Chemotherapy Research Articles

Exploring the role of artificial intelligence in chemotherapy development, cancer diagnosis, and treatment: present achievements and future outlook

BackgroundArtificial intelligence (AI) has emerged as a transformative tool in oncology, offering promising applications in chemotherapy development, cancer diagnosis, and predicting chemotherapy response. Despite its potential, debates persist regarding the predictive accuracy of AI technologies, particularly machine learning (ML) and deep learning (DL).ObjectiveThis review aims to explore the role of AI in forecasting outcomes related to chemotherapy development, cancer diagnosis, and treatment response, synthesizing current advancements and identifying critical gaps in the field.MethodsA comprehensive literature search was conducted across PubMed, Embase, Web of Science, and Cochrane databases up to 2023. Keywords included “Artificial Intelligence (AI),” “Machine Learning (ML),” and “Deep Learning (DL)” combined with “chemotherapy development,” “cancer diagnosis,” and “cancer treatment.” Articles published within the last four years and written in English were included. The Prediction Model Risk of Bias Assessment tool was utilized to assess the risk of bias in the selected studies.ConclusionThis review underscores the substantial impact of AI, including ML and DL, on cancer diagnosis, chemotherapy innovation, and treatment response for both solid and hematological tumors. Evidence from recent studies highlights AI’s potential to reduce cancer-related mortality by optimizing diagnostic accuracy, personalizing treatment plans, and improving therapeutic outcomes. Future research should focus on addressing challenges in clinical implementation, ethical considerations, and scalability to enhance AI’s integration into oncology care.

A Retrospective Analysis of Pembrolizumab With or Without Chemotherapy in Advanced Non-small Cell Lung Cancer: Experience From a Tertiary Care Hospital

A Retrospective Analysis of Pembrolizumab With or Without Chemotherapy in Advanced Non-small Cell Lung Cancer: Experience From a Tertiary Care Hospital

Factors associated with longitudinal progression of the cumulative burden of morbidity and overall mortality after cisplatin-based chemotherapy for testicular cancer.

To comprehensively evaluate the longitudinal progression of cumulative burden of morbidity (CBM) in testicular cancer survivors (TCS) following standard-dose cisplatin-chemotherapy and the impact of modifiable risk factors on morbidity and early-mortality. Participants completed first-line chemotherapy ≥6 months before baseline assessments with comprehensive questionnaires and physical-examinations. Based on follow-up assessments (median: 7 years later), longitudinal progression of adverse health outcomes (AHOs) and CBM score (encompassing AHO number and severity) was examined. Baseline health behaviors and AHOs were evaluated for associations with mortality using mixed-effects parametric proportional-hazards regression to identify modifiable risk factors. Among 616 TCS longitudinally assessed, 23% experienced worsening CBM post-chemotherapy (median: 11 years [IQR = 7-15]). Declines were driven by worsening treatment-related AHOs: tinnitus (29.7%), hearing loss (24.4%), Raynaud's (22.6%), neuropathy (18.5%), and neuropathic-pain (10.7%). Baseline factors associated with worsening neuropathy included lack of aerobic physical-activity (OR = 1.98, 95%CI = 1.06-3.72) and obesity (OR = 1.85, 95%CI = 1.17-2.92). These were also related to worsening neuropathic-pain (OR = 2.82, p = .009; and OR = 2.29; p = .023). Twenty-nine deaths occurred among 1,830 five-year TCS (4.2% cumulative hazard) (median age: 48-years [range = 22-74]). Participants reporting neuropathic-pain (HR = 3.64, 95%CI = 1.45-9.10), no aerobic (HR = 6.56, 95%CI = 2.73-15.8), or no low-impact physical-activity (HR = 3.96, 95%CI = 1.40-11.2) had significantly higher mortality, as did TCS indicating fair (HR = 9.23, 95%CI = 3.08-27.8) or poor (HR = 18.5, 95%CI = 3.30-103) health. Relationships between pain and mortality were mediated through lowered physical-activity (p = .036). Clinically-actionable factors associated with early mortality identify high-risk TCS in need of closer monitoring and targeted interventions. The significant relationship between neuropathic-pain and mortality, mediated by low physical-activity, is the first to our knowledge in TCS.

Implantable Polymer Scaffolds Loaded with Paclitaxel–Cyclodextrin Complexes for Post-Breast Cancer Tissue Reconstruction

