bluuebunny/crossref_metadata_2025 huggingface dataset:
PD-L1 expression as a unique negative predictive biomarker in advanced squamous NSCLC when treated with first-line chemotherapy.
Authors: Wong Zhun Hong Nicky , Zhao Joseph J , Zhu Ke Xin , Yap Dominic Wei Ting , Kumarakulasinghe Nesaretnam Barr , Huang Yiqing , Sundar Raghav
Published: June 2023

e21140

Background: PD-L1 expression has been established as a positive predictive biomarker for immune checkpoint inhibition in advanced non-small cell lung cancer (NSCLC). We hypothesize that PD-L1 serves as a negative predictive biomarker of chemotherapy in squamous NSCLC in contrast to non-squamous NSCLC. Methods: Phase III randomized trials that investigated PD-L1 expression as a biomarker in advanced squamous NSCLC at first-line were identified and included through a systematic search of Embase and PubMed from inception until 24th September, 2022. To investigate the anti-thesis, trials that reported PD-L1 stratified KM plots in non-squamous NSCLC were evaluated too. Only trials that reported PD-L1 stratified KM curves of chemotherapy arms were included. A graphical reconstructive algorithm was used to retrieve survival data from reported Kaplan-Meier (KM) curves. Pooled survival analyses for progression-free and overall survival (PFS, OS) were conducted with Cox proportional hazard models with a shared-frailty term incorporated to account for inter-study differences. Results: Five phase III randomized trials (2 squamous NSCLC and 3 non-squamous NSCLC) reporting PD-L1 stratified KM plots of patients treated with first-line chemotherapy were included. In patients with squamous histology, PD-L1 expression negatively predicted for chemotherapy benefit – patients with higher PD-L1 expression were at a higher risk of tumour progression (PD-L1 ≥50% [n = 187] vs PD-L1 < 1% [n = 247]: HR = 1.474, 95%-CI: 1.171-1.855, p < 0.001; PD-L1 ≥50% [n = 187] vs PD-L1 1-49% [n = 239]: HR = 1.300, 95%-CI: 1.033-1.625, p = 0.025). Conversely, in patients with non-squamous histology, no significant differences in tumour progression was shown between PD-L1 subgroups (PD-L1 ≥50% [n = 137] vs PD-L1 < 1% [n = 242]: HR = 1.238, 95%-CI: 0.919-1.667, p = 0.160; PD-L1 ≥50% [n = 137] vs PD-L1 1-49% [n = 199]: HR = 0.958, 95%-CI: 0.714 -1.285, p = 0.780). No significant difference in OS was found between PD-L1 subgroups dichotomized at 1% & 50% among patients with squamous histology. In contrast, in patients with non-squamous histology, PD-L1 was a positive biomarker for chemotherapy benefit – patients with higher PD-L1 were at a lower risk of mortality (PD-L1 ≥50% [n = 40] vs PD-L1 < 1% [n = 150]: HR = 0.523, 95%-CI: 0.316-0.865, p = 0.012). Conclusions: These findings suggest that PD-L1 expression is uniquely a negative predictor for tumour progression in advanced squamous NSCLC treated with first-line chemotherapy.
Oligo-residual disease in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer: Incidence, pattern of failure and clinical value of local consolidative therapy.
Authors: Zhang Jinmeng , Gao Jie , Jiang Shanshan , Zhou Yue , Guo Tiantian , Ni JianJiao , Zhu Zhengfei , Zhang Zhen
Published: June 2023

e21143

Background: Growing numbers of clinical trials are testing the efficacy of incorporating local therapy into programmed death receptor (ligand) 1 (PD-1/PD-L1) inhibitors in metastatic non-small cell lung cancer (NSCLC), but the optimal timing and patient selection are still controversial. We aimed to examine the patterns of maximum tumor response and treatment failure in PD-1/PD-L1 inhibitor-treated NSCLC, and explore the potential clinical value of local consolidative therapy (LCT) in those with oligo-residual disease (ORD). Methods: Metastatic NSCLC treated with PD-1/PD-L1 inhibitors in three academic centers from May 2018 to December 2021 were retrospectively reviewed and those derived clinical benefit, defined as having objective response or durable stable disease lasting≥6months, were finally enrolled. Patterns of tumor response and treatment failure were extensively analyzed. ORD was defined as residual tumor distribution limited to 3 organs and 5 lesions, otherwise was defined as multiple residual disease (MRD). Local therapies targeting the residual tumor lesions performed after PD-1/PD-L1 inhibitors initiation and before initial disease progression, were considered as LCT. The primary endpoints were the overall survival (OS) and progression-free survival (PFS). Results: Of the 318 patients enrolled, ORD and MRD were documented in 122 (38.4%) and 196 (61.6%) patients, respectively. Those who developed ORD had a significantly longer OS than those with MRD (p = 0.006). The median time to best response was 4 months and more than 50% of the initial disease progression developed only from the residual tumor lesions, providing the preliminary rationale of LCT. Among the 122 patients with ORD, those receiving LCT (n = 39) had significantly longer PFS (p = 0.04) and OS (p < 0.001) than those without LCT. Moreover, LCT remained one of the independent predictors of improved PFS and OS after Cox analyses. Conclusions: Local consolidative therapy seems to be feasible and may provide extra survival benefit for metastatic NSCLC patients with oligo-residual disease after PD-1/PD-L1 inhibitor treatment.
Impact of next generation sequencing on a clinicians’ first line treatment decision in patients with stage IV non-small cell lung cancer.
Authors: Megahed Ahmed , Zheng Dominick , Chen Lie H. , Haque Reina , McGary Eric C
Published: June 2023

