Failure Of Chemotherapy Research Articles

Zinc Oxide Nanoparticles and Cancer Chemotherapy: Helpful Tools for Enhancing Chemo-sensitivity and Reducing Side Effects?

Cancer chemotherapy is still a serious challenge. Chemo-resistance and destructive side effects of chemotherapy drugs are the most critical limitations of chemotherapy. Chemo-resistance is the leading cause of chemotherapy failure. Chemo-resistance, which refers to the resistance of cancer cells to the anticancer effects of chemotherapy drugs, is caused by various reasons. Among the most important of these reasons is the increase in the efflux of chemotherapy drugs due to the rise in the expression and activity of ABC transporters, the weakening of apoptosis, and the strengthening of stemness. In the last decade, a significant number of studies focused on the application of nanotechnology in cancer treatment. Considering the anti-cancer properties of zinc, zinc oxide nanoparticles have received much attention in recent years. Some studies have indicated that zinc oxide nanoparticles can target the critical mechanisms of cancer chemo-resistance and enhance the effectiveness of chemotherapy drugs. These studies have shown that zinc oxide nanoparticles can reduce the activity of ABC transporters, increase DNA damage and apoptosis, and attenuate stemness in cancer cells, leading to enhanced chemo-sensitivity. Some other studies have also shown that zinc oxide nanoparticles in low doses can be helpful in minimizing the harmful side effects of chemotherapy drugs. In this article, after a brief overview of the mechanisms of chemo-resistance and anticancer effects of zinc, we will review all these studies in detail.

The DDUP protein encoded by the DNA damage-induced CTBP1-DT lncRNA confers cisplatin resistance in ovarian cancer

Sustained activation of DNA damage response (DDR) signaling has been demonstrated to play vital role in chemotherapy failure in cancer. However, the mechanism underlying DDR sustaining in cancer cells remains unclear. In the current study, we found that the expression of the DDUP microprotein, encoded by the CTBP1-DT lncRNA, drastically increased in cisplatin-resistant ovarian cancer cells and was inversely correlated to cisplatin-based therapy response. Using a patient-derived human cancer cell model, we observed that DNA damage-induced DDUP foci sustained the RAD18/RAD51C and RAD18/PCNA complexes at the sites of DNA damage, consequently resulting in cisplatin resistance through dual RAD51C-mediated homologous recombination (HR) and proliferating cell nuclear antigen (PCNA)-mediated post-replication repair (PRR) mechanisms. Notably, treatment with an ATR inhibitor disrupted the DDUP/RAD18 interaction and abolished the effect of DDUP on prolonged DNA damage signaling, which resulted in the hypersensitivity of ovarian cancer cells to cisplatin-based therapy in vivo. Altogether, our study provides insights into DDUP-mediated aberrant DDR signaling in cisplatin resistance and describes a potential novel therapeutic approach for the management of platinum-resistant ovarian cancer.

Photoactivated DNA Nanodrugs Damage Mitochondria to Improve Gene Therapy for Reversing Chemoresistance.

Multidrug resistance (MDR) is a major cause of chemotherapy failure in oncology, and gene therapy is an excellent measure to reverse MDR. However, conventional gene therapy only modulates the expression of MDR-associated proteins but hardly affects their existing function, thus limiting the efficiency of tumor treatment. Herein, we designed a photoactivated DNA nanodrug (MCD@TMPyP4@DOX) to improve tumor chemosensitivity through the downregulation of MDR-related genes and mitochondria-targeted photodynamic therapy (PDT). The self-assembled DNA nanodrug encodes the mucin 1 (MUC1) aptamer and the cytochrome C (CytC) aptamer to facilitate its selective targeting to the mitochondria in tumor cells; the encoded P-gp DNAzyme can specifically cleave the substrate and silence MDR1 mRNA with the help of Mg2+ cofactors. Under near-infrared (NIR) light irradiation, PDT generates reactive oxygen species (ROS) that precisely damage the mitochondria of tumor cells and break single-stranded DNA (ssDNA) to activate MCD@TMPyP4@DOX self-disassembly for release of DOX and DNAzyme. We have demonstrated that this multifunctional DNA nanodrug has high drug delivery capacity and biosafety. It enables downregulation of P-gp expression while reducing the ATP on which P-gp pumps out drugs, improving the latency of gene therapy and synergistically reducing DOX efflux to sensitize tumor chemotherapy. We envision that this gene-modulating DNA nanodrug based on damaging mitochondria is expected to provide an important perspective for sensitizing tumor chemotherapy.

Cancer Cell Membrane-Enveloped Dexamethasone Normalizes the Tumor Microenvironment and Enhances Gynecologic Cancer Chemotherapy.