The side effects associated with the chemotherapy of triple-negative breast cancer (TNBC), such as nucleotide-binding oligomerization domain (NOD)-like receptor family (NLR), pyrin domain containing 3 (NLRP3) inflammasome activity, are responsible for the treatment failure and high mortality rates. Therefore, advanced delivery systems have been developed to improve the transport and targeted administration of anti-tumor agents at the tumor sites using tissue engineering approaches. Implantable delivery systems based on biodegradable polymers are an effective alternative due high biocompatibility, porosity, and mechanical strength. Moreover, the use of paclitaxel (PTX)-cyclodextrin complexes increases the solubility and permeability of PTX, enhancing the bioavailability and efficacy of the drug. All of these properties contribute to the efficient encapsulation and controlled release of drugs, preventing the damage of healthy tissues. In the current study, we detailed the synthesis process and evaluation of 3D scaffolds based on gelatin functionalized with methacryloyl groups (GelMA) and pectin loaded with PTX–cyclodextrin inclusion complexes on TNBC pathogenesis in vitro and in vivo. Bio-physio-chemical analysis of the proposed scaffolds revealed favorable mechanical and biological properties for the cellular component. To improve the drug solubility, a host–guest interaction was performed by the complexation of PTX with a cyclodextrin derivative prior to scaffold synthesis. The presence of PTX suppressed the growth of breast tumor cells and promoted caspase-1 activity, the release of interleukin (IL)-1β, and the production of reactive oxygen species (ROS), conditioning the expression levels of the genes and proteins associated with breast tumorigenesis and NLRP3 inflammasome. The in vivo experiments suggested the activation of pyroptosis tumor cell death, confirming the in vitro experiments. In conclusion, the bio-mechanical properties of the GelMA and pectin-based scaffolds as well as the addition of the PTX–cyclodextrin complexes allow for the targeted and efficient delivery of PTX, suppressing the viability of the breast tumor cells via pyroptosis cell death initiation.

Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer: A Nationwide Analysis of Eligibility, Utilization, and Outcomes

Objectives: To investigate neoadjuvant chemotherapy (NAC) eligibility, utilization, and survival outcomes for muscle-invasive bladder cancer patients undergoing radical cystectomy (RC) in a Finnish population. Materials and Methods: Data from the Finnish National Cystectomy Database (2005–2017) was combined with Finnish Cancer Registry survival data. NAC utilization rates were reported, and downstaging rates were calculated based on final pathological staging. Logistic regression analyzed NAC usage and complete response (CR) predictors. Results: Since 2011, 29% of 1157 patients received NAC. Its usage remained consistent, and the number of eligible patients not receiving NAC decreased during the study period. Among NAC patients, pathology T-category was pT0 (34%), pT1-Ta-Tis (16%), pT2 (23%), pT3 (20%), and pT4 (7%) tumors, with pN0 in 82%. In the RC + NAC group, the 5-year overall survival (OS) rates were 89% for patients with no residual disease (pT0N0), 82% for those with organ-confined residual disease (pT1, Tis, Ta, T2/N0), and 49% for patients with non-organ-confined residual disease (pT3+/N+). The corresponding cancer-specific survival (CSS) rates were 93%, 86%, and 57%, respectively. Patients with organ-confined residual disease after NAC had survival outcomes comparable to those who underwent RC alone. Higher age; odds ratio (OR) 0.93, [95% Confidence Interval (CI): 0.90–0.95] and Charlson Co-morbidity Index–score [OR 0.88 (0.79–0.98)] reduced the likelihood of receiving NAC, while a smaller center size increased the probability [OR 1.82 (1.02–3.28)]. More treatment cycles [OR 0.70, (95% CI: 0.51–0.93)] and a favorable GFR [OR 0.38 (0.16–0.88)] were associated with achieving CR. Conclusion: We report that NAC is well-utilized across Finland, with CR rates comparable to recent trials. Additionally, our survival rates are reasonable, and even with organ-confined residual disease after NAC, survival outcomes are similar to those who underwent RC alone.

Two GnRH-mitoxantrone Conjugates, Con-3 and Con-7, Target Endometrial Cancer Cells.

Endometrial cancer is one of the most common gynecological malignancies. Endometrial cancer cells express the gonadotropin-releasing hormone (GnRH) and its receptor (GnRH-R). Among the various therapeutic approaches for the treatment of endometrial cancer is the use of GnRH conjugates, such as the AN-152, created by linking the [D-Lys6] GnRH with the cytotoxic doxorubicin through an ester bond. An undesirable property of these conjugates is their vulnerability to plasma carboxylesterases, which cleave the ester bond to release doxorubicin before reaching the cancer cells. To overcome this problem, we recently developed the Con-3 and Con-7, which are GnRH analogs conjugated through a disulfide bond with the cytotoxic mitoxantrone. In this study, we determined the cytotoxic properties of the Con-3 and Con-7 on the Ishikawa endometrial cancer cells, assuming that their interaction with the GnRH-R of cells exposes the conjugated mitoxantrone to the cellular thioredoxin. The cellular thioredoxin reduces the disulfide bond of Con-3 & Con-7 to release mitoxantrone, which accumulates in the cancer cells and exerts its cytotoxic actions. Indeed, treatment of Ishikawa cells with Con-3, Con-7, or the free unconjugated mitoxantrone increased their apoptosis and decreased their proliferation in a dose- and time-dependent manner, displaying half-maximal inhibitory concentrations (IC50) of 0.64 - 1.15 μM. In specific, the IC50 values on days 2, 3, and 4 were 1.45, 0.64, and 0.83 μΜ, respectively, for Con-3, 0.91, 0.82 μΜ, and 1.00 μΜ, respectively for Con-7 and 1.15, 0.98, 0.78 μM, respectively for mitoxantrone. In contrast, the free, mitoxantrone-unconjugated peptides did not affect the proliferation of Ishikawa cells. The Con-3 and Con-7 could put the basis for the development of a new class of anticancer drugs for endometrial cancer, which will act as "prodrugs" that deliver the cytotoxic mitoxantrone in a GnRH-R-specific manner.

