic and psychological spheres. Advanced cancer represents a complex scenario for patients and the healthcare team. Early palliative care (EPC) has been proven as a clinically meaningful strategy in this context by several randomized trials but not in a resource-limited setting. This study aimed to evaluate the effect of EPC compared with standard oncological care (SOC) in patients with metastatic NSCLC in Mexico. A prospective, randomized clinical trial was conducted at Instituto Nacional de Cancerologia in Mexico. All patients had histologically confirmed metastatic NSCLC without previous treatment. Patients were randomly assigned (1:1) to receive SOC or SOC + EPC. The EPC group was introduced to the palliative care team at baseline after randomization, which was integrated by psychologists, bachelor's in nutrition, specialized nurses, and physicians. Patients randomized to this arm had programmed visits to meet with the team at baseline and through the 2nd, 4th-, and 6th cycles thereafter. The primary endpoint was overall survival (OS); secondary outcomes included quality of life (QoL), anxiety and depression, and symptom intensity. They were assessed using the instruments EORTC QLQ-C30 questionnaire, Edmonton Symptom Assessment Scale (ESAS), and the Hospital Anxiety and Depression Scale (HADS) (clinicaltrials.gov [NCT01631565]). Questionnaires were completed at baseline, at 2nd, 4th, and 6th cycles of treatment. Between March 2012 and June 2015, 201 patients were assessed for eligibility and 146 were enrolled and allocated to receive EPC (73) or SOC (73). Median OS for patients in the EPC vs SOC arm was 18.1 months (95% CI, 7.9-28.4) and 10.5 months (95% CI, 4.7-16.2) (P = .029). Having a poor performance status (HR 1.7 [1.2-2.5]; P = .004) and allocation to the control group (HR 1.5 [1.03-2.3]; P = .034) were independently associated with a worse OS. Those patients with a global QoL > 70 at baseline had a better OS if they were In the EPC arm (38.7 months (95% CI, 9.9-67.6) vs SOC 21.4 months (95% CI, 12.4-30.3)). Mean QoL had a numerical improvement in patients allocated to EPC after 6 cycles of follow-up, nonetheless this difference was not statistically significant (55.1 ± 23.7 vs 56.9 ± 25.3; P = .753). There were no significant differences in anxiety and depression at all study points. EPC is associated with a significant improvement in OS, although, we observed that the greatest benefit of providing EPC was observed in those with a global QoL > 70 at baseline. This study did not identify significant changes in terms of QoL or symptom burden between the study groups after follow-up. Evidence robustly suggests that EPC should be considered part of the multidisciplinary treatment of metastatic NSCLC patients since diagnosis. According to our study, EPC can be implemented in low- or middle-income countries (LMIC).

Six versus four or five cycles of first-line etoposide and platinum-based chemotherapy combined with thoracic radiotherapy in patients with limited-stage small-cell lung cancer: A propensity score-matched analysis of a prospective randomized trial.

The recommended treatment for limited-stage small-cell lung cancer (LS-SCLC) is a combination of thoracic radiotherapy (TRT) and etoposide plus cisplatin (EP) chemotherapy, typically administered over 4-6 cycles. Nonetheless, the optimal duration of chemotherapy is still not determined. This study aimed to compare the outcomes of patients with LS-SCLC who received either 6 cycles or 4-5 cycles of EP chemotherapy combined with TRT. In this retrospective analysis, we utilized data from our prior prospective trial to analyze the outcomes of 265 LS-SCLC patients who received 4-6 courses of EP combined with concurrent accelerated hyperfractionated TRT between 2002 and 2017. Patients were categorized into two groups depending on their number of chemotherapy cycles: 6 or 4-5 cycles. To assess overall survival (OS) and progression-free survival (PFS), we employed the Kaplan-Meier method after conducting propensity score matching (PSM). Among the 265 LS-SCLC patients, 60 (22.6%) received 6 cycles of EP chemotherapy, while 205 (77.4%) underwent 4-5 cycles. Following PSM (53 patients for each group), the patients in the 6 cycles group exhibited a significant improvement in OS and PFS in comparison to those in the 4-5 cycles group [median OS: 29.8 months (95% confidence interval [CI], 23.6-53.1 months) vs. 22.7 months (95% CI, 20.8-29.1 months), respectively, p = 0.019; median PFS: 17.9 months (95% CI, 13.7-30.5 months) vs. 12.0 months (95% CI, 9.8-14.2 months), respectively, p = 0.006]. The two-year and five-year OS rates were 60.38% and 29.87% in the 6 cycles group, whereas 47.17% and 15.72% in the 4-5 cycles group, respectively. Patients diagnosed with LS-SCLC who were treated with EP regimen chemotherapy combined with TRT exhibited notably enhanced survival when administered 6 cycles of chemotherapy, as compared to those who underwent only 4-5 cycles.

