DNA Damage Response and Repair Pathway Alteration and Its Association With Tumor Mutation Burden and Platinum-Based Chemotherapy in SCLC

IntroductionImpairment in DNA damage response and repair (DDR) pathway is known as a predictive biomarker of platinum sensitivity. Recently, DDR alteration is re-emphasized as a predictive biomarker of immune checkpoint inhibitor due to its positive correlation to tumor mutation burden (TMB).MethodsTarget gene sequencing (381 genes) was conducted from 100 extensive disease (ED) and 66 limited disease (LD) patients with SCLC. Detected mutations were classified as double-strand breaks (DSB) (n = 82): homologous recombination (n = 54), non-homologous end joining (n = 19), and Fanconi anemia (n = 32); or single-strand breaks (SSB) (n = 31): mismatch repair (n = 19), base excision repair (n = 7), and nucleotide excision repair (n = 6).ResultsCompared to patients with an intact DDR pathway (n = 70), a higher TMB was observed in patients with homologous recombination (p < 0.001), non-homologous end joining (p = 0.002), mismatch repair (p < 0.001), DSB (p < 0.001), and SSB (p < 0.001). Survival analyses based on TMB level showed no predictive or prognostic values in ED patients. In LD patients, prolonged progression-free survival (hazard ratio [HR] = 0.497, p = 0.015), and overall survival (HR = 0.383, p = 0.010) to concurrent chemoradiotherapy were observed in those with TMB above median. Individual DDR pathway alteration showed no survival benefit in ED patients receiving platinum-based chemotherapy. In LD patients, those with mutations in the Fanconi anemia gene set had shorter progression-free survival (HR = 2.048, p = 0.036) to initial treatment.ConclusionsDDR pathway alterations, both DSB and SSB, in SCLC have a positive correlation with high TMB. However, it has shown limited value in prediction of platinum efficacy.     

dNLR-Based Score Predicting Overall Survival Benefit for The Addition of Platinum-Based Chemotherapy to Pembrolizumab in Advanced NSCLC With PD-L1 Tumor Proportion Score ≥50%

Introduction: Both pembrolizumab (P) as a monotherapy or in combination with platinum-based chemotherapy (PCT) represent standard first-line treatment options for advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score (TPS)≥50%. No predictive biomarkers exist to guide treatment decisions.Methods: 423 consecutive patients with EGFR/ALK/ROS1-wild-type PD-L1 TPS≥50% aNSCLC receiving P (n = 302) or PCT (n = 121) as a first-line treatment were identified in the electronic databases of 5 Israeli cancer centers. Overall survival (OS, months [mo]) was assessed in correlation with blood biomarkers (BB: NLR, dNLR, PLR, SII, LIPI, ALI); a predictive score was developed.Results: In the propensity score matching analysis (n = 236; 118 patients in each group matched for age, sex and ECOG PS), mOS was 17.2mo (95% CI, 13.2-36.5) and 21.3mo (95% CI, 14.8-NR) in groups P and PCT, respectively (P = .44). In group P, NLR, dNLR, PLR, LIPI, and ALI significantly correlated with OS in uni- and multivariate COX regression analyses (P < .05), whereas in group PCT, none of the BB demonstrated a significant correlation. A predictive score was developed (each parameter receiving one point): age≥65, female sex, never-smoking status, adenocarcinoma histology, dNLR≥3. In patients with predictive score 3-5, OS was significantly longer with PCT as compared to P: mOS NR (95% CI, 15.3-NR) and 8.7mo (95% CI, 5.8-13.7) (P = .0005), while OS didn't differ significantly in patients with predictive score 0-2 (P = .61).Conclusion: With the limitations of the retrospective analysis, the proposed dNLR-based score appears to predict OS with P and PCT.     