Prehabilitation during neoadjuvant therapy in patients with cancer of the upper gastrointestinal tract and rectum—the study protocol

AimsThe concept of prehabilitation, defined as interventions aimed at enhancing a patient's functional capacity prior to an impending physiological stressor, may contribute to reduced postoperative morbidity and mortality. The study's goal is to verify or refute the feasibility of a prehabilitation programme for two diagnostic patient groups during neoadjuvant chemo(radio)therapy, which is prescribed before the scheduled surgical procedure. This is a single group study design, with all patients enrolled receiving the intervention.MethodsThis is an interventional feasibility study of a prehabilitation programme in the form of physical training conducted at home. The training consists of progressively dosed walking and strength exercises for selected muscle groups. Data will be monitored telemetrically and also through telephone contact with participants. Primary outcomes include: the percentage of patients interested in participating in the study out of all patients indicated for neoadjuvant therapy at University Hospital Ostrava during the observed period, the percentage of patients who complete the prehabilitation programme until the date of surgery and individual patient compliance. Secondary outcomes include physical fitness parameters obtained from cardiopulmonary exercise testing, grip strength measured by a dynamometer, changes in body composition, EORTC QLQ-C30 quality of life questionnaire, and a questionnaire on the subjective perception of the exercise programme. Both primary and secondary outcomes will be compared between study arms (two diagnostic groups). The study is registered at ClinicalTrials.gov, ID: NCT05646043.ConclusionThe results of this study can serve as a foundation for larger, multicentre, controlled studies in the future.

Cardiotoxicity of Breast Cancer Chemotherapy.

Breast cancer is one of the leading causes of malignancy affecting women in the United States. Although many effective treatments are available, most come with notable side effects that providers and patients must take into consideration. Various classes of chemotherapeutic agents, including anthracyclines and human epidermal growth factor receptor-2 antagonists, are known to be toxic to myocardial tissue. In this review article, we discuss what is reported in the literature regarding the cardiotoxicity of these agents as well as how to monitor and prevent cardiac injury and dysfunction.

Pharmacotherapy and psychological support: Integrating pharmacists into comprehensive cancer care - a literature review.

Cancer presents significant physical and mental challenges to patients. Therefore, psychological assessment is important following a cancer diagnosis, as well as during and after chemotherapy. In cancer treatment, the goal of healthcare providers, including pharmacists, should be to deliver holistic care that addresses important aspects of patients' health, with particular emphasis on their psychological readiness to combat their diseases. This article reviews published literature from Google Scholar and PubMed to examine the relevant pharmacotherapy and psychotherapy approaches to managing psychological issues in cancer patients. This article also discusses how pharmacists can be integrated into cancer patients' mental health care, while highlighting the potential benefits and challenges associated with this approach. We conclude that the integration of pharmacists into psychological care and support for cancer patients holds promise due to their knowledge of cancer chemotherapy, their ability to improve their knowledge about psychological care, and their capacity to collaborate with other healthcare professionals in cancer treatment.

Design, Synthesis, and Molecular Docking Studies of Indolo[3,2-c]Quinolines as Topoisomerase Inhibitors.

The tetracyclic indoloquinoline ring system has attracted considerable interest in the recent past due to its broad spectrum of biological activities and its binding to various types of nucleic acids. This study aims to elucidate their interactions with DNA and their effects on topoisomerases (TOPO) I and II. Several compounds derived from 6-amino-11H-indolo[3,2-c]quinoline with diverse groups on the quinoline ring have been successfully synthesized according to a previously established protocol where all the synthesized indolo[3,2-c]quinoline derivatives were evaluated in vitro against A549, HCT-116, BALB/3T3, and MV4-11 cell lines using MTT (3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyl- tetrazolium bromide) assay. These derivatives were then screened for their topo I and II inhibitory activities. The tested compounds were more effective at killing MV4-11 leukemia cells than the standard cancer drug cisplatin, as shown by the fact that their IC50 values were less than 0.9 μM. On the other hand, cisplatin revealed an IC50 value of 2.36 μM. Moreover, they exhibited inhibitory activity against both Topoisomerase (Topo) I and II. The most potent compound, 5g, demonstrated a suppressive impact on topoisomerase I, with an IC50 value of 2.9 μM compared to the positive control Camptothecin (IC50 1.64 μM) and compound 8 displayed remarkable topoisomerase II inhibitory activity with an IC50 of 6.82 μM compared to the positive control Doxorubicin (IC50 6.49 μM). The cell cycle study for compounds 5g and 8 revealed that cell cycle arrest occurred at the G1/S and S phases, respectively. Compounds 5g and 8 showed a high selectivity index, which suggests that they could be used to develop low-toxicity chemotherapeutic agents. The results of this study demonstrate that compounds 5g and 8 can be considered promising candidates for further anti-cancer drug development, which might be related to inhibiting TOPO I and TOPO II activities.

A microscale thermophoresis-based enzymatic RNA methyltransferase assay enables the discovery of DNMT2 inhibitors

RNA methyltransferases (MTases) have recently become increasingly important in drug discovery. Yet, most frequently utilized RNA MTase assays are limited in their throughput and hamper this rapidly evolving field of medicinal chemistry. This study developed a microscale thermophoresis (MST)-based split aptamer assay for enzymatic MTase investigations, improving current methodologies by offering a non-proprietary, cost-effective, and highly sensitive approach. Our findings demonstrate the assay’s effectiveness across different RNA MTases, including inhibitor characterization of METTL3/14, DNMT2, NSUN2, and S. aureus TrmD, enabling future drug discovery efforts. Using this concept, a pilot screening on the cancer drug target DNMT2 discovered several hit compounds with micromolar potency.

