bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential therapeutic benefit of platinum-doublet chemotherapies with ICIs based on the classification by combined with smoking status and PD-L1 expression in patients with advanced NSCLC.
Authors: Fukuda Akito , Yoshida Tatsuya , Masuda Ken , Shinno Yuki , Okuma Yusuke , Goto Yasushi , Horinouchi Hidehito , Yamamoto Noboru , Ohe Yuichiro
Published: June 2023

e21131

Background: Chemotherapy combined with immune checkpoint inhibitors (Chemo-ICIs) has been the standard of care for advanced NSCLC patients. Smoking status is associated with PD-L1 expression and the TILs within tumor microenvironment, which leads to the efficacy of ICIs. It remains unclear how the combined with PD-L1 expression and smoking status affect the efficacy of Chemo-ICIs. Methods: We retrospectively reviewed advanced NSCLC patients without driver mutation (EGFR, ALK, ROS-1, BRAF) who received Chemo-ICIs from January 2019 to June 2021, and Chemo from January 2014 to December 2016 as a first-line therapy at the National Cancer Center Hospital, Tokyo, Japan. The additional benefit of ICIs to chemotherapy were evaluated by comparing the Chemo-ICIs group with Chemo group. Results: During study period, 225 patients received Chemo-ICIs and 133 received Chemo as a first line therapy. Overall response rate (ORR) and progression free survival (PFS) was significantly better in the Chemo-ICIs group than the Chemo group (ORR: 44.9% vs. 40.2%, p=0.01, and median PFS: 8.2 months vs. 6.2 months, P<0.001). The median overall survival was 27.9 months in Chemo-ICIs and 20.4 months in chemo (P=0.14). In the subgroup analysis of PFS, the benefit of Chemo-ICIs compared to Chemo was not observed in never-smoker patients (8.9months vs 8.8months, P=0.27). In contrast, among smoker patients, Chemo-ICIs showed significant longer PFS compared to Chemo (7.5 months vs 5.7 months, P<0.001). Next, patients received Chemo-ICIs were classified into six groups, based on the smoking status (never smoker or smoker) and PD-L1 expression (TPS: 0%, 1-49%, or 50%). Chemo-ICIs showed better PFS rate at 12 months in the smoker/ TPS ≥50% group (42.2% vs 25.0%, p=0.03), and the never smoker/TPS ≥50% group (75.0% vs 27.3%, p=0.05) compared with Chemo (Table). In patients with 1-49% TPS, compared to the Chemo group, significant PFS benefit of ICIs was observed only in smoker patients (42.2% vs 25.0%, p=0.003), not in never smoker patients (46.2% vs 27.3%, p=0.13). In patients with 0% TPS, although the additional benefit of ICIs to Chemo was not observed both in never and smoker patients, PFS rate at 12 months in never smoker (13.3%) was lowest among all six groups. Conclusions: Our study suggested that additional benefit of ICIs to chemotherapy could be predicted by combined with smoking status and PD-L1 expression.[Table: see text]
Immunotherapy combined with rh-endostatin improved clinical outcomes over ICIs plus chemotherapy for second-line treatment of advanced NSCLC.
Authors: Huang Hongxiang , Zhong Peiyuan
Published: June 2023

e21133

Background: Despite the fact that numerous clinical and preclinical studies have demonstrated the synergistic effects of combining antiangiogenic or chemotherapy with immunotherapy, no data have been found to indicate that combination therapy is more effective and safer as second-line therapy. Methods: We retrospectively compared the effectiveness and safety of ICIs plus rh-endostatin to ICIs plus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). The evaluation indicators were progression-free survival (PFS), safety profile, overall response rate (ORR), disease control rate (DCR) and 1-year survival rate. Results: The median PFS with immunotherapy plus rh-endostatin (IE) was 7.10 months (95% CI, 4.64 to 9.56) versus 5.13 months (95% CI, 4.29 to 5.97) with immunotherapy plus chemotherapy (IC) (HR, 0.56; 95%CI, 0.33 to 0.95). Treatment-related adverse events of grade 3 or 4 occurred in 7.5% of the IE group versus 25.0% of the IC group. The ORR in the IE group was 35.0% versus 20.8% in the IC group ( P = 0.137), and the DCR in the IE group was 92.5% versus 77.1% in the IC group ( P = 0.049). The 1-year survival rate for the IE group was 69.4%, which was higher than the IC group's rate of 61.4%. Conclusions: Our study demonstrates that ICIs in conjunction with endostatin therapy, demonstrate high efficacy and safety, suggesting that such a combination of therapy may be a viable treatment option for pretreated NSCLC patients in the future.
Clinical outcomes and genomic landscape of patients (pts) with EGFR-mutant lung cancer (EGFR+ LC) with central nervous system (CNS) metastases (mets).
Authors: Sui Jane Sze Yin , Wilcox Jessica , Tischfield Samuel , Choudhury Noura J. , Riely Gregory J. , Kris Mark G. , Boire Adrienne Ann , Yu Helena Alexandra
Published: June 2023

