RECIST Research Articles

Zimberelimab combined with concurrent chemoradiotherapy for patients with locally advanced cervical cancer: Early results of efficacy and safety.

e17507 Background: To assess the efficacy and safety of zimberelimab combined with concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC) patients (pts). Methods: This a single arm, open label, prospective phase II study. participants aged 18-75 years of FIGO 2018 IIB-IVA LACC, with histologically confirmed adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma untreated with radiotherapy or immunotherapy for cervical cancer were included. Nineteen enrolled pts received zimberelimab (240 mg, IV, Q2W) for up to one year starting from the first week of radiotherapy, combined with CCRT, including cisplatin (25-40 mg/m2), paclitaxel (35 mg/m2), once a week for up to 5 cycles, intensity modulated radiation therapy (IMRT, 45-50 Gy/25-28 f), with a simultaneous integrated boost of 10-15 Gy to involved metastatic lymph nodes, followed by brachytherapy (30-40 Gy, 5-6 Gy/f, biw). All radiotherapy was completed within 8 weeks. The primary endpoint was objective response rate (ORR) assessed by investigators per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. The secondary endpoints were disease control rate (DCR), progression-free survival (PFS), 3-year overall survival (OS) rate and safety. Results: The median age was 57 years (range, 32 to 71), with 6 pts in stage IIB, 2 pts in stage IIIB, 8 pts in stage IIIC, and 3 pts in stage IVA. All pts completed CCRT successfully, with 18 pts completed 5 cycles of chemotherapy, while only 1 pts received 4 cycles of chemotherapy. The median cycles with zimberelimab treatment was 15 (range, 6 to 26). Grade (G) 3 and higher treatment related adverse events (TRAEs) were observed in 13 pts (13/19, 68.4%), 1 pts had G4 lymphopenia (1/19, 5.3%). The most frequent ≥G3 TRAEs was lymphopenia (11/19, 57.9%), followed by leukopenia (7/19, 36.8%). The ORR was 100%, with complete responses in 18 pts (18/19, 94.7%) and partial responses in 1 pts (1/19, 5.3%). At data cutoff (October 31, 2023), 2 pts had disease progression (2/19, 10.5%), 17 pts have been remaining in disease remission (17/19, 89.5%). Conclusions: Zimberelimab combined with CCRT achieved promising anti-tumor effects and manageable toxicities in LACC pts. Further follow-up results are expected. Trial registration: ClinicalTrials.gov Identifier: NCT05437692. Clinical trial information: NCT05437692 . [Table: see text]

Comparing the efficacy of two generations of EGFR-TKIs: An integrated drug-disease mechanistic model approach in EGFR-mutant lung adenocarcinoma.

e20578 Background: The epidermal growth factor receptor (EGFR) is frequently mutated in patients with lung adenocarcinoma (LUAD), leading to its constitutive activation and subsequent uncontrolled cell proliferation. To counteract this, tyrosine kinase inhibitors (TKIs) targeting EGFR have been developed. However, the emergence of metastases and resistance mutations often undermines the durability of the treatment response. Knowledge-based mechanistic models that replicate existing clinical trial outcomes, tailored to specific population characteristics, provide invaluable assistance in designing future clinical trials. Methods: We have developed physiologically based pharmacokinetic (PBPK) models for gefitinib and osimertinib, two EGFR TKIs, to accurately simulate the drugs' distribution within the primary tumor and metastatic sites following administration. These models were integrated with a mechanistic model of EGFR-mutant LUAD, enabling the representation of the mechanism of action of gefitinib and osimertinib. This model outputs the evolutions of the primary tumor and each metastasis, facilitating the evaluation of patient progression following RECIST criteria. Notably, the model encapsulates the heterogeneity within the tumor, representing various subclones defined by unique mutation profiles, thereby reflecting differential responses to treatment. Calibration of the model was achieved using publicly available data from the NEJ002, FLAURA and AURA3 clinical trials. Rigorous visual predictive checks and statistical tests were employed to ensure the proper behavior of the model. Results: The model adeptly replicated the time to progression in EGFR-mutant LUAD patients receiving gefitinib or osimertinib, whether as first-line or second-line therapy. Furthermore, it accurately mirrored the progression causes as per the RECIST criteria, including the emergence of new metastases in the lung, brain, liver, and bone. With a consistent virtual population as a reference, the combined model facilitated a comparative analysis of the efficacy of both treatments, thereby underscoring its utility in evaluating therapeutic strategies. Conclusions: The faithful replication of real-world data significantly enhances the credibility of our model, rendering it a promising tool for deriving pertinent insights and informing treatment strategies. Following its consecutive prospective validations in the FLAURA2 and MARIPOSA trials, the model is poised to facilitate the generation of synthetic control arms in future clinical trials. This advancement promises a more nuanced analysis of covariate relationships, especially when comparing investigational treatments to established standards of care. Additionally, it potentially reduces the requisite patient cohort size in such trials, optimizing resource utilization.