The aberrant tumor microenvironment (TME), especially immature and leaky vessels, prevents the penetration and accumulation of chemotherapeutics and results in the failure of chemotherapy to treat gynecologic cancer. Herein, dexamethasone (Dex), a glucocorticoid steroid used to moderate tumor extracellular matrix and normalize vessels, was enclosed within a biocompatible material known as poly(lactic-co-glycolic acid) (PLGA), and the obtained Dex@PLGA was further coated with a mouse cervical cancer cell membrane (CM). The formulated Dex@PLGA-CM nanoparticles showed efficient extravascular diffusion within the tumor owing to the homologous targeting abilities inherited from the source cancer cells. The Dex@PLGA-CM nanoparticles greatly reshaped the TME, enhancing the penetration of Doxil and thus markedly improving the therapeutic effect of this drug against cervical cancers. Excitingly, the Dex@PLGA-CM nanoparticles coated with mouse ovarian cancer cell membranes also promoted Doxil-mediated chemotherapy effects in metastatic ovarian cancer when administered intraperitoneally. This work presents an effective nanomedicine for the efficient modification of the TME to enhance the effects of gynecologic cancer chemotherapy.

Efficacy and safety of sintilimab plus bevacizumab in metastatic nasopharyngeal carcinoma after failure of platinum-based chemotherapy: an open-label phase 2 study

There are limited treatment options for patients with metastatic nasopharyngeal carcinoma (mNPC) after failure of platinum-based chemotherapy. In this trial, we assessed the efficacy and safety of sintilimab plus bevacizumab in patients with mNPC where platinum-based chemotherapy has been ineffective. This was a single-centre, open-label, single-arm, phase 2 trial in Guangzhou, China for patients with mNPC progressed after at least one line of systemic therapy. Eligible patients were between 18 and 75 years old, were histologically confirmed differentiated or undifferentiated non-keratinized NPC, were ineffective after platinum-based chemotherapy, and they had at least one measurable metastatic lesion assessed with Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST V.1.1) by investigators and unsuitable for local surgery or radiotherapy. Key exclusion criterion was previous treatment with anti-PD-1/PD-L1 antibodies plus anti-VEGF antibodies and high risk of hemorrhage or nasopharyngeal necrosis. Patients were enrolled and received sintilimab (200mg) plus bevacizumab (7.5mg/kg) intravenously every 3 weeks. Intention-to-treat population was included in primary endpoint analyses and safety analyses. The primary endpoint was objective response rate (ORR) assessed by investigators following the guidelines of RECIST V1.1. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. This trial is registered with ClinicalTrials.gov (NCT04872582). Between July 29, 2021 and August 16, 2022, 33 patients were enrolled. Median age was 46 years (range, 18-64 years), and 63.6% of patients had previously received two or more lines of chemotherapy for metastatic disease. Median follow-up was 7.6 months (range, 4.1-17.5 months). ORR was 54.5% (95% CI, 36.4-71.9%) with 3 complete responses (9.1%) and 15 partial responses (45.5%). Median PFS was 6.8 months (95% CI, 5.2 months to not estimable). Median DOR was 7.2 months (95% CI, 4.4 months to not estimable). Median OS was not reached. The most common potential immune-related adverse event (AE) was Grade 1-2 hypothyroidism (42.4%). Treatment-related grade 3 or 4 AEs occurred in 7 patients (21.2%), including nasal necrosis (3/33), hypertension (1/33), pruritus (1/33), total bilirubin increased (1/33) and anaphylactic shock (1/33). No treatment-related deaths and severe epistaxis occurred. This phase 2 trial showed that sintilimab plus bevacizumab demonstrated promising antitumour activity and manageable toxicities in patients with mNPC after failure of platinum-based chemotherapy. Further trials are warranted, and the detailed mechanisms need to be elucidated. The Guangdong Basic and Applied Basic Research Foundation, the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province, and the Science and Technology Planning Project of International Cooperation of Guangdong Province.

Combined doxorubicin and arctigenin treatment induce cell cycle arrest-associated cell death by promoting doxorubicin uptake in doxorubicin-resistant breast cancer cells.