e21146

Background: CNS mets are a major cause of morbidity and mortality in pts with LC. Up to 50% of pts with EGFR+ LC develop CNS mets over their disease course despite improvements in anti-EGFR therapies. The genomics alterations present in CNS mets in pts with EGFR+ LC and how these may compare to paired systemic samples has not been reported. Furthermore, it is unknown whether there are baseline clinicogenomic features that differ between EGFR+ LC pts with or without (w/wo) CNS mets. Methods: From an institutional database of LC pts with available next-generation sequencing (NGS) completed by MSK-IMPACT, we identified all EGFR+ LCs with molecularly characterized CNS tumor samples (CTS). We subsequently identified all pts with EGFR+ LCs with available paired CTS and systemic tumor samples (STS) profiled with MSK-IMPACT. All pts treated with 1L osimertinib with MSK-IMPACT available on their STS were also identified. We assessed clinicogenomic features of all selected EGFR+ LCs. Comparisons of frequencies of genes altered by somatic alterations were performed using Fisher’s exact test and logistic regression. Results: From 2014 to 2022, 90 EGFR+ LC pts with NGS performed on CTS were identified [brain metastasis (BrM), n = 38; leptomeningeal w/wo BrM (LM), n = 52]. 69 pts (77%) were female, median age 59 (IQR range:53-66 years), and 51 pts (57%) were never smokers. Patterns of EGFR+ were exon 19del (n = 43), L858R (n = 27) and atypical (n = 20). No genomic mutations were differentially altered in pts with LM vs BrM. Paired CTS and STS were available for 28 pts, where numerically higher rates of CDKN2A, CDKN2B loss and RAC1 amplification were seen in the CTS (respectively 43% vs 18%, 43% vs 18%, and 21% vs 0%, q > 0.05 for all). A total of 263 pts on 1L osi had NGS on their STS performed:136 pts (52%) had CNS mets during their disease course to date [94 pts (69%) de novo CNS mets; 42 pts with on-treatment CNS mets with median time to CNS mets of 25 mo (IQR: 13.5-35.3 mo)]. Between pts w/wo a lifetime history of CNS mets, there were no differences in sex, smoking history, EGFR alterations and co-alterations. CARD11 alterations were numerically higher in STS in pts with CNS mets (12% vs 2%, q > 0.05). Conclusions: In patients with EGFR+ LC, there were no genomic alterations that were significantly enriched in CNS mets compared to systemic disease, and no systemic genomic alterations that differentiate pts w/wo CNS mets.
Efficacy and safety study of osimertinib in advanced non-small cell lung cancer (NSCLC) with EGFR mutation.
Authors: Samblás Victoria García , Fernández Madrigal Laura , Rodriguez Garcés Maria Yeray , Inoriza Angel
Published: June 2023

e21150

Background: The frequency of transmission on EGFR is more frequent in women and non-smokers. It is characteristic of the Asian population (10% in the Caucasian race). EGFR tyrosine kinase domain inhibitors (EGFR-TKIs) are the standard first-line therapy in non-small cell lung cancer (NSCLC) with EGFR mutations. The efficacy and safety of osimertinib (third generation TKI-EGFR) were evaluated in the FLAURA phase III clinical trial, comparing it against first and second generation TKI-EGFR (erlotinib and gefitinib) in patients with advanced NSCLC. The objective is to evaluate the efficacy and safety of osimertinib in routine clinical practice at the Juan Ramon Jimenez Hospital. Methods: Descriptive observational, and retrospective study of patients with advanced NSCLC and EGFR + treated TKI-EGFR in the period 2015-2022. We analyzed (IBM SPSS Statistics 22) sociodemographic and clinical variables, toxicity profile, objective response rate (ORR), treatment response and progression-free survival (PFS) with Kappan-Meier curves. Results: We included 41 patients (p). 24 women (58.5%). The median age 66 years. 61% had a smoking habit (39% active smokers and 22% ex-smokers). 1p South American race, rest Caucasians. Present histologies: adenocarcinoma (87.8%), squamous cell (4.9%) and signet ring cells (2.4%). EGFR mutations: 53.7% exon 19 deletion and 36.6% exon 20 mutation and 9.8% were not specified. In 10 p the T790 mutation was analyzed, positive in 14.6%. Stage at diagnosis: IV (87.8%); III (12.2%). Symptoms at diagnosis: persistent cough (22%), pain (22%), dyspnea (19.5%) and constitutional syndrome (12.2%). Status Performance: 0-1 (85.4%). Pulmonary (48.8%), bone (36.6%), lymph node (29.3%), liver (22%), brain (22%), and adrenal (14.6%) metastases. 58.5% received osimertinib in the first line, 17.1% in the second. ORR: 77.4% partial response, 9.7% complete response and 12.9% disease progression. Toxicity (T) 90.9%. Digestive T: Diarrhea: grade G1 36.7%, G2 13.3%, G3 6.7%; nausea: G1 3.3%; hyporexia: G1 25.8%; hypertransaminasaemia: G1 3.2%. Dermal T: skin dryness: G1 20.7%, G2 10.3%, G3 3.4%; onycholysis: G1 19.4%. Asthenia: G1 25.8%, G2 12.9%, G3 12.9%. Pneumonitis: G1 3.2%, G2 3.2%, G3 6.5%. Hematological T: anemia: G1 6.5%, G2 16.1%, G3 3.2%. Dose reduction to 40 mg (37.5%). 12.5% discontinued osimertinib. mPFS in 1st line (L): 14 m (m). mPFS in 2nd L: 8 m. 95% CI (0-31.5). 95% CI (9.8- 18.1. mOS: 21 m (95% CI: 17.73-24.26). Conclusions: Osimertinib presents an adequate safety profile for patients with G1, G2 toxicities, generally easy to manage in clinical practice. A very low percentage of patients had to discontinue treatment. No fatal adverse event was reported. Our results in OS and PFS, although favorable, are somewhat lower than those of the FLAURA clinical trial, possibly due to dealing with real-life patients and/or the size of the sample, which is not entirely sufficiently representative.
How comparable are outcomes for approved PD-1/PD-L1 checkpoint inhibitors (CPI)? A model-informed drug development approach to answer the question.
Authors: Zhao Molly , Mangal Naveen , Witjes Han , Zierhut Matthew L , Chen Ting , Dang Thao , Girish Sandhya , Kasichayanula Sreeneeranj
Published: June 2023