Pre-treatment CT radiomics for predicting immunotherapy response in non-small cell lung cancer(NSCLC): RECIST vs. irRECIST criteria.

e20613 Background: Accurate prediction of how patients with non-small cell lung cancer (NSCLC) will respond to immunotherapy is essential for customizing individual treatment plans. This research explores the use of radiomics analysis from pre-treatment CT scans as a method to predict the effectiveness of immunotherapy in individuals with NSCLC. Methods: This IRB-approved retrospective study investigated radiologic and clinical data from 159 patients with stage III-IV NSCLC treated with immunotherapy. Imaging responses were assessed according to RECIST 1.1 and immune-related RECIST (irRECIST) criteria at least twice during a 24-week period. Responses were categorized as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). 3D radiomics features were extracted from both the tumor and a 1 cm thick peritumoral region. A linear mixed-effect harmonization model was employed to correct for scanner-associated variations. A Random Forest algorithm was used to develop a classification model to predict response according to RECIST 1.1 or irRECIST. The dataset was split into training (70%) and test (30%) sets. The accuracy of predictions was evaluated using confusion matrix statistics and bootstrapping with 1,000 iterations for median and 95% confidence interval (CI). Results: Using RECIST 1.1 criteria, 41 patients (25.2%) achieved PR and CR(0.6), 62 (39.0%) achieved SD, and 56 (35.2%) achieved PD. IrRECIST criteria yielded slightly higher CR/PR rates with 52 patients (32.7%), while SD decreased to 65 (41.0%) and PD remained at 42 (26.4%). For predicting CR/PR and SD responses, the models achieved a sensitivity of 0.45 (95% CI: 0.38-0.50) and 0.64 (0.60-0.68) for irRECIST, compared to 0.34 (0.28-0.38) and 0.55 (0.52-0.60) for RECIST 1.1. The corresponding specificity was 0.85 (0.83-0.87) and 0.63 (0.59-0.67) for irRECIST, compared to 0.91 (0.89-0.93) and 0.67 (0.63-0.72) for RECIST 1.1. For predicting PD response, the models achieved a sensitivity of 0.49 (0.45-0.56) for irRECIST and 0.57 (0.52-0.62) for RECIST 1.1. The models' balanced accuracy for predicting CR/PR, SD, and PD were 0.65 (0.61-0.68), 0.64 (0.61-0.67), and 0.65 (0.63-0.69) for irRECIST, compared to 0.62 (0.59-0.64), 0.61 (0.59-0.64), and 0.62 (0.59-0.64) for RECIST 1.1, respectively. Conclusions: This study demonstrates the potential of pre-treatment CT radiomics to predict immunotherapy responses in NSCLC patients, offering insights into personalized treatment approaches. However, larger studies are needed to validate our findings.

Standard atezolizumab leads to severe overexposure in real-world patients with lung cancer: How far could we go in extending dosing intervals and saving money?

3085 Background: Immune checkpoint inhibitors are given as fixed doses, which may lead to drug exposure exceeding the plasma concentrations required for target engagement. If confirmed, this could pave the way for de-escalating treatments without compromising efficacy while reducing drug-costs. Methods: We monitored plasma concentrations of Atezolizumab in 40 real-world patients. A final set of 33 patients with SCLC or NSCLC were available for full PK/PD analysis. Individual PK parameters were derived using a population pharmacokinetics approach. Individual PK parameters allowed to simulate the full concentration-time profiles and to further simulate for each patient the time to reach the target threshold after the first dose of Atezolizumab. In addition, efficacy (RECIST criteria) and immune-related adverse events, (IRAEs, CTCAE grading) were monitored and statistical analysis was performed to search for possible exposure-response relationships. Results: Overall Response Rate was 55% and no severe IRAEs were observed. All patients had Cmin levels significantly above the target threshold on the first cycle of Atezolizumab. The mean Cmax after the first dose on cycle 1 was 426.1 µg/ml and the mean Cmin was 68.5 µg/ml, i.e. 11-time higher than the target threshold associated with target engagement (i.e., 6 µg/ml). The mean AUC at the first cycle was 4763 µg.d/ml. Exposure metrics and PK parameters at baseline and simulated prior RECIST evaluation were tested together with other covariates (i.e. age, sex, smoking, NLR, number of metastatic sites, line of treatment) as possible predictive markers of response or toxicity. None of the parameters related to Atezolizumab pharmacokinetics or exposure levels were associated with efficacy or toxicity, most likely because all patients had plasma levels well above pharmacologically active concentrations. First-line therapy was associated with better response on univariate analysis, but this effect was lost on multivariate analysis. Further simulations based on time required to fall below the efficacy threshold suggest that dosing intervals could be extended from Q7W to Q19W (mean: Q12W). Considering the annual budget for Atezolizumab at our institution, further simulations showed that the annual drug cost could thus be reduced from 2.5 M€ to 0.6 M€ while ensuring that all patients remain above active concentrations. Conclusions: Our study demonstrates in a real-world setting that standard Atezolizumab given as 1200 mg Q3W infusion leads to severe overexposure of the drug. This strong overexposure was not associated with more severe treatment-related toxicities. Finally, our study suggests that PK-guided dosing with Atezolizumab could help customizing the dosing interval while maintaining efficacious trough levels and that Q12W could be an alternate scheduling leading to significant cut in drug costs.

Immunotherapy for local/regional control of locally advanced orbital and periocular squamous cell carcinoma.

e18034 Background: Periocular squamous cell carcinoma can be of eyelid skin, ocular surface (bulbar) or palpebral conjunctival, or of lacrimal sac/nasolacrimal duct mucosal origin, is relatively rare, and presents unique anatomic considerations due to proximity to the eye and inherent risk to ocular structures associated with high dose radiation therapy. We herein report on 17 patients with orbital or periocular SCC who were treated with immunotherapy (IO) to decrease surgical morbidity or to avoid high dose radiation therapy. Methods: Retrospective review of all previously unreported patients with orbital, conjunctival, or periocular SCC who were treated with IO either in the neoadjuvant setting prior to surgery or for treatment of periocular SCC with perineural spread into the orbit and skull base. Results: 17 patients, 12 men and 5 women (Age range: 44-92; median=70 years old) with orbital (n=6), conjunctival (n=5), or lacrimal sac/duct (n=2) squamous cell carcinoma (SCC), or periocular SCC with perineural spread into the orbit and skull base (n=4) who were treated with IO either as single drug (n= 11) or in combination with chemotherapy (n= 6 ). In all patients either cemiplimab or pembolizumab was used. In 13 patients IO was used in the neoadjuvant setting prior to planned surgery. In 4 patients with perineural spread as they had non surgically resectable disease, IO was used to avoid high dose radiation therapy with its inherent significant risk of ocular toxicity. Overall, 3 patients achieved complete response, 10 patients achieved partial response, and 4 patients had stable disease, using RECIST criteria. One of 5 patients with conjunctival SCC also had nodal metastasis at presentation and achieved a dramatic complete response of both the conjunctival tumor and the nodal metastasis and managed to avoid surgery altogether. This patient had a very high tumor mutation burden (TMB). One patient developed diabetic ketoacidosis as a side effect of IO; otherwise the adverse effects were low grade. Conclusions: IO either as single drug or in combination with chemotherapy has a fairly high response rate in patients with ocular adnexal, conjunctival or orbital SCC and in patients with periocular SCC with perineural spread in the orbit and skull base. Future prospective trails using IO for orbital and ocular adnexal SCC should be planned and should aim to correlate molecular data such as TMB with response.

