bluuebunny/crossref_metadata_2025 huggingface dataset:
The prognostic impact of KRAS, TP53, STK11 and KEAP1 mutations and the influence of the NLR in NSCLC patients treated with immunotherapy.
Authors: Proulx-Rocray Francis , Routy Bertrand , Nassabein Rami Mohamad , El Ouarzadi Omar , Belkaid Wiam , Tran-Thanh Danh , Florescu Marie , Tehfe Mustapha , Blais Normand
Published: June 2021

e21010

Background: ICIs changed the way NSCLC is treated, but not all patients benefit from it. PD-L1 level is used to predict response to therapy, but its performance is sub-optimal. KRAS is important in NSCLC tumorigenesis, but the impact of its mutations in patients treated with ICIs is unclear. Similarly, studies evaluating co-mutations in TP53, STK11 and KEAP1 as well as the NLR showed that they may predict the benefit of ICIs. Methods: We conducted a retrospective study including all consenting patients with NSCLC treated with ICIs at the CHUM between July 2015 and June 2020. OS and PFS were compared in co-mutation subgroups using Kaplan-Meier and logrank methods. Co-mutations in TP53, STK11 and KEAP1 as well as the NLR were accounted for. Overall response rate (ORR) and safety data was also compared in subgroups and will be detailed at the meeting. Results: We included 100 patients with known KRAS status. From these, 50 were wild-type ( KRASWT) and 50 were mutated ( KRASMut). The most frequent mutation was G12C (54%). Co-mutation status for TP53, STK11 and KEAP1 were known for, respectively, 40, 39 and 38 patients. Co-mutations for these genes were present in respectively 19 (47.5%), 8 (20.5%) and 4 (10.5%). Data comparing KRASMut and KRASWT showed non-significant differences in survival (median OS of respectively 21.1 vs. 17.7 months, p = 0.27). The presence of STK11 and/or KEAP1 mutations was associated with a negative impact on survival when compared with wild-type (median OS 7.4 vs 20.4 months, p = 0.001). When the presence of a KRAS mutation was compounded with STK11 and KEAP1, KRASMut (vs KRASWT) trended to a better prognosis in STK11+KEAP1WT tumors (median OS of 21.1 for KRASMut vs 15.8 for KRASWT, p = 0.15), but not in STK11+/-KEAP1Mut tumors (7.4 for KRASMut vs 7.0 for KRASWT). No influence on survival was seen in relationship to the TP53 co-mutation. Interestingly, the NLR was significantly higher with STK11 mutations (6.66Mut vs 3.59WT, p = 00012), slightly lower with TP53 mutations (3.23Mut vs 4.82WT, p = 0.047) but not impacted by KEAP1 (3.72Mut vs 4.20WT, p = 0.72) or KRAS mutations (4.32Mut vs 5.21WT, p = 0.34). Conclusions: The STK11 and KEAP1 mutations are significant adverse predictors of ICI therapy benefit. The NLR is strongly impacted by STK11 mutations but not by KEAP1 mutations suggesting marked differences in the resistance mechanism for both mutations. In STK11-KEAP1WT tumors, KRAS mutations seems to be associated with improved survival in NSCLC patient treated with ICIs.
Analysis of correlations between driver mutations and biomarkers with response to immunotherapy in patients with metastatic non-small cell lung cancer (NSCLC).
Authors: Yio Jiang , Wolf Brian , Yang Amber , Bayewitz Ashrei Y. , Xu Yiqing
Published: June 2021

e21022

Background: Next-generation sequencing (NGS) performs genomic profiling on tumor tissue and provides information on mutations on 300+ selected genes. While driver mutations have targeted therapy options, apt therapies for passenger mutations are not clearly defined. The level of PD-L1 expression and the total mutation burden (TMB) score for NSCLC have independent predictive values in response to check-point inhibition immunotherapy. Using NGS data, we aimed to evaluate the correlations of driver mutations and other biomarkers with immunotherapy response. Methods: We performed a retrospective analysis on the NGS results for NSCLC patients treated between November 2011 and February 2018. Patients were identified from the Foundation Medicine Company database and were linked to records at our cancer center. Patients’ demographics and treatment data were assessed. Results: 99 NSCLC patients (44 males and 55 females) were included with a median age of 65 (range 32-89). Races included Asian (n=42), Caucasian (n= 40), African American (n=8), and Hispanic (n=7). 49 patients possessed driver mutations, which were EGFR (n=22), ALK (n=5), RET (n=5), ROS (n=2), BRAF (n=5), MET amplification (n=5), BRCA 1 or 2 (n=4), and NTRK (n=2); 3 patients had both a driver and a non-driver mutation. In the entire cohort, 40 patients (58 total, 69%) had PD-L1 tumor proportion score (TPS) > 0% and 31 (53%) had TPS ≥10%. 30 patients (48 total, 63%) had TMB <10 and 18 (37%) had TMB ≥10. Patients with driver mutations had a lower probability of high TMB (p=0.007), but no difference in PD-L1 expression (p=0.61). PD-L1 TPS score had no correlation with TMB high or low scores (Table). In patients with driver mutations, other mutations were detected by NGS. In EGFR+ patients, the most common additional mutations were TP53 and CDKN2A/B. 23 patients received immunotherapy; the response rate in non-mutation carriers was 45.4% (5/11). Among the 7 patients with an EGFR mutation, 4 had PD-L1 TPS ≥30% and none had TMB ≥10; based on RECIST 1.1, stable disease (SD) was the best response in 2 patients. One patient with a BRAF mutation and another patient with an ALK mutation had partial responses (PR); both had TMB ≥ 10. Conclusions: NGS provides additional information in NSCLC patients with driver mutations. In patients with driver mutations, while PD-L1 expression may not be associated with response to immunotherapy, a high TMB level may be a predictive biomarker, which warrants further study.[Table: see text]
Penpulimab in combination with anlotinib as first-line treatment in advanced nonsquamous non-small-cell lung cancer.
Authors: Han Baohui , Chen Jianhua , Wang Ziping , Li Xingya , WANG Lin , Wu Lin , Xie Qiang , Zhao Yanqiu , Wang Mengzhao , Lu Junguo , Shi Huaqiu , Ye Feng , Mei Xiaodong , Yao Weirong , Yue Lu , Jiang Da , Zhao Jian , Zhang Shucai , Chen Gongyan , Jiao Shunchang
Published: June 2021