First-line (1L) tislelizumab (TIS) plus chemotherapy (CT) vs placebo (PBO) plus CT in advanced/metastatic esophageal squamous cell carcinoma (ESCC): RATIONALE-306 Japanese subgroup analysis with longer follow-up.

420 Background: In the global phase 3 RATIONALE-306 study (NCT03783442), TIS + CT showed a significant overall survival (OS) benefit vs PBO + CT as 1L therapy for advanced/metastatic ESCC. After a minimum 3-year follow-up, the hazard ratio (HR) for OS was 0.70 for all randomized patients (pts) and for pts with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥10%.We report results for the Japanese subgroup. Methods: Eligible pts enrolled in Japan were randomized (1:1) to receive intravenous TIS 200 mg or PBO every 3 weeks + investigator-chosen CT (platinum + fluoropyrimidine/paclitaxel) until disease progression or intolerable toxicity. The primary endpoint was OS in the intent-to-treat (ITT) population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and OS in pts with PD-L1 TAP score ≥10%. Results: Of 649 randomized pts, 66 (10.2%) were Japanese, median age was 67 years, 89.4% were male, and 28.8% had PD-L1 TAP score ≥10%. At study entry, Eastern Cooperative Oncology Group performance status was 0 for 77.3% pts and 97.0% had metastatic disease. As of Nov 24, 2023, 78.8% vs 84.8% Japanese pts on TIS + CT vs PBO + CT received post-systemic therapy (ITT: 51.5% vs 57.9%). After a minimum follow-up of 37.9 months, TIS + CT showed improvements vs PBO + CT in median OS (24.5 vs 15.1 months [mo]; HR: 0.75) in all pts and in pts with PD-L1 TAP score ≥10% (HR: 0.79), median PFS (HR: 0.77) and ORR (63.6% vs 45.5%) (Table). Treatment-related adverse events (TRAEs) with TIS + CT vs PBO + CT in Japanese pts were 45.5% vs 36.4% for any grade (ITT: 69.8% vs 60.7%); 27.3% vs 6.1% for grade ≥3 (ITT: 32.1% vs 20.2%); 24.2% vs 3.0% for serious TRAEs (ITT: 19.8% vs 8.4%); TRAEs led to treatment discontinuation in 3.0% vs 6.1% (ITT: 13.3% vs 6.5%). No TRAEs leading to death were reported in Japanese pts (ITT: 1.5% vs 0.6%). Conclusions: After 3 years, TIS + CT continued to demonstrate robust efficacy and a tolerable safety profile in Japanese pts as 1L therapy for advanced/metastatic ESCC in the RATIONALE-306 study, consistent with the overall population. Clinical trial information: NCT03783442 . Efficacy outcomes. JapanTIS + CT(n=33) JapanPBO + CT(n=33) OverallTIS + CT(n=326) OverallPBO + CT(n=323) Median OS, mo (95% CI) 24.5 (17.6, 26.9) 15.1 (8.0, 22.5) 17.2 (15.8, 20.1) 10.6 (9.3, 12.1) HR (95% CI) 0.75 (0.43, 1.30) - 0.70 (0.59, 0.83) b - PD-L1 TAP score ≥10%, n (%) 12 (36.4) 7 (21.2) 116 (35.6) 107 (33.1) Median OS by PD-L1 TAP score ≥10%, mo (95% CI) 25.5(10.9, NE) 16.8(0.9, NE) 16.6(15.3, 23.4) 10.0(8.6, 13.3) HR (95% CI) 0.79 (0.26, 2.36) - 0.70 (0.52, 0.95) b - Median PFS a , mo (95% CI) 6.8 (4.4, 8.5) 4.5 (4.1, 6.7) 7.3 (6.9, 8.3) 5.6 (4.9, 6.0) HR (95% CI) 0.77 (0.45, 1.32) - 0.60 (0.50, 0.72) b - ORR a , n (%) 21 (63.6) 15 (45.5) 207 (63.5) 137 (42.4) a Investigator assessed. b Stratified. CI, confidence interval; NE, not estimable.

EORTC-1203 GITC "INNOVATION": Integration of trastuzumab (T), with or without pertuzumab (P), into perioperative chemotherapy of HER-2 positive stomach cancer: Overall survival results.