e21160

Background: National Comprehensive Cancer Network (NCCN) guidelines strongly recommend biomarker testing for patients with advanced non-small cell lung cancer (NSCLC), specifically with broad, panel-based sequencing via NGS. Our study characterized how clinicians utilized NGS testing to make first line treatment decisions in patients with stage IV NSCLC. Methods: We conducted a cross-sectional study of members within an integrated healthcare system (Kaiser Permanente Southern California) diagnosed with stage IV NSCLC who completed NGS testing (Strata Oncology) between May 2019 to June 2021. Treatment start dates were used to divide patients into those who started treatment before and after NGS results, and those who did not receive treatment after NGS results. Patients harboring alterations in seven genes (EGFR, ALK, ROS-1, BRAF, KRAS, RET, and MET) were considered candidates for targeted first line therapy. Results: A sample of 760 patients with stage IV NSCLC completed NGS testing. The mean time from NGS order to result was 25 days. Of the 760 in the sample, 284 (37%) and 262 (34%) initiated treatment before and after NGS results were reported, respectively, while the remaining 214 (28%) did not receive any treatment up to 120 days after the NGS results were reported. 43% (323/760) of the sample was found to have a targetable mutation on NGS, of whom only 38% (124/323) initiated first line treatment with a targeted therapy. 56/124 (45%) were treated with targeted therapy prior to NGS results and 68/124 (55%) were treated with targeted therapy after NGS results. 61% (118/193) of EGFR, ALK, or ROS mutated patients started targeted therapy. 67/323 with a driver mutation did not receive any treatment and were referred to hospice. For those patients who initiated targeted therapy prior to NGS results, it suggests that clinicians ordered single gene testing in parallel with NGS, and that these results were available prior to NGS. Conclusions: NGS tests results were not exclusively used to inform first line treatment decisions in most patients with stage IV NSCLC, as most patients found to have a targetable mutation, were not treated with targeted therapy. Possible explanations include lengthy turnaround times for NGS testing and the availability of more timely single gene testing.
Prediction of brain metastases progression and overall survival in patients with metastatic non-small cell lung cancer treated by immune checkpoint inhibitors using a radiomic model.
Authors: Henon Clemence , Hendriks Lizza , Carré Alexandre , Mezquita Laura , Reuzé Sylvain , Ammari Samy , Aldea Mihaela , Robert Charlotte , Le Pechoux Cecile , Audigier-Valette Clarisse , Mazieres Julien , Lefebvre Corentin , Rabeau Audrey , Duchemann Boris , Botticella Angela , Planchard David , Deutsch Eric , Besse Benjamin , Sun Roger
Published: June 2023

e21169

Background: Brain metastases (BMs) incidence is high in patients with metastatic non-small cell lung cancer (NSCLC). Immune Checkpoints Inhibitors (ICIs) are now standard of care for metastatic NSCLC in the first-line or beyond settings. However, less than half of patients will have a tumor response, and the determinants of BMs response to ICIs remain unknown. This study aims to evaluate the value of radiomics to predict control/progression of BMs at a lesion level, and outcomes at a patient level in the BM+ NSCLC population treated by ICIs. Methods: We conducted a retrospective multicenter (5 European centers) study including consecutive patients with NSCLC BMs and available baseline MRI before ICIs (evaluation cohort) or chemotherapy (control cohort) with a 2:1 ratio, between 2011 and 2021. After modified RANO (Response Assessment in Neuro-Oncology) assessment of individual BMs, we developed a radiomic model to predict BMs control/progression to ICIs at the first brain follow-up imaging. The ICIs cohort was split into two datasets used for (i) model training with 5-fold cross-validation and (ii) model testing. The Chemotherapy cohort was used to ensure the specificity of our model to ICIs-treated patients. Results: Ninety-four and 49 patients were included in the ICIs and Chemotherapy cohorts respectively, of which 56 (59.6%, N = 227 BMs) and 39 (79.6%, N = 192 BMs) patients had available brain follow-up imaging. The ICIs cohort was specifically enriched in radiomic features which were significantly associated to BMs progression. Our final model, based on extreme gradient boosting (xgboost) on BMs > 10mm from the training set (N = 39 BMs), could predict individual BMs progression to ICIs with an area under curve (AUC) of 0.77 (p-value = 0.029, 95% CI [0.56-0.98]) in the test set (N = 20 BMs). We further generated a radiomic score to stratify BM+ NSCLC ICIs-treated patients between High-Risk or Low-Risk groups according to the predicted individual BMs progression. High-risk patients were associated with worse overall survival (OS) (median OS of 6.3 months, 95% CI [3.02-10.49]) compared to Low-risk patients (median OS of 11.87 months, 95% CI [7.02-21.90], p = 0.042). The prognostic value of the radiomic score on OS was validated in a multivariate analysis in the ICIs cohort (Table). Conclusions: To our knowledge, this is the first study to explore the value of radiomics in the prediction of BMs response to immunotherapy. Prospective evaluation will confirm the generalizability of our model in clinical practice.[Table: see text]
Biomarkers to predict the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer with actionable genetic alterations.
Authors: Jun Soojin , Jung Hyun Ae , Ahn Myung-Ju , Ahn JinSeok , Lee Se-Hoon , Sun Jong Mu , Park Sehhoon , Cho Juhee
Published: June 2023

