bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-efficiency and expanded access modeling of toripalimab versus pembrolizumab in locally advanced or metastatic nonsquamous non-small cell lung cancer.
Authors: MacDonald Karen , Pondel Marc , Abraham Ivo 
Published: July 2024

e20590 Background: Toripalimab, a novel anti-PD-1 antibody, demonstrated significant PFS and OS benefit in combination with pemetrexed and platinum (toripalimab+PemPlat) in advanced nonsquamous non-small cell lung cancer (nsNSCLC) over placebo+PemPlat in the CHOICE-01 trial (median PFS: 9.7 vs 5.5 months; median OS: NE vs 17.0 months), though not currently approved for this indication. FDA-approved pembrolizumab+PemPlat was similarly found to extend PFS and OS over placebo+PemPlat in metastatic nsNSCLC patients in KEYNOTE-189 (median PFS: 9.0 vs 4.9 months; median OS: 22.0 vs 10.7 months). The current wholesale acquisition cost (WAC) of pembrolizumab is $11,115 per dose. The WAC of toripalimab, recently approved for nasopharyngeal carcinoma, is 80% of pembrolizumab. In this simulation we modeled the cost-efficiency of the toripalimab regimen versus pembrolizumab in nsNSCLC and the budget-neutral expanded access to additional toripalimab enabled by savings. Methods: Utilizing WAC drug costs and treatment administration costs, we estimated the cost-efficiency of the toripalimab regimen for the median PFS 9.7 months observed in CHOICE-01 versus the pembrolizumab regimen for the median PFS 9.0 months observed in KEYNOTE-189. We assumed that 14 cycles of toripalimab+Pem (with carboplatin in cycles 1-4) are administered over 9.7 months and 13 cycles of pembrolizumab+Pem (with carboplatin in cycles 1-4) are administered over 9.0 months. From the differential, we estimated the potential expanded access to additional toripalimab treatment on a budget-neutral basis. The model was replicated utilizing an ex ante toripalimab average sales price (ASP) of 80% of pembrolizumab ASP. Results: The pembrolizumab regimen costs $176,705 over 9.0 months (13 cycles) while the toripalimab regimen costs $159,136 over 9.7 months (14 cycles) at the respective WACs, for savings of $17,569 per patient. This would enable the purchase of 1.6 additional toripalimab+pemetrexed maintenance cycles on a budget-neutral basis for every patient treated. For every 9 patients treated with toripalimab instead of pembrolizumab, one additional patient could be treated with the full toripalimab regimen (all agents) for 9.7 months. Extrapolated to the US incident nsNSCLC population of 49,647 patients, if only 5% of patients are treated with toripalimab instead of pembrolizumab estimated savings of $43,611,849 provide access to 3,849 additional toripalimab+pemetrexed maintenance cycles or 274 full toripalimab regimens (all agents for 9.7 months) budget-neutrally. Similar results were seen in the ex ante ASP model. Conclusions: If approved for use in advanced nsNSCLC, toripalimab is estimated, at its market-entry WAC, to save $17.6 thousand per patient over a median PFS 9.7 months treatment duration compared to the pembrolizumab regimen over a median PFS 9.0 months of treatment.
Prediction of oncogene mutation status in non-small cell lung cancer leveraging radiomics from CT scans: A systematic review and meta-analysis with a special focus on artificial-intelligence-based methods.
Authors: Fuster-Matanzo Almudena , Picó Peris Alfonso , Bellvís Bataller Fuensanta , Jiménez Pastor Ana , Weiss Glen J. , Martí-Bonmatí Luis , Lázaro Sánchez Antonio David , Banna Giuseppe Luigi , Addeo Alfredo , Alberich-Bayarri Angel 
Published: July 2024

e20603 Background: In non-small cell lung cancer (NSCLC), alternative strategies to determine patient oncogene mutation status are essential to overcome some of the drawbacks associated with current methods. We aimed to review the use of radiomics alone or in combination with clinical data and to evaluate the performance of artificial intelligence (AI)-based models on the prediction of oncogene mutation status. Methods: A PRISMA-compliant literature review was conducted. The Medline (via Pubmed), Embase, and Cochrane Library databases were searched for studies published through June 30, 2023, predicting oncogene mutation status in patients with NSCLC using radiomics. Independent meta-analyses evaluating the performance of AI-based models developed with radiomics features or with a combination of radiomics features plus clinical data for the prediction of different oncogenic driver mutations were performed. A meta-regression to analyze the influence of methodological/clinical factors was also conducted. Results: Out of the 615 studies identified, 89 evaluating models for the prediction of epidermal growth factor-1 (EGFR), anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma virus (KRAS) mutations were included in the systematic review, including a total of 32,084 patients. A total of 38 met the inclusion criteria for the meta-analyses (encompassing 17,066 patients). The AI algorithms' sensitivity/false positive rate (FPR) in predicting EGFR, ALK, and KRAS mutations using radiomics-based models was 0.753 (95% CI 0.721–0.783)/0.346 (95% CI 0.305–0.390), 0.754 (95% CI 0.639–0.841)/ 0.225 (95% CI 0.163–0.302), and 0.744 (95% CI 0.605–0.846)/0.376 (95% CI 0.274–0.491), respectively. A meta-analysis of combined models was only possible for EGFR mutation, revealing a sensitivity/FPR of 0.800 (95% CI 0.767–0.830)/0.335 (95% CI 0.279–0.396). No statistically significant results were obtained in the meta-regression. Conclusions: Radiomics with a specific focus on CT-based models may represent valuable non-invasive tools for the determination of oncogene mutation status in NSCLC. Further investigation is required to analyze whether clinical data might boost their performance.