e21072

Background: Penpulimab is a human IgG1 monoclonal antibody (mAb) directed against human programmed cell death-1 (PD-1). Penpulimab, with its unique binding epitope, was engineered to eliminate Fc-mediated effector function that compromises anti-tumor immune cell function, and to optimize receptor occupancy by improving duration of drug binding. As a promising multi-target tyrosine kinase inhibitor (TKI), anlotinib significantly improved overall survival in advanced NSCLC patients (pts) in the phase 3 trial ALTER0303. Antiangiogenesis therapy combined with PD-1/PD-L1 inhibitors has shown excellent efficacy in advanced NSCLC pts. This is the trial evaluating chemo-free combination of penpulimab plus anlotinib in treatment-naive advanced NSCLC pts regardless of PD-L1 expression (NCT03866980). Methods: Pts with previously untreated, stage IIIB/IIIC/IV non-squamous NSCLC without sensitizing mutation of the epidermal growth factor receptor (EGFR) gene or translocation of the anaplastic lymphoma kinase (ALK) gene were enrolled. Eligible pts received penpulimab 200mg Q3W in combination with anlotinib 12mg QD (2 weeks on 1 week off) until loss of clinical benefit or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included ORR, disease control rate (DCR), duration of response (DoR) and overall survival. Results: As of January 13, 2021, 26 pts had received the combination therapy of penpulimab plus anlotinib (median age 59.5yrs [range 30-71], 76.9% male, 76.9% ECOG PS 1), with a median treatment duration of 3.5 months. Of 21 pts who have had at least one tumor assessment, the ORR was 57.1% (12 PRs) and DCR was 90.5% (12 PRs, 7 SDs). Median PFS has not been reached, and eleven responders remain in response. Treatment-related adverse events (TRAEs) occurred in 53.8% of pts (≥G3 TRAEs occurred in 15.4% [4/26]). Treatment-related SAEs occurred in 15.4% [4/26], and 7.7% of pts [2/26] had drug interruption or discontinuation due to TRAEs. Most common TRAEs (≥15%) were ALT increased, AST increased, hyperthyroidism and hypertension (15.4% each). Conclusions: The combination of penpulimab plus anlotinib as first-line treatment for locally advanced/metastatic NSCLC showed the promising efficacy with a manageable safety profile, thereby suggesting that this combination therapy may be a viable chemo-free treatment strategy for locally advanced/metastatic NSCLC pts. Clinical trial information: NCT03866980.
The effect of sex and BMI on outcomes in patients with metastatic non-small cell lung cancer treated with immunotherapy.
Authors: Jin Jingxiao , Visina Jacqueline , Burns Timothy F. , Diergaarde Brenda , Stabile Laura P.
Published: June 2021

e21085

Background: Recent studies suggest that among non-small cell lung cancer (NSCLC) patients treated with immunotherapy (IT), those who are male and/or have higher body mass index (BMI) benefit most; however, the role of other factors such as pretreatment weight loss is not clear. We conducted a retrospective study to further characterize the relationship between sex, BMI and response to IT in NSCLC. Methods: Patients with stage IV NSCLC treated with IT between 2017 and 2019 at UPMC Hillman Cancer Center were included. Demographic and clinical data were obtained from medical records. Chi-square test was used to compare baseline patient characteristics, best response (CR, PR and SD vs. PD), and presence of immune-related adverse events (iRAEs) between BMI and sex categories. Cox proportional hazards models were used to assess the effect of BMI and sex on progression free survival (PFS) and overall survival (OS). Analyses were conducted overall as well as stratified by treatment regime (1st line monotherapy, non-1st line monotherapy, and concurrent chemotherapy). Results: The study population consisted of 297 patients; 50.2% female (N=149), 87.8% white (N=261), and mean age at IT initiation 68 yrs (range: 36-91 yrs). Median follow-up time: 21 months. At IT initiation, 27 patients were underweight (BMI <18.5), 107 normal weight (BMI 18.5-24.9), 96 overweight (BMI 25-29.9), and 67 obese (BMI ≥30). Among underweight patients, weight loss pretreatment (≥10 lbs) was significantly more common ( P=0.02), and response to IT significantly worse (33% vs 61% good response; P=0.005) compared to those with BMI ≥18.5. No significant difference in response was observed between normal, overweight and obese patients, nor between men and women. The presence of iRAEs did not differ by BMI or sex. Females had better OS than males [HR (95%CI): 0.65 (0.47-0.90)] but PFS was similar. In stratified analyses, better OS among females was limited to the concurrent chemotherapy group [0.52 (0.30-0.92)]. Overall, underweight patients had worse OS than those with BMI ≥18.5 [1.71 (1.01-2.92)]; this was not significant after adjusting for pretreatment weight loss [1.48 (0.87-2.53)]. No difference was observed in OS and PFS between normal, overweight and obese patients. In stratified analyses, underweight individuals had worse OS [4.12 (1.55-10.94)] and PFS [3.87 (1.44-10.38)] than those with BMI ≥18.5 when treated with 1st line monotherapy. Weight loss pretreatment was independently associated with worse OS [2.20 (1.51-3.20)] and PFS [1.47 (1.05-2.05)]. Conclusions: In contrast to prior reports, NSCLC patients receiving IT did not benefit from higher BMI or male sex. Females treated with concurrent chemotherapy had improved OS, and pretreatment weight loss was an indicator of poor prognosis. Further study is required to understand the pathobiology behind these predictors.
Efficacy and pattern failures of early SBRT to primary tumor in advanced EGFR mutation lung cancer (Target-SBRT): A single-arm phase 2 study.
Authors: Lv Dongqing , Xu Hailing , Ding Jiapei , Lin Ling , Zhou Chao , Wu Xiaomai , Meng Yinnan , Wang Wei , Kong Feng-Ming Spring , Yang Haihua
Published: June 2021

