Platinum-containing Chemotherapy Research Articles

EPID-04. CAUSES AND LONG-TERM COURSE OF OTOTOXICITY IN PEDIATRIC MEDULLOBLASTOMA AND EPENDYMOMA PATIENTS – CUMULATIVE PLATINUM AND COCHLEAR IRRADIATION DOSE MATTER

Abstract BACKGROUND Ototoxicity is a well-known side effect of treatment with platinum-containing chemotherapy and radiotherapy (RT). Nevertheless, precise dose-effect relationships are still lacking. METHODS Patients from the HIT2000 trial receiving first-line treatment for medulloblastoma (MB) or ependymoma (EPN) who were alive at last follow-up and had at least one audiogram prior to and after administration of chemotherapy with cisplatinum and radiotherapy were included into this study. Treatment details (incl. cochlear irradiation dose [CID]) and audiological outcome were analyzed. The ototoxicity was graded using the HIT scoring. RESULTS Courses of 101 patients were analyzed. Median audiology follow-up was 6 years [range: 1.0–18.1 years]. Ototoxicity grade ≥1 was documented for n=66 patients (65.4%). For n=27 this resulted in treatment modification. Univariable analyses revealed different proportions of ototoxicity (grade ≥1) regarding histology (CMB: 50/65, LCAMB: 3/3, DMB/MBEN: 8/12, EPN: 5/21; p<0.001), tumor location (supratentorial: 3/9, infratentorial: 63/92; p<0.001), metastatic status at diagnosis (M0: 46/77, M+: 20/24; p=0.003), radiation field (CSI: 59/75, local RT: 6/21, no RT: 1/5; p<0.001), CID (continuous variable, p=0.001) and cumulative cisplatinum dose (continuous variable, p<0.001). Certainly, disease specific parameters (histology/staging) were related to treatment intensity (cisplatinum/irradiation dose). Multivariable analyses confirmed the impact of cumulative cisplatinum dose (p=0.01) and CID (p=0.04). ROC-analyses allowed the definition of cut-offs for high risk of ototoxicity grade ≥1 (cisplatinum: 70mg/m2 BSA, CID: 37.5 Gy) and ototoxicity risk estimation, when applying doses above the respective cut-offs (cisplatinum dose increase by 1mg/m2 BSA results in 4% higher risk for ototoxicity grade ≥1; CID dose increase by 1 Gy results in 4.6% higher risk for ototoxicity grade ≥1). CONCLUSIONS Ototoxicity affects a majority of children receiving adjuvant treatment for MB and EPN. To avoid disabilities and negative effect on quality of live, dosage of cisplatinum and radiotherapy should be scrutinized and reduced whenever possible.

Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial.

The vascular endothelial growth factor pathway plays a key role in the pathogenesis of gastric cancer. In the multicenter, double-blind phase 3 FRUTIGA trial, 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on fluorouracil- and platinum-containing chemotherapy were randomized (1:1) to receive fruquintinib (an inhibitor of vascular endothelial growth factor receptor-1/2/3; 4 mg orally, once daily) or placebo for 3 weeks, followed by 1 week off, plus paclitaxel (80 mg/m2 intravenously on days 1/8/15 per cycle). The study results were positive as one of the dual primary endpoints, progression-free survival (PFS), was met (median PFS, 5.6 months in the fruquintinib arm versus 2.7 months in the placebo arm; hazard ratio 0.57; 95% confidence interval 0.48-0.68; P < 0.0001). The other dual primary endpoint, overall survival (OS), was not met (median OS, 9.6 months versus 8.4 months; hazard ratio 0.96, 95% confidence interval 0.81-1.13; P = 0.6064). The most common grade ≥3 adverse events were neutropenia, leukopenia and anemia. Fruquintinib plus paclitaxel as a second-line treatment significantly improved PFS, but not OS, in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma and could potentially be another treatment option for these patients. ClinicalTrials.gov registration: NCT03223376 .

Influence of malnutrition according to the glim criteria on the chemotherapy toxicities in patients with advanced lung cancer.