e21175

Background: Although the efficacy of immune checkpoint inhibitors (ICI) in patients with actionable genetic alterations (AGAs) in non-small-cell lung cancer (NSCLC) has been known to be modest, some patients demonstrated improved survival. Thus, this study aimed to find predictive biomarkers for ICI in patients with NSCLC with various AGAs and to identify the predictive biomarkers for ICI efficacy. Methods: We compared the progression-free survival (PFS) of 324 advanced NSCLC patients who received ICI monotherapy (as over second-line therapy) by different AGAs from January 2018 and July 2022 at the Samsung Medical Center. To identify predictive markers of ICI, we adjusted the impacts on PFS of ICI in smoking status, PD-L1 expression, TP53, KEAP, STK11 mutation status, and steroid use during ICI monotherapy. Results: The median age was 63.1 years (range, 27.8–84.8) and 53.1% of patients was male, and 46.3% of patients was an ex-/or current smoker. A total of 324 patients were included with the following AGAs: EGFR mutation (n = 149, 46.0%), ALK rearrangement, (n = 12, 3.7%), KRAS mutation (n = 72, 22.2%), HER2 mutation or amplification (n = 34, 10.5%), and MET ex14 skipping or amplification (n = 32, 9.9%), ROS1 rearrangement (n = 9, 2.8%), BRAF V600E (n = 9, 2.8%), and RET rearrangement (n = 7, 2.2%). The median PFS was 2.0 months (95% confidence interval, 1.8–2.2) in the total AGA group. The 6-month PFS rate was 25.8% (19.5–34.3) in the group with KRAS/ BRAF V600E/ MET/ HER2 and 12.8% (8.6–19.1) in the group with EGFR/ ALK/ ROS1/ RET (P < 0.01). In the group with KRAS/ BRAF V600E/ MET/ HER2, KEAP, or STK11 wild-type (P = 0.03), PD-L1 (≥1%) (P < 0.01) and steroid use during ICI monotherapy due to immune-related adverse events (IRAE) (P < 0.01) were related to a favorable PFS of ICI; however, no statistical significance was found for TP53 mutation and smoking status for PFS of ICI. In the group with EGFR/ ALK/ ROS1/ RET, PD-L1(≥ 50%) was the only factor that was related to a favorable PFS, and not TP53 mutation status, KEAP, or STK11. Conclusions: This study showed a difference in PFS among each type of AGAs. Although there are limitations due to the small number of patients, the KRAS/ BRAF V600E/ MET/ HER2 group had a favorable PFS compared with the EGFR/ ALK/ ROS1/ RET group . KEAP/STK11/PD-L1 status and steroid use due to IRAE predicted favorable PFS of ICI in the KRAS/ BRAF V600E/ MET/ HER2 group .
Immune therapy related adverse events in metastatic non-small cell lung carcinoma patients at a rural academic center.
Authors: Pasli Melisa , Muzaffar Mahvish , Kannaiyan Radhamani
Published: June 2023

e21203

Background: Immune checkpoint inhibitors (ICIs) have revolutionized treatment for stage IV non-small cell lung cancer (NSCLC) patients. Immune related adverse events (irAEs) are the diverse immunologic side effects of patients receiving ICIs and may result in significant patient morbidity, subsequently impacting quality of life. If severe enough, irAEs may lead to hospitalization and may necessitate administration of immunosuppressants or IL-6 receptor antagonists. Our study sought to characterize irAEs in a patient population receiving ICIs at a rural tertiary care center. Methods: This was an IRB-approved retrospective cohort study using SPSS version 28. Patients with stage IV NSCLC receiving ICIs at ECU Health Medical Center were analyzed and 190 patients met inclusion criteria. Results: Of our cohort, 66.3% (n = 126) experienced at least one irAE of any grade, 46.3% (n = 88) were hospitalized due to grade 3 or 4 irAE, 55.7%(n = 106) were either started on steroids or had a dose increase to treat the irAE, 48.9% (n = 93) received immunosuppression to treat the irAE, and 41.5% (n = 79) had immunotherapy held either temporarily or permanently due to the irAE. 25.7% (n = 49) were rechallenged and 18.9% (n = 36) experienced an irAE after being rechallenged. 34.7% (n = 66) experienced pneumonitis, 22.1%(n = 42) constitutional symptoms, 17.8%(n = 34) gastrointestinal, 10.5%(n = 20) neurological, 10.5%(n = 20) dermatological, 6.8%(n = 13) endocrine, 3.6%(n = 7) hematological, 3.1%(n = 6) musculoskeletal, and 3.1%(n = 6) cardiovascular irAEs. When adjusting for race, sex, line of therapy, and histological type, logistic regression analysis yielded no significant difference in the probability of developing an irAE when comparing patients treated with nivolumab versus atezolizumab and pembrolizumab. Patients treated with atezolizumab (OR:0.17; p = 0.020; 95% CI:0.039-0.757) and pembrolizumab (OR:0.20; p = 0.021; 95% CI:0.055-0.785) were less likely to be hospitalized for an irAE when compared to patients treated with nivolumab. When rechallenged, no difference was noted in recurrent irAE development when comparing pembrolizumab and nivolumab. Cox regression analysis demonstrated that patients treated with atezolizumab (OR:0.36; p = 0.010; 95% CI:0.167-0.781) and pembrolizumab (OR:0.29; p < 0.001; 95% CI:0.291-0.148) had better OS when compared to nivolumab. No difference was evident when comparing White and Black patients experiencing any grade irAE (n = 69, n = 53), grade 3 or 4 irAE (n = 44, n = 40), OS (n = 104, n = 80), and PFS (n = 104, n = 80). Conclusions: Our demonstrated irAE side effect profile is similar to those of published studies. No racial disparities were noted in our cohort when analyzing for any grade irAEs, grade 3 or 4 irAEs, OS, and PFS. Our study yields clinically pragmatic insight into better understanding how various factors, such as ICI selection and race, may impact patient outcomes.
Comparing survival and clinical characteristics of patients with non-small cell lung cancer who received immune checkpoint inhibitor therapy less than and more than 2 years.
Authors: Rose Brandon Edward , Edwards Kyle , Kareff Samuel A. , Ramos Leana , El-Abbar Nora , Lopes Gilberto , Rodriguez Estelamari
Published: June 2023