Chemotherapy failure is often caused by drug resistance, for which no effective treatment strategy has been established. Many studies have been undertaken with the aim of overcoming drug resistance using natural products. Arctigenin (ATG), a natural product, has been investigated for its anti-cancer effects in HER2-overexpressing, ER-positive, and triple-negative breast cancer cells. We investigated the efficacy of ATG against self-established doxorubicin (DOX)-resistant breast cancer cells (MCF-DR and MDA-DR cells) derived from MCF-7 and MDA-MB-231 cells, respectively. ATG was found to increase DOX intracellular levels by downregulating multidrug Resistance 1 (MDR1) mRNA expression in DOX-resistant cells. In addition, combined treatment with DOX and ATG (DOX/ATG) reduced the viability of and colony formation by DOX-resistant cells. DOX/ATG also significantly induced G2/M cell cycle arrest by suppressing the Cyclin D1/CDK4/RB pathways and suppressed the expressions of MDR1 and Cyclin D1 by inhibiting the Mitogen-activated protein kinase (MAPK)/Activating protein-1 (AP-1) signaling pathways. Furthermore, DOX/ATG induced DNA damage and attenuated the expressions of RAD51 and Ku80. However, PARP1 (Poly [ADP-ribose] polymerase1) cleavage and AIF (Apoptosis-inducing factor) induced apoptosis did not occur despite DNA damage-induced cell death. Rather, flow cytometry showed that DOX/ATG caused necrosis. In summary, DOX/ATG increased intracellular DOX levels by inhibiting MDR1 and inducing G2/M arrest by inhibiting the Cyclin D1/CDK4/RB pathways and causing necrosis by damaging DNA. Our results suggest that ATG might be used as an adjuvant to enhance the efficacy of DOX in DOX-resistant breast cancer.

CopA3 treatment suppressed multidrug resistivity in HCT-116 cell line by p53-induced degradation of hypoxia-inducible factor 1α

The major reason for multidrug resistance is the failure of chemotherapy in many tumors, including colon cancer. Hypoxia-inducible factor (HIF)-1α is a crucial transcription factor that simulates multiple cellular response to hypoxia. HIF-1α has been known to play a vital role towards tumor resistance; however, its mechanism of action is still not fully elucidated. N this study, we found that HIF-1α remarkably modulated drug resistance-associated proteins upon CopA3 peptide treatment against colon cancer cells. Abnormal rates of tumor growth along with high metastatic potential lacks the susceptibility towards cellular signals is a key characteristic in many tumor types. Moreover, in growing tumors, cells are exposed to insufficient nutrient supply and low oxygen availability. These stress force them to switch into adaptable and aggressive phenotypes. Our study investigated the interaction of HIF-1α and MDR gene association upon CopA3 treatment in the tumor microenvironment. We demonstrate that the multidrug resistance gene is associated with tumor resistance to chemotherapeutics, which upon CopA3 treatment promotes p53 activation and proteasomal degradation of HIF-1α, effecting the angiogenesis response to hypoxia. p53 downregulation augments HIF-1-dependent transcriptional activation of VEGF in response to oxygen deprivation.

Propranolol, Promising Chemosensitizer and Candidate for the Combined Therapy through Disruption of Tumor Microenvironment Homeostasis by Decreasing the Level of Carbonic Anhydrase IX

Resistance to chemotherapy represents a persisting medical problem, ranking among main causes of chemotherapy failure and cancer mortality. There is a possibility to utilize and repurpose already existing therapeutics which were not primarily intended for oncological treatment. Overactivation of adrenergic receptors and signaling dysregulation promotes tumor progression, metastatic potential, immune system evasion, tumor angiogenesis and drug resistance. The non-selective beta-blocker propranolol, approved in infantile haemangioma treatment, has a high potential for use in cancer therapy. We analyzed the effects of propranolol and 5-fluorouracil combination on sensitive and resistant cells derived from colorectal carcinoma in monolayers, single-component and co-culture spheroids and in vivo mouse models. Our results revealed that propranolol is able to exert its effect not only in chemosensitive colorectal cells, but also in 5-fluorouracil resistant cells. Propranolol disrupts the hypoxic adaptation machinery by inhibiting HIF1α, carbonic anhydrase IX, and activates apoptosis, which may be important in the management of chemo-resistant patients. We showed that propranolol slows down the growth of xenografts formed from colorectal cancer cells, even from cells already adapted to the β-blocker. We provide clear evidence that blockade of β-adrenergic receptors affects essential signaling pathways modulating tumor microenvironment and thus the response to anticancer therapy. Our findings indicate that propranolol could be repurposed to serve as chemosensitizer in combined therapy aimed at disrupting homeostasis of tumor microenvironment.

Transcriptome Profiling of Cisplatin Resistance in Triple-negative Breast Cancer: New Insight into the Role of PI3k/Akt Pathway.

Aggressive nature of triple negative breast cancer (TNBC) is associated with poor prognosis compared with other breast cancer types. Current guidelines recommend the use of Cisplatin for the management of TNBC. However, the development of resistance to cisplatin is the primary cause of chemotherapy failure. In the present study, we aimed to develop a stable cisplatin-resistant TNBC cell line to investigate the key pathways and genes involved in cisplatin-resistant TNBC. The MDA-MB-231 cell was exposed to different concentrations of cisplatin. After 33 generations, cells showed a resistant phenotype. Then, RNA-sequencing analysis was performed in cisplatin-resistant and parent cell lines. The RNA-sequencing data was verified by quantitative PCR (qPCR). The IC50 of the resistant cell increased to 10-fold of a parental cell (p<0.001). Also, cisplatin-resistant cells show cross-resistance to other drugs, including 5- fluorouracil, paclitaxel, and doxorubicin. Resistant cells demonstrated reduced drug accumulation compared to the parental cells. Results showed there were 116 differentially expression genes (DEGs) (p<0.01). Gene ontology analysis revealed that the DEGs have several molecular functions, including binding and transporter activity. Functional annotation showed that the DEGs were enriched in the drug resistancerelated pathways, especially the PI3K-Akt signaling pathway. The most important genes identified in the protein-protein interaction network were heme oxygenase 1 (HMOX1) and TIMP metallopeptidase inhibitor 3 (TIMP3). We have identified several pathways and DEGs associated with the PI3KAkt pathway, which provides new insights into the mechanism of cisplatin resistance, and potential drug targets in TNBC.