e21130

Background: It is evitable for advanced NSCLC harboring EGFR mutation with 1st TKI to develop resistance with 9-13 months of PFS and 19-27 months of OS. Initial progression of TKI treatment in NSCLC was 47.2% from the primary sites, 20.4% from the new sites and 32.6% from the primary and new sites. We hypothesized that early stereotactic body radiation therapy (SBRT) to primary tumor in advanced EGFR mutation NSCLC combined with EFGR-TKI treatment could prolong targeted resistance and explored its pattern failures. Methods: Eligible patients pathologically confirmed advanced NSCLC with Exon19 deletion or Exon21 L858R mutation were enrolled (ChiCTR-OIN-17013920). Each patient received EGFR TKI (Icotinib 125mg tid or gefitinib 250mg qd) and early SBRT (40-60 Gy/5-8F/5-10d) for primary tumor about 1 months from the beginning of EGFR TKI until disease progressed. Initial progression in sites of original disease (primary/metastatic) was defined as original site failure (OF) and appearance of new lesions as distant site failure (DF). Simultaneous OF/DF was labeled as ODF. The primary endpoint was PFS and the second endpoints were pattern failures, OS as well as adverse effects (AEs). Study was designed to enroll 50 patients to detect 6 months’ extension of PFS. Results: The study was closed after 41 patients enrolled due to the use of more effective 3rd EGFR-TKI.There were 37 PR and 4 SD after one month of TKI treatment and the average tumor shrinkage rate was 42.5%. The average interval from TKI to SBRT was 1.43 months (0.87-2.77 months). Median PFS and OS were 15.2 months (95% CI 13.1-17.4) and 27.6 months (95% CI 23.1-32.1), respectively. Of 37 patients who progressed, 6 (16.2%) had OF, 21 (56.8%) had DF, and 10 (27.0%) had ODF. The lung was the most common site of initial progression. As for toxicity, there was no ≥Grade 3 AEs and Grade 1-2 radiation Pneumonitis was the most frequent AEs. Conclusions: Early SBRT for primary tumor generated prolonged PFS without serious radiation pneumonitis in advanced EGFR mutation NSCLC patients with TKI treatment. This combined therapy obtained remarkably lower primary tumor progression rate and favorable OS. Clinical trial information: ChiCTR-OIN-17013920.
Effects of a mucosal coating spray in non-small cell lung cancer patients with nasal mucositis.
Authors: Wang Fang , Liu Hui , Zeng Zhen , Wang Shasha , Qin Haifeng
Published: June 2021

e21160

Background: Targeted therapy opens a new era in the treatment of non-small cell lung cancer (NSCLC). At the same time, it also faces a serious problem, that is, the adverse events brought by new drugs, which not only affect the quality of patients’ life, but may even endanger their lives. Nasal mucositis (NM) may cause significant discomfort for the patients, and even result in the interruption of treatment. Episil (mucosal coating spray) oral liquid is a preservative-free oral liquid gel that can be used for the management of pain associated with oral lesions of various etiologies. Our study prospectively assessed effects of mucosal coating spray oral liquid in NSCLC patients with NM. There is no similar studies at home and abroad. Methods: Our study enrolled 15 patients who experience nasal mucositis after targeted therapy (Table). We designed a specific questionnaire according to Oral Mucositis Daily QuestionnaireOMDQ), Oral Mucositis Assessment Scale (OMAS), and the Patient-Reported Oral Mucositis Symptom (PROMS) to evaluate the change of life quality in NSCLC patients. All the patients needed to complete the questionnaire included in the statistical analysis. Evaluations were made before and after 5 treatment days. Results: All the patients were evaluated. Among patients, 87% suffered from NM grade 2 and 33% were with bleeding at study start, quality of life scores improved significantly after 5 treatment days with mucosal coating spray. Only 1 patient’s pain score reduced not that well because of nonstandard medication. No drug-related adverse reactions were found. Conclusions: Mucosal coating spray can effectively improve the nasal mucositis caused by targeted therapy in NSCLC patients. It may provide a new and effective therapy strategy for them, but large sample and additional clinical trials are also needed, especially for bevacizumab as one agent of combination protocol.
Effect of excess weight on immune-related adverse events from immune checkpoint inhibitor in lung cancer.
Authors: Osataphan Soravis , Jan Yu Jen , Stafford Katherine A. , Lam Prudence B.
Published: June 2021

e21183

Background: Immune checkpoint inhibitors (ICIs) are effective therapies for advanced lung cancer however they are also associated with immune-related adverse events (irAEs). Obesity has been shown to be correlated with both ICIs’ anti-tumor efficacy particularly in melanoma and non-small cell lung cancer (NSCLC). However, there have been conflicting reports between the relationship between BMI and the incidence of irAEs. Methods: We conducted a retrospective cohort study on the use of immune checkpoint inhibitor in advance lung cancer from Mount Auburn Hospital, a community-based teaching hospital in the United States, between 2016 to 2020. We studied the association between overweight (BMI of more than 25 kg/m2) versus normal weight patients (BMI 18.5 - 24.99 kg/m2) and incidence of irAEs or progression free survival. Results: A total of 51 patients with advanced lung cancer were treated with either Pembrolizumab, Nivolumab, Durvalumab or Atezolizumab. NSCLC accounted for 90.2% of the histological findings and adenocarcinoma represented 45.0% of the cohort. Among these patients 61.0% were classified as. There was a trend to increase in the incidence of irAEs in overweight compared to normal weight patients (48.3% vs. 25.0%, OR 1.91, 95% CI 0.56-6.99, p = 0.308). The most common irAEs in this cohort was thyroid dysfunction. The overweight group also had a higher baseline blood glucose level (120.5 ± 39.9 mg/dL vs. 92.9 ± 13.8 mg/dL, p < 0.01). However, no difference in progression free survival was found between the two groups (HR 1.19, 95%CI 0.58-2.42, p = 0.6). Conclusions: Although limited by sample size, here we reported a real-world experience where excessive weight may be an important predictor of irAEs development in patients with lung cancer.
Pulmonary sarcomatoid carcinoma: Retrospective analysis from a single center.
Authors: Kumar Suresh Kumar , Nandhana Ravindra , Dhanawat Aditya , Noronha Vanita , Patil Vijay Maruti , Menon Nandini , Kumar Rajiv , Joshi Amit , Tibdewal Anil , Jiwnani Sabita S. , Choughule Anuradha , Mahajan Abhishek , Janu Amit , Banavali Shripad Dinanath , Prabhash Kumar
Published: June 2021