e21214

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the management of non-small cell lung cancer (NSCLC). The current standard of care based on ICI trial design is to discontinue ICI treatment after 2 years, disease progression, or intolerance. The disease progression patterns and survival of patients treated with ICIs beyond 2 years have not been well described in real-world clinical settings. Methods: We retrospectively analyzed 689 patients with advanced NSCLC who received ICI treatment at the University of Miami between June 2004 and February 2020. Patients who survived ≥ 2 years after starting ICI were defined as long-term survivors (LTS) and were divided into two treatment groups: ICI < 2 years or ≥ 2 years. The primary outcome measured was overall survival (OS). The secondary outcomes were demographic, clinical, and pathologic characteristics. Results: A total of 689 patients with advanced NSCLC were administered immunotherapy. Amongst this group, 186 (27%) were designated as LTS, 53 (28%) were treated with ICI ≥ 2 years, and 133 (72%) were treated < 2 years. LTS who were treated for ≥ 2 years had a median OS of 77.4 months compared to 46.2 months for LTS who were treated for less than 2 years (p = 0.0045). The 3-year OS for the ≥ 2 year cohort was 85.9%, compared to 70.8% for the < 2 year cohort. The characteristics of the < 2 year and ≥ 2 year cohort are described in detail in Table 1. There were no statistically significant differences in median age, gender, race, ethnicity, tobacco use, histology, PD-L1 status, or BMI. Conclusions: In this real-world analysis, prolonged ICI therapy provided a long-term benefit with a 15.1% increase 3-year OS in LTS. Patients in both groups had similar demographic characteristics. PD-L1 expression was increased in the > 2 year group. Larger prospective trials are needed to reveal the potential benefits and toxicities of increased ICI treatment length in patients with advanced NSCLC. [Table: see text]
Hospitalization for immune related toxicity and overall survival (OS) among patients with metastatic non-small cell lung cancer (NSCLC) treated with first-line pembrolizumab.
Authors: Khorasanchi Adam , Zhao Songzhu , Wei Lai , Li Mingjia , Ho Kevin , Abu-Sbeih Hamzah , Alexander John Howard , Goodyear Evelyn , Secor Austin , Shields Peter G. , He Kai , Kaufman Jacob , Memmott Regan Michelle , Alahmadi Asrar , Carbone David Paul , Otterson Gregory Alan , Meara Alexa Simon , Presley Carolyn J , Owen Dwight Hall
Published: June 2023

e21215

Background: Few studies have investigated the association between patients with NSCLC hospitalized due to complications of ICI and subsequent OS. Immune related adverse events (irAEs) are autoimmune syndromes, side effects of ICIs. We evaluated the rates of irAEs among patients with metastatic NSCLC hospitalized within 1 year of pembrolizumab treatment and OS. Methods: This retrospective study included 102 patients (out of 411 total patients screened) with Stage IV NSCLC treated with a first-line pembrolizumab regimen (alone or in combination with chemotherapy) at the Ohio State University from 2018-2022 who developed an irAE. A chart review was completed for patient demographics, unplanned hospitalizations (irAE or any reason) within 1 year of ICI, and type of irAEs leading to hospitalization. Descriptive statistics were summarized and compared by irAE hospitalizations (Yes vs No) or any reason hospitalizations (Yes vs No). Kaplan-Meier survival analysis and log-rank test were used to assess the associations between these two groups with OS. Results: Twenty-one percent (21/102) of patients were hospitalized for irAE within 1 year, for the following irAE types: 7 pneumonitis (33.3%), 6 colitis (28.6%), 2 dermatitis (9.5%), 1 hepatitis (4.8%), 1 myalgia (4.8%), 1 neurological (4.8%), and 1 hypophysitis (4.8%). 68 were hospitalized for any reason including irAE, infections, cancer progression, and pain. Patients age, gender, race, and body mass composition were similar between two groups. Patients with irAE hospitalization had shorter OS (13.8 m, 95% CI 2.73-NR) than those without irAE hospitalization (53.6 m, 95% CI 33.18-NR, p = 0.0105). Hospitalization irAE rates were not significantly different between pembrolizumab alone and pembrolizumab-chemotherapy, however overall hospitalization rate was higher in pembrolizumab-chemotherapy (77%) than pembrolizumab alone (55%), p = 0.0214. Conclusions: This study suggests patients who are hospitalized following ICI treatment may have worse outcomes. Hospitalization rates overall were higher for patients treated with pembrolizumab-chemotherapy than pembrolizumab alone. Further investigation is needed to confirm these findings as our study was limited to patients who experienced irAEs during treatment.
Ethnic disparities in biomarker testing and targeted therapy use in metastatic lung adenocarcinoma: A 2014-2021 analysis.
Authors: Pereslete Alyssa , Ozair Ahmad , Khosla Atulya Aman , Bellur Shreyas S , Hurmiz Charlie , Marada Suresh , McCracken Andrea , Watson Mark Layton , Ahluwalia Manmeet Singh ,   Guardian Research Network Collaborators
Published: June 2023