The role of TCGA molecular classification in clear cell endometrial carcinoma.

Clear cell endometrial carcinoma (CCEC) represents a relatively rare and heterogeneous entity. Based on The Cancer Genome Atlas (TCGA) molecular classification, the risk stratification and management of endometrial cancer (EC) have been improved. Although the relationship of CCEC with the TCGA classification is less well understood, data has emerged to suggest that molecular classification plays an important role in the prognosis and management of CCEC. Most of patients with CCEC are characterized by p53abn or NSMP type and the prognosis of these patients is poor, whereas those with MMRd or POLEmut seem to have a favorable prognosis. Adjuvant therapy is recommended in CCEC with p53abn and NSMP. Advanced/recurrent CCEC with MMRd benefit much more from immune checkpoint inhibitors after the failure of platinum-based chemotherapy. In addition, bevacizumab plus chemotherapy upfront seems to improve outcomes of advanced/recurrent patients whose tumors harbored mutated TP53, including CCECs with p53abn. Further studies which exclusively recruit CCEC are urgently needed to better understand the role of molecular classification in CCEC. This review will provide an overview of our current understanding of TCGA classification in CCEC.

Raptor couples mTORC1 and ERK1/2 inhibition by cardamonin with oxidative stress induction in ovarian cancer cells.

A balance on nutrient supply and redox homeostasis is required for cell survival, and increased antioxidant capacity of cancer cells may lead to chemotherapy failure. To investigate the mechanism of anti-proliferation of cardamonin by inducing oxidative stress in ovarian cancer cells. After 24 h of drug treatment, CCK8 kit and wound healing test were used to detect cell viability and migration ability, respectively, and the ROS levels were detected by flow cytometry. The differential protein expression after cardamonin administration was analyzed by proteomics, and the protein level was detected by Western blotting. Cardamonin inhibited the cell growth, which was related to ROS accumulation. Proteomic analysis suggested that MAPK pathway might be involved in cardamonin-induced oxidative stress. Western blotting showed that cardamonin decreased Raptor expression and the activity of mTORC1 and ERK1/2. Same results were observed in Raptor KO cells. Notably, in Raptor KO cells, the effect of cardamonin was weakened. Raptor mediated the function of cardamonin on cellular redox homeostasis and cell proliferation through mTORC1 and ERK1/2 pathways.

Efficacy and safety of sintilimab plus bevacizumab in metastatic nasopharyngeal carcinoma after failure of platinum-based chemotherapy: An open-label phase II study.

6031 Background: There are limited treatment options for patients with metastatic nasopharyngeal carcinoma (mNPC) after failure of platinum-based chemotherapy. In this trial, we assessed the efficacy and safety of sintilimab plus bevacizumab in mNPC patients where platinum-based chemotherapy has failed. Methods: This was a single-center, open-label, single-arm, phase II trial for mNPC patients progressed after at least one line of systemic therapy. Patients were enrolled and received sintilimab (200 mg) plus bevacizumab (7.5mg/kg) intravenously every 3 weeks. The primary end point was objective response rate (ORR) assessed by investigators following the guidelines of RECIST 1.1. Key secondary end points were progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. This trial is registered with ClinicalTrials.gov (NCT04872582). Results: Thirty-three patients were enrolled. Median age was 46 years (range, 18-64 years), and 63.6% of patients had previously received two or more lines of chemotherapy for metastatic disease. Median follow-up was 7.6 months (range, 4.1-17.5 months). ORR was 54.5% (95% CI, 36.4- 71.9%) with 3 complete responses (9.1%) and 15 partial responses (45.5%). Median PFS was 6.8 months (95% CI, 5.2 months to not estimable). Median DOR was 7.2 months (95% CI, 4.4 months to not estimable). Median OS was not reached. The most common potential immune-related AE was grade 1-2 hypothyroidism (42.4%). Treatment-related grade 3 or 4 adverse events (AEs) occurred in 7 patients (21.2%), including nasal necrosis (9%), hypertension (3%), pruritus (3%), total bilirubin increased (3%) and anaphylactic shock (3%). No treatment-related deaths and severe epistaxis occurred. Conclusions: This phase II trial showed that sintilimab plus bevacizumab demonstrated promising antitumor activity and manageable toxicities in mNPC patients after failure of platinum-based chemotherapy. Clinical trial information: NCT04872582 .