e21188

Background: Pulmonary sarcomatoid carcinoma (PSC) constitutes a heterogeneous group of poorly differentiated non-small cell lung cancer (NSCLC). Since these are rare tumors, no definitive randomized trials or clinical guidelines are available for management. This is the largest single centre study of patients with pulmonary sarcomatoid carcinoma. Methods: We retrospectively evaluated all patients with pulmonary sarcomatoid carcinoma between January 2013 to September 2020 at the Tata Memorial Hospital, Mumbai, India. Cases were identified from the pathology database. Baseline demographic, treatment data and outcomes were obtained from a prospectively maintained database in the Department of Medical Oncology. Results: A total of 151 patients with PSC were diagnosed during this period. Among these, 129 patients were included for survival analysis. The median age at diagnosis was 61 years (range, 18-87) with a majority of them being males (81.5%) and smokers (73%). A significant percentage of patients presented with poor performance status (PS was 2-4 in 48%). A majority of patients had T4 (73%) or N3 nodal status (44%). The clinical stage was stage I in 2%, stage II in 2.7%, stage III in 25.9%, and stage IV in 69.4%. The initial treatment modalities include surgery (10.9%), radical chemoradiotherapy (CRT, 3.9%), palliative chemotherapy (46.5%), palliative radiotherapy (7%), and best supportive care (31.8%). The median follow-up duration for the entire cohort was 32 months (95% CI 15.0 to 48.9). The median OS for the entire patient cohort was 5 months (95% CI 3.4 to 6.5). The median OS of patients who received curative surgery was 18 months (95% CI: 2.59 to 33.4) and the corresponding 1- and 5-year survival rates for patients who underwent surgery were 64% and 33% respectively. The median OS for patients who received CRT was 11 months (95% CI: 2.99 to 19). The median OS for the patients who received palliative radiotherapy alone was 4 months (95% CI: 1.91 to 6.08), for palliative chemotherapy was 8 months (95% CI: 5.24 to 10.75) and for patients who received only best supportive care was 1 month (95% CI: 0.43 to 1.57, p = 0.001). The median PFS and ORR for first, second- and third-line palliative chemotherapies were 4 months (95% CI: 2.95 to 5.04) and 15.1%, 4 months (95% CI: 0.33 to 7.67) and 13.3%, and 1 month (95% CI 0.21 to 1.78) and 0%. In a multivariate analysis, independent prognostic factors included the presence of brain metastasis (p 0.018, HR, 2.47, 95% CI 1.34-4.49) and administration of palliative chemotherapy (p = 0.037, HR2.2, 95% CI 1.04-4.94). Conclusions: PSC usually presents in advanced stages and carries a poor prognosis. Effective therapeutic options are required to improve the outcomes.
Survival outcomes with the use of immunotherapy (IO) in patients (pts) with metastatic non-small cell lung cancer (mNSCLC) at a large hybrid cancer institute.
Authors: Young Joanna Alyse , Clarkson Christina , He Jiaxian , Slaughter Daniel , Haggstrom Daniel Ernest , Carrizosa Daniel R. , Mileham Kathryn Finch
Published: June 2021

e21192

Background: Landmark trials have shown increased survival in pts who receive IO for NSCLC as compared to chemotherapy (chemo). Median overall survival (mOS) ranged from 17-26 months (mo); however, mOS in several published “real-world” retrospective studies are lower, ranging from 8-12 mo, with about 4-5 months on IO treatment. We sought to define mOS of pts with mNSCLC who received IO as monotherapy or in combination with chemo as first line therapy at Levine Cancer Institute. Methods: We retrospectively reviewed 315 adult pts with mNSCLC without driver mutations diagnosed between 2016 and 2019. The Kaplan-Meier method was used to estimate and compare OS between IO and IO + chemo. Univariate and multivariate Cox models were used to evaluate risk factors (RF) for OS. RFs considered included age, sex, race, smoking status, histology, first-line treatment type, and metastatic (mets) sites. Results: Baseline pt characteristics were: 40% female, 77% white, 20% Black, 34% current smokers and 60% former smokers. Median age was 69 years (45-88) in pts receiving IO alone and 63 years (28-84) in pts receiving IO + chemo. Tumor characteristics were: 76% adenocarcinoma and 17% squamous cell carcinoma. PD-L1 TPS distribution was: 39% for 0%, 22% for 1-49%, and 39% for ≥50%. Distribution of mets was 10% adrenal, 40% bone, 30% brain, 14% liver, 31% lung. mOS for pts receiving IO and IO + chemo as first line therapy was 17 and 14.8 mos, respectively (P = .209). Median duration of IO received was 4.25 months (0 to 43.6). mOS as stratified by PD-L1 TPS was 14.5 mos for PD-L1 0%, 13.3 mos for PD-L1 1-49%, and 19.5 mos for PD-L1 ≥50% (P = .163). OS was significantly different between IO and IO + chemo after adjusting for age. No OS differences were seen between white and Black or between all pts vs pts with brain mets (brain-specific interventions not reviewed). The table summarizes significant findings only (P < 0.05). Conclusions: Pts with mNSCLC treated first-line with IO either alone or with chemo at Levine Cancer Institute lived longer than those in similar published “real-world” cohorts. Median OS was highest in patients with PD-L1 TPS ≥50%, although not statistically significant. While not unusual to identify worse outcomes in those with bone and liver mets, interestingly brain metastasis was not associated with worse survival. In this cohort, when adjusted for age, IO alone trends toward improved survival. Although there was no OS difference based on race, further investigation will seek to uncover any other disparities contributing to outcomes, such as insurance status and zip code mapping. To our knowledge, this provides the largest analysis of this patient population outside of a clinical trial.[Table: see text]
Treatment pattern post-osimertinib failure in EGFR mutated NSCLC in India-CRSF202002 study.
Authors: Gupta Kushal , Raut Nirmal Vivek , Goyal Gautam , Talele Avinash , Karpe Ashay , Poladia Bhavesh Pradip , Goel Alok , Kannan Ram Abhinav , Talreja Vikas , Prasad Manu , Basu Trinanjan , Singh Ashish , Kothari Rushab , Chandrasekharan Arun , Rajamanickam K. Deepan , Ramaswamy Anant , Ghosh Joydeep , Doshi Vipul , Bhosale Bharatsinha Baburao
Published: June 2021