e21216

Background: Racial and ethnic disparities have been demonstrated to be widespread in lung cancer, including in the US. Despite insurance coverage for standard biomarker testing, testing rates remain low in minority populations. This work sought to analyze institutional data to assess whether there existed ethnic disparities in biomarker testing rates and receipt of targeted therapy between Hispanic/Latino and non-Hispanic/Latino patients of metastatic lung adenocarcinoma (mAdenoCa). Methods: A retrospective study was conducted and reported following ‘strengthening the reporting of observational studies in epidemiology’ (STROBE) guidelines. All Hispanic white and non-Hispanic white patients of mAdenoCa seen at our tertiary care institution in South Florida from 01/2014 to 12/2021 were identified and included through Guardian Research Network (GRN) platform. Socio-demographic, clinicopathological, and tumor molecular features along with treatment-related characteristics were analyzed via descriptive and comparative statistics. Results: A total of 268 mAdenoCa patients were included, of which 179 patients were Hispanic or Latino and 89 were not Hispanic or Latino. Biomarker testing data is reported in the table. Data of MET, KRASG12C, VKIRAS, and HER3 was not available in all cases. The unadjusted product-limit survival analysis indicated worse outcomes for Hispanic whites as compared to non-Hispanic counterparts. There were no differences found regarding targeted therapy use in either population. Conclusions: While metastatic lung adenocarcinoma patients at our center showed no differences in biomarker testing or targeted therapy use, the non-availability of data regarding several key mutations indicates a major dearth of testing. Future studies need to evaluate actionable strategies for improving the existing low testing rates in patients with mAdenoCa, particularly in racial and ethnic minorities. [Table: see text]
Patient characteristics and treatment patterns in BRAF-mutated unresectable or metastatic melanoma in the United States: A snapshot from real-world data.
Authors: Mesana Laura , Chen Kristina , Li Benjamin , Rezai Nana , Noshad Sina , Zhao Yajin , Abraham Anup
Published: June 2023

e21506

Background: BRAF mutations are found in 40-60% of patients with unresectable/metastatic melanoma (m-melanoma). Recently, several new BRAF-targeted therapies (TT) have been approved, transforming the treatment landscape for patients with BRAF-mutated (BRAFm) unresectable/m-melanoma. This analysis aimed to describe patient characteristics and treatment patterns in BRAFm unresectable/m-melanoma patients receiving treatment during November 2015-June 2021. Methods: A retrospective analysis using Flatiron Health’s database was conducted. Adult patients with unresectable/m-melanoma who had evidence of the BRAF-V600 activating mutation were included. Patients were indexed at first-line (1L) therapy initiation. Treatments of interest were classified into immuno-oncology (IO) therapies and TT. All analyses were descriptive. Results: 671 unresectable/m-melanoma patients (average age: 62.7 years, 64.1% male) were included. Among them, 64.4% of patients received IO, 34.4% received TT, and 1.2% received IO+TT. In 1L, ipilimumab+nivolumab and dabrafenib+trametinib were the most common IO (50.9%) and TT (71.9%), respectively. The median duration of 1L was 8.0 months (9.7 months in IO and 6.7 months in TT). Among IO-treated patients, 28.5% had Eastern Cooperative Oncology Group (ECOG)≥1, 23.4% had elevated lactate dehydrogenase (LDH) levels, and 4.9% had 3+ metastases identified. Among TT-treated patients, 42.9% had ECOG≥1, 27.3% had elevated LDH, and 7.8% had 3+ metastases identified. Approximately one-third of the patients (n = 204) received their 1L treatment prior to being tested for BRAF mutation; the majority of whom (90.2%) received IO. 273 patients (40.7%) advanced to a second line (2L). In 2L, 14.3% of patients received the same class of therapy as in 1L, 44.7% switched from 1L IO to 2L TT, and 35.2% switched from 1L TT to 2L IO. In 2L, ipilimumab+nivolumab (50.0%) in IO and dabrafenib+trametinib (60.7%) in TT were the most common combinations. The median duration of 2L was 5.0 months (3.7 months in IO and 6.5 months in TT). Conclusions: Despite the recent availability of TT combinations for BRAFm unresectable/m-melanoma, IO is about twice as frequently prescribed than TT in 1L. One-third of the patients received treatment before BRAFm testing results were available and most of them were prescribed IO. These findings along with elevated ECOG scores, the proportion of 3+ metastases, and elevated LDH levels seen in TT patients, suggest TT is often offered to patients with a high disease burden in the current practice settings.
Low dose anti-PD(L)-1: A potentially effective alternative for greater accessibility in solid malignancies.
Authors: Souza Iza Andrade de A. , Netto João Pedro Homse , São José Barbara Garcia , Abdalla Kathia , Topanotti Marina , Fernandez Fabio Leite Couto , Guedes João Daniel Cardoso , Fares Aline Fusco , Araujo Daniel Vilarim
Published: June 2023