Patient-reported outcomes as a prognostic marker of survival in patients with advanced nonsmall cell lung cancer treated with immunotherapy

There has been minimal research on the prognostic value of patient-reported outcomes (PROs) for immune checkpoint inhibitors (ICIs). The relative performance of PROs compared to established markers such as Eastern Cooperative Oncology Group Performance Status (ECOG-PS) and the Lung Immune Prognostic Index (LIPI) is unknown. In our study, data from the advanced nonsmall cell lung cancer (NSCLC) single-arm atezolizumab trials BIRCH, FIR and randomised-trials OAK, POPLAR (atezolizumab vs docetaxel) were pooled. The study included 1548 participants who initiated atezolizumab. The associations between pretreatment PROs and overall survival (OS) and progression-free survival (PFS) were modelled using Cox proportional hazards regression. Prediction performance was assessed using the C-statistic (c). PROs were recorded via the EORTC QLQ-C30 and QLQ-LC13. Patient-reported physical function, fatigue, global health, appetite, role function, pain, dyspnoea, social function, constipation, nausea-vomiting, emotional function and coughing were significantly associated with OS and PFS on univariable and adjusted analysis (P < .05). Physical function (c = 0.654), fatigue (c = 0.653) and global health (c = 0.650) were the most predictive variables for OS. Comparatively, the OS prediction performance of physical function (c = 0.65) was superior to ECOG-PS (c = .59) and LIPI (c = 0.63). On multivariable analysis physical function, ECOG-PS and LIPI were all significant (P < .001). In conclusion, PROs were identified as independent prognostic factors for OS and PFS in advanced NSCLC patients receiving ICI therapy. Further, patient-reported physical function was more predictive of OS than ECOG-PS and LIPI and contained independent information. This highlights the value of PROs as prognostic and stratification factors for clinical use and research trials of ICIs.     

BAP1 Loss by Immunohistochemistry Predicts Improved Survival to First-Line Platinum and Pemetrexed Chemotherapy for Patients With Pleural Mesothelioma: A Validation Study

IntroductionPleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumor BAP1 status is a predictive biomarker for survival in patients receiving first-line combination platinum and pemetrexed therapy.MethodsPM cases (n = 114) from Aalborg, Denmark, were stained for BAP1 on tissue microarrays. Demographic, clinical, and survival data were extracted from registries and medical records. Surgical cases were excluded. BAP1 status was associated with overall survival (OS) by Cox regression and Kaplan-Meier methods. Results were validated in an independent cohort from Perth, Australia (n = 234).ResultsBAP1 loss was found in 62% and 60.3% of all Danish and Australian samples, respectively. BAP1 loss was an independent predictor of OS in multivariate analyses corrected for histological subtype, performance status, age, sex, and treatment (hazard ratio = 2.49, p < 0.001, and 1.48, p = 0.01, respectively). First-line platinum and pemetrexed-treated patients with BAP1 loss had significantly longer median survival than those with retained BAP1 in both the Danish (20.1 versus 7.3 mo, p < 0.001) and Australian cohorts (19.6 versus 11.1 mo, p < 0.01). Survival in patients with BAP1 retained and treated with platinum and pemetrexed was similar as in those with best supportive care. There was a higher OS in patients with best supportive care with BAP1 loss, but it was significant only in the Australian cohort (16.8 versus 8.3 mo, p < 0.01).ConclusionsBAP1 is a predictive biomarker for survival after first-line combination platinum and pemetrexed chemotherapy and a potential prognostic marker in PM. BAP1 in tumor is a promising clinical tool for treatment stratification.     

Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial

IntroductionWe report the final results of the phase 3 IMpower132 study evaluating atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) in patients with nonsquamous NSCLC.MethodsChemotherapy-naive patients with stage IV nonsquamous NSCLC without sensitizing EGFR or ALK genetic alterations were randomized in a one-to-one ratio to receive four or six cycles of carboplatin or cisplatin plus pemetrexed (PP) or APP every 3 weeks, followed by maintenance therapy with atezolizumab plus pemetrexed or pemetrexed alone. Co-primary end points were overall survival (OS) and investigator-assessed progression-free survival (PFS).ResultsThe intention-to-treat population included 578 patients (APP, n = 292; PP, n = 286). At the primary PFS analysis (May 22, 2018; median follow-up, 14.8 mo), APP exhibited significant PFS improvement versus PP (median = 7.6 versus 5.2 mo, stratified hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.49–0.72, p < 0.0001). OS for the APP group was numerically better but not statistically significant at the interim (May 22, 2018; median = 18.1 versus 13.6 mo, stratified HR = 0.81, 95% CI: 0.64–1.03, p = 0.0797) and final analyses (July 18, 2019; median = 17.5 versus 13.6 mo; stratified HR = 0.86, 95% CI: 0.71–1.06, p = 0.1546). The OS and PFS results favored APP versus PP across subgroups. Grade 3 or 4 treatment-related adverse events occurred in 54.6% (APP) and 40.1% (PP) of patients; grade 5 treatment-related events occurred in 3.8% and 2.9%, respectively.ConclusionsIMpower132 met its co-primary PFS end point but not its co-primary OS end point, with numerical improvement for OS in the APP arm. APP had a manageable safety profile, with no new or unexpected safety signals identified.     

Checkpoint Inhibitors in Metastatic EGFR-Mutated Non–Small Cell Lung Cancer—A Meta-Analysis

IntroductionWe performed a meta-analysis to assess the role of immune checkpoint inhibitors as second-line therapy in EGFR-mutant advanced NSCLC.MethodsRandomized trials comparing immune checkpoint inhibitors against chemotherapy were identified. We retrieved the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) of the intention-to-treat population and EGFR mutation–defined subgroups. We used the fixed-effects inverse variance–weighted method to pool estimates of treatment efficacy. Statistical tests were two sided.ResultsIn the three included studies that compared immune checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68, 95% CI: 0.61–0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR = 0.66, 95% CI: 0.58–0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n = 186, HR = 1.05, 95% CI: 0.70–1.55, p < 0.81; treatment-mutation interaction p = 0.03).ConclusionIn EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do not improve OS over that with docetaxel. Mechanisms of acquired resistance to first-line tyrosine kinase inhibitor therapy should be elucidated to guide selection of second-line treatment for these patients.     

Atezolizumab in Combination With Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial

IntroductionCytotoxic agents have immunomodulatory effects, providing a rationale for combining atezolizumab (anti-programmed death-ligand 1 [anti–PD-L1]) with chemotherapy. The randomized phase III IMpower131 study (NCT02367794) evaluated atezolizumab with platinum-based chemotherapy in stage IV squamous NSCLC.MethodsA total of 1021 patients were randomized 1:1:1 to receive atezolizumab+carboplatin+paclitaxel (A+CP) (n = 338), atezolizumab+carboplatin+nab-paclitaxel (A+CnP) (n = 343), or carboplatin+nab-paclitaxel (CnP) (n = 340) for four or six 21-day cycles; patients randomized to the A+CP or A+CnP arms received atezolizumab maintenance therapy until progressive disease or loss of clinical benefit. The coprimary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS) in the intention-to-treat (ITT) population. The secondary end points included PFS and OS in PD-L1 subgroups and safety. The primary PFS (January 22, 2018) and final OS (October 3, 2018) for A+CnP versus CnP are reported.ResultsPFS improvement with A+CnP versus CnP was seen in the ITT population (median, 6.3 versus 5.6 mo; hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.60–0.85; p = 0.0001). Median OS in the ITT population was 14.2 and 13.5 months in the A+CnP and CnP arms (HR = 0.88, 95% CI: 0.73–1.05; p = 0.16), not reaching statistical significance. OS improvement with A+CnP versus CnP was observed in the PD-L1–high subgroup (HR = 0.48, 95% CI: 0.29–0.81), despite not being formally tested. Treatment-related grade 3 and 4 adverse events and serious adverse events occurred in 68.0% and 47.9% (A+CnP) and 57.5% and 28.7% (CnP) of patients, respectively.ConclusionsAdding atezolizumab to platinum-based chemotherapy significantly improved PFS in patients with first-line squamous NSCLC; OS was similar between the arms.     