Neoadjuvant Chemotherapy in Patients with HER2-Negative Breast Cancer: A Report from Clinical Breast Cancer Registry of Iran.

Neoadjuvant chemotherapy (NCT) has become an increasingly popular approach in management of breast cancer (BC). This study was conducted to evaluate the pathologic response and 36-month recurrence and survival rates of patients with human epidermal growth factor receptor 2 (HER2)-negative BC treated with different NCT regimens. A total of 163 female patients with HER2-negative BC who received NCT during 2017-2020 were identified from the Clinical Breast Cancer Registry of Iran and entered the study. The prescribed NCT regimens included 4 cycles of doxorubicin plus cyclophosphamide, 4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of paclitaxel, 4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of docetaxel or 6 cycles of doxorubicin plus cyclophosphamide plus docetaxel (TAC). Thirty-two patients (19.6%) experienced pathologic complete response (pCR). TAC regimen, triple negative-BC and ki67>10% were significantly associated with increased pCR. The recurrence, overall survival (OS) and disease-free survival (DFS) rate at 36 months for all patients were 16.6%, 84.7% and 79.8%, respectively. Type of neoadjuvant regimen as well as age, hormone receptor status, Ki67, grade, clinical stage, type of surgery and pathologic response to chemotherapy did not significantly influence the survival and recurrence; however, TAC results in improved recurrence, OS and DFS rates. This study provides further evidence that NCT is a viable treatment option for patients with HER2-negative BC. The TAC regimen resulted in a significantly higher pCR rate compared to other regimens, but did not result in a significant improvement in recurrence, OS and DFS and rates.

Perioperative Chemotherapy for Gastro-Esophageal or Gastric Cancer: Anthracyclin Triplets versus FLOT.

Background: The FLOT4-AIO trial (2019) showed improved survival with perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) compared to anthracyclin triplets in gastric cancer treatment. It is unclear whether these results extend to real-world scenarios in the Netherlands. This study aimed to compare outcomes of perioperative FLOT to anthracyclin triplets in a real-world Dutch gastric cancer population. Methods: Patients diagnosed with resectable (cT2-4a/cTxN0-3/NxM0) gastric or gastro-esophageal junction carcinoma between 2015-2021 who received neoadjuvant FLOT or anthracyclin triplets were selected from the Netherlands Cancer Registry. The primary outcome was overall survival (OS), analyzed through multivariable Cox regression. Secondary outcomes included pathological complete response (pCR), neoadjuvant chemotherapy cycle completion, surgical resection rates, and adjuvant therapy. Results: Adjusted OS showed no significant survival benefit (HR = 0.88, 95% CI 0.77-1.01, p = 0.07), even though the median OS was numerically improved by 8 months with FLOT compared to anthracyclin triplets (48.1 vs. 39.9 months, p = 0.16). FLOT patients were more likely to undergo diagnostic staging laparoscopies (74.2% vs. 44.1%, p < 0.001), had higher rates of completing neoadjuvant chemotherapy (OR = 1.35, 95% CI 1.09-1.68, p = 0.007), receiving adjuvant therapy (OR = 1.34, 95% CI 1.08-1.66, p = 0.08), and achieving pCR (OR = 1.52, 95% CI 1.05-2.20, p = 0.03). No significant differences were observed in (radical) resection rates. Conclusion(s): Real-world data showed no significant OS improvement for FLOT-treated patients compared to anthracyclin triplets, despite more staging laparoscopies. However, FLOT patients demonstrated higher rates of neoadjuvant therapy completion, proceeding to adjuvant therapy, and increased pCR rates. Therefore, we recommend the continued use of neoadjuvant FLOT therapy in the current clinical setting.