Impact of radiation dose to the immune cells in stage IV non-small cell lung cancer in the era of immunotherapy.
Authors: He Junyi , Liu Yingxin , Li Butuo , Yu Jinming , Wang Linlin 
Published: July 2024

e20608 Background: Thoracic radiotherapy now is widely accepted in advanced lung cancer. It is not only been used as palliative therapy but also been involved in Systemic treatments in advanced lung cancer, especially in immune era. However, radiotherapy impairs immune system which can be evaluated by estimated dose of radiation to immune cells (EDRIC). Here, we sought to examine the prognostic impact of the EDRIC in advanced NSCLC in the context of immunotherapy, and to identify the factors influencing EDRIC in this population. Methods: We retrospectively enrolled patients with stage IV NSCLC who had received first-line immunotherapy and thoracic radiation therapy. EDRIC is a specific formulation using a model developed by Jin et al and improved by Ladbury et al, calculated using radiation fraction, mean lung dose (MLD), mean heart dose (MHD), and mean body dose (MBD). Spearman’s rank correlation was used to assess the correlation between variables.Associations between EDRIC [analyzed continuously and categorically (<5.7Gy vs ≥5.7Gy)] and overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and Cox proportional methods. Results: We conducted a retrospectively analysis of 152 patients with stage IV NSCLC patients. GTV (r = 0.2023, p = 0.0137), PTV (r = 0.4139, p < 0.0001) and N (r = 0.1897, p = 0.0193) stage showed a positive correlation with EDRIC. Negative correlations of lymphocyte nadir with EDRIC (r = -0.3172, p < 0.0001), during/pre lymphocyte nadir with EDRIC (r = -0.2102, p = 0.0093), during/post lymphocyte nadir with EDRIC (r = -0.2750, p = 0.0006) were found. Median PFS was shorter among the EDRIC ≥5.7Gy group (10.2months vs 18.6months; p < 0.0001). Median OS was also shorter among the EDRIC ≥5.7Gy group (19.8 months vs 30.2months; p = 0.024). For ORR (38% vs 46%; p = 0.413) and DCR (84% vs 92%; p = 0.304), there was no statistical significance between EDRIC≥5.7Gy and EDRIC < 5.7Gy. Analyzed as a continuous variable, EDRIC was the only factor associated with worse PFS (HR = 1.001, p = 0.018) and OS (HR = 1.002, p = 0.001) in multivariate analysis. Conclusions: In the era of immunotherapy, EDRIC is an independent predictor for PFS and OS in advanced NSCLC, warranting investigation into techniques to optimize radiation dose to the immune compartment.
Mutation pattern of EGFR gene in Peruvian patients with non-small cell lung cancer.