e21523

Background: Anti-PD(L)1 agents changed the treatment landscape of multiple tumor types yielding long-term responses in a significant proportion of patients. However, these drugs are costly and not accessible to patients from most countries. Mounting data suggest that lower doses of anti-PD(L)1 can be as efficacious as label-approved doses at lower costs. Herein we compare the outcomes of patients treated with low-dose anti-PD(L)1 agents (LD) and patients treated with conventional doses (CD) at a single tertiary hospital. Methods: This is an observational historical cohort study evaluating the outcomes of patients treated with anti-PD(L)-1 agents (either at LD or CD) at Hospital de Base, São José do Rio Preto - Brazil. We included patients older than 18yo, with solid malignancies and treated with any anti-PD(L)1 agent. Patients were classified as having received LD if the dose administered at the first cycle was below the label dose. Data were abstracted from electronic medical records. Efficacy outcomes, including overall survival (OS), progression-free survival (PFS), and overall response rate (ORR), were evaluated. Log-rank test and Chi-square or Fisher's exact test were used as appropriate. A p-value of 0.05 was considered statistically significant. Results: From January 2020 to October 2022, a total of 43 patients were included: 26 (60.4%) received LD and 17 (39.6%) received CD. The mean age of LD and CD was 66.9 (SD 14.5) and 64.8 (SD 9.7), respectively. Most patients presented with ECOG 0 or 1 (64% LD and 66% CD), had metastatic disease at treatment onset (92% LD and 94.1% CD), and were treated in the first line (50% LD and 64% CD). Most frequent tumor sites were melanoma (38.5% LD, 56.3% CD) and lung (29.9% LD, 18.8% CD). Only 23.1% and 17.6% of tumours in LD and CD were tested for PD-L1 expression, of which 83% and 33% had PD-L1 > 1. Most patients from both groups were treated with pembrolizumab (92.3% LD and 82.4% CD). The mean dose of pembrolizumab was 89.6 mg (1.5 mg/kg) for LD and 171 mg (2.1 mg/kg) for CD. After a median follow-up of 23 months, there was no significant difference in median OS (mOS), mPFS, and ORR between LD and CD (Table). A sensitivity analysis with patients receiving pembrolizumab was performed and had similar results (Table). Conclusions: Our study suggests there is no difference between patients treated with LD and CD anti-PD(L)1 in terms of OS, PFS, and ORR. The numerically shorter OS and PFS in the CD group may be due to selection bias and should be interpreted cautiously. LD anti-PD(L)1 could be an alternative to expand access in places where CD is not affordable. [Table: see text]
Efficacy and safety of BRAF/MEK inhibitor rechallenge in patients with advanced melanoma: Systematic review and meta-analysis.
Authors: Priantti Jonathan N. , Vilbert Maysa , Madeira Thiago , Moraes Francisco Cezar A , Koch Hein Erica C. , Cavalcante Ludimila
Published: June 2023

e21535

Background: Approximately 50% of patients with melanoma harbor a BRAF mutation and are eligible for targeted therapy (TT) with BRAFi/MEKi. In spite of a response rate of nearly 70%, roughly half of patients will progress within a year due to development of resistance. Rechallenging patients with BRAFi/MEKi may be an alternative to overcome resistance and improve outcomes. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of BRAFi/MEKi rechallenge in patients with advanced melanoma. Methods: PubMed, Scopus, the Cochrane Library, ASCO publications, ESMO, and AACR databases were searched for relevant studies. Rechallenge was defined as patients treated with BRAFi/MEKi that developed disease progression or had significant adverse effects and went on an interval treatment or drug holiday, before being reintroduced to BRAFi/MEKi. Efficacy was assessed by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Heterogeneity was examined with the I(2) statistics and random-effect model was used to pool studies. Results: Seven studies met inclusion criteria, with a total of 400 patients. The medium follow-up ranged from 6.8 to 15.7 months. Elevated LDH was seen in 48.5% (194/400) of patients, and 53% (164/310) had brain metastases (BM). Prior to rechallenge, 83% (333/400) of patients received immunotherapy as interval treatment, mainly anti-PD-1 and/or anti-CTLA-4, and 10% (40/400) were on a drug holiday. During the rechallenge, 79% (317/400) of patients were treated with the combination of BRAFi/MEKi, whereas 21% (83/400) were treated with BRAFi alone. In a pooled analysis, the median PFS was 5 months (95% CI 4.0 – 5.9), and median OS was 9.8 months (95% CI 9.3 – 20.4). The 1-year OS rate was 42.63% (95% CI 30.25 - 55.02). ORR was 34.25% (95% CI 28.50 - 40), and DCR was 65.01% (95% CI 57.31 - 72.72). Prognostic markers such as BM and elevated LDH were not statistically significant. Treatment was well tolerated without unexpected adverse events. Conclusions: This meta-analysis indicates that advanced melanoma patients with refractory disease benefit from rechallenge with BRAFi/MEKi, particularly from high DCR, with a promising effect on 1-year OS rate. Further randomized controlled trials are warranted to investigate these findings. [Table: see text]
Prognostic significance of pseudoprogression defined with lowered threshold iRECIST criteria in advanced melanoma treated with immune checkpoint inhibitor therapy.
Authors: Park Joseph S. , Janicek Milos Josef , Lerner Adam
Published: June 2023

e21536

Background: The advent of immune checkpoint inhibitor (ICI) therapy has dramatically improved survival in advanced melanoma. Unique to ICI therapy, pseudoprogression (PP) is characterized by an initial radiographic increase in tumor size followed by shrinkage. Modifications to RECIST have been proposed in order to better distinguish this phenomenon from progressive disease (PD). In iRECIST, a > 20% initial increase in target lesions is required to define PD or PP. Here, we assessed whether lowering this threshold would enhance identification and prognostication of pseudoprogression. Methods: In this single-center retrospective cohort study, we analyzed 37 patients with stage IV melanoma treated with PD-1 or CTLA inhibitors. The outcome was overall survival. Imaging from the staging, 1st and 2nd restaging scans were blindly assessed by a radiologist and assigned summed scores of primary tumor and up to 5 metastases. In lowered threshold iRECIST (LT-iRECIST), PP was defined as score increase > 5% on 1st restaging followed by decrease < -5% on 2nd restaging. PD was defined as score increase > 5% on both 1st and 2nd restaging. Regression was defined as score decrease < -5% on both 1st and 2nd restaging. Survival odds and hazard ratios were calculated with univariate Cox regression. The analysis was repeated with the threshold set to ±20% (traditional iRECIST). Results: In the overall cohort, median survival was 861 days. Median time to 1st and 2nd restaging scans was 112 days and 214 days respectively. 5 patients (13.5%) met criteria for PP with traditional iRECIST compared to 9 (24.3%) with LT-iRECIST. Two-year survival odds for PD, PP and regression were 20%, 80% and 66.7% respectively with traditional iRECIST, and 12.5%, 88.9% and 58.3% with LT-iRECIST. Hazard ratios for PP and regression were 0.329 (p > 0.1) and 0.296 (p > 0.1) respectively with traditional iRECIST, and 0.111 (p < 0.01) and 0.269 (p < 0.05) with LT-iRECIST. Conclusions: Harnessing the first two restaging scans and lowering the threshold from 20% to 5% in iRECIST led to identification of a group of patients in whom pseudoprogression is associated with a significant survival benefit. In advanced melanoma treated with ICI, adopting this iRECIST modification may allow early discrimination of pseudoprogression and its associated favorable outcome. [Table: see text]
Multi-omics analysis of atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma.
Authors: Dai Jie , Mao Lili , Xu Tianxiao , Li Lifeng , Lin Jing , Zhang Guoliang , Chen Yu , Bai Xue , Li Caili , Si Lu , Guo Jun
Published: June 2023