e21201

Background: Osimertinib is one of the favoured treatment options in EGFR mutated NSCLC and was established as a treatment option in last 2-3 years. However the treatment pattern post-osimertinib failure is not established. Hence we conducted this audit to study the pattern of treatment post-osimertinib failure in India. Methods: This was a retrospective multi-centric audit of adult (age ≥18 years) EGFR mutated NSCLC patients who were treated with osimertinib and had failed. The treatment pattern of these patients was noted. Descriptive statistics were performed. Median with range was estimated for continuous variables while the percentage with 95% CI were estimated for ordinal and nominal variables. Results: We had 25 patients who had failed on osimertinib. Oligo-progression versus widespread progression was seen in 5 (20%) and 20 (80%) patients respectively. The median age was years 56.5 year (Range-26-71) with 4/25 (16%) of patients were elderly (≥65 years). Male-to-female ratio was 18:7 (72% males, 28% females).The ECOG PS at failure were 0-1 in 12 patients (48%), 2 in 11 patients(44%) and 3-4 in 2 patients (8%) patients. The treatment offered were platinum doublet in 14 patients (56%) with variable combinations with TKIs in 5 patients (20%) and bevacizumab in 4 patients(16%). A repeat NGS for assessing the mechanism of resistance was done in patients revealed new mutations in 6 patients (24%) with EGFR Exon 20 T790M being most common in 3 patients (12%). Conclusions: We conclude that, in real-world practice, platinum-doublet formed the backbone of treatment post-osimertinib progression, with variable combinations, most commonly, along with TKIs or bevacizumab. No standard guidelines for the treatment of patients post-osimertinib progression are available with variable responses and tolerability. Larger and prospective studies are needed to identify the best options of therapies in such patients.
Associated factors for poor response in advanced EGFR-mutated NSCLC patients under tirosine kinasa inhibitors: Peruvian real-world data.
Authors: Motta Guerrero Rodrigo , Aliaga Carlos , Runciman Gozzer Thanya Katherine , Carracedo Carlos F. , Failoc Virgilio , Leon Alejandro
Published: June 2021

e21214

Background: Although tirosine kinasa inhibitors (TKI) are the first line of therapy in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations, some patients do not have benefit with TKI. The aim of this study is to determinate if there are associated factors with poor response with TKI. Methods: This is an observational study of a single institution patient cohort. Clinical records of advanced NSCLC patients harboring EGFR mutations that have received TKI as first line therapy in ALIADA cancer center since january 2015 until december 2019 were evaluated. Clinical records with incomplete data were excluded. Type of EGFR mutation, type of TKI agent, BMI, neutrophil, lymphocyte, platelets, neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) were evaluated in all cases. Poor responders where defined as NSCLC patients who progressed within 3 months with erlotinib or afatinib and 6 months within osimertinib. The statistical analysis was performed with SPSS version 20 and MINITAB 14. Results: 46 patients were finally included. Mean age was 63.6 ± 11.7 years, 54.4% of patients were female and 93% had adenocarcinoma histology. Mean neutrophil, lymphocyte and platelet counts were 4.82, 1.96 and 396.07 respectively; meanwhile mean NLR was 4.85 and mean PLR 282.36. 45% of patients were overweight or obese. 65.2% of all mutations were EGFR exon 19 deletions, 19.6% were exon21 L858R substitution and 10% EGFR uncommon mutations (de novo exon20 T790 mutations and exon18 G719X substitution). 45.7% of patients received erlotinib, 37% received afatinib and 17.3% osimertinib. 61.5% of patients achieved partial response, 17.3% achieved complete response, 9.6% stable disease and 28.3% of patients were poor responders to TKI treatment. In bivariate analysis, odds ratio for poor response was more associated with uncommon mutations (OR = 8.21, IC95% = 1.94-97.18; p = 0.025) and patients with neutrophil > 4.82 (OR = 1.65, IC 95% = 1.08-2.52; p = 0.020). Odds ratio for poor response decreases 95% with erlotinib (OR = 0.05, IC95% = 0.00-0.58; p = 0.016). There was no statistical association with the rest factors. In the logistic regression model, poor response to TKI are related to uncommon EGFR mutations (OR = 8.21, 95% CI = 1.3-51.99; p = 0.009) and neutrophils > 4.82 (OR: 1.85, 1.13 -3.05). Conclusions: Disease progression is a phenomenon present in patients with EGFR-mutated NSCLC. According to our data, poor response is associated with uncommon EGFR mutations, TKI agent (erlotinib) and neutrophil count level. We need larger studies to validate our results.
Adjuvant PD-1 inhibitor versus high-dose interferon α-2b for Chinese patients with cutaneous and acral melanoma: A retrospective cohort analysis.
Authors: Wang Jiuhong , Li Jingjing , Liu Xing , Wen Xizhi , Li Dandan , Ding Ya , Jiang Hang , Huang Fuxue , Zhang Xiaoshi
Published: June 2021