e21152

Background: Treatment strategies in metastatic non-small cell lung cancer (mNSCLC) have been implemented by anti-PD-(L)1 based therapies. This work aimed to develop a model-based meta-analysis (MBMA) to compare ORR, median PFS (mPFS), median OS (mOS), and treatment-related adverse events Grade 3-5 (TRAEs Gr3+) among anti-PD-(L)1 therapies in mNSCLC. Methods: A curated database of phase 1, 2, and 3 study results in mNSCLC patients treated with at least one FDA-approved PD-(L)1 CPI was used for these analyses. The ORR, mPFS, mOS, and TRAEs Gr3+ analysis datasets included results from 40, 39, 35 and 45 studies, and represented 13324, 13220, 13029, and 21077 patients, respectively. Treatments included: platinum doublet (Pt), pembrolizumab (+/- Pt), nivolumab (+/- Pt and +/- ipilimumab), atezolizumab (+/- Pt), and cemiplimab. Models were developed to quantify drivers of variability on outcomes across trials (i.e., treatment, covariates, random effects). The following covariates were evaluated: PD-L1 expression, line of therapy, ECOG PS, histology, geography/race, sex, age, and smoking status. Results: Treatment naïve patients showed better efficacy than treatment experienced patients, while higher PD-L1 expression was associated with improvement for CPI-containing therapies. Asian-majority trials and patients with PS 0 achieved higher mOS. After adjusting for covariates, similar efficacy was observed across PD-(L)1 within both mono- and combination therapy groups (Table 1). No clinically meaningful covariates were identified for TRAEs Gr3+. Rates were comparable between chemotherapy +/- PD-(L)1, but lower for PD-(L)1 monotherapy. Conclusions: MBMA enables an appropriate comparison of CPI-containing therapy using published study results. To our knowledge, this is the first such analysis in mNSCLC comparing efficacy and safety across PD-(L)1 based therapies. Results suggest PD-(L)1 CPI have similar treatment outcomes in mNSCLC, and PD-L1 expression may be more impactful on clinical benefit of monotherapy compared to CPI combination with chemotherapy. [Table: see text]
Efficacy and safety study with alectinib in advanced ALK-positive non-small-cell lung cancer.
Authors: Fernández Madrigal Laura , Samblás Victoria García , Amor Urbano María , Inoriza Angel
Published: June 2023

e21153

Background: 5% of patients with non-small-cell lung cancer (NSCLC) have a translocation of the ALK (anaplastic lymphoma kinase) gene on chromosome 2. The phase III clinical trial (ALEX study) analyzed the efficacy and safety in patients with a diagnosis of NSCLC and ALK mutation -positive (ALK+) randomized to alectinib versus crizotinib. The objective of our study is to describe our results with alectinib. Methods: Observational and descriptive study of patients with advanced NSCLC and ALK+ treated with alectinib in the period 2019-2022. Sociodemographic and clinical variables, toxicity profile, objective response rate (ORR), treatment response and progression free survival (PFS) were extracted and entered into IBM SPSS Statistics 22 for statistical analysis. Results: 7 patients received treatment. The median age was 46 years. Baseline characteristics: male (57%); non- Asian race (100%); non-smoker (57%), ECOG 0-1 (100%). All had adenocarcinoma histology. 57% had liver metastasis and 37% central nervous system metastasis at the time of diagnosis. The most frequent symptom was dyspnea (43%). Only one patient was previously terated with 2 lines of chemotherapy and a 3rd line with crizotinib prior to alectinib. Adjuvant chemotherapy was administered in one patient. The rest of the participants received alectinib as first line. The most frequent toxicities were: grade 1-2 increased alanine and aspartate aminotransferase (70%); grade 1 anemia (28.6%); grade 1 increased blood bilirubin (28.6%), skin toxicities (71.5%), myalgia (57%), visual disorders (28.6%); constipation (28.6%) and sinus bradycardia (14.5%). A 28.6% incidence of dose reductions due to adverse events (AEs) with alectinib. One patient had to discontinue treatment with alectinib due to grade 4 AEs consisting of toxic pneumonitis.Hospital admission was required. The ORR was 57.2%. Complete response ocurred in 28.6% of patients. The median response to treatment was 16 months and the median PFS was 16 months. Conclusions: The sociodemographic characteristics of our patients were similar to those described in the ALEX trial. However, the AEs were higher in our study. The ORR was lower in our study, despite obtaining a high percentage of complete responses. We have a reduced number of patients who have been treated with alectinib to obtain final conclusions efficacy.
Prevalence of KRAS p.G12C mutation in patients with metastatic non-small cell lung cancer in Argentina.
Authors: Mendoza Bertelli Andrea , Otero Pizarro Maria Mercedes , Fernandez Maria Paz , Dibarbora Delfina , Cantarella Maria Florencia , Mahmoud Yamil Damian , Girotti Romina , Guttlein Leandro , Chico Isagani , Brandalise Patrícia , Dutra Carolina , Salanova Ruben
Published: June 2023