Safety and Efficacy of Cryotherapy for the Treatment of Renal Angiomyolipoma Related to Tuberous Sclerosis Complex: The Cryo-TSC Study

Purpose: Tuberous sclerosis complex (TSC) is a rare autosomal dominant inherited disease, in which approximately 60% to 80% of patients have bilateral angiomyolipoma (AML). There is a need for repeatable local treatments of TSC-AML. Cryotherapy is an option for renal tumors; however, its safety and efficacy for vascular tumors, such as TSC-AML, are unclear. The aim of this study was to establish the safety and efficacy of cryotherapy for TSC-AML. Materials and Methods: This was an open-label, single-arm, prospective phase II study to evaluate the safety and efficacy of cryotherapy for TSC-AML of ≤ 4 cm. Cryotherapy was performed using the CryoHit device with a percutaneous approach. Safety was assessed 1, 2, 6, and 9 months after cryotherapy, and efficacy was assessed 3 and 9 months after cryotherapy. The efficacy of cryotherapy was evaluated using the modified RECIST or RECIST criteria by independent central review. The primary end point was the disease control rate, and secondary end points were the overall response rate, safety, renal function, quality of life, and whether additional treatment was required. Results: The disease control rate was 100%, and the overall response rate was 93.3%. After 9 months of follow-up, the median estimated glomerular filtration rate decreased slightly (from 89.2 mL/min/1.73 m2 to 79.4 mL/min/1.73 m2). Quality of life was stable, and no additional treatment was needed. Three Grade 3 adverse events (hematuria, chronic kidney disease, and elevated aspartate aminotransferase) were observed in 3 patients, respectively, but no additional treatments were required. Conclusions: Cryotherapy for TSC-AML can be performed safely and efficiently. Cryotherapy can be a new therapeutic option for TSC-AML. Trial Registration Number: jRCTs072200039.

Liquid biopsy in patients with metastatic pancreatic cancer using an optimized targeted sequencing approach: Data from the pancreatic cancer registry PanDaDETECT.

e16303 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) conveys a dismal prognosis, and biomarkers for clinical diagnostics and treatment monitoring are urgently needed. Detection of circulating tumor DNA (ctDNA) using liquid biopsy (LB) has been shown to correlate with treatment response in other tumor entities. Here, we evaluated the feasibility of LB by targeted next generation sequencing (NGS) in metastatic PDAC, using an NGS approach optimized for PDAC. Methods: Patients from our PanDaDETECT registry with metastatic PDAC were included. Plasma samples were collected at initial diagnosis and every three months during palliative treatment. Targeted NGS of plasma samples was performed using a small, custom-generated gene panel optimized for LB provided by Qiagen (QiaSeq Targeted DNA Panel), covering the four most frequently mutated genes in PDAC with full exon coverage (KRAS, TP53, SMAD4 and CDKN2A). Sequencing was performed on the Illumina NextSeq 550 platform. LB results were compared to matched tissue NGS data from tumor samples. Results were correlated with the serological biomarker Ca 19-9 and radiographic response data. All patients provided written informed consent. The responsible ethics committee approved the study. Results: From 2020 to 2022, 57 patients were included and underwent plasma NGS at least at initial diagnosis. For 52 of these patients a tissue NGS result was available, and in 49 patients (94,2%), at least one of the four genes covered by our LB panel was mutated in the tumor tissue. In 35 patients, our LB approach detected ctDNA in the plasma sample at initial diagnosis (61,4%). Comparing tissue and plasma sequencing data at initial diagnosis, our LB approach detected ctDNA in 32 out of 49 patients who had a known mutation in tissue NGS in at least one of the four genes covered by the LB panel (65,3%). For 22 patients with positive ctDNA detection in plasma NGS, follow-up plasma samples after three months of treatment were available. In this subgroup, detection of ctDNA showed a superior correlation with radiographic response assessed by RECIST criteria than the serological biomarker Ca 19-9. In patients with a partial response or stable disease as defined by RECIST, ctDNA levels decreased markedly, while remaining elevated in patients showing disease progression. For 11 patients, plasma NGS at 6 months of treatment or later was performed, the results at these later time points correlated well with clinical and radiographic response in 9 out of 11 patients. Conclusions: Our LB approach optimized for PDAC is feasible and shows a good correlation with serological and radiographic response. Our optimized NGS panel covering only four genes is able to detect ctDNA in a majority of PDAC patients. LB by targeted NGS has the potential to detect a broad spectrum of relevant mutations in PDAC in an automatable and cost-effective matter.