e21539

Background: A multicenter, open-label, single-arm phase II study has demonstrated that atezolizumab plus bevacizumab showed promising efficacy and manageable safety in patients with advanced mucosal melanoma, with an ORR of 45.0%. Here, we report the multi-omics analysis results with the aim of identifying potential biomarkers of response to this combination therapy. Methods: Patients with available samples were included in this study. The FFPE tissue was performed for DNA and RNA co-extraction and underwent whole exome sequencing (WES) and transcriptome sequencing. The responses were classified as complete response (CR) and partial response (PR) for responders and stable disease (SD) and progressive disease (PD) for non-responders per RECIST v1.1. Mutational signature, SNVs clonality, copy-number variations, differential expression genes, GSEA, and the immune microenvironment analysis were performed and analyzed for correlation with clinical benefits. Results: A total of 29 patients with FFPE samples underwent WES and/or transcriptome sequencing, including 1 CR, 15 PR, 9 SD, and 4 PD. As of January 11, 2023, the median follow-up time was 31 months (range, 5.0 to 37.0 months). Compared with non-reponders, responders had a significantly longer PFS (median 14.0, 95% CI 9.1 to 16.9 months vs 2.0, 95% CI 1.5 to 2.5 months, P< 0.001) and OS (median 35.0, 95% CI 20.4 to 49.6 months vs 14.0, 95% CI 5.5 to 22.5 months, P =0.005). Of the patients who underwent WES analysis, TMB and TNB were not associated with response, PFS or OS; but 53.3% (8/15) of responders harbored NRAS/PKHDL1 mutation, whereas only 16.7% (2/12) of non-reponders harbored NRAS/PKHDL1 mutation ( P= 0.112). Transcriptome analysis revealed that compared with non-reponders, responders displayed more significant angiogenesis, T cell cytotoxicity and interferon gamma response gene expression signatures. CIBERSORT analysis showed that responsders had higher proportions of cytotoxic immune cells, and non-responders had higher a higher proportion of B cells. The expression of CD274 was not associated with the response, and the expression of CD276 was significantly higher in responders than that in non-responders ( P =0.014). Weighted gene co-expression network analysis showed that the high expression of genes associated with the p38 MAPK pathway presented in cold tumor environments ( P =0.052) and was negatively correlated to the PFS ( P< 0.001) and OS ( P< 0.001). Conclusions: These molecular profiles indicated that the inflammatory cell infiltration and tumor angiogenic status was associated with response to anti-PD-L1 and anti-VEGF combination treatments, and targeting p38 MAPK pathway may further improve the survival of patients with mucosal melanoma.
Survival outcomes of metastasectomy and primary site resection in melanoma patients with isolated brain metastasis: A SEER analysis.
Authors: Fahmawi Suhib , Al-Ani Abdallah , Asfour Issa , Manthri Sukesh
Published: June 2023

e21541

Background: Approximately 40–50% of Stage IV melanoma patients eventually develop brain metastases which is associated with poor prognosis. Breakthroughs in targeted and immunotherapies have improved long-term survival in advanced melanoma patients. In this new era, there is a paucity of evidence for the role of metastatectomy for melanoma patients with brain metastasis. Here, we investigate the survival benefit of metastasectomy and primary site resection in melanoma patients with isolated brain metastasis. Methods: A total of 636 patients with melanoma with isolated brain metastasis at diagnosis were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2019. Patients younger than 18 years, cases with missing information including age, gender, race, unknown stage, unknown primary site resection status, unknown metastasis site, or known metastasis to the lung, liver, or bones were excluded. Cox regression analysis estimated the prognostic value of metastasectomy and primary site resection, presented by hazard ratios (HR), among melanoma patients. Survival ratios were controlled for age, race, gender, and type of melanoma. All analyses were performed on STATA v17. Results: About 49.37% of melanoma patients with isolated brain metastasis underwent metastasectomy. Of the included sample, 25% (n = 159) underwent primary site resection. Cox regression demonstrated that metastasectomy was associated with improved survival outcomes in melanoma patients with isolated brain metastasis (HR 0.51, CI 0.42 – 0.63, p < 0.001). Pooled primary site resection procedures were associated with improved survival (HR 0.64, CI 0.49 – 0.83, p = 0.001) compared to not having a primary site resection. When stratified per procedure type, “wide excision or re-excision of lesions with margins > 1 cm and microscopically negative margins” was associated with improved survival (HR 0.27, CI 0.133 – 0.56, p < 0.001) compared to not having surgical resection, all other primary site resection procedures had no significant improvement in survival with p > 0.05. Conclusions: Metastasectomy and primary site resection significantly improved survival in melanoma patients with isolated brain metastasis. Wide excision with > 1cm negative margins presents itself as the most effective surgical treatment modality in terms of improving survival for these patients. Thus, it should be attempted whenever feasible.
A cilia-related marker predicting suitability for immunotherapy in melanoma.
Authors: Zhu Changbin , Chen Yanhua , Yu Rongshan , Xiao Xu , Kong Yan
Published: June 2023