IDH inhibitors or chemotherapy in relapsed or refractory IDHmut acute myeloid leukemia.

e19043 Background: Venetoclax and IDH inhibitors provide novel treatment options for acute myeloid leukemia (AML). The optimal sequencing of these therapies in the relapsed or refractory setting remains unknown. The purpose of this study was to analyze the overall survival of patients receiving IDH inhibitors, venetoclax-based lower-intensity therapy, and conventional chemotherapy with fludarabine-based regimens in patients undergoing salvage following failure of intensive chemotherapy. Methods: We identified 74 patients with IDH1mut or IDH2mut mutated AML treated from January 1, 2013 to January 1, 2022 at VCU Massey Cancer Center in this single-institution, retrospective study. Forty-eight patients were treated with front-line intensive induction, 19 of whom had relapsed or refractory disease. These were grouped into three salvage cohorts: IDH inhibitors with or without a hypomethylating agent (HMA) (N = 3), intensive fludarabine-based salvage (FLAG) (N = 9), and venetoclax + HMA (N = 7). Patients who received more than one of these salvage therapies were excluded from the analysis. Performance status, disease characteristics, and treatment regimens at salvage were recorded. Demographics of the three cohorts were compared using the Kruskal-Wallis test; we computed the overall survival with the Kaplan-Meier method, using the log-rank test for comparison. Patients alive at the end of the study or lost to follow-up were censored on the date of last contact. Results: Patients in the FLAG cohort were significantly younger than the IDH inhibitor or venetoclax cohorts ( p = 0.009). Patients in the venetoclax cohort had significantly more comorbidities assessed by the Charlson Comorbidity Index score ( p = 0.026) than the intensive chemotherapy salvage cohort. ELN 2022 genetic risk was not significantly different between cohorts ( p = 0.263). In the IDH inhibitor cohort, the median overall survival was not reached at a median follow-up time of 11.8 months. The median overall survival of the FLAG cohort was 14.3 months, and the median survival of the venetoclax cohort was 9.4 months. Overall survival significantly favored the IDH inhibitor cohort ( p = 0.030). The FLAG cohort was associated with significantly improved survival compared to the venetoclax cohort ( p = 0.048). Conclusions: Despite patients in the IDH inhibitor cohort being significantly older, the use of IDH inhibitors, with or without a hypomethylating agent, in the second line following the failure of intensive chemotherapy was associated with significantly superior overall survival compared to FLAG or venetoclax-based salvage. These findings should be interpreted with caution, given the limitations of retrospective studies and significantly elevated comorbidities in the venetoclax cohort. Prospective trial designs are needed to provide further evidence for optimal therapeutic sequencing.

Docetaxel as a subsequent line after progression to platinum-based chemotherapy and immunotherapy.

e21197 Background: Docetaxel was the standard of care for patients with non-small cell lung cancer (NSCLC) after platinum-based chemotherapy failure. The introduction of immune checkpoint inhibitors (ICIs) has radically altered the first-line treatment for advanced/metastatic NSCLC without driver mutations. However, limited clinical data are known after failure of chemotherapy and immunotherapy. Efficacy of docetaxel after progressing to platinum-based chemotherapy and checkpoint inhibitors are scarce. The aim of this study is to evaluate docetaxel in patients with advanced NSCLC after chemotherapy and ICIs failure in a real-world scenario. Methods: Retrospective, single centre study, including patients treated with docetaxel after progression to platinum-based chemotherapy and immunotherapy. We analysed demographic characteristics, treatments received and survival. Long survivors to Docetaxel were defined as those who lived more than 12 months after initiating Docetaxel. Results: 65 patients were included in this study. Median age was 67.0 years and 67.7% were male. 63.1% were adenocarcinoma, 24.6% squamous-cell carcinoma and 12.3% other histologies. Objective response rate (ORR) for docetaxel was 21.0%, with a control disease rate of 42.1%. 55.7% experienced toxicity from the treatment. Median progression-free survival (PFS) and overall survival (OS) were respectively 2.0 months (1.3-2.7, IQ 95%) and 6.0 months (4.6-7.4, IQ 95%). 16 patients (24.6%) were long survivors. Differential characteristics of long survivors are shown in Table. Conclusions: Docetaxel displayed poor survival results in our study after progression to platinum-based chemotherapy and ICIs, arising the necessity of developing new therapies for this scenario. Despite these results, almost 25% of the patients lived more than one year. Objective response to docetaxel was significantly associated with surviving more than one year, and better ECOG and lacking hepatic metastases showed a non-significant trend. Clinical biomarkers predicting benefit of Docetaxel in this scenario are lacking. [Table: see text]