Ethnic and clinical differences in gBRCA and HRD mutated breast and ovarian cancers and their response to PARP inhibitors.

e13102 Background: Hereditary mutations of the homologous recombination (HR), the key DNA double-strand break repair pathway, are one of the well-known causes of breast and ovarian cancers. Few reports exist on these mutations and the utilization of PARP inhibitors in the Middle Eastern region. Methods: This is a single-center retrospective study of breast and ovarian cancer patients who underwent genetic testing for g BRCA and HR defects (HRD) respectively between August 2021 and May 2023. Data was summarized using descriptive statistics and compared using counts and percentages. Response to treatment was assessed using RECIST criteria. Results: The prevalence of pathogenic mutations was 22.8%, with 26.3% of breast cancers harboring g BRCA mutations and 24% of ovarian cancers showing HRD positivity. Middle Eastern patients comprised 40% of the g BRCA-positive breast cancer group, while Asians accounted for 66% of the HRD-positive ovarian cancer patients. In mutated breast cancer, 53.3% had a positive family history of cancer. 33.3% of mutated breast cancer group and 66.6% of the ovarian cancer group received PARPis. Objective response to PARPi was 40% and 100% in breast and ovarian cancers, respectively. Conclusions: Our study revealed a high prevalence of g BRCA mutations (26.3%) in breast cancer and HRD positivity (24%) in ovarian cancer). Ethnic profiles differed between these cancers, with Middle Eastern and Southeast Asian patients dominating the breast and ovarian groups, respectively. Interestingly, the TNBC rate in breast cancer remained around 20% regardless of g BRCA status. While disparities between HRD groups were more pronounced in ovarian cancer, as expected, unexpected trends emerged in breast cancer. Further research with larger cohorts is needed to confirm these findings. [Table: see text]

Evaluation of mixed response in tumor size and survival in patients with rare cancers treated with dual checkpoint inhibitor therapy (DART SWOG S1609).

2514 Background: RECIST criteria evaluate changes in tumor burden and have been utilized in cancer research for decades. Changes in the sum of maximum diameters of “target” lesions are used to designate patients into response categories, including complete response, partial response, stable disease, and progressive disease. However, not much is known about the implications of mixed response, where lesions within a patient show contrasting responses to systemic treatment. Here we evaluate the data from the Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609 to investigate the association between mixed response and survival among patients treated with dual checkpoint inhibitor therapy. Methods: A total of 796 patients were enrolled on the S1609 DART trial, a basket trial evaluating ipilimumab plus nivolumab across solid rare tumor subtypes. All patients had RECIST-measurable disease at the study entry. Patients were excluded from the analyses due to: ineligibility, n=47; not receiving any protocol therapy, n=23; death before day 65 (landmark for analysis based on first scan), n=86; 1 target lesion, n=153. Thus, 487 patients were analyzed. A 5mm cut-off for increase/decrease in lesions was used to define a mixed response. Cox regression models were used to evaluate associations between survival (landmarked at day 65, stratified by basket) and response category (reference of Stable Disease). Results: 6 groups were identified among the 487 patients: no lesions changed more than 5 mm (n = 105), all lesions increased more than 5mm (n = 69), all lesions decreased more than 5mm (n = 39), one+ lesion increased more than 5mm and one+ lesion decreased more than 5 mm (n = 24), one+ lesion increased more than 5mm and one+ lesion did not change more than 5 mm (either direction) (n =155), one+ lesion decreased more than 5mm and one+ lesion did not change more than 5 mm (either direction) (n =95). Hazard ratios and median survival (mOS) are shown (Table). Conclusions: This is the first evaluation of the association between mixed response and survival outcomes among patients with various tumors receiving dual checkpoint therapy. Our results suggest that survival outcomes are driven by the “worst” performing lesion; in other words, having an increase in any lesion is associated with worse outcomes, even if not all lesions increase. [Table: see text]

Safety and efficacy of camrelizumab and apatinib in combination with IMRT in unresectable hepatocellular carcinoma: A non-randomised phase 2 study.

e16157 Background: This study aimed to assess the efficacy and safety of combining Camrelizumab (an anti-programmed death 1 antibody) and Apatinib (a tyrosine kinase inhibitor) with intensity-modulated radiotherapy (IMRT) in patients with unresectable hepatocellular carcinoma (HCC). Methods: This non-randomized phase 2 study enrolled patients with unresectable HCC who were either systemic treatment-naïve or refractory/intolerant to first-line targeted therapy. The enrolled patients received IMRT at a dose of 50-60 Gy in 25-30 fractions, with the target volume encompassing all visible lesions. Patients were administered Camrelizumab intravenously at a dose of 200 mg every 3 weeks and Apatinib orally a dose of 250 mg once daily during IMRT, continuing for 2 years or until unacceptable toxicity or disease progression. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), local control (LC) rate, overall survival (OS) and adverse events. Results: From October 2020 to January 2024, 33 patients were included in the preliminary analysis (31 men and 2 women; median age, 57 years [range, 39-77 years]). Among them, 30 patients were diagnosed with BCLC stage C (90.9%). The median number of lesions was one (range, 1-5), with a median tumor diameter of 6.0 cm (range, 2.6-16.0 cm). Tumor thrombus was observed in 22 cases (66.7%), and lymph node metastases was found in 6 cases (18.2%). The ORR based on RECIST 1.1 and modified RECIST criteria were 78.8% and 90.9%, respectively, with a complete response (CR) rate of 12.1% and 54.5%, respectively. The median follow-up time was 20.0 months (range, 3.3-38.6 months). The LC rate at 2 years was 88.3% (95% CI, 68.1-96.1%). The median PFS was 17.5 months (95% CI, 12.6-NA), and the PFS rate at 2 years was 43.9% (95% CI, 26.1-73.8%). The median OS was 25.9 months (95% CI, 14.0-NA), and OS rate at 2 years was 58.5% (95% CI, 41.9-81.6%). According to CTCAE 5.0, grade 3-4 treatment-related adverse events were observed in 27 patients (81.8%), with the most common being thrombocytopenia (42.5%), leukopenia (33.3%) and hypertension (39.4%). No treatment-related deaths occurred. Conclusions: The combination of systematic therapies involving Camrelizumab and Apatinib with local-regional treatment of IMRT showed promising outcomes and manageable toxicities in patients with unresectable HCC. These findings warrant to be confirmed in phase 3 prospective studies. Clinical trial information: ChiCTR2000035052.