Abstract 4758: Targeting cellular pH as a novel therapeutic strategy in CDK4/6 inhibitor resistant breast cancer

Abstract Cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i) are part of standard of care therapy in combination with antiestrogens for the treatment of metastatic estrogen receptor positive (ER+) breast cancer. Of the three major CDK4/6i, only ribociclib and abemaciclib, but not palbociclib, have shown significant improvement in overall survival in the clinic. However, resistance to CDK4/6i is prevalent and advanced metastatic ER+ breast cancer remains incurable. Other studies have focused on cell cycle or growth factor alterations in resistant tumors but targeting these pathways have not been clinically validated. Beside inhibiting the cell cycle, CDK4/6i are known to induce lysosomes in sensitive cells but the role of lysosomes in CDK4/6i resistance remains elusive. Recently, we have shown that CDK4/6i resistant breast cancer cells gain metastatic potential relative to sensitive cells and this is potentially due to deregulated lysosomes, which can be targeted with lysosome destabilizers. Here we show that all three CDK4/6i induce rapid lysosomal acidification in sensitive cells, which suggests a role of cellular pH in CDK4/6i-mediated cell death. However, in resistant cells, lysosomal acidification following CDK4/6i treatment was diminished. Therefore, we hypothesize that cellular pH is tightly regulated in CDK4/6i resistant cells and this pathway can be targeted to inhibit cell viability. Interestingly, protein levels of carbonic anhydrase IX (CA9), an important regulator of cellular pH, is significantly elevated in resistant cells. Increased CA9 levels correlate with impaired overall survival in breast and other cancers. Small molecule inhibitor of CA9, S4 or clinical-grade SLC-0111, inhibits growth of resistant cells when combined with CDK4/6i plus antiestrogens. Thus, our study highlights the role of pH changes in CDK4/6i resistant breast cancer and offer therapeutic strategies to treat this incurable disease. Citation Format: Erin R. Scheidemann, Diane M. Demas, Ayesha N. Shajahan-Haq. Targeting cellular pH as a novel therapeutic strategy in CDK4/6 inhibitor resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4758.

Abstract 3830: Comparison of individual patient data from real-world experience with the ADAURA study for resected stage IB-IIIA EGFR-mutated non-small cell lung cancer

Abstract Introduction: In recent data of ADAURA study, adjuvant osimertinib demonstrated clinically significant improvement in overall survival in completely resected stage IB-IIIA with epidermal growth factor receptor (EGFR)-mutated NSCLC. Among 205 patients who experienced recurrence in the placebo arm, 89.8% of patients received subsequential treatment and 79.0% of patients in the placebo arm received EGFR-TKI after recurrence. Methods: This study included patients with completely resected EGFR-mutated NSCLC who confirmed to pathologic stage II-IIIA between November 2015 and February 2019 at Samsung Medical Center (SMC data). They did not receive adjuvant EGFR-TKI. To compare overall survival between the SMC data and the ADAURA study, the individual patient data (IPD) approach was applied. We assessed the overall survival of individual patient data from real-world experience in comparison to the ADAURA study. Results: A total of 547 patients were included in this study, with 51.0% at stage IB, 23.8% at stage II, and 25.2% at stage IIIA. The median follow-up duration was 71.4 months (range 1-92). At the time of data lock, 241 patients experienced recurrence in the SMC data. Among them, 230 patients (95.4%) received subsequent treatment, and 214 patients (88.8%) received EGFR-TKI after recurrence. In the stage IB and II, there was no difference of overall survival between the SMC data (reference) and the osimertinib arm of the ADAURA study (HR=0.83, 95% CI, 0.36-1.90, p=0.66 in stage IB; HR=1.08, 95% CI, 0.58-2.03, p=0.81 in stage II). However, in the stage IIIA, the 5-year survival rate was 68% in the SMC data and 85% in the osimertinib arm of the ADAURA study (HR=0.42, 95% CI, 0.24-0.73, p&amp;lt;0.01). In the stage IB-IIIA, the 5-year survival rate was 85% in the SMC data (reference), 78% (HR=1.68, 95% CI, 1.25-2.25, p&amp;lt;0.01) in the placebo arm of the ADAURA study, and 88% (HR=0.81, 95% CI, 0.56-1.16, p=0.24) in the osimertinib arm of the ADAURA study. In the stage II-IIIA, the 5-year survival rate was 77% in the SMC data (reference), 73% (HR=1.29, 95% CI, 0.92-1.82, p=0.14) in the placebo arm of the ADAURA study, and 85% (HR=0.62, 95% CI, 0.41-0.93, p= 0.02) in the osimertinib arm of the ADAURA study. Conclusions: In this study, the majority of patients received EGFR-TKIs after recurrence. The 5-year overall survival in the real-world data demonstrated superiority over the placebo arm of the ADAURA study. In stage IB and II disease, there was no significant difference between the SMC data and the osimertinib arm of the ADAURA study. Consequently, patients with pathologic stage IIIA are considered strong candidates for adjuvant osimertinib. Citation Format: Hyun Ae Jung, Junho Lee, Boram Park, Sehhoon Park, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn. Comparison of individual patient data from real-world experience with the ADAURA study for resected stage IB-IIIA EGFR-mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3830.