e21516

Background: The clinical efficacy of PD-1 inhibitors as an adjuvant treatment for Asian melanoma patients has not yet been determined. Methods: Thus, this single-centre, retrospective study analysed the clinical data of 90 Chinese patients with completely resected, stage III cutaneous or acral melanoma who received either adjuvant PD-1 inhibitor or high-dose interferon α-2b (HDI). Propensity score matching (PSM) was used to control baseline differences between the two treatment groups. The primary end point was recurrence-free survival (RFS), and the secondary end points included distance metastasis-free survival (DMFS) and incidence of first distant metastatic sites. Results: Anti-PD-1 treatment resulted in significantly longer RFS (18-month RFS, 53.3% versus 26.7%; 95% CI, 0.097-0.975; P < 0.05) and DMFS (18-month DMFS, 70.9% versus 46.1%; 95% CI, 0.13-0.945; P < 0.05) than HDI in cutaneous melanoma patients. However, adjuvant anti-PD-1 treatment had no advantage over HDI in acral melanoma patients (18-month RFS, 30.0% versus 35.9%; P > 0.05; 18-month DMFS, 36.5% versus 63.6%; P > 0.05). The incidence of lung metastasis at first in the anti-PD-1 group was found to be significantly lower (12.5% versus 48.5%; P < 0.05) in cutaneous melanoma patients than in acral melanoma patients, but no difference in metastatic sites were observed between the two treatment groups among acral melanoma patients. The incidence of treatment-related AEs was similar between the two treatment groups. Conclusions: In conclusion, adjuvant anti-PD-1 treatment was well tolerated and yielded a significantly better prognosis than HDI in Chinese patients with stage IIIB/C cutaneous melanoma, but a significant difference was not observed in those with acral melanoma.
Outcomes of stage IV melanoma in the era of immunotherapy (IO): A National Cancer Database (NCDB) analysis.
Authors: Sussman Tamara A. , Wei Wei , Funchain Pauline , Gastman Brian
Published: June 2021

e21520

Background: The majority of data for IO in melanoma stems from trials that have specific inclusion criteria and often exclude important populations. In this analysis, we present the first real-world evidence of outcomes for stage IV patients (pts) with cutaneous melanoma receiving IO from 2015–2017 (addition of anti-PD-1 therapies) and factors associated with receipt of IO, and compare these outcomes with pts receiving IO (likely interferon and interleukin-2) from 2004–2010, and IO (addition of ipilimumab) from 2011–2014. Methods: The NCDB was analyzed to identify pts with stage IV melanoma from 2004–2017. Pts were categorized into receipt of IO or not during time periods 2004–2010, 2011–2014, and 2015–2017. Overall survival (OS) was analyzed by Kaplan-Meier, log-rank, and Cox proportional hazard models; IO status was analyzed using logistic regression. Results: 24,544 pts were analyzed from 2004–2017. Overall, 5,238 pts (21.3%) that received IO had improved median OS compared to those that did not (20.2 vs. 7.4 mos; p<0.0001). 4.1% received IO from 2004-2010, 7.8% from 2011-2014, and 9.4% from 2015-2017. Three-year OS significantly improved in pts treated with IO across treatment years; p<0.0001 (Table). Similarly, median time to IO initiation improved over time: 62 days in 2011-2014 vs. 49 days in 2015-2017 (p<0.0001). In the overall cohort, age<65 years, female gender, private insurance, no comorbidities, residence in metropolitan area, and treatment at academic centers were associated with better OS (p<0.0001 for all). Race was not associated with differences in OS (p=0.07). Multivariate analysis for 2015-2017 demonstrated that lack of treatment with IO [HR 1.98, 95%CI 1.81-2.17], radiation therapy [HR 1.20, 95%CI 1.09-1.32], presence of liver metastases [HR 1.87, 95%CI 1.63-2.13], and lack of surgery [HR 1.68, 95%CI 1.45-1.93] were independently associated with worse OS (p<0.0001 for all). In multivariate analysis, receipt of IO from 2015-2017, was associated with age<65 years [OR 1.27, 95%CI 1.08-1.50], African American race [OR 5.88, 95%CI 1.60-28.58], lack of comorbidities [OR 1.43, 95%CI 1.23-1.66], and treatment at academic centers [OR 1.44, 95%CI 1.26-1.65] (p<0.05 for all). Conclusions: OS was improved in stage IV melanoma pts receiving IO, with the highest OS rate in 2015-2017. Our findings that represent a real-world population are consistent with recent trials, like KEYNOTE 006 and CheckMate 067 where 3-year OS for anti-PD-1 therapy was 50% and 52%, respectively. In our study, African Americans demonstrate a 5-fold increase in likelihood of receiving IO, a population underrepresented in clinical trials. Significant socioeconomic factors may impact receipt of IO and survival.[Table: see text]
Four-year survival follow-up of toripalimab (JS001) as salvage therapy in Chinese melanoma patients.
Authors: Tang Bixia , Chi Zhihong , Chen Yingbo , Liu Xiufeng , Wu Di , Chen Jing , Song Xin , Wang Weifeng , Dong Lihou , Song Haifeng , Wu Hai , Qin Shukui , Guo Jun , Zhang Xiaoshi , Yao Sheng , Feng Hui
Published: June 2021