Cancer-associated malnutrition is highly prevalent in advanced lung cancer, and 50% of global cancer-related deaths are attributed to cancer-associated malnutrition. Platinum-containing chemotherapy is the standard treatment for advanced lung cancer. Unfortunately, it can cause exacerbated toxicities, which can also have a negative impact on patient's prognosis and quality of life. The Global Leadership Initiative on Malnutrition (GLIM) criteria have been proposed as the world's first accepted diagnostic criteria for malnutrition. However, the effectiveness of GLIM criteria in predicting chemotherapy toxicities in patients with advanced lung cancer is unclear. The aim of this study was to apply the GLIM criteria to assess the prevalence of pre-treatment diagnosis of malnutrition in patients with advanced non-small cell lung cancer (NSCLC) and to determine the impact of nutritional status on patient's chemotherapy toxicity. We conducted a study of hospitalized patients with pathologically and clinically diagnosed advanced NSCLC who presented to our hospital from May 2021 to January 2022. Initially, the Nutritional Risk Screening-2002 (NRS-2002) was used for nutritional risk screening, and nutritional status was assessed using the Scored Patient-Generated Subjective Global Assessment (PG-SGA) and GLIM criteria. Chemotherapy toxicity was assessed and graded according to CTCAE5.0, and chemotherapy efficacy was assessed according to RECIST1.1. Kappa test was used to analyze the agreement between PG-SGA and GLIM criteria. Univariate and multivariate logistic regression analyses were used to determine the relationship between malnutrition and chemotherapy toxicity. A total of 215 patients with advanced NSCLC were evaluated for nutritional status. Most of the patients had normal BMI (61.86%) before the start of treatment, 40% were well-nourished as assessed by the PG-SGA tool, and 51.17% were well-nourished as assessed by GLIM criteria. Consistency analysis showed moderate agreement (Kappa = 0.463, P < 0.001) and their correlation was also moderate (Spearman, rs = 0.475, P < 0.001). The objective response rate (ORR) (P = 0.040) and disease control rate (DCR) (P < 0.001) were significantly lower in malnourished patients diagnosed according to GLIM criteria than in well-nourished patients. Multivariate analysis showed that malnutrition (OR = 1.531,95%CI 0.757-3.009; OR = 6.623,95%CI 1.390-31.567, P = 0.046) diagnosed by GLIM criteria was an independent predictor of chemotherapy toxicity. Conclusions Malnutrition diagnosed by GLIM criteria better predicts toxicity during chemotherapy, determines the degree of clinical benefit of chemotherapy, and may affect patient prognosis.

Pharmacoeconomic evaluation of first-line combination therapy with immunotherapy drugs and platinum-containing chemotherapy in adult patients with metastatic non-squamous non-small cell lung cancer

Objective: to evaluate the pharmacoeconomic efficacy of “atezolizumab + bevacizumab + paclitaxel + carboplatin” drug combination compared to “pembrolizumab + pemetrexed + carboplatin” combination in adult patients with non-small cell lung cancer (NSCLC) in the first line of therapy.Material and methods. The modeling was applied for cost minimization analyzis of using compared therapy regimens with comparable efficacy, and to estimate the impact on the healthcare budget when increasing the proportion of patients in the target population receiving “atezolizumab + bevacizumab + paclitaxel + carboplatin” combination. Published adjusted indirect comparison data were used in modeling. The calculations were based on the registered prices according to the state register of maximum selling prices.Results. The use of “atezolizumab + bevacizumab + paclitaxel + carboplatin” combination instead of “pembrolizumab + pemetrexed + carboplatin” combination will decrease the direct medical costs of therapy per 1 patient for 2 years by 28,165.00 rubles (–0.4%). The budget impact analysis showed that an increase in the proportion of patients receiving “atezolizumab + bevacizumab + paclitaxel + carboplatin” combination from 50% (current therapy practice) to 100% (considered therapy practice) will reduce the budget load for the population of 6,240 patients over 2 years by 256.1 million rubles (–0.64%).Conclusion. The results of pharmacoeconomic analysis demonstrated that the use of “atezolizumab + bevacizumab + paclitaxel + carboplatin” combination in first-line therapy for metastatic NSCLC is economically feasible and reduces the load on the budget compared to “pembrolizu- mab + pemetrexed + carboplatin” scheme.

Targeted and immunotherapy for the management of advanced urothelial carcinoma of the bladder.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. The activity of targeted and immunotherapy for the management of advanced bladder cancer is reviewed. Platinum-based chemotherapy is standard first-line treatment for advanced bladder cancer. Pembrolizumab is approved alone as first-line therapy for patients who are ineligible for any platinum-based chemotherapy and with enfortumab for patients ineligible for cisplatin-based chemotherapy. Avelumab is approved for maintenance therapy in patients who have not progressed with first-line platinum-containing therapy. Pembrolizumab, avelumab, and nivolumab are approved second-line therapy in patients who experience progression during or after platinum-containing chemotherapy. Erdafitinib is indicated for advanced disease that has susceptible FGFR2 or FGFR3 genetic alterations and has progressed during or after treatment with at least one line of platinum-containing chemotherapy. Enfortumab vedotin and sacituzumab govitecan are antibody-drug conjugates. They are both approved for patients who have received anti-PD-L1 or anti-PD-1 therapy and treatment with platinum-containing chemotherapy. Enfortumab is also indicated for patients who are ineligible to receive cisplatin-based therapy and have received one or more prior lines of therapy. Six targeted and immunotherapeutic agents have been approved for patients with advanced urothelial bladder cancer. They all have demonstrated activity in patients for whom disease has progressed during or after platinum-based therapy. Pembrolizumab, with and without enfortumab, has demonstrated first-line activity, and avelumab is a key maintenance therapy after first-line treatment. The results of additional clinical trials should provide evidence to establish the exact role in therapy of each agent in patients with advanced disease.