e21560

Background: Cilia exert tumor suppressor effects in several tumor types including melanoma, and scientists found that blocking cilia growth in drug-resistant cancer cell lines may restore cancer cells' sensitivity to immunotherapy. Therefore, we hypothesized that cilia might be used as a predictive biomarker for melanoma immunotherapy. Methods: Through literature search, a total of six sets of RNA-seq and WES data of melanoma samples receiving PD-1/CTLA-4 immunotherapy were collected. GSVA was used to obtain an enrichment score between the samples and a set of 112 ciliary genes, based on which ciliary signatures were screened for prognosis. The ciliary characteristic gene set was further optimized by LASSO regression, then a risk model was constructed by combing stepwise regression and COX regression. Log-rank test was used to verify survival differences between high and low risk groups in other independent data sets, and Wilcox test was used to explore differences in other clinical characteristics between high and low risk groups. Imaging mass spectrometry (IMC) and spatial position imaging (SPI) data were used to analyze cell states in tumor tissues. All analyses were performed by R 4.0.3. Results: A total of 10 cilia pathways related to prognosis were screened out in the training set, and 13 genes were picked out from these 10 pathways as selected features. Combining LASSO and COX regression, a risk model consisting of 5 genes were finally obtained. Patients in the high-risk (HR)group classified by this model had a significantly worse prognosis than the low-risk (LR) group in both the training and test sets (p < 0.05, respectively). In addition, by analyzing immune infiltration and pathway enrichment, it was found that LR group was in the state of immune activation, and its immune score was significantly higher than that of HR group. Further analysis showed the model had no significant correlation with other clinical features, such as pathological stage, tumor mutation burden and NF1/KRAS/BRAF gene mutations, indicating that the model was relatively independent. By IMC data analysis, it was found that the number of tumor cells in LR and HR groups were similar (107082 vs 11928), but the number of lymphocytes in LR group was significantly higher than that in HR group (71578 vs 5313). Moreover, among the 35 protein markers related to immunotherapy, 16 (45.7%) proteins were up-regulated and 0 protein was down-regulated in LR group. By analyzing SPI of multiple regions of these samples, it was also observed that tumor tissues in LR group were mostly in a state of lymphocyte infiltration, while these in HR group were in a state of immune rejection or immune desert. Conclusions: The model constructed based on cilia-related features in this study can independently identify melanomas with high risk of recurrence or progression, and provide a theoretical basis for exploring whether targeted cilia structure therapy can be used as a treatment for melanoma.
Utility of circulating tumor DNA as a tool to detect minimal residual disease in patients with metastatic cancer and durable response following treatment with immune checkpoint inhibitors.
Authors: Afzal Muhammad Zubair , Corea-Dilbert Flanklin E. , Wankel Bret , Palmer John P. , Pirruccello Jonathan P. , Kale Soham , Sharma Aditya , Lu Ziyao , Ibrahim Samer , Cao Yuanzhen , Sarwar Tayyaba , Shirai Keisuke
Published: June 2023

e21563

Background: Circulating tumor DNA (ctDNA) is tumor-derived fragment of DNA circulating in plasma. ctDNA has been used to detect minimal residual disease (MRD) in early-stage cancers after curative intent therapy. However, ctDNA based MRD concept is not investigated in metastatic disease. There is a lack of clarity around optimal timing to stop immune checkpoint inhibitors (ICI) in melanoma and lung cancer patients who have achieved durable response (DR) and MRD may have a role here to select right patients to stop therapy at an optimal time. Methods: This is prospective study on metastatic lung cancer and melanoma patients with DR treated with ICI. DR is identified as objective response (CR/PR) by modified WHO criteria lasting ≥6 months continuously. We utilized Signatera assay by Natera. Signatera uses tissue from original biopsy of the patients and develop multiplex PCR based personalized assay to detect MRD. The level of ctDNA is reported in mean tumor molecules per mL. We obtained ctDNA assay at baseline, month 3 and month 6 at their routine follow up visits. If applicable, ctDNA assay was done at the time of progression, and 3 months after resuming treatment. Results: We identified 29 melanoma and 17 Lung cancer (both small cell and non-small cell) patients with metastases and DR. Median age was 69 years in both cohorts. Median duration of ICI was 14 months in melanoma and 24 months in lung cancer cohort. ctDNA assay was obtained in 26 melanoma and 13 lung cancer patients. One small cell lung cancer patient had detectable ctDNA at baseline, although radiographically, the patient had DR. The rest of the patients in both cohorts had undetectable ctDNA. 2 melanoma patients developed detectable ctDNA on subsequent assays and their therapies were changed. One small cell lung cancer patient has persistently detectable ctDNA on subsequent assays but remained in DR. A total of 10 patients in both cohorts decided to stop their therapy following several -ve ctDNA assay. Conclusions: The role of ctDNA needs to be investigated in advanced/metastatic settings as MRD may have a role to identify patients who may benefit from treatment break. MRD surveillance may also support radiographic assessment. [Table: see text]