e21155

Background: KRAS is mutated in ∼30% of non-small-cell lung cancer (NSCLC). Most of the mutations involve codon 12 of exon 2, with G12C mutation being the most frequent (~12%). Differences in mutational frequency have been demonstrated in patients of different ethnicities and smoking status. However, the effects of ancestry and environmental factors have not been exhaustively described for the Argentine population. Methods: An observational study was conducted in a cohort of 1810 patients. Specifically, 1510 retrospective tissue samples and 300 prospective tissue samples were analyzed by quantitative PCR(qPCR) using AmoyDx KRAS Mutation Detection Kit. A validation was also performed on 181 tissue samples by digital droplet PCR (ddPCR) with the commercial kit PrimePCR ddPCR Mutation Detection Assay Kit: KRAS p.G12C (Biorad). Statistical analyses were performed to address the association of KRAS p.G12C across demographics characteristics such as smoker-ex smoker / no smoker condition, sex, age, geographical distribution, histological subtype, metastasis or primary tumor and organ site of metastasis. Results: A prevalence of 14.48% in KRAS p.G12C was observed comparable with those observed in other populations. A significant association was observed between clinical variables and KRAS p.G12C prevalence: the proportion of KRAS p.G12C is increased in stage IV samples compared to stage III (p = 0.012) and in active smokers/ex-smokers compared to non-smokers (p < 0.0001). The proportion of KRAS p.G12C decreases in samples from the pleura as a biopsy site. Our results suggest that there is a 92.05% concordance between qPCR KRAS p.G12C kit and ddPCR. Conclusions: This study represents a deep understanding of KRAS p.G12C mutational landscape in the Argentine population and its association with demographic and clinical characteristics and demonstrates that qPCR is a feasible methodology for routine testing.
Restaging scans frequency heterogeneity in patients being treated for stage IV non-small cell lung cancer (NSCLC).
Authors: Sacchi de Camargo Correia Guilherme , Mooradian Ariana , Zhao Yujie , Lou Yanyan , Manochakian Rami
Published: June 2023

e21161

Background: Patients with stage IV NSCLC undergo frequent restaging scans (RS). While vital to assess treatment response, RS add anxiety and financial burdens to patients. The ideal frequency of RS is unclear. The numerous treatment options available, such as targeted therapy (TT) and immunotherapy (IO), and the variability in frequency of RS in the trials that led to their approval reflect this uncertainty. Due to the lack of clear guidelines about their ideal interval in daily practice, we reviewed the heterogeneity in frequency of RS in those trials, comparing it to the reported progression-free survival (PFS). Methods: In this study, we reviewed the FDA-approved drugs for stage IV NSCLC since 10/18/2016 and selected the TT and IO. Each trial that led to approval was reviewed, collecting the frequency of RS and the median PFS for the intervention (IA) and control arms (CA). Results: 18 TT drugs and 12 IO regimens, with and without chemotherapy (chemo), were found. Among them, the frequency of RS varied from every 4 to 9 weeks (w) upfront, later modified to every 6 to 12 w until disease progression. The median PFS for both groups in the IA ranged from 2.8 to 19.4 months (m), and from 3.0 to 12.4 m in the CA. The TT group had drugs directed at 7 different mutations, and it presented more discrepancy in terms of restaging frequency. The period between RS varied from every 4 to 8 w initially, later modified to every 6 to 12 w. However, 11 of 18 trials had an interval of every 6 w. The shortest median PFS in the IA arm was 5.4 m, and 5.6 m in the CA. While the longest median PFS was 19.4 m in the IA and 12.4 m in the CA. The IO group included 5 regimens with chemo and 7 without. The interval between RS varied from 6 to 9 w originally, to every 8 to 12 w later. Yet, 8 of 12 regimens’ trials scanned patients every 6 w initially. The median PFS in the IA ranged from 2.8 to 10.3 m, and between 3.0 to 6.5 m in the CA. Conclusions: We observed notable heterogeneity among trials regarding the frequency of RS in patients treated for stage IV NSCLC. When comparing these intervals to the median PFS, we noted the shortest PFS reported is longer than most adopted intervals. This may indicate RS were obtained more frequently than needed. The increased frequency of RS raises a burden for patients and the medical system, while contributing to disparities. This finding, coupled with further comparisons between the frequency of RS in trials and in daily practice, may pave the way for prospective studies analyzing the ideal interval for RS. This can lead to a more efficacious and less burdensome strategy for patients. [Table: see text]
UCLA l-08: A phase ib/II study of combined HER inhibition adding necitumumab and trastuzumab to osimertinib in patients with refractory EGFR-mutated lung cancer.
Authors: Goldman Jonathan W. , Cummings Amy Lauren , Arzoo Karo K. , Hu Eddie Hong-Lung , Garon Edward B. , Kirimis Evangelia K. , Olevsky Olga , DiCarlo Brian Anthony , Davidson Sheldon J. , Kaul Anita , Noor Zorawar Singh , Mendenhall Melody A. , Wong Deborah J.L. , Huang Holly K.T. , Velez Maria A , Chauv James , Yarden Yosef , Slamon Dennis J.
Published: June 2023

e21165

Background: Patients (pts) with metastatic EGFR-mutated NSCLC who have progressed on osimertinib have limited treatment options. Dual EGFR with HER2 blockade results in complete and long-term reversal of osimertinib resistance in preclinical models. Methods: This is an investigator-initiated, single arm, open label phase 1b/2 study to identify the recommended phase 2 dose (RP2D), safety, tolerability, and preliminary efficacy of the combination of osimertinib, necitumumab, and trastuzumab (ONT) in adults with histologically confirmed, metastatic NSCLC with an activating and sensitizing EGFR mutation who have progressed on osimertinib as their most recent treatment. Study pts receive daily oral osimertinib in conjunction with necitumumab and trastuzumab intravenously every other week. In phase 1b, a 3+3 dose-escalation design is used to determine the RP2D (Table 1). In phase 2, if ≥ 2 responses are seen out of 10 pts treated at the RP2D, an additional 10 pts will be accrued. Patient reported outcomes (PRO-CTCAE) and quality of life (FACT-L) data are collected prospectively. Efficacy is assessed as objective response rate (ORR) based on RECIST 1.1 criteria. Results: 22 pts (median age = 63; range = 40-82) have been enrolled and treated. The most commonly observed treatment-related AEs seen at any DL included acneiform rash (63.6%), headache (45.5%), nausea (40.9%), dry skin (36.4%), diarrhea (31.8%), paronychia (27.3%), oral mucositis (27.3%), vomiting (22.7%), fatigue (18.2%), chills (18.2%), and anorexia (18.2%). Grade 3 treatment-related toxicities were acneiform rash (22.7%), diarrhea (4.5%), decreased lymphocyte count (4.5%) and hypertension (4.5%). There were no treatment-related Grade ≥ 4 AEs. 12 evaluable pts were enrolled in phase 1b [3 at Dose Level (DL) 1, 3 at DL 2, and 6 at DL 3]; 3 non-evaluable pts were replaced. Pts treated at DL 1 and DL 2 had no dose-limiting toxicities (DLTs) and 1/6 pts at DL 3 had a DLT (persistent grade 3 rash). Due to grade 2 and 3 rash and paronychiae occurring after cycle 1 at DL 3, DL2 was determined to be the RP2D.The proportion of evaluable phase 1b pts achieving partial response or stable disease was 58.3% (7/12). Seven pts have been enrolled at DL2. Conclusions: ONT toxicities are manageable, and the combination has promising preliminary efficacy in refractory EGFR-mutated metastatic NSCLC. Evaluation of phase 2, stage 1 is expected to be completed by April 2023 and will be reported at the meeting. Clinical trial information: NCT04285671 . [Table: see text]
Sintilimab, SBRT and GM-CSF for metastatic NSCLC: A prospective, multicenter, phase II trial.
Authors: Ni JianJiao , Wu Lin , Chu Qian , Han Chengbo , Ai Xinghao , Dong Xiaorong , Zhu Zhengfei
Published: June 2023