Predictors of response and surgical approach after neoadjuvant chemotherapy in receptor-positive/HER2-negative stage II-III breast cancer patients treated in two private cancer care centers in Lima, Peru: Real-world data.

e12659 Background: The role of neoadjuvant chemotherapy (NAC) in hormone receptor-positive HER2-negative breast cancer (BC) is controversial, its main benefit being to improve the surgical outcome in both breast and axilla. The aim of this study was to evaluate the response to NAC, as well as possible predictors and the type surgery performed after primary treatment. Methods: Observational, retrospective study from a database of 1356 consecutive cases of BC between 2016 and 2022 in two private oncology centers in Lima Metropolitana. There were 726 new cases of hormone receptor-positive HER2-negative BC (53.5%), of which those patients with clinical stage II-III who received NAC were considered (n=122, 16.8 % of luminal HER2-negative). Results: The average age of the sample was 46.6 years (range 25-72) with a predominance of luminal B subtype (60.7%) and clinical stage II disease (51.6%), as well as an average delay time to treatment of 33.9 days. Chemotherapy choice was AC every 3 weeks followed by weekly paclitaxel (98.4%). The pathological complete response (pCR) rate was of 16.4% in the breast, 29.1% in the lymph nodes and 13.9% in both. None of the variables studied (age, histologic grade and type, clinical stage, tumor size, number of nodes, hormone receptors, Ki-67 and HER2 low) were predictors of pCR. According to RECIST criteria, tumor shrinking in the breast occurred in the majority of patients (partial and complete response: 86.1%) and eight out of ten patients achieved a tumor size reduction of more than 50%. The rate of mastectomy was 67.2% and radical axillary dissection, 70.5%. Conclusions: In our cohort, we found a pCR rate similar to that reported in the world literature. No predictors of pCR were found. Despite the high proportion of tumor response at breast and node level, the surgical approach was mostly radical. The multidisciplinary BC committee in our setting should be strengthened in order to make better decisions on the surgical approach for patients with hormone receptor-positive HER2-negative stage II-III BC who receive NAC.

A phase ib-II study of dabrafenib, trametinib, cetuximab plus irinotecan in patients with BRAF mutant metastatic colorectal cancer: Subgroup analysis and biomarker identification.

e15581 Background: About 5%-12% of patients with metastatic CRC (mCRC) have BRAF mutations in which BRAF V600E mutated was most common, accounts for approximately 90% of cases of BRAF mutation mCRC. Therefore, multi-drug combination therapy with BRAF inhibitor has been tried. The efficacy results of this study have been reported in 2023 ASCO GI (#156). The ORR was 30% (3/10), the DCR was 80% (8/10). After a median follow-up of 19.7 months, the median PFS was 7.5 months. Here, we reported the results of subsequent analyses. Methods: In this phase Ib-II trial, 15 patients with BRAF-mutant mCRC received Dabrafenib, trametinib, cetuximab plus irinotecan combination therapy. Whole exome sequencing was conducted in 8 proficient mismatch repair (pMMR) mCRC patients with BRAF V600E-mutant. Patients were followed up clinically and radiographically. Response was defined as Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) were defined according to the response definitions of the RECIST criteria. Results: 3 mCRC patients (CR or PR) were divided into response group, 5 mCRC patients (SD or PD) were divided into non-response group. Age (59.6±4.22 vs 39.0±9.93), Gender (male 66.67% vs 80%), ECOG score (0.67 vs 0.60), ALT flare rate (66.67% vs 60%) were similar in the two group. Patients in response group have better 2-year survival rate (66.7% vs 0%, P < 0.05). Furthermore, response-related Differential Expression Genes (DEGs) (log2fc > 1, P < 0.05) were analyzed. Meanwhile, GO and KEGG pathway analysis was conducted based on DEGs. Results showed that MAPK signaling pathway related genes were down-regulated in response group such as EGF, FGF18, HGF, IGF1, MAPK10, NGF. While Apoptosis related genes were up-regulated in response group such as BCL2L1, AIFM1, DAXX. Moreover, Antigen processing and presentation related genes such as CALR, CANX, HSPA8 were enriched in response group, which indicated a more active immune microenvironment. On the contrary, Hedgehog signaling pathway related genes such as GLI1, HHIP, BOC were enriched in non-response group. Next, we verified the clinical significance of DEGS in TCGA CRC cohort database using Cox-regression analysis. Results showed that expression of IGF1, NGF, CAMK2B, CCNA1 were associated with poor prognosis and CANX, HSPA8 were associated with better prognosis, which is in accordance with our sequencing results. Conclusions: Inhibition of MAPK signaling and promoted Apoptosis was found in BRAF V600E-mutant mCRC patients who were response to Dabrafenib, trametinib, cetuximab plus irinotecan. It's worth noticing that immune activation occurred in responsive patients, indicated a potential benefit from immunotherapy combination therapy. Moreover, Hedgehog signaling pathway may be target in rescue therapy in mCRC patients. Clinical trial information: ChiCTR2200063316.

Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: Lenvamel, a multicenter retrospective study of the French Group of Skin Cancers.