e21522

Background: Toripalimab, a PD-1 monoclonal antibody received conditionally approval in China as a salvage therapy for metastatic melanoma in 2018 based on a phase II trial with confirmed objective response rate of 17.3%. With four-year survival follow-up, here we report long-term survival results and related predictive biomarkers (NCT03013101). Methods: Patients with advanced melanoma who had failed prior systemic treatments were given toripalimab at 3 mg/kg i.v. Q2W until disease progression, intolerable toxicity or 2-year of treatment. Pts were followed for survival every 3 mo after discontinuation of treatment. Pts were transferred to an extension study after 2-year treatment. The Primary endpoint for the extension study was overall survival (OS). Results: 127 pts were enrolled, including50 (39.4%) acral, 22 (17.3%) mucosal, 29 (22.9%) nonacral cutaneous, and 26 (20.5%) unknown primary subtypes. After a median follow-up of 16.5 mo (range, 0.9-48.8), 74 (58%) pts had died. Median duration of response was 25.6 mo (95%CI:12.8-NE). Median OS was 22.0 mo (95%CI: 15.3-32.5). The OS rates for year 1 to 4 were 67.1%, 48.2%, 38.0% and 31.7% respectively. The median OS of complete response (CR)/ partial response (PR) (n = 22), stable disease (SD) (n = 51), progression disease (PD) (n = 54) were not reached, 34.0 mo and 9.7 mo, respectively. The median OS of non-acral cutaneous, unknown primary, acral and mucosal melanoma subtypes were 46.1, 37.3, 16.9 and 10.3 mo, respectively. The median OS of PD-L1+ (n = 26) and PD-L1- (n = 84) patients were 46.1 and 14.4 mo (P = 0.026, HR = 0.45, 95%CI 0.26-0.76). The median OS of TMB high (n = 20), TMB low (n = 78) was 16.0 and 22.3 mo with no statistically significance (P = 0.49, HR = 1.28, 95%CI 0.63-2.58). Conclusions: Salvage treatment with toripalimab leads to long-term survival benefit in advanced melanoma patients, especially for those with non-acral cutaneous and unknown primary subtypes, CR/PR/SD as best response or PD-L1+.
PALB2 mutation as a predictive biomarker for immunotherapy in patients with advanced melanoma: Results from (a pooled analysis of) five multicenter, randomized clinical trials.
Authors: You Changxuan , Zheng Yating , Huang Mengli
Published: June 2021

e21537

Background: PALB2, a gene in the homologous recombination repair (HRR) pathway, has been shown to be associated with the efficacy of platinum based chemotherapy, and PARP inhibitor therapy in breast, prostate, ovarian, and pancreatic cancers. However, their predictive value of PALB2 remained unknown in patients with advanced melanoma. Methods: Five independent cohorts (Miao2018, Samstein2018, Allen 2015, Hugo2016, and Synder2014. study cohort) with data from 672 patients with advanced melanoma were used to analyze the correlation with immunogenic marker, and the prognostic effect of PALB2 on immunotherapy. Results: A pooled analysis of five independent cohorts of 672 advanced patients melanoma show that 31 (4.6%) harbored PALB2 mutation ( PALB2mut). PALB2mut (72.63Muts/Mb) was associated with higher tumor mutation burden (TMB) (P < 0.001) than PALB wild-type ( PALB2wt) (19.71Muts/Mb). The same phenomenon has also been observed in TNB, PALB2mut (1983 counts) was associated with higher tumor neoantigen burden (TNB) than PALB2wt (603.5 counts) (P = 0.0147). The objective response rate (ORR) of immunotherapy was 53.33% for the patients with PALB2mut and 24% for the PALB2wt subgroup (P = 0.027). The PALB2mut patients had significantly improved median overall survival (mOS) than the PALB2wt group (Not reach versus 29 months, hazard ratio (HR) = 0.38, 95%CI 0.19−0.73, P = 0.003). A subgroup analysis of CTLA4 inhibitor treatment found that PALB2mut was associated with better ORR (50% versus 18.3%, P = 0.016) on immunotherapy, and mOS in the PALB2mut group was significantly better than that in the PALB2wt group (Not reach versus 21 months, HR = 0.3, 95%CI 0.13−0.68, P = 0.002). However, in the subgroup receiving PD-L1 inhibitor treatment, no ORR benefit was found in the PALB2mut group (66.67% versus 56.76%, P = 1), and there was no difference on mOS between PALB2mut and PALB2wt (Not reach versus 31 months, HR = 0.45, 95%CI 0.11−1.8, P = 0.254). Conclusions: PALB2 mutations was associated with a higher TMB and TNB level. PALB2 may serve as a positive predictor of immunotherapy (CTLA4 inhibitor therapy) in patients with advanced melanoma and their clinical value warrants further investigation.
CCND1 amplification profiling identifies a subtype of melanoma associated with poor survival and an immunosuppressive tumor microenvironment.
Authors: Chen Yu , Jun Liu , Lin Jing , Wang Xuefeng , Zheng Xiao-bin , Gao Xuan , Chen Gang , Xiong Jiani , Lan Bin , Chen Chuan-ben , Si Lu , Xia Xuefeng
Published: June 2021

e21552

Background: Melanoma is generally regarded as an immunogenic type of tumor that will respond to immune checkpoint therapy. However, melanoma tumors with CCND1 amplification respond poorly to checkpoint therapy. Further understanding of how CCND1 amplification modifies the effect of checkpoint therapy is necessary to design future clinical trials. Methods: We used the data from the Geneplus Institute (n = 302), The Cancer Genome Atlas (TCGA) (n = 367),and the Memorial Sloan Kettering Cancer Center (MSKCC) (n = 350) to identify the incidence of CCND1 amplification and the relationship between CCND1 amplification and survival in melanoma patients and explored molecular mechanisms. Results: The frequency of CCND1 amplification co-occurring with BRAF V600, NRAS, NF1, and KIT mutations was low in these three cohorts. Data from TCGA did not show a statistically significant correlation between CCND1 amplification levels and prognosis of melanoma patients irrespective of immune checkpoint inhibitors (ICIs). In contrast, we found opposite results using the MSKCC cohort where CCND1 amplification was an unfavorable prognostic factor for melanoma patients. This was especially true for patients received ICIs who were harboring a high tumor mutation burden (TMB). The TCGA data showed that CCND1 amplification were related to a higher proportion of immunosuppressive cells (Treg cells and M2 macrophages) and a lower proportion of immunity boosting cells (follicular helper T-cells, naive B-cells, CD8+ T-cells). Furthermore, GSEA analysis from the TCGA database suggests that the signaling pathways such as oxidative phosphorylation, reactive oxygen species, adipogenesis, fatty acid metabolism, DNA repair, and myc targets were differentially enriched in melanoma tumors with CCND1 amplification. Finally, we found that angiogenesis related molecules (HIF1A, VEGFA, VEGFR1, FGF2, FGFR1, FGFR4, HGF, PDGFA, PDGFRA, ANGPT1, and ANGPT2) were remarkable decreased in a CCND1 High Amplification group from the TCGA database. Conclusions: Melanoma with CCND1 amplificationis an independent genomic subtype associated with a poor prognosis, an immunosuppressive TME, activated oxidative and lipid metabolism, and down-regulated angiogenesis. Taken together, avoiding ICIs and antiangiogenic agents, while employing CDK4/6 inhibitors alone or in combination with ICIs, targeting oxidative and lipid metabolism pathway may be effective and promising therapeutic strategies for melanoma patients harboring CCND1 amplification.
Development and validation of an improved pathologic nodal classification system for cutaneous melanoma.
Authors: Nguyen Anthony Tuan , Luu Michael , Nguyen Vina , Hamid Omid , Faries Mark B. , Gharavi Nima M. , Lu Diana J. , Mallen-St. Clair Jon , Ho Allen S. , Zumsteg Zachary Stephan
Published: June 2021