CONTACT-01: A Randomized Phase III Trial of Atezolizumab + Cabozantinib Versus Docetaxel for Metastatic Non-Small Cell Lung Cancer After a Checkpoint Inhibitor and Chemotherapy.

Although checkpoint inhibitors have improved first-line treatment for non-small cell lung cancer (NSCLC), a therapeutic need remains for patients whose disease does not respond or who experience disease progression after anti-PD-L1/PD-1 immunotherapy. CONTACT-01 (ClinicalTrials.gov identifier: NCT04471428) evaluated atezolizumab plus cabozantinib versus docetaxel in patients with metastatic NSCLC who developed disease progression after concurrent or sequential treatment with anti-PD-L1/PD-1 and platinum-containing chemotherapy. This multicenter, open-label, phase III trial randomly assigned patients 1:1 to atezolizumab 1,200 mg intravenously once every 3 weeks (q3w) plus cabozantinib 40 mg orally once daily or docetaxel 75 mg/m2 intravenously once every 3 weeks. The primary end point was overall survival (OS). One hundred eighty-six patients were assigned atezolizumab plus cabozantinib, and 180 docetaxel. Minimum OS follow-up was 10.9 months. Median OS was 10.7 months (95% CI, 8.8 to 12.3) with atezolizumab plus cabozantinib and 10.5 months (95% CI, 8.6 to 13.0) with docetaxel (stratified hazard ratio [HR], 0.88 [95% CI, 0.68 to 1.16]; P = .3668). Median progression-free survival was 4.6 months (95% CI, 4.1 to 5.6) and 4.0 months (95% CI, 3.1 to 4.4), respectively (stratified HR, 0.74 [95% CI, 0.59 to 0.92]). Serious adverse events (AEs) occurred in 71 (38.4%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 3/4 treatment-related AEs occurred in 73 (39.5%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 5 AEs occurred in 14 (7.6%) and 10 (6.0%) patients in the atezolizumab plus cabozantinib and docetaxel arms, respectively (treatment-related in four [2.2%] and one [0.6%], respectively). Atezolizumab plus cabozantinib after disease progression following anti-PD-L1/PD-1 immunotherapy and platinum-containing chemotherapy for metastatic NSCLC did not improve OS compared with docetaxel. Safety was consistent with known profiles of these agents.

Anti-angiogenic therapy or immunotherapy? A real-world study of patients with advanced non-small cell lung cancer with EGFR/HER2 exon 20 insertion mutations.

For patients with EGFR/HER2 exon20 insertions, platinum-containing double-drug chemotherapy is still the standard treatment method. First-generation TKIs have almost no therapeutic activity against EGFR exon 20 insertions. The efficacy of second-and third-generation TKIs is still controversial. Immunotherapy research is scarce, and there is an urgent need for more evidence and new treatment options for this group of patients. We reviewed patients with advanced NSCLC with EGFR/HER2 exon 20 insertion mutations treated in Shanghai Chest Hospital and Shanghai Pulmonary Hospital from 2015 to 2022 and assessed the efficacy of receiving chemotherapy, anti-angiogenic therapy and immunotherapy, including objective response rate (ORR) and disease control rate (DCR), and compared progression-free survival (PFS) and overall survival (OS). Of the 126 patients included in the study, 51 patients had EGFR20ins mutations and 7 5 patients had HER2-20ins mutations. In the first-line treatment, bevacizumab + chemotherapy (Beva+Chemo), ICI+chemotherapy (ICI+Chemo), compared with chemotherapy alone (Chemo), ORR: 40% vs 33.3% vs 15% (p=0.0168); DCR: 84% vs 80.9% vs 67.5% (p=0.1817); median PFS: 8.3 vs 7.0 vs 4.6 months (p=0.0032), ICI+Chemo has a trend of benefiting on OS. Stratified analysis showed that compared with chemotherapy, ICI+Chemo was more effective for EGFR20ins mutation with median PFS: 10.3 vs. 6.3m (P=0.013); Beva+Chemo was more effective for HER2-20ins mutation, with a median PFS: 6.6 vs. 4.3m (p=0.030). In the second-line treatment of EGFR20ins mutation, bevacizumab + chemotherapy has a significant advantage in PFS compared with targeted therapy, median PFS:10.8 vs 4.0 months (P=0.016). For patients with EGFR20ins mutation, compared to chemotherapy, ICI+Chemo prolongs PFS, and after chemotherapy progression, bevacizumab combined with chemotherapy seems better than Furmonertinib-based targeted therapy on PFS. For HER2-20ins mutation, Beva+Chemo may be a better choice.