Outcomes of stage IV non-small cell lung cancer patients after failure of platinum-based chemotherapy in clinical trials and real-world settings: A literature review.

e18859 Background: To report the outcomes of therapeutic regimens being evaluated for patients with stage IV non-small cell lung cancer (NSCLC) that has progressed on or after platinum-based chemotherapy in clinical trial and real-world settings. Methods: A systematic literature review was undertaken to identify clinical trials and real-world studies evaluating treatments for stage IV NSCLC after progression with platinum-based chemotherapy. Studies were included in the review if they were published between September 2017 and September 2021, in English, and included an outcome of interest. The outcomes of interest were overall response rate, progression-free survival, overall survival, the incidence of grade 3-4 adverse events, and discontinuation due to adverse events. Results: A total of 23 studies were identified, comprising of 17 clinical trials and six real-world studies. The total sample size ranged from 12 to 1,253 patients in clinical trials and 11 to 383 patients in real-world studies. A total of 28 and six treatment regimens were evaluated within the clinical trials and real-world studies respectively. Six clinical trials evaluated outcomes in the second-line setting, one in the third-line, three in a mix of second-line and above, and seven did not report the specific treatment line(s). There were no real-world studies exclusively in the second-line setting, one in the third-line, three in a mix of second-line and above, and two did not report the specific treatment line(s). Ramucirumab + docetaxel was the only treatment regimen evaluated in both the clinical trial and real-world studies. In the real-world studies, nivolumab was the most common treatment evaluated (n = 3). The real-world studies were conducted in India (n = 2), China, Colombia, Germany, and the United States. The overall response rate (ORR) ranged from 3% to 66% and a rate of &gt; 15% was reported for one or more treatment regimens in 86% (12/14) of clinical trials. ORR ranged from 10% to 36% in real-world studies. Median progression-free survival ranged from 1 to 5 months in clinical trials and 3 to 8 months in real-world studies. In clinical trials, a median PFS of &gt; 6 months was observed in 71% (10/14) of studies. Median overall survival (OS) ranged from 5 to 15 months in clinical trials and 3 to 18 months in real-world studies. Discontinuation due to adverse events ranged from 3-15% in clinical trials and 9-20% in real-world studies. Conclusions: Patients with stage IV NSCLC that has progressed on or after platinum-based chemotherapy experienced a limited response and a high burden of adverse events with the treatment regimens evaluated in both the clinical trial and real-world settings.

IFCT-2105 lurbiclin real-world effectiveness and treatment sequences in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) who received lurbinectedin as part of the French Early Access Program (EAP-ATU).

8584 Background: Novel options are needed for pts with ES-SCLC after the failure of first-line chemotherapy. Lurbinectedin demonstrated efficacy in a landmark phase II study [Trigo et al. Lancet Oncol. 2020 May;21(5):645], and was granted EAP-ATU in France in June 2020. Methods: Multicenter, retrospective cohort of consecutive pts with histologically or cytologically confirmed ES-SCLC, who received at least one dose of treatment with lurbinectedin as part of the French EAP-ATU from June 2020 until March 2021, and gave consent for the data collection, were enrolled in 47 sites. Primary and secondary endpoints were description of clinical characteristics, and exposure to treatment, response, PFS, OS, safety. Results: 312 pts – 64% male, median age 65 years, 72% PS0-1, 47% with brain metastasis, 58% with previous immunotherapy – were enrolled. Lurbinectedin was administered as second-line in 44% of pts; 58% were chemotherapy-refractory. Pts received a median number of 3 cycles of lurbinectedin. Concurrent radiotherapy on metastases was delivered to 38% of pts. Lurbinectedin was discontinued because of progression/death/toxicity/other reasons in 83%/8%/5%/4% of pts. Grade3/4 events were observed in 9%/5% of pts. Response rate was 22% [95%CI 17-27%], disease control rate was 38% [95%CI 32-44%]. After a median follow-up of 20.8 months, median PFS and OS were 1.9 [95%CI 1.8-2] and 4.7 [95%CI 4-5.4] months; 6-month PFS and OS were 7% [4-10%] and 42% [95%CI 37-48%]. PS≤2 and chemotherapy-free interval≥90days were associated with significantly longer OS (HR = 0.71 [95%CI 0.53-0.95] and HR = 0.58 [95% CI 0.44-076] respectively). Main sites of progression were the lung (39% of pts), the brain (39% of pts), the liver (30% of pts), and the mediastinum (30% of pts). Subsequent treatment was administered to 154 pts after discontinuation of lurbinectedin, mostly consisting of topotecan (26% of pts); response/disease control rates, and median PFS of first subsequent treatment were 11% [95%CI 6-17%], 35% [95%CI 27-44%], and 1.9 [95%CI 1.7-2.3] months. Conclusions: Lurbinectedin provides an additional option from second-line for ES-SCLC, with efficacy outcomes comparable to that of historical treatments.