e21563

Background: Given recent therapeutic advances and evolving patterns of lymph node (LN) evaluation for cutaneous melanoma, accurate and precise LN staging is needed to guide adjuvant treatment and future investigations. Current staging was developed primarily for patients undergoing completion LN dissection (CLND) for node-positive disease and do not produce LN classification groups with continuously increasing mortality. Thus, we developed and validated an improved LN classification system for cutaneous melanoma. Methods: Retrospective cohort analysis of 105,785 patients with cutaneous melanoma who underwent surgery from 2004 to 2015 in the National Cancer Database. Extent of LN dissection (sentinel LN biopsy [SLNB] and/or CLND) was available for patients diagnosed 2012 onward. Multivariable models were generated with number of positive LNs modeled using a non-linear restricted cubic spline function. Recursive partitioning analysis (RPA) was used to derive a modified LN classification system based on LN variables independently associated with overall survival (OS). The proposed LN classification system was validated in 85,499 patients from SEER-18. Results: Number of positive LNs (1-2 LN+: hazard ratio [HR] 2.48 per LN, 95% CI, 2.37-2.61, P< 0.001; ≥3 LN+: HR 1.10 per LN, 95% CI, 1.07-1.13, P< 0.001), clinically detected metastases (HR 1.35, 95% CI 1.27-1.42; P< 0.001), and in-transit metastases (HR 1.48; 95% CI 1.34-1.65; P< 0.001) were associated with OS. An RPA-derived LN classification system using these variables demonstrated continuously increasing mortality risk for each proposed LN classification group (HR: 1.83, 2.72, 3.79, 4.56, 6.15, and 8.25 for the proposed N1a-N3b groups, Table, P< 0.001). By contrast, AJCC 8E produced a more haphazard mortality profile (HR: 1.83, 3.81, 2.59, 2.71, 4.51, 3.44, 6.06, 8.15, and 6.90 for N1a-N3c). As a sensitivity analysis, the proposed system continued to accurately predict outcomes when we excluded patients undergoing CLND for microscopic LN metastases. Lastly, we validated this system for OS and cause-specific mortality in SEER-18 ( P< 0.001). Conclusions: A modified and simplified LN classification system can accurately predict mortality in cutaneous melanoma in an era of increasing use of SLNB without CLND and should be considered for future staging systems.[Table: see text]
Comorbidity affects Вcl-2 levels in mitochondria in C57BL/6 mice with transplantable B16/F10 melanoma.
Authors: Neskubina Irina V. , Frantsiyants Elena M. , Bandovkina Valeria A. , Cheryarina Natalia D. , Shikhlyarova Alla I. , Surikova Ekaterina I. , Kaplieva Irina V. , Nemashkalova Ludmila A. , Pozdnyakova Viktoria V. , Przhedetskiy Yuriy V. , Przhedetskaya Viktoria Yu. , Ilchenko Maria G. , Agarkova Elena I. , Maksimova Natalia A. , Khokhlova Olga , Zakharova Natalia A. , Kit Oleg I.
Published: June 2021

e21581

Background: Overexpression of the Bcl-2 protein inhibits apoptosis and promotes carcinogenesis. Stress causes signaling leading to cell buffering with Bcl-2 protein above acceptable levels. The purpose of the study was to analyze the influence of comorbidity – chronic neurogenic pain (CNP) – on the Bcl-2 levels in mitochondria of cells of melanoma, the heart, skin and brain in female mice with growing tumors. Methods: Female С57ВL/6 mice were divided into groups: intact group (n = 21); control group with a CNP model – bilateral sciatic nerve ligation (n = 21); group M – B16/F10 melanoma (n = 63); CNP+M group – B16/F10 melanoma was transplanted 3 weeks after the CNP model creation (n = 63). The concentration of Bcl-2 (ng/mg of protein) was determined in mitochondrial samples by ELISA (Thermo Fisher Scientific, Austria). Statictical analysis of results: Statistica 10.0. Results: CNP decreased the Bcl-2 level in heart mitochondria by 1.3 times (p < 0.05), but increased it in skin and brain mitochondria by 5.8 and 1.3 times, respectively. Similar changes were observed in melanoma growth 1 week after its transplantation: Bcl-2 levels decreased in heart mitochondria by 1.3 times, and increased in the skin and brain by 8.9 and 1.3 times, respectively. After 2 weeks of the tumor growth, Bcl-2 in brain mitochondria decreased by 1.7 times, and it started declining in the skin by the 3rd week – by 4 times, compared to intact females. Bcl-2 in tumor mitochondria exceeded the values in the skin by more than 4 times throughout the experiment. Tumor growth in presence of CNP caused a decrease in Bcl-2 in brain mitochondria by 2.4 times after 3 weeks, and in the heart and skin – by 2 and 1.7 times, respectively, after 2 weeks. Bcl-2 in tumor mitochondria in presence of CNP was lower than in the intact skin on average by 1.8 times throughout the experiment. Conclusions: CNP as a comorbidity caused a modulating effect on the mechanisms of survival and apoptosis of cells both in the tumor and in the main organs providing the vital functions of the body - the brain and heart, and also affects the target organ of melanoma - the skin. The results demonstrated the ability of comorbidity to change levels of Bcl-2 in mitochondria depending on the stage of tumor development.