Physicianreported treatment patterns and outcomes in metastatic bladder cancer in the USA: the CancerMPact® Survey 2020.

Aim: This study assessed physician-reported treatment patterns for metastatic bladder cancer. Materials & methods: A total of106 USA-based physicians were surveyed in 2020 using the CancerMPact® online survey. Results: Among cisplatin-eligible patients, 86.1% received first-line (1L) platinum-containing chemotherapy, most commonly cisplatin plus gemcitabine, and 9.8% received immune checkpoint inhibitor monotherapy. Among cisplatin-ineligible patients, 46.5% received 1L platinum-containing chemotherapy, most commonly carboplatin plus gemcitabine and 46.2% received 1L immune checkpoint inhibitor therapy. Approximately 44% of patients who received 1L treatment received second-line (2L) therapy after progression. Conclusion: Platinum-containing chemotherapy was the most widely reported 1L treatment approach. A high proportion of patients received no 2L therapy. Validation in an updated dataset is warranted following the practice-changing approvals of avelumab 1L maintenance and additional 2L options.

Peripheral neuropathy and nerve electrophysiological changes with enfortumab vedotin in patients with advanced urothelial carcinoma: a prospective multicenter cohort study.

Enfortumab vedotin is a novel antibody-drug conjugate used as a third-line therapy for the treatment of urothelial cancer. We aimed to elucidate the effect of enfortumab vedotin-related peripheral neuropathy on its efficacy and whether enfortumab vedotin-induced early electrophysiological changes could be associated with peripheral neuropathy onset. Our prospective multicenter cohort study enrolled 34 patients with prior platinum-containing chemotherapy and programmed cell death protein 1/ligand 1 inhibitor-resistant advanced urothelial carcinoma and received enfortumab vedotin. The best overall response, progression-free survival, overall survival, and safety were assessed. Nerve conduction studies were also performed in 11 patients. The confirmed overall response rate and disease control rate were 52.9% and 73.5%, respectively. The median overall progression-free survival and overall survival were 6.9 and 13.5months, respectively, during a median follow-up of 8.6months. The patients with disease control had significantly longer treatment continuation and overall survival than did those with uncontrolled disease. Peripheral neuropathy occurred in 12.5% of the patients. The overall response and disease control rates were 83.3% and 100%, respectively: higher than those in patients without peripheral neuropathy (p = 0.028 and p = 0.029, respectively). Nerve conduction studies indicated that enfortumab vedotin reduced nerve conduction velocity more markedly in sensory nerves than in motor nerves and the lower limbs than in the upper limbs, with the sural nerve being the most affected in the patients who developed peripheral neuropathy (p = 0.011). Our results indicated the importance of focusing on enfortumab vedotin-induced neuropathy of the sural nerve to maximize efficacy and improve safety.

Enfortumab vedotin prolongs overall survival in metastatic urothelial carcinoma following pembrolizumab therapy in real-world data.

In December 2021, enfortumab vedotin (EV), an antibody-drug conjugate directed against nectin-4, was approved in Japan as a new treatment after platinum-containing chemotherapy and PD-1/PD-L1 inhibitors. This study evaluated, using real-world data, the efficacy and safety of EV therapy in patients with metastatic urothelial carcinoma (mUC). Fifty-five patients with mUC who discontinued pembrolizumab therapy due to disease progression between June 2018 and April 2023 at Yokohama City University Hospital were evaluated retrospectively. Of the 55 patients, 25 received EV therapy (EV group) and 30 did not (non-EV group). All patients who underwent EV therapy were diagnosed with disease progression after the approval of EV in Japan. The median (range) follow-up period after pembrolizumab discontinuation was 6.3 (0.7-31.1) months. There were eight (32.0%) deaths due to cancer in the EV group and 27 (90.0%) in the non-EV group. The overall survival (OS) after pembrolizumab discontinuation was not reached in the EV group versus 2.6 months in the non-EV group (p < 0.001). A multivariate analysis revealed that EV therapy (EV vs. non-EV group; hazard ratio 0.26; 95% confidence interval 0.16-0.41; p < 0.001) was an independent prognostic factor for OS. EV prolonged OS in mUC following pembrolizumab therapy in real-world data.

Chemotherapy versus personalized therapy for EGFR mutant lung adenocarcinoma resistance to EGFR-tyrosine kinase inhibitors: a retrospective dual-center study.