Efficacy and safety of nivolumab for patients with pre-treated type B3 thymoma and thymic carcinoma: results from the EORTC-ETOP NIVOTHYM phase II trial

Thymic malignancies are rare intrathoracic tumors, which may be aggressive and difficult to treat. They represent a therapeutic challenge in the advanced/metastatic setting, with limited treatment options after the failure of first-line platinum-based chemotherapy. They are frequently associated with autoimmune disorders that also impact oncological management. NIVOTHYM is an international, multicenter, phase II, two-cohort, single-arm trial evaluating the activity and safety of nivolumab [240 mg intravenously (i.v.) q2 weeks] alone or with ipilimumab (1 mg /kg i.v. q6 weeks) in patients with advanced/relapsed type B3 thymoma or thymic carcinoma, after exposure to platinum-based chemotherapy. The primary endpoint is progression-free survival rate at 6 months (PFSR-6) based on RECIST 1.1 as per independent radiological review. From April 2018 to February 2020, 55 patients were enrolled in 15 centers from 5 countries. Ten patients (18%) had type B3 thymoma and 43 (78%) had thymic carcinoma. The majority were male (64%), and the median age was 58 years. Among the 49 eligible patients who started treatment, PFSR-6 by central review was 35% [95% confidence interval (CI) 22% to 50%]. The overall response rate and disease control rate were 12% (95% CI 5% to 25%) and 63% (95% CI 48% to 77%), respectively. Using the Kaplan-Meier method, median progression-free survival and overall survival by local assessment were 6.0 (95% CI 3.1-10.4) months and 21.3 (95% CI 11.6-not estimable) months, respectively. In the safety population of 54 patients, adverse events (AEs) of grade 1/2 were observed in 22 (41%) patients and grade 3/4 in 31 (57%) patients. Treatment-related AEs of grade 4 included one case of neutropenia, one case of immune-mediated transaminitis, and two cases of myocarditis. Nivolumab monotherapy demonstrated an acceptable safety profile and objective activity, although it has been insufficient to meet its primary objective. The second cohort of NIVOTHYM is currently ongoing to assess the combination of nivolumab plus ipilimumab.

Alliance A092104: A randomized phase 2/3 study of olaparib plus temozolomide versus investigator’s choice for the treatment of patients with advanced uterine leiomyosarcoma after progression on prior chemotherapy.

TPS11584 Background: Uterine leiomyosarcoma (uLMS) is an aggressive sarcoma subtype with frequent metastatic relapse. Advanced uLMS is treated with gemcitabine/docetaxel or anthracycline-based regimens. After failure of initial chemotherapy, remaining options provide limited benefit (trabectedin: objective response rate (ORR) 11%, median progression-free survival (mPFS) 4.0 months (mo); pazopanib: ORR 11%, mPFS 3.0 mo; dacarbazine: ORR 9%, mPFS 1.5 mo). 18-23% of uLMS harbor deleterious alterations in homologous recombination (HR) DNA repair genes. HR-deficient cancers are unable to effectively repair double-stranded DNA breaks and may be sensitive to poly ADP-ribose polymerase (PARP) inhibitor-based strategies. In preclinical studies, the combination of temozolomide (T), an alkylating agent, and olaparib (O), a PARP inhibitor, markedly suppressed proliferation of uLMS models. Among 22 uLMS patients with median 3 prior lines, O+T demonstrated mPFS 6.9 mo and ORR 27% (Ingham M. et al. ASCO 2021: #11506). In correlative analysis, alterations in HR genes including PALB2 and RAD51B or absence of RAD51 foci formation by a functional assay were observed in patients with prolonged PFS (Bose S. et al. ASCO 2022: #11509). Based on these results, we designed a randomized phase 2/3 study to further evaluate O+T in advanced, pretreated uLMS. Methods: Alliance for Clinical Trials in Oncology A092104 is a randomized, open-label phase 2/3 clinical trial of O+T versus investigator’s choice in advanced uLMS. Eligible patients have ECOG performance status ≤2, progression on ≥ 2 prior treatment lines and measurable disease. Patients are randomized 1:1 to receive T 75 mg/m2 orally daily + O 200 mg orally twice daily on days 1-7 in 21-day cycles (Arm 1) or investigator’s choice of trabectedin 1.5 mg/m2 over 24 hours every 21 days or pazopanib 400-600 mg orally daily (Arm 2). For phase 2, the primary endpoint is PFS. The design evaluates for an improvement in PFS from 4 mo to 8 mo, requires 70 patients, and yields 90% power and 1-sided alpha 0.10. If phase 2 is positive, phase 3 will enroll. For phase 3, the primary endpoint is overall survival (OS). The design evaluates for an improvement in OS from 13 mo to 23 mo, requires 165 patients (including 70 from phase 2) and yields 90% power with 1-sided alpha 0.025. Secondary endpoints include ORR, duration of response, safety and patient-reported outcomes. Archival tissue will be collected and evaluated with a RAD51 foci formation assay. Genomic sequencing results will be obtained where available. The study opened to accrual in 1/2023. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT05633381 .