LBA331 Background: 10-20% of GC are HER-2 positive. The role of perioperative anti-HER2-directed treatment is yet undefined. Methods: This randomized, open-label phase II-trial investigates the benefit of perioperative chemotherapy (CT) alone or in combination with either T or T and P for HER-2+ gastric (GC) and esophagogastric junction cancer (EGJC). 172 patients (pts) with centrally confirmed, positive HER-2 status and resectable GC or EGJC (UICC TNM stages Ib-III) were included. Pts were randomized in a 1:2:2 ratio to: Arm A (CT alone) (35 pts); Arm B (CT+ T [8mg/kg, followed by 6mg every 3 weeks]) (67 pts); Arm C (CT + T+ P [840mg every 3 weeks]) (70 pts). CT was initially cisplatin (80 mg/m 2 d1) and capecitabine (2 x 1000 mg/m 2 /d d1) for 3 cycles before and after surgery. After publication of FLOT-4 (Al-Batran, Lancet 2019), the protocol was amended. CT changed to four cycles FLOT, with FOLFOX or CAPOX as alternative for pts ineligible for FLOT. In arm B and C, T and P were continued beyond CT at the same dose for a total of 17 cycles. Out of 172 pts randomized, 161 fulfilled all key eligibility criteria and started their allocated treatment (per protocol population). Centrally determined major pathological response rates (mpRR) were 33.3%, 53.3% and 37.9% in Arm A: B: C after amending the protocol while, in contrast, they were 8.3%, 16.7% and 12.5% before (ASCO 2024, abstract 4057). Here, we present progression-free-(PFS) and overall survival (OS) after a median follow-up of 4.3 years. Results: In Arm A: B: C, 63.6%, 64.7%, 50.4% and 51.9%, 61.0%, 47.9% of pts were progression-free at 3 and 5 years. As compared to CT alone, HRs for PFS versus CT+T were 0.88 (90% CI, 0.51 to 1.53) and for CT+T+P 1.40 (90% CI, 0.82 to 2.37). Survival rates at 3 and 5 years in arm A: B: C were 75.6%, 76.9%, 65.2% and 60.5%, 67.5% and 62.6 %. As compared to CT alone, HRs for OS for CT+T and CT+T+P were 0.89 (95% CI, 0.42 to 1.88)) and 1.29 (95% CI, 0.62 to 2.66). For results before and after amendment see table. Conclusions: Non-significant advantages in terms of PFS and OS were observed for the addition of T to CT before, but not after the amendment. CT+T+P was detrimental. These results reflect the challenge of using mpRR as surrogate for survival in the perioperative treatment of GC. Clinical trial information: NCT 02205047 . PFS and OS results before and after amendment. Before amendment: Arm PFS (%) at 3 Years (95% CI) Hazard Ratio (95% CI) OS (%) at 3 Years (95% CI) Hazard Ratio (95% CI) CT(N=14) 57.1(28.4, 78.0) 1.00 78.6(47.3, 92.5) 1.00 CT+T(N=26) 64.2(42.5, 79.5) 0.64(0.24, 1.72) 83.6(62.0, 93.5) 0.77(0.25, 2.44) CT+T+P(N=28) 50.4(30.1, 67.6) 1.18(0.48, 2.93) 68.3(46.3, 82.8) 1.28(0.44, 3.75) After amendment: CT(N=19) 68.4(42.8, 84.4) 1.00 73.3(47.2, 87.9) 1.00 CT+T(N=38) 65.0(47.5, 78.0) 1.12(0.46, 2.75) 72.2(54.3, 84.0) 0.99(0.37, 2.69) CT+T+P(N=36) 50.4 (32.9, 65.7) 1.62(0.67, 3.90) 62.2(42.6, 76.8) 1.30(0.49, 3.48)

Influence of data review on community physicians’ treatment preferences in frontline esophageal cancer (EC).

501 Background: EC remains a global health challenge with a rising incidence and poor prognosis despite advancements in treatment modalities. Standard therapies include surgery, chemotherapy (CT), radiation therapy, and recently, targeted and immunotherapy. The PD-L1 inhibitors pembrolizumab (pembro) and nivolumab (nivo) received FDA approval for frontline treatment in EC in March and May 2021, respectively, based in part on the KEYNOTE-590 (KN590) and CheckMate 648 trials. In this study, we aimed to uncover rationale in physician preference for PD-L1 inhibitors in EC. Methods: US-based oncologists convened at two in-person meetings in April 2024 to discuss clinical and real-world data presented at the 2024 ASCO GI Cancers Symposium. Among data discussed included the KN590 5-year update. Survey questions were fielded at the meeting to capture participants’ impressions. Demographics were captured via an online survey ahead of the meeting. Responses from participants who manage EC and responded to all survey questions were aggregated. Results: 86 participants qualified; and, collectively, are 76% community physicians with 18 years average in clinical practice, see 18 patients median on clinic days, and spend 83% of their time in direct patient care on average. ECOG PS status (50%), tumor histology (52%), and location/stage (48%) were reported as critical factors in treatment decision-making; only 14% said PD-L1 status was a major factor. Participants were queried on a hypothetical patient case of esophageal squamous cell and adenocarcinoma before and after reviewing the KN590 data. Prior to reviewing KN590, physician preferences in the squamous cell 1L setting were split between nivo+CT and pembro+CT; following data review, pembro+CT was favored nearly 3:1. In the adenocarcinoma 1L setting, preference shifted from 60/40 nivo+CT to 60/40 pembro+CT, see Table. The cohort were most impressed with the overall survival (87%) and objective response rates (40%), and 55% would consider pembro+CT for both squamous cell and adenocarcinoma disease while 37% would consider it for PD-L1 CPS>10 squamous cell disease only. Conclusions: Our study showed PD-L1 status was not a major factor in clinical decisions. The shift in treatment preference toward pembro+CT for both patient cases following KN590 data review suggests an impact for data review to influence physician behavior. This highlights the importance of educational initiatives to disseminate clinical updates to providers. It is still to be determined the optimal platform and length for these initiatives, and to quantify their effectiveness. 65-year-old male patient with advanced EC;PD-L1 CPS ≥10;ECOG PS of 1 Squamous cell disease Adenocarcinoma Before After Before After Fluoropyrimidine (FP) + platinum (P)-based CT 1% 1% 1% 0% FP +P-based CT + nivo 55% 27% 60% 36% FP + P-based CT + pembro 43% 71% 38% 63% Nivo + ipilimumab 1% 1% 0% 1% None of the above 0% 0% 0% 0%

Changes in peri-operative chemotherapy and radiation use among patients with resected pancreatic ductal adenocarcinoma (PDAC) between 2004-2021 in the US SEER dataset.