Advanced lung adenocarcinoma patients often develop resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), leaving uncertainties regarding subsequent treatment strategies. Although personalized therapy targeting individual acquired resistances (ARs) shows promise, its efficacy has not been systematically compared with platinum-containing doublet chemotherapy, a widely accepted treatment after EGFR-TKIs failure. A retrospective dual-center study was conducted involving patients with advanced lung adenocarcinoma and EGFR mutations who developed resistance to EGFR-TKIs between January 2017 and December 2022. Eligible patients were adults aged 18years or older with an Eastern Cooperative Oncology Group score of 0-1, normal organ function, and no prior chemotherapy. Patients were divided into the chemotherapy group (CG) or personalized therapy group (PG) based on the treatment received after disease progression. The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). Of the 144 patients enrolled, there were 53 patients in the PG and 91 patients in the CG. The PG acquired resistance to EGFR-TKIs through the MET amplification (27, 50%) and small cell lung cancer transformation (16, 30%) and 18% of them reported multiple resistance mechanisms. The ORR of the PG was similar to that of the CG (34% vs. 33%, P = 1.0) and the PFS of the PG patients was not statistically different from that of their CG counterparts [4.2months (95% CI: 3.6-4.8months) vs. 5.3months (95% CI: 4.6-6.0months), P = 0.77]. These findings suggest that the therapeutic efficacy of chemotherapy approximates to that of personalized therapy, which signifies that chemotherapy is still a reliable choice for patients who develop resistance to EGFR-TKIs and that further research is awaited to explore the benefit of personalized treatment.

Fruquintinib plus paclitaxel versus paclitaxel as second-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma (FRUTIGA): A randomized, multicenter, double-blind, placebo-controlled, phase 3 study.

438780 Background: Fruquintinib (F), a highly selective and potent oral inhibitor of VEGFRs 1, 2, and 3, significantly improved the OS in metastatic colorectal cancer ( Li J, et al, JAMA 2018; Dasari A, et al, LANCET 2023). FRUTIGA was a randomized, double-blind, placebo (PBO)-controlled, phase 3 study evaluating the efficacy and safety of F plus paclitaxel (PTX) vs PTX alone in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma who experienced disease progression (PD) on fluoropyrimidine- or platinum-containing first-line chemotherapy. Methods: Eligible pts were randomized 1:1 to receive F (4 mg, once daily, 3 weeks on/1 week off) or matching PBO orally, plus PTX (80 mg/m2, intravenously, days 1/8/15 per cycle) in 4-week cycles until PD or intolerable toxicity; treatment of PTX was allowed for up to 6 cycles. PFS and OS were dual-primary endpoints with α split and recycle. The study was considered positive when at least one endpoint met statistical significance. Results: 703 pts were randomized (F+PTX 351 vs PBO+PTX 352), and 699 pts received at least 1 dose of study drug (350 vs 349). PFS was significantly improved with F+PTX vs PBO+PTX (median PFS [mPFS] 5.55m vs 2.73m; HR = 0.569; p &lt; 0.0001). The overall response rate was significantly higher in F+PTX group (42.5% vs 22.4%, p &lt; 0.0001). Median OS (mOS) was 9.63m with F+PTX and 8.41m with PBO+PTX (HR = 0.956; p = 0.6064). Given an imbalance of pts receiving subsequent antitumor therapies (F+PTX 52.7% vs PBO+PTX 72.2%), post-hoc analyses were performed using cox-proportional hazards model adjusting for subsequent antitumor therapies and baseline factors. Results showed a nominal statistically significant improvement in OS with F+PTX (HR range 0.793-0.828; p range 0.0105-0.0350 with different subsequent antitumor therapy factors). Furthermore, among pts with lymph node metastases and non-diffuse G/GEJ adenocarcinoma (190 vs 208), mPFS was even more prolonged (6.08m vs 2.69m; HR = 0.454; p &lt; 0.0001) and OS also showed a nominal statistically significant improvement (mOS 9.56m vs 7.85m; HR = 0.767; p = 0.0233). The most common TEAEs of Grade ≥ 3 were neutropenia (60.0% vs 36.4%), leukopenia (42.9% vs 23.5%), and anemia (11.7% vs 10.6%). The safety profile was consistent with F and PTX. No new safety signals were identified. Conclusions: FRUTIGA (NCT03223376) was a positive study by reaching statistical significance for one primary endpoint, PFS, and demonstrated improvement in the other primary endpoint, OS, that was not statistically significant, possibly due to the imbalance of subsequent antitumor therapies. These data support F+PTX as a potential new second-line treatment option for pts with advanced G/GEJ adenocarcinoma. Clinical trial information: NCT03223376 .

Outcomes of pediatric extracranial germ cell tumors: A single center experience in a developing country.

The purpose of this study was to analyze the outcomes of extracranial GCT in children in a developing country and to assess prognostic factors. The data on 141 children (<18years old) with extracranial GCT, confirmed histopathologically, collected over the past 9years (from February 2013 to June 2022) were retrospectively studied. The patients underwent the same therapy with platinum-containing chemotherapy regimens. In the malignant GCT group, OS and EFS were 81.0 ± 4% and 73 ± 5%, respectively. OS and EFS in the teratoma group were 90 ± 5% and 85 ± 6%. In univariate analysis, parameters like stage of disease, tumor localization, AFP level ≥10,000ng/mL, serum AFP kinetics and resection status were found to be statistically significant prognostic factors. In the multivariate analysis, the significant adverse factors were the resection status, initial AFP level ≥10,000ng/mL and serum AFP kinetics slow down (p = .000). Good survival rates can be achieved in developing countries with adequate compliance with treatment protocols. The analysis demonstrates high efficacy of platinum-containing chemotherapy regimens. In our opinion, the protocol used in high-income countries can be implemented in low-income countries with the financial support from the government. The qualification of specialists is also important.