Programmed Death-Ligand 1 Heterogeneity and Its Impact on Benefit From Immune Checkpoint Inhibitors in NSCLC

IntroductionProgrammed death-ligand 1 (PD-L1) expression may vary in different disease sites and at different time points of the disease course. We aimed to investigate PD-L1 heterogeneity and its usefulness as a predictive value for immune checkpoint inhibitor (ICI) therapy in patients with NSCLC.MethodsPD-L1 expression was analyzed in 1398 patients with NSCLC. The predictive value of PD-L1 for ICIs in 398 patients with metastatic NSCLC was assessed.ResultsPD-L1 was significantly associated with biopsy sites (p = 0.004). Adrenal, liver, and lymph node (LN) metastases had the highest PD-L1 expression as a continuous variable and at 1% or 50% cutoff. PD-L1 expression was lower in bone and brain metastases. Among 112 patients with two specimens tested, 55 (49%) had major changes in PD-L1 falling into different clinically relevant categories (<1%, 1%–49%, ≥50%) at different time points. Previous ICI therapy was associated with significant decrease in PD-L1 compared with treatment-naive counterparts (p = 0.015). Patients with metastatic NSCLC treated with ICI (n = 398) were divided into three cohorts on the basis of biopsy sites: lung (n = 252), LN (n = 85), and distant metastasis (n = 61). Higher PD-L1 in lung or distant metastasis specimens was associated with higher response rate, longer progression-free survival, and overall survival. However, PD-L1 in LN biopsies was not associated with either response or survival.ConclusionsPD-L1 varies substantially across different anatomical sites and changes during the clinical course. PD-L1 from different biopsy sites may have different predictive values for benefit from ICIs in NSCLC.     

Systemic Inflammatory Markers of Survival in Epidermal Growth Factor–Mutated Non–Small-Cell Lung Cancer: Single-Institution Analysis,Systematic Review,and Meta-analysis

BackgroundSystemic inflammatory response (SIR) may influence prognosis in epidermal growth factor receptor (EGFR)-mutated (m) non–small-cell lung cancer (NSCLC). Pretreatment SIR markers (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio [LMR], lactate dehydrogenase [LDH], and lung immune prognostic index [LIPI]) were assessed as prognostic factors in NSCLC survival.Patients and MethodsRetrospective survival analysis (overall survival [OS] and progression-free survival [PFS]) of EGFR-mutated NSCLC patients at Princess Margaret Cancer Centre were performed separately for early (I-IIIa) and late (IIIb-IV) stage disease for individual SIR variables, dichotomized by optimal cutoff points by Kaplan-Meier survival analysis and multivariable Cox proportional hazard modeling. A systematic review and meta-analysis of known SIR studies in patients with late-stage EGFR-mutated were also performed.ResultsFrom 2012 to 2019, in 530 patients, significant adjusted hazard ratios (aHR) for OS comparing high versus low NLR were 2.12 for early stage and 1.79 for late stage disease. Additionally, late stage cohorts had significant associations, as follows: high versus low derived NLR, aHR = 1.53; LMR, aHR = 0.62; LDH, aHR = 2.04; and LIPI, aHR = 2.04. Similar patterns were found for PFS in early stage NLR (aHR = 1.96) and late stage NLR (aHR = 1.46), while for PFS, only late stage derived NLR (aHR = 1.34), LDH (aHR = 1.75), and LIPI (aHR = 1.66) were significant. A meta-analysis confirmed that NLR, LMR, LDH, and LIPI were all significantly associated with OS and PFS in the late stage.ConclusionThis primary study and meta-analysis demonstrated that LMR and LDH were significantly associated with late stage EGFR-mutated NSCLC outcomes, and the LIPI scoring system was prognostic. NLR remained an independent prognostic factor across all stages and could represent an early marker of immuno-oncology interactions.     