697 Background: PDAC peri-operative management changed over 20 years. Randomized data supports adjuvant and multiagent chemotherapy (CT), while peri-operative chemoradiotherapy (RT) was used selectively in the US. We examined recent trends in treatment with outcomes in surgically resected PDAC patients. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) 17 dataset, we identified surgically resected primary M0/MX PDAC cases from 2004-2021 over 3-year periods (P1-P6). Neoadjuvant (NCT), adjuvant (ACT), or multiagent (MACT) CT scheduling was included. χ² analysis assessed cohort characteristics over time and multinomial logistic regression assessed odds of CT allocation adjusted by cohort characteristics. Multivariable Cox proportional hazards model assessed treatment-related overall survival (OS) adjusted for cohort characteristics. Results: Among 55,293 cases of M0/MX PDAC, 21,904 (40%) completed surgery. Median age was 66 years; stages were T1/T2/T3/T4 (8.0/25/59/6.0%) and N0/N+ (38/54%). RT use declined (P1:P6, 41%->18% p<0.001) while CT use increased (P2:P6, 63%->79%, p<0.001). NACT (P2:P6, 4.1%->23% p<0.001) and MACT (P2:P6, 1.6%->20%, p<0.001) use increased while ACT decreased (P2:P6, 58%->36%, p<0.001). CT is likely to be allocated to young patients (<65yo) with Stage II-III tumors located at the pancreatic head (OR>1.00, p<0.001). Median OS increased over time (P1:P6, 18mo->32mo, p<0.001). Multivariable analysis shows that Adjuvant RT (HR 0.84 [0.81-0.87], p<0.001) and all CT (NCT: HR 0.71 [0.66-0.77], p<0.001; ACT: HR 0.63 [0.60-0.66], p<0.001; MACT: HR 0.65 [0.60-0.71], p<0.001) improved OS. Conclusions: This study shows decreased RT and increased CT adoption from 2004-2021. Median OS improved over the years, potentially due to peri-operative advances during this study period. Trends in treatment use over 3-year periods. RTN (%) CTN (%) Neo CTN (%) MACTN(%) P1: 2004-2006N=2661 1087 (41) 0 (0) a 0 (0) a 0 (0) a P2: 2007-2009N=3185 1185 (37) 2021 (63) 129 (4.1) 50 (1.6) P3: 2010-2012N=3536 1226 (35) 2460 (70) 267 (7.6) 138 (3.9) P4: 2013-2015N=3947 1210 (31) 2880 (73) 434 (11) 244 (6.2) P5: 2016-2018N=4224 971 (23) 3256 (77) 676 (16) 491 (12) P6: 2019-2021N=4351 787 (18) 3430 (79) 1003 (23) 857 (20) a No cohorts reported chemotherapy use during period 1. RT: Radiation Therapy; CT: Chemotherapy; NCT: Neoadjuvant Chemotherapy; MACT: Multiagent Chemotherapy.

A real-world study of treatment patterns among patients (pts) with metastatic colorectal cancer (mCRC) receiving third-line (3L) or fourth-line (4L) treatment in the US.