Real-world treatment patterns, testing patterns, and clinical outcomes of first-line (1L) therapy for metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma (mGC/GEJC/EAC).

275 Background: GC/GEJC/EAC are among the leading causes of cancer-related morbidity and mortality worldwide. Nivolumab + fluoropyrimidine- + platinum-containing chemotherapy (NIVO+chemo) has demonstrated superior efficacy in patients with advanced non-HER2-positive (HER2-) GC/GEJC/EAC versus chemo alone in the CheckMate 649 trial. The objective of this study was to characterize real-world treatment and PD-L1 testing patterns in the 1L setting for mGC/GEJC/EAC since the FDA approval of NIVO+chemo on April 16, 2021. Methods: This retrospective observational study used the electronic medical record data from the ConcertAI Patient360 database. Adult patients with HER2- mGC/GEJC/EAC and 1L initiation date (index date) between April 16, 2021 and October 31, 2022 were included. PD-L1 testing patterns and 1L regimens were described overall and stratified by PD-L1 testing. The analyses of clinical outcomes are currently ongoing. Results: A total of 161 patients with mGC/GEJC/EAC met the inclusion criteria. The median age at index was 67.0 years, 76.4% were male, and the median follow-up time from index date was 6.7 months. 81 (50.3%) patients had evidence of receiving at least one PD-L1 test (median [interquartile range] time from first test to 1L initiation: 0.4 [-0.1, 1.0] months) among whom 28 (34.6%) had the first test documented after 1L initiation. Overall, 1L immunotherapy-based regimens were received by 63 (39.1%) patients, with NIVO+chemo being the most common (n = 47; 29.2%). 1L fluoropyrimidine- + platinum-containing chemotherapy and other chemotherapies were received by 51 (31.7%) and 42 (26.1%) patients, respectively. Among patients with evidence of PD-L1 testing, 31 (38.3%) received NIVO+chemo, and 37 (45.7%) received chemotherapy alone. Among those without evidence of PD-L1 testing, 56 (70.0%) received chemotherapy alone, and 16 (20.0%) received NIVO+chemo. Conclusions: These preliminary findings show an early uptake of NIVO+chemo in the advanced or metastatic GC/GEJC/EAC patient population. With a majority of PD-L1 untested patients receiving chemotherapy only as 1L therapy, there is an opportunity for these patients to potentially benefit from immuno-oncology containing regimens. Further analyses are needed to characterize the chemotherapy only treated patient population.

Clinical pharmacology profile of the claudin 18.2 antibody zolbetuximab.

316 Background: Zolbetuximab is an investigational first-in-class chimeric (mouse/human) monoclonal antibody directed against the tight junction protein claudin 18.2 (CLDN18.2). Zolbetuximab is currently being developed as first-line treatment of patients with locally advanced unresectable or metastatic HER2– gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, in combination with fluoropyrimidine- and platinum-containing chemotherapy. Methods: The clinical pharmacology of zolbetuximab (pharmacokinetics [PK] and impact of covariates, potential for drug-drug interactions and QTc prolongation, exposure-response [E-R] for efficacy and safety, immunogenicity [antidrug antibodies; ADAs]) was characterized from 9 studies in adults with advanced CLDN18.2-positive adenocarcinoma of the stomach, esophagus, or GEJ. Results: Zolbetuximab exhibited dose-proportional PK at doses of 33 to 1000 mg/m2. Based on population PK modeling using data from 714 participants, zolbetuximab exposure (Table) was not meaningfully affected by sex, race/ethnicity, age, mild/moderate renal impairment, or mild hepatic impairment. Gastrectomy was predicted to increase Cave by 36%. Coadministration of zolbetuximab with chemotherapy did not show clinically meaningful changes in drug exposures of zolbetuximab or chemotherapy. At therapeutic doses, zolbetuximab had no clinically meaningful effect on QTc prolongation. In phase 3 studies, zolbetuximab (800 mg/m2 loading dose/600 mg/m2 Q3W) had a manageable safety profile and was associated with significant prolongation of progression-free survival (PFS) and overall survival (OS). E-R analyses suggested that higher zolbetuximab exposure may further prolong PFS and OS but with increased probability of gastrointestinal events and infusion-related reactions. E-R model simulations suggested comparable zolbetuximab efficacy and safety between the 800/600 mg/m2 Q3W regimen and an alternative 800/400 mg/m2 Q2W regimen for use in combination with chemotherapy. ADAs were detected in 4.4% of patients in phase 3 studies with no apparent impact on zolbetuximab PK, efficacy, or safety. Conclusions: The clinical pharmacology of zolbetuximab was well characterized using data from 9 clinical trials. The integrated data support the proposed 800/600 mg/m2 Q3W regimen as well as an 800/400 mg/m2 Q2W regimen in combination with chemotherapy. Clinical trial information: NCT00909025 , NCT01671774 , NCT03528629 , NCT04086758 , NCT01197885 , NCT01630083 , NCT03505320 , NCT03504397 , NCT03653507 . [Table: see text]