Response and re-treatment response to immune checkpoint inhibitor treatment in advanced cervical cancer: A follow up study.

e17516 Background: Single agent checkpoint inhibitor immunotherapy (CII) was approved in June 2018 for second line treatment for metastatic cervical cancer after failure of platinum-based chemotherapy. Clinical trials recommended 2 years of treatment, however the optimal duration of treatment, outcome after stopping treatment and response after re-initiation of immunotherapy is still largely unclear. Methods: A cohort of 10 patients who were started on CII before September 31, 2019, with an initial analysis published in July 2021 were eligible. We performed an updated review of the duration of response, outcome off treatment after 2 years, and outcome after re-initiation of CII. Results: The current median follow up is 40 months (range, 2.0-50.8 months), 4 patients did not respond to treatment and have passed away, while six patients remain alive. The previous report showed 7 responders, with 3 complete responses (CR) at a median follow up of 20.7 m. With prolonged treatment, 6 patients achieved CR or stable minimal disease. After more than 2 years of treatment, 2 continued treatment for 39m and 50 m. Among the 4 patients who stopped treatment, 2 of them are 18 m and 20 m off treatment and remain no evidence of disease. Another 2 patients developed asymptomatic recurrence detected on surveillance CT (at 9 m and 12 m respectively), both with small volume of disease in the retroperitoneal and pelvic lymph nodes. They were both re-initiated on CII, and showed a CR and partial response (PR) respectively, on 3-6 month follow up CT scans, now 11.7 m and 3.5 m on treatment. A median PD-L1 combined expression score (CPS) was similar between responders (n=6) (20) and non-responders (26) (n=4) in the entire cohort overall, and was 83 in the group of patients who discontinued treatment after 2 years and have been without evidence of disease since (n=2). Conclusions: Patients who respond to immune checkpoint inhibitors may have durable response off treatment and may respond again to re-treatment in the event of recurrent disease. Our limited data suggest that providers can use CPS to aid in decision making. [Table: see text]

AI-driven real-time patient identification for randomized controlled trials.

e13565 Background: In India, clinical trial recruitment is a challenging process, often relying on the time- and labor-intensive process of investigators reviewing handwritten charts to identify potential candidates. We developed an AI-driven, real-time solution to address this issue and demonstrated its feasibility by identifying patients that would have been candidates for a 2017-2018 study of metastatic breast cancer (mBC) patients who failed prior chemotherapy. The original trial recruited 46 patients across 16 sites over 7 months in India. Methods: The study protocol was reviewed and applied to six years (2017-2022) of retrospective electronic medical records (EMR) data from a cancer hospital in India’s National Capital Region. Trial inclusion and exclusion criteria were translated to data elements which were extracted from both structured (e.g., lab) and unstructured (e.g., clinical notes) EMR data. For the unstructured data specifically, natural language processing algorithms were developed and implemented over the span of three weeks to extract the specific data elements. The veracity of the extracted data was confirmed via manual review by an oncologist. To assess the sensitivity of the results to the study criteria and provide a range of the potential candidate population size, the criteria were applied in two ways – as a strict application (e.g., ECOG must be reported and must be &lt; = 2) and as a relaxed application (e.g., ECOG may be unreported or, if reported, must be &lt; = 2). Results: Among the initial cohort of 112,239 females between 18 and 65 years of age, 3,203 (3%) were identified as having mBC and failure of prior chemotherapy or relapse. 537 patients remained after applying all inclusion criteria (ECOG status &lt; = 2, LVEF &gt; = 50%, no prior radiotherapy, prior chemo completed 4+ weeks prior, adequate bone marrow, renal, and hepatic function). Exclusion criteria (prior taxane exposure, 2+ prior chemotherapies, cardiac conditions, CNS lesions, motor/sensory neurotoxicities, HBV/HCV/HIV infection) were then applied, resulting in 37 patients that would be potential candidates for the trial, per the strict application of criteria. The relaxed version of the analysis yielded a candidate pool that was five times larger than the strict application, which was largely driven by cases where information was unavailable in the EMR. Conclusions: We demonstrated that the use of an AI-driven platform to apply clinical trial criteria to Indian real-world data can provide an efficient solution to identifying candidate trial patients. Once the criteria are defined and algorithms are developed, patient identification can happen in real time and reduce patient recruitment timelines by months. Future applications will include other cancer types and expand the breadth of data elements extracted to enable the rapid assessment of additional inclusion and exclusion criteria.