64 Background: There are limited real-world data describing 3L and 4L treatments for pts with mCRC. However, the landscape is evolving with new options becoming available, including fruquintinib, a highly selective oral inhibitor of all 3 VEGF receptors, approved by the US FDA in November 2023. This study aimed to understand pt characteristics and real-world treatment patterns in 3L and 4L to characterize the standard of care, adherence to guidelines, and identify unmet needs among pts with mCRC in the US, prior to recent changes in the landscape. Methods: A retrospective study of adults with mCRC who had received ≥3L of therapy between 1/1/2018 and 3/31/2023 in the US-based Flatiron electronic health records database. In two cohorts, defined by initiating 3L and 4L systemic treatment, pt demographics, clinical characteristics, and treatment by line of therapy were summarized. Results: Overall, 5401 pts were included in the 3L cohort and 2868 pts in the 4L cohort: median age at baseline was 63 and 62 years (yrs), 56% and 56% were male, 43% and 43% had a KRAS variant, and 46% and 49% had liver metastasis, respectively. 96% of pts in the 3L cohort received standard chemotherapy (CT) +/- targeted therapy as 1L treatment (55% CT + anti-vascular endothelial growth factor [VEGF] therapy; 34% CT only; 7% CT + anti-epidermal growth factor receptor [EGFR] therapy). In 2L, 87% of pts had standard CT-containing regimens (53% CT + anti-VEGF therapy; 19% CT alone; 15% CT + anti-EGFR therapy). A similar treatment history was observed for the 4L cohort. Commonly used 3L regimens in the 3L cohort were trifluridine/tipiracil (TAS-102; 11%), regorafenib (rego; 10%), and standard CT-containing regimens (54%; including: 12% FOLFIRI + bevacizumab [bev], 7% FOLFOX + bev, 4% FOLFIRI, 3% FOLFOX, and 15% standard CT + anti-EGFR therapy). Approximately 47% (n=2513) of pts did not receive subsequent treatments after 3L. In the 4L cohort, use of TAS-102 (16%) and rego (15%) increased slightly in 4L, accompanied with a moderate decrease in CT-containing regimens (42%; including 6% FOLFOX + bev, 5% FOLFIRI + bev, 3% FOLFOX, 3% FOLFIRI, and 12% standard CT + anti-EGFR therapy). Approximately 4% of pts in the 3L and 4L cohorts received TAS-102 + bev in 3L and 4L, respectively. Pts receiving standard CT-containing regimens were slightly younger (<65 yrs: 3L 57%, 4L 58%) and had better Eastern Cooperative Oncology Group performance status (ECOG PS; 0-1: 3L 77%, 4L 77%) vs pts receiving TAS-102 (<65 yrs: 3L 54%, 4L 58%; ECOG PS 0-1: 3L 70%, 4L 68%) or rego (<65 yrs: 3L 50%, 4L 53%; ECOG PS 0-1: 3L 68%, 4L 70%). Conclusions: Characterization of treatment patterns in US pts from 1/2018 to 3/2023 showed that standard CT +/- targeted therapy was used frequently in 3L and 4L, demonstrating an unmet need for additional therapies. Approval of novel treatments, such as fruquintinib, may help to address this need.

Neutrophils in cancer drug resistance: Roles and therapeutic opportunities.

The tumor microenvironment (TME) is closely associated with the therapeutic response and clinical outcome of cancer drug therapies, which mainly include immunotherapy, chemotherapy and targeted therapy. Neutrophils that infiltrate tumors, also known as tumor-associated neutrophils (TANs), constitute a primary part of the TME. However, the functional importance of TANs in cancer drug therapy has long been overlooked because of their relatively short life span. Recent studies have shown that TANs play crucial protumoral or antitumoral roles in cancer drug treatment, largely because of their diversity and plasticity. This review describes the development, heterogeneity and recruitment of neutrophils in the context of cancer and emphasizes the role and mechanisms of TANs in cancer drug resistance. Additionally, several potential neutrophil-targeted strategies are discussed.

Individual patient data (IPD) pooled analysis on the optimal therapeutic management of patients with microsatellite instability-high (MSI) resectable gastroesophageal adenocarcinoma (GEA).

455 Background: Patients with resectable MSI/dMMR GEA showed improved survival and modest if any benefit from chemotherapy. Preoperative treatment with immune checkpoint inhibition (ICI) showed high rate of major-complete pathologic response in single arm trials possibly allowing the design of chemotherapy/surgery-free approaches. Methods: This was a multinational IPD analysis including patients with resectable GEA with MSI/dMMR status enrolled in INFINITY and NEONIPIGA phase II trials, with dual CTLA-4/PD-(L)1 ICI followed by surgery +/- adjuvant ICI; PROSECCO retrospective study, with perioperative FLOT chemotherapy and surgery, and the dataset of our previous IPD analysis on MAGIC, CLASSIC, ARTIST and ITACA-S randomized trials of patients treated with surgery alone or plus older perioperative/adjuvant chemo(radio)therapy regimen. Primary endpoint was the evaluation of rates of pathologic complete response (pCR) defined as TRG1a Becker and major-complete pathologic response (pCR/MPR) defined as TRG1a/b Becker according to preoperative treatment schedule in patients who underwent surgery. Univariable and multivariable analyses were conducted using a random effects logistic model adjusted with propensity score. Secondary endpoints were event-free survival (EFS) and overall survival (OS) according to the therapeutic strategy in the overall study population. Multivariable mixed-effects Cox models weighted with propensity score were performed. Results: The IPD included 197 patients. Of these, 49 received ICI +/- surgery, 27 FLOT chemotherapy plus surgery, 33 surgery alone and 88 older chemo(radio)therapy regimens plus surgery. In the 69 patients resected after neoadjuvant ICI or FLOT standard of care treatment, ICI demonstrated a higher rate of pathologic response compared to chemotherapy (pCR 61.9% vs 3.7%, OR 54.8 p=0.002; pCR/MPR 78.6% vs 10%, OR 39.3 p<0.001). In ITT population, no significant difference in OS and EFS was shown in patients treated with ICI, FLOT plus surgery, old chemo(radio)therapy plus surgery or surgery alone. Conclusions: In resectable MSI/dMMR GEA, upfront ICI showed comparable survival outcomes to surgery alone, with limitations of study design and sample size. The impact on survival of ICI versus surgery alone should be investigated prospectively to avoid overtreatment or identify specific risk categories with benefit. The high rate of major-complete pathologic response may allow to study or perform organ sparing surgery procedures or non-operative management to reduce surgical morbidity/mortality and improve quality of life. OS EFS HR 2.5-97.5% CI p HR 2.5-97.5% CI p Ref: Surgery only - - - - - - Chemo+surgery 1.16 0.27-4.98 0.84 1.10 0.39-3.07 0.85 FLOT+surgery 1.10 0.19-6.22 0.92 2.38 0.90-6.27 0.08 ICI +/- surgery 1.97 0.43-8.96 0.38 1.39 0.51-3.77 0.52

Investigation of synergistic effects in trials of combination therapies with immune-checkpoint inhibitors in advanced gastric or gastroesophageal junction cancer.