Combination of pembrolizumab and lenvatinib in second-line therapy for MSS/pMMR advanced endometrial cancer: literature review and a case report

Despite the existing standard treatments for endometrial cancer, the prognosis for these patients remained poor until recently. None of currently available cytostatics ensured long-term disease control and long-term survival of patients receiving standard platinum-based therapy. Poor treatment outcomes in patients with advanced endometrial cancer necessitated changes in therapeutic approaches and development of more effective treatment regimens. Better understanding of carcinogenesis mechanisms, emergence of a new molecular classification of endometrial cancer, and implementation of tailored treatment approaches based on tumor types led to a significant breakthrough in the treatment of advanced endometrial cancer. Currently, the most effective second-line therapy for endometrial cancer with high level microsatellite instability (MSI-h) or deficient mismatch repair system (dMMR) (25 % of cases), and no indications for surgery is pembrolizumab monotherapy. Most of cancers (about 75 %) are represented by microsatellite-stable and mismatch repair proficient tumors (MSS/рMMR). Patients with such tumors demonstrating disease progression after systemic therapy should receive a combinations of the immune checkpoint inhibitor pembrolizumab and the multi-targeted tyrosine kinase inhibitor lenvatinib. In this article, we review relevant literature and report a case of successful treatment of MSS/pMMR advanced endometrial cancer with a combination of pembrolizumab and lenvatinib as a second-line therapy (after disease progression in response to platinum-containing first-line chemotherapy), which ensured long-term disease control.

A phase II open-label study of enfortumab vedotin in patients with previously treated locally advanced, recurrent, or metastatic pancreatic adenocarcinoma (EPIC).

TPS719 Background: Nectin-4 is a type I transmembrane protein member of the nectin family involved in the formation and maintenance of adherens junctions. In contrast to its limited expression in normal tissues, aberrant overexpression of nectin-4 has been identified in various solid tumors, including in pancreatic adenocarcinoma. About 71% of human PDAC specimens stain positive and 13% stain strongly positive for nectin-4. Mechanistically, nectin-4 has been associated with various pro-oncogenic cellular processes, including the promotion of tumor cell proliferation and metastasis via WNT- βcatenin pathway activation. It interacts with ERBB2/HER2 and activates Rac1 (small G protein) to ultimately upregulate PI3K-AKT pathway signaling, leading to cell survival and proliferation. Enfortumab vedotin (EV) is an antibody-drug conjugate that delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) to cells expressing Nectin-4. EV is FDA approved as a single agent for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy based on the EV-301 Trial which demonstrated overall survival benefit. Taken together, the above data and the efficacy of EV seen in bladder cancer warrants the evaluation of EV in advanced pancreatic adenocarcinoma. Methods: Design: Open-label, phase II single-arm trial of EV (n=28) in previously treated locally advanced, recurrent, or metastatic pancreatic adenocarcinoma. Treatment schedule: EV 1.25 mg/kg administered IV on D1, D8, D15 every 28 days until disease progression or unacceptable toxicity. Imaging assessment will be done every 8 weeks. A biopsy prior to therapy and a biopsy on treatment (between days 15-21 of cycle 1) is required. Eligibility: Patients with previously treated, locally advanced, recurrent, or metastatic pancreatic adenocarcinoma. Inclusion criteria also include ECOG PS 0-1 and at least 1 line of prior therapy. Objectives: The primary objective is to determine anti-tumor activity by overall response rate using RECIST 1.1. Secondary objectives include safety, duration of response, disease control rate, progression-free survival and overall survival. Exploratory objectives include Nectin-4 expression (H-score) in tumor tissue and the relationship between the mutational profile of the tumor and response. Statistical Plan: A Simon’s two-stage Minimax design will be used. In the first stage, 18 pts will be accrued. If there is less than 1 response in these 18 pts, the study will be stopped for futility. Otherwise, 10 additional pts will be accrued for a total of 28 pts. The null hypothesis will be rejected if 3 or more responses are observed in 28 pts. Enrollment is currently ongoing. Clinical trial information: NCT05915351 .

Real-world outcomes on platinum-containing chemotherapy for EGFR-mutated advanced nonsquamous NSCLC with prior exposure to EGFR tyrosine kinase inhibitors.