Authors: Ruiz Rossana , Galvez-Nino Marco , Santos Marco , Doimi Franco , Mas Luis , Belmar-Lopez Carolina 
Published: July 2024

e20615 Background: The correct characterization of EGFR mutations is crucial to the proper management of NSCLC patients due to the possibility to treat these patients with specific targeted therapies. Herein we report the incidence, mutation pattern and novel mutations of EGFR mutation in Peruvian NSCLC patients. Methods: Between 2016 and 2023 a total of 1489 NSCLC patients from public and private centers were referred to ONCOGENOMICS laboratory for somatic mutation testing. Next Generation Sequencing (NGS) was performed using the Ampliseq for Illumina FOCUS or Custom panel and run on the Illumina MiSeq. Raw data were processed automatically on the BaseSpace Sequence Hub (Illumina) and aligned to the hg19 reference genome The default limit of detection (LOD) was set at 5% allelic frequency (VAF) in tissue samples and 0.5% VAF in cfDNA samples. Results: The study included 1401 NSCLC patients, 61.8% were women. Clinical stages were distributed III (22.5%), IV (77.5%). All tumors were adenocarcinoma. Incidence of EGFR-mutated NSCLC was 33.4% (450), 68.9% were women. We found 519 EGFR mutations in 450 tumors. Classical or common EGFR mutations; L858R or ex19del corresponded to 86.4% with 331 and 383 cases, respectively and L858R or ex19del + T790M corresponded to 13.6% with 2 cases onset and 50 cases in progression. EGFR T790M de novo mutations were found in 4 cases onset. In one case at diagnosis was detected a T790M-like 3R mutant EGFR p.(C797S); c.2390G > C, a drug resistance point mutation in ex20.Non-classical or atypical EGFR mutations corresponded to 14.0% (63/450) of cases. Non-classical EGFR mutations were categorized as follows according to Janning et al.: (i) More frequent uncommon EGFR mutations - 39.7% (25/63) including G719X, S768I, E709X and L861Q (22/25); G719X + S768I (1/25); and combinations with classical EGFR mutation L858R + S768I (2/25). (ii) EGFR exon 20 insertions - 44.5% (28/63), including a novel mutation EGFR p.(769_770VDinsGFV);c.2308_2309ins. All were located in the loop following the C-helix. And (iii) very rare mutations - 15.9% (10/63) including very rare point mutations in ex19 (1/10), ex18del (4/10), ex19ins (1/10) and complex mutations (ex19del + very rare point mutation in ex19 (4/10).Two point mutation no reported previously were found, EGFR, ex19, p.(S752F);c.2255C > T and EGFR, ex19, p.(T751P);c.2251A > C, both as co-mutations with classical EGFR ex19del mutation. Conclusions: The present study underscores the value of NGS to optimally address EGFR mutations, specially the rare and novel ones due to its higher sensitivity and specificity compared to other techniques. This approach is particularly important for the Latin American population which is underrepresented in genomic databases. Clinical correlation of this genomic findings is ongoing.
Enhanced dacarbazine efficacy in advanced melanoma patients previously treated with immune checkpoint inhibitors in Korea.
Authors: Lee Soo Jung , Na Jihyun , Lee In Hee , Lee Jeeyeon , Lee Seok-Jong 
Published: July 2024

e21528 Background: Immune checkpoint inhibitors (ICI) have revolutionized advanced malignant melanoma treatment. But the lack of effective options post-ICI failure presents a significant challenge. Despite its modest efficacy, chemotherapy with dacarbazine remains practical choice in metastatic melanoma patients after ICI failure. Researchers suggested an increased efficacy of chemotherapy in melanoma patients previously treated with ICI. In this study, we aimed to assess the efficacy of dacarbazine of patients with or without prior ICI treatment. Methods: 71 patients with histologically confirmed malignant melanoma, who diagnosed and underwent chemotherapy between 2011 and 2023 at the Kyungpook National University Chilgok Hospital (Daegu, Korea) were included in this retrospective study. We included patients who had received either dacarbazine single or CVD(Cisplatin, Vinblastine, Dacarbazine) regimen for an unresectable stage IIIC, IIID or IV acral, cutaneous, mucosal melanoma according to American Joint Committee on Cancer(AJCC) 8th edition. Results: Among a total of 71 individuals, there were 16 patients who had not previously received pembrolizumab treatment (DTI-only group). There were 55 patients in the pembrolizumab (pem-DTI group) experienced group. The median PFS was 2.3 months in the DTI-only group and 3.9 months in the pem-DTI group, reflecting a significant PFS difference of 1.6 months. And the median OS was 6.8 months in the DTI-only group and 19.0 months in the pem-DTI group, demonstrating a statistically significant difference. In the univariate and multivariate analysis for PFS, the use of pembrolizumab was advantageous compared to non-use (HR 0.246, 95% CI 0.106-0.576, p= 0.001). The only favorable condition in the univariate analysis for OS was the use of pembrolizumab compared to non-use (HR 0.198, 95% CI 0.068-0.574, p= 0.003). The mean duration of response for the DTI-only group was 4.64 months, while for the pem-DTI group, it was 8.11 months, indicating that the pem-DTI group exhibited a longer duration. Conclusions: We have demonstrated superior PFS and OS in the group of metastatic melanoma patients who received dacarbazine after prior treatment with pembrolizumab compared to those treated with dacarbazine alone. Dacarbazine may still be a valid option after failure of ICI +/- targeted treatment. Future studies should focus on the immunomodulatory effects of dacarbazine on the tumor microenvironment, which could be harnessed to potentially enhance sensitivity to immune checkpoint-based therapy.