e21172

Background: PD-1/PD-L1 inhibitors have transformed the therapeutic landscape in metastatic non-small cell lung cancer (NSCLC). However, the objective response rate (ORR) remains limited in unselected population. Incorporating SBRT to PD-1/PD-L1 inhibitors may improve treatment efficacy and the anti-tumor immunity induced by SBRT may be enhanced by GM-CSF, which plays a pivotal role in dendritic cell differentiation and maturation. The current trial (NCT04106180) is the first prospective, multicenter, phase II study assessing the safety and efficacy of a PD-1 inhibitor (Sintilimab), SBRT and GM-CSF in metastatic NSCLC patients without sensitizing driver mutations. Methods: Metastatic EGFR/ALK negative NSCLC pts who had failed first-line standard chemotherapy were eligible. Pts received SBRT (8 Gy*3) to one lesion, followed by Sintilimab (200 mg d1, every 3 weeks) and GM-CSF (125 μg/m2 d1-d14, cycle 1) within 3 weeks after SBRT. Sintilimab would be given continuously until disease progression, unacceptable toxicity, or up to 35 cycles. Primary end point is ORR. Secondary end points are safety, out-of-field response rate, overall survival (OS), progression free survival (PFS). The trial was designed to enroll 56 patients and if ≥17 pts evaluated had an objective response, it was regarded as positive. Results: By the time of 2022/10/30, the trial was early closed after 18 of the 51pts enrolled from 6 academic centers documented PR. The majority of pts were male, ECOG 1 and non-squamous NSCLC, having more than 5 lesions at baseline, with a median age of 62 (range, 32-74). The sites of SBRT included lung (n = 20), regional lymph node (n = 16), pleural nodule (n = 5), vertebra (n = 3), distant lymph node (n = 3), liver (n = 2) and others (n = 2). Treatment-related adverse event (TRAE) occurred in most pts and grade 3 TRAE occurred in 6 (11.8%) pts. No grade 4-5 TRAE occurred and the most common grade 3 TRAEs were ALT/AST elevation (n = 2), transient acute heart failure (recovered within 7 days) (n = 1), leucopenia/neutropenia (n = 2), pneumonitis (n = 1) and creatinine elevation (n = 1). With a median follow-up of 19.2 (range, 4.6-35.4) months, 49 pts had evaluable efficacy, with 18 PR, 15 SD and 16 PD. Median PFS and OS were 5.9 (95% CI, 3.9-9.2) and 16.2 (95% CI, 12.6-34.1) months, respectively. The results of biomarker testing will also be presented. Conclusions: Triple combination of Sintilimab, SBRT and GM-CSF is safe and shows promising efficacy in metastatic EGFR/ALK negative NSCLC. Clinical trial information: NCT04106180 .
Patients harboring uncommon EGFR exon 19delins variants of advanced non-small-cell lung cancer and response to osimertinib: A multi-center retrospective study.
Authors: Lu Zhiqin , Yi Yali , Luo Yuxi , Zeng Zhimin , Luo Hui , Shu Yun , Liu Anwen
Published: June 2023

e21184

Background: This study aims to investigate the efficacy of different EGFR inhibitors therapy in patients with advanced non-small-cell lung cancer (NSCLC) harboring atypical EGFR exon 19delins variants. Methods: Targeted sequencing database of 1426 treatment-naive patients with advanced NSCLC were retrospectively screened for EGFR exon 19 deletion (19del) variants in a multi-center study from January 2017 to January 2022, and 34 patients with uncommon EGFR exon 19 deletion-insertions (19delins) were included. The response rate, and progression-free survival (PFS) were analyzed according to the radiographic images. Results: We identified 3 previously unreported uncommon EGFR exon 19delins variants. Among the 34 patients who had uncommon EGFR19delins, 24 patients received first-generation, and 10 patients received third-generation as front-line EGFR TKI therapy, the median progression-free survival (mPFS) was significantly longer for patients who received first-generation than those with third-generation (19.1 months vs 6.9 months; HR: 0.18, 95% CI: 0.062-0.507; p < 0.001). At progression, EGFR T790M was the main acquired mechanism of resistance (8/14; 57.2%). There were 22 patients who received osimertinib therapy, the overall ORR and DCR were 54.5% and 81.8%, respectively, and the overall mPFS was 6.9 months. But no significant difference was observed in mPFS between first-line osimertinib and second-line osimertinib therapy (6.9 months vs. 3.8 months; p = 0.206). Conclusions: The uncommon EGFR exon 19delins variants of advanced NSCLC have longer mPFS for the first-generation compared with the third-generation as front-line EGFR TKI therapy, and respond poor to third-generation EGFR inhibitors, regardless of whether osimertinib was used as first-line or second-line therapy. Patients with uncommon EGFR exon 19delins may be a biomarker of poor efficacy with the third-generation EGFR TKI therapy.
Prevalence of STK11, KEAP1, and KRAS mutations/co-mutations and associated clinical outcomes for patients newly diagnosed with metastatic non-small cell lung cancer.
Authors: Dabbous Firas , Wang Ching-Yu , Simmons Daniel , Huse Samuel , Jassim Rami
Published: June 2023