Transarterial chemoembolization plus immune checkpoint inhibitor as postoperative adjuvant therapy for hepatocellular carcinoma with portal vein tumor thrombus: A multicenter cohort study

PurposeThis study aimed to assess the efficacy and safety of postoperative adjuvant transarterial chemoembolization (PA-TACE) plus immune checkpoint inhibitor (ICI) for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT).Patients and methodsThis study was conducted on three centers from June 2018 to December 2020. Patients were divided into the PA-TACE (n = 48) and PA-TACE plus ICI groups (n = 42). The recurrence-free survival (RFS) and overall survival (OS) curves were depicted by Kaplan-Meier method, and the differences between the two groups were compared using log-rank test. Univariate and multivariate Cox analyses were performed to identify independent risk factors for RFS and OS. Adverse events (AEs) were assessed according to the Common Terminology Criteria for AEs (CTCAE) version 5.0.ResultsThe median RFS of the PA-TACE plus ICI group was significantly longer than the PA-TACE group (12.76 months vs. 8.11 months; P = 0.038). The median OS of the PA-TACE plus ICI group was also significanfly better than the PA-TACE group (24.5 months vs. 19.1 months; P = 0.032). PA-TACE plus ICI treatment was an independent prognostic factor for RFS (HR: 0.54, 95% CI: 0.32–0.9, P = 0.019) and OS (HR: 0.47, 95% CI: 0.26–0.86, P = 0.014). Only one patient experienced grade ≥3 immune-related AEs in the PA-TACE plus ICI group.ConclusionsPA-TACE plus ICI treatment had better efficacy in preventing recurrence and prolonging survival than PA-TACE alone for HCC patients with PVTT after R0 resection. This novel treatment modality may be an appropriate option for HCC with PVTT.     

Enhanced Bellmunt Risk Score for Survival Prediction in Urothelial Carcinoma Treated With Immunotherapy

IntroductionThe discrimination performance of Bellmunt risk score for immune checkpoint inhibitor (ICI) therapy is largely unknown. This study aimed to validate and enhance discrimination of the Bellmunt score in patients with urothelial carcinoma treated with ICIs.Patients and MethodsCox proportional hazard analysis were used to validate overall survival (OS) discrimination performance of the Bellmunt score in patients with urothelial carcinoma treated with atezolizumab in IMvigor210. The c-statistic (c) was used to evaluate the ability of C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), PD-L1 gene expression level on immune cells (PD-L1 ICs), albumin, time from prior chemotherapy, and tumor site count to enhance the Bellmunt score. External validation of an enhanced Bellmunt score utilized the independent atezolizumab arm of IMvigor211.ResultsIn IMvigor210, Bellmunt score displayed moderate OS discrimination (c = 0.66). Addition of CRP (one point for CRP>30 mg/L) to the Bellmunt score resulted in greatest improvement in performance (c = 0.70), followed by NLR (c = 0.69). On external validation, CRP-Bellmunt score had superior performance (OS c = 0.67, PFS c = 0.60) than original Bellmunt score (OS c = 0.64, PFS c = 0.59) with 30% of patients reclassified into a higher risk group. Patients with CRP-Bellmunt score of 0, 1, 2, or 3-plus had 1-year OS probabilities of 63%, 44%, 21%, and 15%, respectively.ConclusionCRP inclusion within the Bellmunt score enhanced the ability to discriminate high risk patients misclassified using the original model. We propose that the CRP-Bellmunt score may enable improved patient stratification in ICI clinical trials and provide more accurate prognostic information for patients with urothelial carcinoma initiating ICIs.     