Comparison of adjuvant targeted and anti-PD1 immunotherapy in BRAF-mutated stage III cutaneous melanoma: Retrospective, single center cohort study.
Authors: Akhmetianova Angelina , Orlova Kristina V. , Nazarova Valery V. , Baryshnikov Kirill A. , Samoylenko Igor , Ivanilov Kirill , Demidov Lev V. 
Published: July 2024

e21558 Background: Targeted therapy (TT) and anti-PD1 immunotherapy (IT) are standard of adjuvant stage III melanoma treatment. However, no comparative prospective randomized trials (head-to-head) were conducted. Data limited to a few retrospective studies. Both treatment regimens were registered in Russia in 2019. We aimed to compare adjuvant options in Russian melanoma pts. Methods: We conducted a single-center retrospective observational study approved by the IRB. We included all pts age 18 and older (one patient, female, was 14) with BRAF-mutated stage III melanoma who were treated at the N.N.Blokhin NMRC of Oncology MoH and received adjuvant therapy between Jan 2019 and Dec 2022. The primary endpoint was RFS, the secondary endpoint - OS. Cox regression analysis was used to identify prognostic factors for RFS (including substage, thickness and ulceration of primary tumor). Results: A total of 209 pts were included, mostly BRAF V600E/K, 92 (44%) male and 117 (56%) female. Median age was 50,6 years (range: 14-81). 93 (44,4%) pts received TT, 103 (49,3%) pts received IT and 13 (6,3%) didn’t receive adjuvant therapy (observation only). The observation group wasn’t analyzed due to a small number of pts. At a median follow-up of 27 mo, median RFS was 30 mo (95% CI 23-56) in TT group and wasn’t reached in IT group; median OS wasn’t reached in both groups. There weren’t statistical differences between TT and IT groups in RFS (HR 0,84, 95% CI 0,53-1,34, p = 0,47) and OS (HR 0,59, 95% CI 0,26-1,34, p = 0,21), even though at 12 mo, the rate of RFS was higher in the TT group (91.4%) compared IT group (67%), at 18 mo – 79,5% and 63,1%, 24 mo – 68,8% and 61,1% respectively. TT group had numeric but not significant RFS benefit in most subgroups. HR values for substage, thickness and ulceration are presented in the table below. Tx+T0 pts (TT, n = 7; IT, n = 13) and unknown status of ulceration (TT, n = 7; IT, n = 16) was not presented for some pts. Conclusions: Differences between TT and IT wasn't reached at a median follow-up of 27 mo. But IT-treated pts had more and earlier recurrences than TT pts. In BRAF mutated pts, adjuvant TT might prevent early recurrences more effectively than IT. These results need to be interpreted with caution given its retrospective and non-randomized nature and potential selection biases. Additional time to follow-up and biomarker analysis was planned. [Table: see text]
Immunotherapy toxicity prediction in patients with melanoma using machine learning algorithms.