405 Background: Combinations of immune checkpoint inhibitors (ICI) and chemotherapy (CT) have been approved for gastric cancer. However, there is a hypothesis that this combination may blunt antitumor immune responses because most chemotherapeutic agents also target lymphocytes. The primary objective was to investigate that the ICI and CT does not interfere each other’s therapeutic effects in advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) patients. Methods: The reconstructed individual patient data was electronically extracted from the Kaplan-Meier curve of phase III randomized controlled trials (RCTs). The observed PFS curve of each constituent monotherapies was used to estimate simulated PFS curves expected under a model of independent drug action. If the observed curve demonstrated significantly better PFS than simulated curve, the combination of ICI and CT may have a synergistic effect, implying a superior outcome compared to simply adding the component monotherapy. Results: The study included 2,538 unresectable advanced, recurrent, or metastatic GC or GEJC patients from three RCTs comparing pembrolizumab (KEYNOTE-061, KEYNOTE-062 and KEYNOTE-859). In patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater, the 1-year and median PFS of the observed and simulated curves were 28.0% vs. 27.9%, and 6.89 months vs. 6.88 months, respectively. One sample log-rank test showed no significant differences between the observed and simulated curves (p = 0.107). In the subgroups with PD-L1 CPS ≥10 or <1, the 1-year PFS of the observed and simulated curves was 34.7% vs 32.8%, and 28.5% vs 26.8%. Conclusions: The observed PFS of ICT involving pembrolizumab was comparable to the simulated PFS estimated from the data for each monotherapy regardless of the magnitude of PD-L1 CPS. Although it was not clear whether potential synergies existed for ICT, these findings at least suggest that the benefits of ICI and CT are not interfering each other, thereby providing theoretical support for the efficacy of ICT in patients with advanced GC or GEJC.

Real-world biomarker testing patterns, first line treatment and drivers of treatment choice in patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma in the United States and Europe.

353 Background: For first line (1L) treatment (tx) in HER2- gastric/gastroesophageal junction (G/GEJ) adenocarcinoma (AC), clinical guidelines recommended platinum-fluoropyrimidine (PF) chemotherapy (CT) in patients (pts) with a PD-L1 combined positive score (CPS) <5 and PF CT in combination with immunotherapy (IO) for CPS ≥5. There is little contemporary evidence into IO tx uptake in the real world. This real world study examined biomarker testing, 1L tx characteristics, and reasons for 1L tx choice in pts with HER2- G/GEJ AC to identify unmet needs and opportunities for optimal clinical practice. Methods: Data were derived from the Adelphi G/GEJ Cancer Disease Specific Programme: a systematic approach involving multi-national, multi-faceted data sources including cross-sectional surveys capturing data from physicians and their consulting pts. Physicians reported pt demographics, clinical characteristics, tx received and reasons for tx decisions, via chart review. Data were collected across US and Europe (EU: France, Germany, Spain, the UK) between Oct 2022 to Apr 2023. All pts were alive at data collection and analyses were descriptive. Results: Overall, 243 treating physicians (US n=60/EU n=183) provided data on 642 HER2- pts (US n=83/EU n=559) receiving 1L tx at data collection. For pts from US/EU, median age was 66/67 years, 84%/79% had an ECOG of 0-1 and 52%/75% had metastatic disease at data collection. In the US/EU, 87%/80% of pts were tested for PD-L1 status respectively, of which 63%/69% had a known CPS. For US/EU, 67%/45% of pts (n=30/n=139) had a CPS ≥5. Differences in biomarker testing rates were observed in US v EU pts respectively for MSI/dMMR (66% v 58%), NTRK-gene fusion (31% v 4%) and FGFR2 (27% v 3%). Of US/EU physicians, 70%/85% (n=60/n=183), reported the main reason for conducting biomarker testing was ‘to inform tx decisions’. Cost related concern (50%/39%) and time constraints (23%/15%) were the main perceived barriers to testing. Among pts with PD-L1 CPS <5, 27% of US pts and 2% of EU pts received IO + CT; in pts with CPS ≥5, 63% of US pts and 76% of EU pts received IO + CT. Whilst progression free survival/overall survival benefit were the most common reasons selected by physicians for 1L tx choice across the US/EU (75%/74% and 60%/61%), differences across regions were reported for tx choice based on maintaining and improving pt’s QoL (4%/28%) and pt’s performance status (2%/24%). Conclusions: PD-L1 testing was not performed by 19% of physicians and approximately one third of pts with CPS ≥5 across the US/EU were not receiving IO + CT in 1L. As informing 1L tx choice was a key driver for biomarker testing, there may be scope for improvement in 1L tx by increasing testing rates. Further studies are needed to address barriers to biomarker testing and uptake of IO in pts who can benefit from 1L IO tx.