9546 Background: Treatment options for patients (pts) with advanced melanoma who experience resistance to immunotherapy (ICI) +- targeted therapy are lacking. Studies suggest the anti-tumour activity of combined pembrolizumab and lenvatinib in pts progressing on ICI. We report the clinical outcomes of combined lenvatinib and anti-PD-1 in this population. Methods: This French multicenter real-world study was conducted from 09/2020 to 07/2023. The primary endpoint was objective response rate (ORR) according to the RECIST criteria (v.1.1). Secondary endpoints were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS) and duration of response (DOR). Results: Of the 67 pts included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV M1c or M1d disease. Baseline characteristics are presented (Table). Overall ORR was 28.4% (95%CI, 18–41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. ORR was 71.4% (95%CI, 29–96%) for mucosal melanoma, 32,8% (95%CI, 21–46%) for pts pre-treated with anti-PD-1 + anti-CTLA-4, and 31,5% (95%CI, 20–46%) for BRAF wild-type melanoma. Median DOR was 3.1 (IQR, 1.3–4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5–3.7) and 9.8 (95% CI, 5.6–13.9) months respectively. Grade 3–4 TRAEs occurred in 16 pts (24%, no grade 5); common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). Conclusions: Our study demonstrates an interesting response rate and acceptable safety profile of this combination, with manageable toxicities, in an immuno-refractory population with poor prognostic factors. Pts pre-treated with anti-PD-1+ anti-CTLA-4, and those with BRAF wild-type melanoma seemed to benefit more from this strategy. Our study also provides promising data (considering the small sample) for pts with mucosal melanoma. Our data support this treatment option for refractory melanoma, though not yet approved by the health authorities, and highlight the need for new strategies. [Table: see text]

TACE-HAIC combined with donafenib and immunotherapy for hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT): A retrospective analysis.

e16174 Background: The probability of Chinese hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) is relatively large and the long-term survival of this part of patients is poor. Systemic therapy, transcatheter arterial chemoembolization (TACE), and hepatic artery infusion chemotherapy are widely used in HCC patients with PVTT. We want to explore the efficacy and safety of TACE plus hepatic arterial infusion chemotherapy combined with Donafenib, anti-PD-1 antibody in uHCC patients with PVTT. Methods: We retrospectively analyzed the patients who were diagnosed as uHCC with PVTT and received the treatment of TACE plus HAIC combined with Donafenib, anti-PD-1 antibody as first-line therapy from Dec 2021 to Jun 2023 in Harbin Medical University Cancer Hospital. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progress free survival (PFS), overall survival (OS) and safety. Results: Of 106 patients included in the analysis, all of them received first-line treatment of TACE (embolization of pirarubicin hydrochloride 40mg, iodized oil 10-20ml with or without gelatin sponge) plus HAIC (oxaliplatin 85 mg/m2 2h, leucovorin 400 mg/m2 1h, fluorouracil bolus 400 mg/m2 in the first 10 minutes, and fluorouracil infusion 2400 mg/m2 for 46h) combined with donafenib 200mg bid, anti-PD-1 antibody Q3W. The median age was 58 years (IQR, 52-64). The study population was predominantly male (79.2%), and 79.2% were HBV-positive. All HCC patients are accompanied by PVTT, most of which are VP3(72.6%).The rate of patients with extrahepatic metastasis were 16.0%. All patients were classified as BCLC stage C and 84.0% were classified as CNLC stage IIIa. As of December 2023, 106 patients had received at least one imaging evaluation, 11 (10.4%), 60 (56.6%) and 28 (26.4%) of them achieved complete response, partial response and stable disease, and the overall objective response rate and disease control rate was 67.0% and 93.4% per modified RECIST criteria respectively. With 16.3 months of median follow-up time, the 12-month PFS rate was 81.3% and the 12-month OS rate was 90.1%. The median PFS and OS were not reached. 103 of all patients had at least one treatment-related AE (TRAE), and treatment-related deaths did not occur in this study. Grade 3 TRAEs occurred in 33 (31.1%) patients, and no grades 4 or 5 were reported. The most common Grade 3 TRAEs included aspartate transaminase increased (18.9%), platelet count decreased (14.2%) and blood bilirubin increased (8.5%). Conclusions: TACE-HAIC combined with Donafenib and immunotherapy are effective and tolerable for uHCC patients with PVTT.

#1883 SUrvey of renal Biopsy database and Anti-cancer dRUg therapy in Japan (SUBARU-J study)