Authors: Sharma Lakshya , Mohan Esha , Balaji Vaishnavi , Wong Jonathan , Joshi Adwait , Mporas Iosif , Shi Jiaqi , Zhao Yi , Stoll-D'Astice Amy C. , Tailor Vipula , Powell Georgie , Alrifai Doraid , Shah Riyaz N.H. , Waters Justin S. , Adeleke Sola Michael 
Published: July 2024

e21567 Background: Immune checkpoint inhibitor (ICI) related toxicity is common in melanoma patients, but identifying who will experience toxicity can be challenging. Precision medicine tools that accurately predict ICI toxicity could improve patient outcomes. This study aimed to use Machine Learning (ML) to predict ICI toxicity in patients with melanoma. Methods: 384 datasets were available for patients started on immunotherapy between 2014-2023 in a single, large regional cancer center in Kent, U.K. Raw data was preprocessed using a standard scaling function and one hot encoding, followed by SMOTE to balance the imbalanced classes. Six ML algorithms were developed using 80% of the training data, tested on 20% of validation data and used the Grid Search Cross-Validation technique for hyperparameter optimization. Shapley Additive Explanations (SHAP) explainable artificial intelligence was used to interpret the toxicity prediction model to improve the interpretation and transparency of the decision boundary. Results: Of the 384 patients, 112 patients (29%) had completely resected disease and then had adjuvant treatment while 272 (71%) were unresectable or had metastatic disease and had palliative treatment intent. In the metastatic setting, the commonest immunotherapy regimen was Pembrolizumab (155, 57%), followed by Ipilimumab/Nivolumab (85, 31%). The commonest regimen in the adjuvant setting was Pembrolizumab (86, 77%). 95 patients (25%) experienced ICI-related toxicity. The number of patients with Grades 1-4 toxicity was 2 ,4, 18 and 4 respectively, the remaining had unspecified toxicity grades. The commonest class of toxicity (CTCAE v5) was gastrointestinal (36, 38%), followed by endocrine (20, 21%) and skin (19, 20%). Linear Regression and Gaussian Naïve Bayes predicted toxicity with the most accuracy, 92% (Table 1). The model showed that increasing age, female gender and not receiving Nivolumab predicted toxicity. Regardless of the regimen or treatment intent, our ML model could also predict immunotherapy response with 90% accuracy. Conclusions: These ML algorithms used clinically available data to predict ICI toxicity accurately. Key predictors of toxicity included increasing age, female gender and not receiving Nivolumab in the setting of both adjuvant and palliative intent. Future work will aim to externally validate these models in other centers. We will also explore if models could be trained for use in patients treated with nivolumab in combination with new anti-LAG-3(relatlimab). [Table: see text]
A randomized, open-label phase II/III efficacy and safety study of atezolizumab in combination with FLOT versus FLOT alone in patients with gastric cancer and adenocarcinoma of the oesophagogastric junction and high immune responsiveness: The IKF633/DANTE trial, a trial of AIO in collaboration with SAKK.
Authors: Al-Batran Salah-Eddin , Lorenzen Sylvie , Heuer Vera , Angermeier Stefan , Ettrich Thomas Jens , Homann Nils , Haag Georg Martin , Kurreck Annika , Stein Alexander , Heinemann Volker , Ronellenfitsch Ulrich , Zander Thomas , Kubicka Stefan , Siebenhuener Alexander Rheinhard , Kopp Christina , Pauligk Claudia , Goetze Thorsten 
Published: July 2024

TPS4184 Background: Despite recent advances, long-term survival of patients with locally advanced, operable esophagogastric adenocarcinoma (EGA) is below 50%. Immune checkpoint inhibitors in the neoadjuvant setting of this tumor type have lately been shown to increase pathological responses in all comers (IKF633/DANTE pII, KEYNOTE-585, Matterhorn), but the effect on survival is still unknown. The IKF633/DANTE pIII trial evaluates the efficacy and clinical activity of atezolizumab (ATZ) with perioperative FLOT in patients (pts) with locally advanced, resectable EGA considered having an immune-responsive profile. Methods: IKF633/DANTE is conducted as a randomized, multinational, multicenter, prospective, investigator-initiated, open label phase II/III trial. For the phase III portion, pts with histologically confirmed EGA of a clinical stage ≥cT2 and/or cN+ without evidence of distant metastases and with at least one immune response criterium (MSI, PD-L1 CPS≥1, TMB ≥10/MB or EBV+) are eligible. Pts are stratified acc. to nodal stage (cN- vs. cN+), tumor site (GEJ type I vs. GEJ type II/III vs. gastric) and PD-L1 expression levels (CPS≥5 vs. CPS<5). Pts are randomized 1:1 to receive 4 pre- and post-operative cycles FLOT/ATZ, followed by 8 cycles ATZ maintenance (Arm A) or 2x4 perioperative cycles FLOT alone (Arm B). In total, 556 pts will be enrolled, thereof 379 pts in phase III. This estimates to a recruitment time of 30 months plus 18 months follow-up for 80% statistical power and a significance level of p<0.05 (two-sided log rank test). The primary endpoint is event-free survival (EFS) with a target hazard ratio of 0.72, reflecting a clinically relevant improvement to 41.65 months in arm A. Main secondary endpoints are pCR, overall survival (OS) also in high immune-responsive subgroups (CPS ≥5/ CPS≥ 10/ MSI), R0 resection rate and safety/tolerability. In addition, a prospective biomarker study with serial circulating tumor DNA (ctDNA) analysis accompanying therapy is performed to explore the prognostic impact of ctDNA on efficacy and survival parameters, as well as on relapse incidence. Recruitment of phase III started in Aug 2023 and is still ongoing. Clinical trial information: NCT03421288 .