e21186

Background: Data on the prevalence of emerging mutations /co-mutations (e.g., STK11, KRAS, and KEAP1) and associated clinical outcomes in metastatic non-small cell lung cancer (mNSCLC) patients are lacking therefore the objective of this study is to address these gaps in the current data. Methods: This study used the Flatiron clinico-genomic database and included newly diagnosed patients (≥18 years old) with stage IV NSCLC and known histology/PD-L1 status. Patients enrolled in clinical trials, with positive/missing EGFR or ALK, other malignancies, mixed histology, or without structured data within 90 days of diagnosis were excluded. The prevalence of STK11, KEAP1, KRAS mutations and co-mutations for each combination were evaluated in the overall study cohort and stratified by histology and PD-L1 status ( > or ≤1%). The overall survival (OS) from the date of diagnosis with stage IV was analyzed using Kaplan-Meier methods. Results: Of the 17,020 patients with NSCLC, 964 met the selection criteria and were included in the study. The prevalence of STK11, KEAP1, and KRAS is 18%, 15%, and 35%, respectively. With the exception of KRAS, the prevalence of all selected mutations and the co-mutations is higher in patients with PD-L1 negative and non-squamous NSCLC. The prevalence of KRAS is higher in patients with PD-L1 positive and non-squamous NSCLC (Table). The median OS was 10.1 months (95% CI, 8.6, 11.2) for the overall population, and 6.6 (5.7-8.3), 7.1 (5.8-8.8) and 9.9 (7.6-11.9) months in patients with STK11, KEAP1, and KRAS mutations, respectively. The median OS in patients with co-mutations ranges from 6.1 to 6.7 months. Conclusions: STK11, KEAP1, and KRAS mutations and co-mutations are common in mNSCLC patients. Current treatments, particularly in STK11, KEAP1, and co-mutation patients, are associated with poor OS. To address these harder to treat subgroups new treatment options or clinical trials should be considered. [Table: see text]
Examining molecular testing practices and targeted therapy use in advanced/metastatic non-small cell lung cancer (mNSCLC): A quality improvement initiative across ten community cancer centers.
Authors: Lopes Gilberto , Delcuze Bethany , Dewald Ilona , McKinnon Kelly E. , Carter Jeffrey D. , Heggen Cherilyn
Published: June 2023

e21191

Background: A growing number of targeted therapy approvals for mNSCLC have dramatically increased requirements for molecular testing. Identifying and addressing real-world challenges mNSCLC care teams face due to resulting workflow shifts is essential to optimize patient outcomes. Methods: In March–September 2022, 126 health care professionals (HCPs) who treat NSCLC at 10 US community oncology clinics completed surveys assessing practice patterns, challenges, and confidence related to biomarker testing and targeted therapy use. HCPs (N = 105) participated in interdisciplinary audit and feedback (AF) sessions to examine clinical evidence and develop clinic-specific action plans to address identified gaps. Results: Participants represented the interprofessional NSCLC care team: medical oncologists (32%), pathologists (1%), radiation oncologists (1%), pulmonologists (2%), PCP/other physicians (5%), advanced practice professionals (22%), nurses (19%), and other HCPs (e.g. patient navigator, practice manager; [19%]). At the time of the program there were 9 NCCN-recommended biomarkers for mNSCLC. Less than half of HCPs reported regular testing for 4 of these biomarkers (Table 1). The majority of HCPs were somewhat (52%) or very/extremely (23%) likely to start treatment prior to receiving molecular testing results. Top reported barriers to integrating molecular diagnostics into routine practice were biopsy tissue availability/quality (45%) and determining whether to begin treatment prior to receipt of molecular testing results (43%). Gap-oriented clinic action plans aimed to improve communication between oncologists, pulmonologists, and pathologists to increase quality and efficiency of testing. A targeted therapy toolkit was developed with a panel of oncology and pathology experts and distributed to participants to address gaps in knowledge of testing practices and guidelines. HCP confidence in biomarker testing increased from 72% to 92% following the intervention. More HCPs correctly answered knowledge (43% pre-AF vs 61% post-AF) and competence (29% pre-AF vs 54% post-AF) questions following participation in the AF sessions. Conclusions: While molecular testing is critical for mNSCLC care, HCPs report sub-optimal rates of conducting testing prior to treatment and incorporating results into treatment planning. Here, we highlight an unmet need for improved interdisciplinary communication and coordination in mNSCLC care teams and an educational intervention strategy that can be used to improve HCP biomarker and targeted therapy use in mNSCLC. [Table: see text]
Osimertinib rechallenge in advanced EGFR non-small cell lung cancer patients.
Authors: Uy Natalie F. , Tratt Micah , Eaton Keith D. , Santana-Davila Rafael , Baik Christina S
Published: June 2023