Front-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is the standard of care for treating patients with advanced nonsquamous NSCLC with the common sensitizing EGFR exon 19 deletion and exon 21 L858R point mutations. However, EGFR TKI resistance inevitably develops. The optimal subsequent therapy remains to be identified, although platinum-containing chemotherapy regimens are often administered. Our objectives were to describe baseline characteristics, survival, and subsequent treatment patterns for patients with advanced nonsquamous NSCLC with EGFR exon 19 deletion or L858R mutation who received a platinum-based combination regimen after front-line EGFR TKI therapy. This retrospective study used a nationwide electronic health record-derived deidentified database to select adult patients with advanced nonsquamous NSCLC, evidence of EGFR exon 19 deletion or L858R mutation, and ECOG performance status of 0-2 who initiated platinum-containing chemotherapy, with or without concomitant immunotherapy, from 1-January-2011 to 30-June-2020 following receipt of any EGFR TKI as first-line therapy or, alternatively, a first- or second-generation EGFR TKI (erlotinib, afatinib, gefitinib, dacomitinib) as first-line therapy followed by the third-generation EGFR TKI osimertinib as second-line therapy. Data cut-off was 30-June-2022. The Kaplan-Meier method was used to estimate overall survival (OS) after initiation of pemetrexed-platinum (n=119) or any platinum-based combination regimen (platinum cohort; n=311). The two cohorts included two-thirds women (65%-66%) and 57%-58% nonsmokers; median ages were 66 and 65 years in pemetrexed-platinum and platinum cohorts, respectively. Median OS was 10.3 months (95% CI, 8.1-13.9) from pemetrexed-platinum initiation and 12.4 months (95% CI, 10.2-15.2) from platinum initiation; 12-month survival rates were 48% and 51%, respectively; 260 patients (84%) had died by the end of the study. The suboptimal survival outcomes recorded in this study demonstrate the unmet need to identify more effective subsequent treatment regimens for patients with EGFR-mutated advanced nonsquamous NSCLC after EGFR TKI resistance develops.

A new prognostic model in chemotherapy-treated patients with recurrent or metastatic head and neck cancer: An analysis of ECOG-ACRIN E1305

IntroductionFor patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) periodic reassessment of prognostic factors provides valuable information that can aid in patient stratification. Patients and methodsThis post hoc analysis included all patients with R/M HNSCC enrolled in the ECOG-ACRIN E1305 phase III clinical trial who received first-line treatment with platinum-containing chemotherapy doublet with or without bevacizumab. Overall survival (OS) was estimated using the Kaplan-Meier method. Prognostic factors for OS were identified using univariate and multivariable analyses. A new prognostic model for OS was built retaining the prognostic factors which were significant in the final multivariable analysis (P < 0.05). ResultsAll 403 study participants were included in the analysis. The median OS in the whole study cohort was 11.8 months (90% confidence intervals [CI], 10.6–13.2). The new prognostic model for OS comprised four risk factors (ECOG performance status [1 versus 0], primary tumor location [other versus oropharynx], presence of bone or liver metastasis, and prior radiation to the head and neck); patients with ≤ 2 (n = 249) and > 2 risk factors (n = 154) had a median OS of 15.2 and 7.6 months, respectively (Hazard ratio, 2.14; 95% CI, 1.73–2.66; P < 0.0001). ConclusionsThe new proposed model includes 4 clinical prognostic factors that can be readily assessed at baseline. Similar models have the potential to improve trial design and optimize stratification of patients with R/M HNSCC.

Complete radiological response when using pembrolizumab in the mono mode in the 2nd-line drug therapy of MSI-h / dMMR-positive advanced endometrial cancer. A clinical case

Until recently, the prognosis of patients with advanced endometrial cancer remained disappointing despite the standard treatment methods. None of the drugs in the arsenal of oncologists-chemotherapists provided long-term disease control and long-term survival of patients who received standard platinum-containing first-line chemotherapy. It is obvious that the poor results of treatment in patients with advanced endometrial cancer required a change in treatment approaches and indicated the need to develop more effective treatment regimens. A deeper understanding of the mechanisms of carcinogenesis, the emergence of new molecular classification of endometrial cancer and division of treatment approaches depending on the tumor biological potential has led to significant breakthrough in the treatment of advanced endometrial cancer. One of the most significant achievements is discovery of the function of microsatellite instability (MSI) and disorders in the repair system of unpaired bases of deoxyribonucleic acid (MMR) as a predictor of high efficient immunotherapy – a new direction of systemic drug therapy for the advanced endometrial cancer. The paper presents a clinical case of successful treatment of MSI-h / dMMR-positive advanced endometrial cancer using pembrolizumab as a second-line therapy (in the presence of refractoriness to standard platinum-based chemotherapy of the 1st line) in a mono mode with a complete radiological response of the tumor to treatment.