Abstract Background and Aims The frequency of consultations for renal complications associated with anti-cancer drug therapy has greatly increased in recent years, but the actual situations remain yet to be fully understood. We aimed to investigate the clinical outcomes of anti-cancer drug therapy-associated renal complications, using the Japan Renal Biopsy Registry (J-RBR), a nationwide registry system in Japan. Method This nationwide survey was performed in 449 cases with “drug-induced” checked in J-RBR database from 2018 to 2021. In total 449 subjects, top-ranked histopathological diagnoses were as follows, TIN (49.8%), TMA (14.5), MN (10.0), MCNS (6.5), FSGS (4.4), Vasculitis (2.2) and others (12.2). Regardless of the causative agent, TIN was the most common diagnosis. Though, it was followed by TMA or MN in anti-cancer drug (n = 139)- or non-anticancer drug (n = 190)-related cases, respectively. Because there was also TMA included as 2nd highest in causative-agent unidentified cases (n = 120), we employed total 259 subjects of anti-cancer drug-related and causative-agent unidentified for this survey. Our surveillance files investigating on renal pathology, medications and cancer prognosis were distributed. Of the 224 cases with a file uploaded, a total of 135 anti-cancer drug-related cases confirmed by the information were analyzed. Patients’ clinical data collected at pre- and post-biopsy as well as histopathological diagnoses were used for epidemiological and clinicopathological analyses. Mann-Whitney U test or chi-square test was used for continuous or categorical variables. Overall survival (OS) was estimated using Kaplan–Meier method and compared by log-rank test. Results In total 135 subjects, top-ranked histopathological diagnoses were as follows: tubulointerstitial nephritis (TIN; 64 cases), thrombotic microangiopathy (TMA; 48), focal segmental glomerulosclerosis (FSGS; 5), IgA nephropathy (IgAN; 4), acute tubular necrosis (ATN; 3), minimal change nephrotic syndrome (MCNS; 3), crescentic glomerulonephritis (CrGN; 2), membranoproliferative glomerulonephritis (MPGN; 2) and others (4). 80% of TIN and 75% of TMA, the most frequent diagnoses in our survey, were associated with immune-checkpoint inhibitors (ICI) and anti-angiogenic therapy (AAG), respectively. All IgAN, MCNS and CrGN cases were ICI-related. Proton pump inhibitors and antibiotics were used concomitantly in TIN (p = 0.054) and TMA (p < 0.001), respectively. Among cases with TIN, their OS in the subgroups of targeted therapy (Tx), and the combination with Tx and conventional cytotoxic agents (Combi) seemed to be worse than that of cytotoxic agents alone (CTx); it may be due to more cases in the Tx and Combi subgroups with treatment response category of progressive disease (by RECIST criteria). In contrast, among TMA cases, OS in each of the three subgroups of Tx, CTx, and Combi seemed to be overlapped, suggesting the prognostic impact of TMA on OS. The serum LDH level was higher in TMA associated with CTx (CTx-TMA) than that with others (Fig. 1: 393.2 vs. 225.1 U/L, p = 0.06). Of note, Kaplan-Meier curves for OS in TMA cases with increased LDH (>220 U/L) showed poor prognosis in CTx-TMA than in others-TMA (Fig. 2: p = 0.018). Conclusion Our nationwide survey using J-RBR registry database with renal biopsy data provides a snapshot of kidney complications associated with anti-cancer drug therapy. Higher LDH in CTx-TMA cases may be associated with systemic TMA, probably leading to the poor prognosis. To explore the detail of anti-cancer drug-associated TMA and other complications, further research employing more sample size is warranted in the future.

Abstract IA006: Towards ctDNA-guided treatment of muscle-invasive bladder cancer

Abstract Cancer cells release cell-free DNA with tumor-specific molecular alterations into circulation, known as circulating tumor DNA (ctDNA). Numerous studies have underscored the biomarker potential of ctDNA in detecting minimal residual disease across various cancer types, including bladder cancer. The rapid clearance of ctDNA from circulation, typically under two hours, makes it an ideal candidate for real-time monitoring of tumor burden following surgical interventions and throughout oncological treatments. For ctDNA measurements to be effectively incorporated into clinical decision-making, it is crucial to conduct ctDNA-guided intervention trials that demonstrate tangible clinical benefits. Current trials focusing on muscle-invasive bladder cancer (MIBC) are supported by recent exploratory sub-analyses of completed clinical trials, which have shown that ctDNA can effectively guide treatment decisions in this context. Beyond guiding adjuvant treatments, ctDNA holds potential for directing bladder preservation strategies, potentially in combination with urinary tumor-derived DNA (utDNA) measurements. The need for treatment de-escalation, such as in neoadjuvant chemotherapy (NAC), is underscored by the observation that a significant proportion of patients undergo treatments that result in considerable adverse effects without achieving pathologic response. Traditional decision-making in cancer treatment, largely reliant on imaging-based criteria like the Response Evaluation Criteria in Solid Tumors (RECIST), often does not adequately reflect the ultimate clinical endpoint of overall survival. A ctDNA-based measure that considers ctDNA dynamics during treatment could serve as a superior tool or complement to current strategies. In conclusion, ctDNA has demonstrated significant promise as a biomarker in both retrospective and prospective studies for risk assessment in MIBC. The clinical value of ctDNA-guided treatment will soon be determined by ongoing clinical trials (TOMBOLA, IMvigor011, MODERN). In my presentation I will address the potential clinical impact of ctDNA analyses, the technological aspects involved, how urine analyses may supplement these findings, and future directions in the field. Citation Format: Lars Dyrskjøt. Towards ctDNA-guided treatment of muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA006.

Potential Advantage of Magnetic Resonance Imaging in Detecting Thoracic Wall Infiltration in Pleural Mesothelioma. A Retrospective Single Center Analysis.

Abstract Background Thoracic wall infiltration in pleural mesothelioma (PM) can be an important prognostic factor when determining the extent of resection. Currently, standardized imaging for restaging after neoadjuvant systemic therapy comprises contrast enhanced Computed Tomography (CT) or Positron Emission Tomography (PET/CT) scan. Aims However, thoracic Magnetic Resonance Imaging (MRI) could be a better discriminator of chest wall infiltration prior to surgery. To increase the preoperative staging accuracy, we introduced a MRI protocol at our center. Methods A retrospective analysis of this prospective new imaging protocol was performed from 07/2018 to 08/2023, including descriptive analysis for patient`s sex, age, nicotine consumption, asbestos exposure, histological subtype, TNM-stage, RECIST criteria and number of neoadjuvant therapy cycles. Preoperative restaging included routine imaging and MRI. After histological diagnosis of PM, neoadjuvant therapy was conducted, followed by partial pleurectomy or extended pleurectomy/decortication, with intraoperative biopsies of suspicious chest wall lesions. The CT/MRI results were compared to the intraoperative biopsies. Sensitivity and specificity of both modalities were analyzed. Results Twenty-five patients (mean age 65.4, 12% female) with possible chest wall infiltration were included out of the 35 patients with PM treated during the observation period. Of the 10 patients with actual chest wall infiltration, 9 (90%) had a T-Stage of 3 or higher, 9 (90%) had PM of epithelioid histologic subtype and 4 (40%) a R2-Resection. The mean overall survival of all patients was 18.88 months (8-58). In our study, thoracic MRI showed a high sensitivity (90%) and specificity (100%) for the detection of chest wall infiltration, especially when compared to the CT scan (sensitivity of 10%). Conclusion With the adjunctive use of thoracic MRI we demonstrated a higher sensitivity for detection of chest wall infiltration compared to conventional imaging prior to surgery. This may facilitate the preoperative assessment of the extent of resection. Nevertheless, larger studies are required to confirm these results.

Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study

The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P<0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P<0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P<0.0001; 47.3% vs 29.7%, P<0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Chordoma Genetic Aberrations and Targeted Therapies Panorama: A Systematic Literature Review.

Background: Chordomas pose a challenge in treatment due to their local invasiveness, high recurrence, and potential lethality. Despite being slow-growing and rarely metastasizing, these tumors often resist conventional chemotherapies (CTs) and radiotherapies (RTs), making surgical resection a crucial intervention. However, achieving radical resection for chordomas is seldom possible, presenting therapeutic challenges. The accurate diagnosis of these tumors is vital for their distinct prognoses, yet differentiation is hindered by overlapping radiological and histopathological features. Fortunately, recent molecular and genetic studies, including extracranial location analysis, offer valuable insights for precise diagnosis. This literature review delves into the genetic aberrations and molecular biology of chordomas, aiming to provide an overview of more successful therapeutic strategies. Methods: A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 28 January 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "chordomas", "molecular biology", "gene aberrations", and "target therapies". The studies included in this review consist of preclinical cell studies, case reports, case series, randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on genetic and biological aberrations in chordomas. Results: Of the initial 297 articles identified, 40 articles were included in the article. Two tables highlighted clinical studies and ongoing clinical trials, encompassing 18 and 22 studies, respectively. The clinical studies involved 185 patients diagnosed with chordomas. The tumor sites were predominantly sacral (n = 8, 44.4%), followed by clivus (n = 7, 38.9%) and lumbar spine (n = 3, 16.7%). Primary treatments preceding targeted therapies included surgery (n = 10, 55.6%), RT (n = 9, 50.0%), and systemic treatments (n = 7, 38.9%). Various agents targeting specific molecular pathways were analyzed in the studies, such as imatinib (a tyrosine kinase inhibitor), erlotinib, and bevacizumab, which target EGFR/VEGFR. Common adverse events included fatigue (47.1%), skin reactions (32.4%), hypertension (23.5%), diarrhea (17.6%), and thyroid abnormalities (5.9%). Clinical outcomes were systematically assessed based on progression-free survival (PFS), overall survival (OS), and tumor response evaluated using RECIST or CHOI criteria. Notably, stable disease (SD) occurred in 58.1% of cases, and partial responses (PRs) were observed in 28.2% of patients, while 13.7% experienced disease progression (PD) despite targeted therapy. Among the 22 clinical trials included in the analysis, Phase II trials were the most prevalent (40.9%), followed by I-II trials (31.8%) and Phase I trials (27.3%). PD-1 inhibitors were the most frequently utilized, appearing in 50% of the trials, followed by PD-L1 inhibitors (36.4%), CTLA-4 inhibitors (22.7%), and mTOR inhibitors (13.6%). Conclusions: This systematic review provides an extensive overview of the state of targeted therapy for chordomas, highlighting their potential to stabilize the illness and enhance clinical outcomes.

Response- and Progression-Based End Points in Trial and Observational Cohorts of Patients With NSCLC

Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to assess therapeutic response in clinical trials but not in routine care; thus, RECIST-based end points are difficult to include in observational studies. Clinician-anchored approaches for measuring clinical response have been validated but not widely compared with clinical trial data, limiting their use as evidence for clinical decision-making. To compare response- and progression-based end points in clinical trial and observational cohorts of patients with non-small cell lung cancer (NSCLC). This retrospective cohort study used patient-level data from the IMpower132 trial (conducted April 7, 2016, to May 31, 2017) and a nationwide electronic health record (EHR)-derived deidentified database (data collected January 1, 2011, to March 31, 2022). Patients in the observational cohort were selected according to the inclusion and exclusion criteria of the IMpower132 trial. All patients in the observational cohort had stage IV NSCLC. All patients were randomized to or received first-line carboplatin or cisplatin plus pemetrexed. End points included response rates, duration of response, and progression-free survival, compared between the trial and observational cohorts before and after weighting. Response rates for the observational cohort were derived from the EHR. A total of 769 patients met inclusion criteria, 494 in the observational cohort (median [IQR] age, 67 [60-74] years; 228 [46.2%] female; 45 [9.1%] Black or African American; 352 [71.3%] White; 53 [10.7%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial) and 275 in the trial cohort (median [IQR] age, 63 [56-68] years; 90 [32.7%] female; 4 [1.5%] Black or African American; 194 [70.5%] White; 65 [23.6%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial). All 3 end points were comparable between the study cohorts. Trial patients had a higher number of response assessments compared with patients in the weighted observational cohort. The EHR-derived response rate was numerically higher than the objective response rate after weighting (100.3 of 249.3 [40.2%] vs 105 of 275 [38.2%]) due to higher rates of observed partial response than RECIST-based partial response. Among patients with at least 1 response assessment, the EHR-derived response rate remained higher than the objective response rate (100.3 of 193.4 [51.9%] vs 105 of 256 [41.0%]) due to a higher proportion of patients in the observational cohort with no response assessment. In this study, response- and progression-based end points were similar between clinical trial and weighted observational cohorts, which increases confidence in the reliability of observational end points and can inform their interpretation in relation to trial end points. Additionally, the difference observed in response rates (including vs excluding patients with no response assessment) highlights the importance of future research adopting this 2-way approach when evaluating the relationship of EHR-derived and objective response rates.