e21196

Background: Treatment after front line osimertinib (osi) for epidermal growth factor receptor (EGFR) mutated advanced non-small cell lung cancer (NSCLC) remains a clinical challenge. Interval chemotherapy after osi may eradicate clones responsible for EGFR tyrosine kinase (TKI) resistance, which may re-sensitize the tumor to EGFR inhibition. We describe outcomes of metastatic EGFR NSCLC patients who undergo osi rechallenge. Methods: NSCLC patients with confirmed EGFR mutation were retrospectively reviewed from a single institutional database from 1/2010-12/2022. We identified patients who received osi after interval therapy following initial osi progression. Patient characteristics and tumor type were collected via chart review. Response was determined using RECIST 1.1. Results: Seventeen patients with osi rechallenge after initial progression were identified. Median age at time of osi rechallenge was 62 yrs (range 42-73). Patients were predominantly female (n = 11, 65%), white (n = 9, 53%) and Asian (n = 8, 47%), never smokers (n = 13, 77%). Patients had either del19 mutation (n = 10, 59%) or L858R mutation (n = 7, 41%). Twelve patients (71%) received a 1st or 2nd generation EGFR TKI (erlotinib n = 10, afatinib n = 2) prior to initial osi; eight patients (47%) had confirmed T790M mutation. Eight patients (47%) had CNS metastases prior to osi rechallenge. Twelve patients (71%) had ECOG 0-1 at time of rechallenge. Patients had a median of 4 (range 2-5) lines of therapy prior to osi rechallenge. Median time between initial osi discontinuation and osi rechallenge was 13.8 months (range 3.2-50.7). In the interim, 17 patients (100%) received chemotherapy, 2 (12%) received immunotherapy monotherapy, 3 (18%) received antibody drug conjugate, and 1 (6%) received TKI. Sixteen patients had follow-up restaging CT scans; 1 died before restaging imaging was obtained. Two patients achieved partial response (PR) (13%), and 6 patients had stable disease (SD) as the best response (38%). Median duration of initial osi was 13.9 months (range 1.9-26.4), and median duration of osi rechallenge was 3.6 months (range 1.0-10.3). Patients who had PR/SD were on osi for 7.5 months (range 2.7-10.3). Ten (59%) patients received osi rechallenge for at least 3 months duration, and 6 (35%) received osi rechallenge for at least 6 months duration. Conclusions: Osi rechallenge is a potential option for advanced EGFR NSCLC patients to obtain disease control at later lines of therapy. Further research is needed to characterize mechanisms of targeted therapy resistance and better select patients who can benefit from EGFR TKI re-exposure.
Clinical outcomes of chemotherapy rechallenge in patients with metastatic non-small cell lung (NSCLC) who progressed on immunotherapy maintenance after front line platinum doublets and immunotherapy.
Authors: Wang Kaiwen , Fossella Frank V. , Negrao Marcelo Vailati , Cascone Tina , Gay Carl Michael , Le Xiuning , Vokes Natalie I , Bueno Hume Celyne , Hassan Amy Aida , Gibbons Don Lynn , Lee J. Jack , Heymach John , Zhang Jianjun
Published: June 2023

e21205

Background: Maintenance immunotherapy (IO) is commonly utilized in metastatic NSCLC patients (pts) who did not progress after initial treatment with platinum doublet and IO. Upon progression, docetaxel with or without ramucirumab remains the treatment of choice, which is associated with poor response and high toxicity. We explored the option of rechallenge of original chemotherapy agents in this patient population. Methods: We queried MD Anderson Cancer Center GEMINI database to perform a retrospective review in pts who received chemotherapy (chemo) rechallenge with or without IO after progression on or after IO maintenance from 03/2016 – 12/2022 at MD Anderson Cancer Center. We assessed clinical response and progression free survival (PFS) with initial triplet treatment and rechallenge with chemotherapy. Clinical response was defined as clinical benefit based on clinician’s radiographic and clinical assessment. PFS was defined as the time interval free of disease progression. Demographics and results were summarized with descriptive statistics. Results: 20 patients received chemo rechallenge with or without IO after progression on IO maintenance. Upon chemo rechallenge, 7 pts received pemetrexed; 10 pts (50%) received carboplatin and pemetrexed; 19 pt received chemo rechallenge with IO. Median duration of initial IO maintenance was 9.4 months. Median duration of chemo rechallenge was 5.2 months. 10 (50%) pts discontinued chemo due to progression after receiving chemo rechallenge; 2 (10%) pts discontinued chemo rechallenge due to toxicities; 3 (15%) pts remained on therapy at the data cutoff of 2/10/2023. Median PFS with initial triplet was 14.3 months. Median PFS with chemo rechallenge was 7.4 months, longer than the histological control of 3-5 months from docetaxel +/- ramucirumab. Conclusions: Our single center retrospective review demonstrated that chemo rechallenge after progression on IO maintenance post front-line chemo-IO therapy had good tolerability and reasonable PFS, which may offer a reasonable alternative option to docetaxel+/-ramucirumab. Future studies are needed to confirm this result using docetaxel +/- ramucirumab as a control. [Table: see text]
Prevalence of actionable oncogenic alterations (AGA) among patients with advanced (adv) non-squamous (NSQ) non-small cell lung cancer (NSCLC) by age, sex, and race in the United States (US).
Authors: Oskar Sabine , Zu Ke (Kirsten) , Arunachalam Ashwini , Kao Yu-Han , Chen Cai , Zhao Bin , Aggarwal Himani
Published: June 2023