Abstract 3201: Preclinical development of a novel Romidepsin nanoparticle for the treatment of T-Cell lymphoid malignancies

Abstract The histone deacetylase inhibitors (HDACi) have long been regarded as an important class of drugs for treating T-cell lymphoid malignancies (TCL). Romidepsin (Romi), a bicyclic peptide, was approved for patients with relapsed or refractory cutaneous (CTCL) and peripheral T-cell lymphomas (PTCL). Unfortunately, the approval of Romi for relapsed/refractory PTCL was withdrawn due to a negative Phase 4 post-marketing requirement. Given its potent activity against Class I HDACs, Romi is considered one of the most effective HDAC inhibitors studied and used in patients with TCL. Herein, we report on a first-in-class nanoparticle of Romi (NanoRomi) with a superior safety and efficacy profile compared to the free drug in preclinical models of PTCL and large granular lymphocyte leukemia (LGLL). We developed a first-in-class NanoRomi using our proprietary amphiphilic di-block copolymer-based nanochemistry platform. NanoRomi was characterized in cell viability, flow cytometry, and western blotting (WB) assays to determine the concentration-effect relationships with regard to the induction of apoptosis and histone acetylation in cell lines representative of TCL and LGLL, as well as primary LGLL patient PBMC samples. In addition, we performed extensive in vivo modeling using murine xenografts of CTCL, including repeated dose toxicity, biodistribution, efficacy, and survival studies. Cytotoxicity assays demonstrated superior/comparable activity of NanoRomi (IC50: 1.1-2.3 nM) compared to free Romi (IC50: 4.8-10.6 nM) across all PTCL and LGLL cell lines studied, while in primary LGLL samples, NanoRomi exhibited superior cytotoxicity (2-fold) compared to Romi. WB analysis showed that NanoRomi induced apoptosis and increased acetylation of histone H3 and H4 in a time and concentration-dependent manner in cell lines representing CTCL, ALK+-ALCL, and LGLL. Repeat dose toxicity studies in CTCL xenografts confirmed that the overall tolerability of NanoRomi was substantially better than Romi. Tracking studies with a fluorescent dye (DiO) in the NanoRomi demonstrated preferential localization of NanoRomi in tumors of mice compared to the normal organs after 6 hours of drug administration. NanoRomi exhibited superior efficacy in the murine CTCL xenograft models, including a significant improvement in overall survival compared to Romi. Collectively, these data show that NanoRomi exhibits markedly superior pharmacokinetics, tolerability, and efficacy in models of TCL. We anticipate that the improved activity and tolerability of NanoRomi relate to the altered pharmacologic profile and superior bioavailability of the drug, which optimizes the effects of the drug for its influence on epigenetic biology. This unique platform offers the prospect of improving the tolerability and efficacy of epigenetic treatment strategies in these challenging diseases. Citation Format: Ipsita Pal, Anuradha Illendula, Andrea Joyner, Tess M. Deddens, Deepthi P. Damera, Todd E. Fox, Marya E. Dunlap-Brown, Kallesh D. Jayappa, Thomas P. Loughran, David J. Feith, Owen A. O'Connor. Preclinical development of a novel Romidepsin nanoparticle for the treatment of T-Cell lymphoid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3201.