e21206

Background: Identification of AGA in NSCLC has improved the understanding of lung cancer pathogenesis and introduced targeted therapies directed against specific genomic alterations. Given the limited data on the prevalence of AGA by demographics, we evaluated prevalence of AGA by age at diagnosis (dx), sex, and race. Methods: A descriptive study used the US nationwide de-identified Flatiron Health-Foundation Medicine NSCLC clinico-genomic database. Eligible patients were adults with a dx of adv NSQ NSCLC from Jan-2016 to Sep-2020 who initiated a first line therapy. The prevalence of AGA for each age, sex, or race stratum was calculated. Results: The cohort included 3938 patients; 67.9% White, 52.9% female, and median age at dx was 68 y. Table 1 presents the prevalence of AGA. The prevalence of EGFR and BRAF V600E mutations increased with age at dx. ALK rearrangement and ROS1 fusion were more prevalent among patients < 50 y vs ≥50 y while MET exon 14 skipping mutation was more prevalent among patients ≥75 y vs < 75 y. EGFR and KRAS G12C mutations were more prevalent in female vs male. Compared to White or Black, Asians had a higher prevalence of EGFR mutations and lower prevalence of KRAS G12C. Conclusions: The prevalence of certain AGA among patients with adv NSCLC vary by demographics, which may contribute to disproportionate disease burden in certain strata. These results highlight the need to enhance diversity of clinical trial populations and ensure the disease burden across demographics in the general population are represented in clinical trials. [Table: see text]
High-confidence AI-based biomarker profiling for H&E slides to optimize pathology workflow in lung cancer.
Authors: Ofek Efrat , Haj Razan , Molchanov Yossef , Yacobi Rinat , Mayer Chen , Barliya Tilda , Gazy Inbal , Dvir Addie , Hayun Ido , Zalach Jonathan , Paz Yaacov Nurit , Peled Nir , Bar Jair , Barshack Iris
Published: June 2023

e21207

Background: In recent years AI methodologies have been increasingly adopted in the oncology space as part of the clinical decision process. Our previous research has shown accurate detection of actionable biomarkers based on AI algorithms applied to Hematoxylin & Eosin (H&E) scanned slides. While investigating a wide actionable biomarker panel, this profiling process can also flag patients with no actionable biomarkers. In Non-Small Cell Lung Cancer (NSCLC), EGFR, ALK, and ROS1 are the most commonly tested actionable alterations and the primary exclusion criteria for immunotherapy. Here we present a novel AI-based solution that can accurately and almost instantaneously detects patients without the main actionable biomarkers from the H&E image alone, thus helping prioritize the pathology lab workflow and navigate patients to a faster and more optimal diagnosis route. Methods: A retrospective cohort of 435 NSCLC patients was collected from the Sheba Medical Center pathology department. All cases (from primary and metastatic sites) with documented results for EGFR mutations, ALK, and ROS1-fusions were included. Molecular profiling was based on Oncomine Comprehensive, Dx target, or Solid tumor DNA assays, with 4 cases also supported by the Idylla EGFR mutation test. Deidentified digital whole slide images (WSIs) were run using Imagene’s AI classifier and compared to the officially reported results. The classifier was generated using self-supervised algorithm, combined with multiple instance learning algorithms applied using untagged and tagged FFPE H&E scan (40x or 20x magnification) from Imagene’s internal database (including TCGA research network slides). A categorical prediction (positive/negative) inferred on the validation set by the combined AI classifier model. Results: The combined AI model for detecting EGFR, ALK and ROS1 actionable alteration resulted in 127 patients (29.4% of the cohort) reported with no EGFR actionable mutation, ALK, or ROS1 fusions. Only two patients (1.57% of the negatively detected patients) were found to be false negative ( EGFR: p.G719D and p.L858R), demonstrating 98.43% accuracy. Conclusions: Image-based molecular detection can serve as an accurate and fast detection method to be used in the clinical setting for monitoring and prioritizing current pathology workflow. Specifically, it can detect a major fraction of the non-targetable patients and optimize their diagnostic flow.
Impact of a pathologist-driven molecular testing protocol on veterans with non-small cell lung cancer.
Authors: Li Rui , Frias Kletecka M. Carmen , Shin Daniel Sanghoon
Published: June 2023

e21209

Background: Precision medicine has shifted the paradigm of cancer treatment in the last two decades. Currently, with over ten targetable mutations in non-small cell lung cancer (NSCLC) and increasingly emerging biomarkers for immunotherapy, genomic testing is necessary for every NSCLC patient. However, this multiple biomarker-defined treatment approach is often compromised by many challenges including slow turnaround time (TAT), high rate of quantity not sufficient (QNS) resulting in inaccurate molecular testing or needs for second biopsy. These barriers lead to increased risk of developing medical complications from re-biopsy or treatment delay as well as additional social and financial support, which is not always available for veterans. A recent study reported that up a one third of veterans with NSCLC containing highly actionable mutations were not prescribed targeted treatment, among which, 25% of patients do not have a documented molecular testing results. Herein, we reported a pathologist-driven protocol to enhance the implement of molecular testing on guiding NSCLC treatment in veteran population. Methods: A pathologist-driven molecular testing protocol is applied West Los Angeles VA hospital since 2018. First, in preparation for diagnosis and molecular testing, tissue block will be cut in serial sections in the following priority: 2 slides for H&E, 4 slides for IHC, 2 slides for PD-L1 staining. An additional slide is made for quality control (QC) purpose before 10 additional slides are cut for molecular testing and 6 for FISH studies. The reminder of the tissue block will be cut in serial sections and preserved in a vial along with tissue shaved at initial block effacement. Every tissue block will be exhausted. Upon initial evaluation of H&E slides, the reviewing pathologist, independent of the treating oncologist, will order molecular testing including EGFR, ALK, ROS and BRAF by NGS if NSCLC is identified. PD-L1 IHC staining is also ordered automatically regardless of the histology. If a clinically actionable mutation is detected, a mutation notification is immediately sent via email by the molecular pathologist to alert the treating oncologist. Results: After implementing this protocol, we observed a decreased rate of QNS (~30% reduction) and subsequently the need for 2ndbiopsy dropped substantially. We also observed a faster TAT between initial cancer diagnosis (within 7 days) and the resulting of molecular testing to guide subsequent treatment. Conclusions: Refined tissue processing and pathologist driven ordering system can significantly impact initial management of patients with NSCLC as it reduces the rate of QNS and repeat biopsy/TAT. This protocol can be easily implemented in VA system or other community based healthcare system.