Benefit Versus Risk Assessment of Melflufen and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Analyses From Longer Follow-up of the OCEAN and HORIZON Studies

IntroductionMelphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS) but directionally different overall survival (OS) favoring pomalidomide (hazard ratio [HR], 1.10) in OCEAN.MethodsThese analyses further investigated prognostic subgroups impacting survival in updated data from the randomized, phase 3 OCEAN study (NCT03151811; date: February 3, 2022) and the phase 2 HORIZON study (NCT02963493; date: February 2, 2022).ResultsIn OCEAN, subgroups prognostic for OS were age (P = .011; <65 years favored pomalidomide) and no previous autologous stem cell transplant (ASCT) or progression >36 months after ASCT (P = .001; favored melflufen). Overall, 245 of 495 (49%) patients randomized had received a previous ASCT, of which 202 (82%) had progressed within 36 months following their ASCT. When excluding patients who had progressed <36 months post-ASCT (melflufen group, n = 145; pomalidomide group, n = 148), median OS was 23.6 months with melflufen and 19.8 months with pomalidomide (HR, 0.83 [95% CI, 0.62-1.12]; P = .22). Among patients with triple-class refractory disease in HORIZON, patients who had progressed <36 months post-ASCT (n = 58) had a lower response rate and shorter duration of response and PFS than the remaining patients (n = 52). Safety was consistent with previous reports.ConclusionThese analyses demonstrate a consistent benefit for melflufen and dexamethasone in patients with relapsed/refractory multiple myeloma who have not received an ASCT or progressed >36 months after receiving an ASCT (ClinicalTrials.gov identifier: NCT03151811).     

Extracapsular lymph node involvement is a robust survival predictor in esophageal cancer patients: A pooled analysis

BackgroundAlthough extracapsular lymph node involvement (EC-LNI) has been proposed to be incorporated into the staging system of esophageal cancer, the prognostic value of EC-LNI remains controversial with conflicting data available, especially in the era of neoadjuvant therapy.MethodsAn electronic literature search was undertaken using four public databases. Studies investigating the effects of EC-LNI on survival were included. In addition to analysis of the entire cohort, subset analyses were also performed to assess the impact of EC-LNI on patients receiving different treatment modalities.ResultsA total of 20 studies were included in this meta-analysis. Pooling 13 studies on overall survival (OS), we observed that presence of EC-LNI was associated with significantly worse OS (HR = 2.09, 95%CI: 1.63–2.68; p < 0.01). Nine studies describing disease-free survival (DFS) included, the pooled data revealed that presence of EC-LNI was associated with significantly worse DFS (HR = 1.89, 95%CI: 1.63–2.20; p < 0.001). Subset analyses of patients receiving neoadjuvant therapy demonstrated a survival disadvantage of EC-LNI on OS (HR = 1.928, 95%CI: 1.196–3.107; p = 0.007) and DFS (HR = 1.985, 95%CI: 1.585–2.487; p < 0.001). Similar result was also seen in patients receiving primary surgery (OS: HR = 2.219, 95%CI: 1.720–2.864; p < 0.001; DFS: HR = 1.659, 95%CI: 1.285–2.141; p < 0.001).ConclusionEC-LNI is a strong prognostic predictor of inferior survival in patients with esophageal cancer irrespective of treatment modality. The currently pooled evidence indicates that EC-LNI has great potential to be incorporated into the future staging system.     

Brief Report: Exploratory Analysis of Maintenance Therapy in Patients With Extensive-Stage SCLC Treated First Line With Atezolizumab Plus Carboplatin and Etoposide

IntroductionIn the phase 1/3 IMpower133 study, atezolizumab plus carboplatin and etoposide (CP/ET) followed by maintenance atezolizumab for first-line treatment of extensive-stage SCLC (ES-SCLC) led to improvement in both overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET followed by maintenance placebo. We explored the benefit of atezolizumab versus placebo in the subset of patients who reached the IMpower133 maintenance phase and the safety profile of maintenance therapy.MethodsPatients with untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo, followed by maintenance atezolizumab or placebo. The primary end points were OS and investigator-assessed PFS. A multivariate Cox model from the start of maintenance treatment was used to evaluate the treatment effect and account for lead-time bias; a generalized linear model was used to identify prognostic or predictive characteristics for reaching the maintenance phase.ResultsA similar proportion of patients in each arm received at least the first dose of maintenance therapy (atezolizumab: 77%, n = 154 of 201; placebo: 81%, n = 164 of 202) and were included in the maintenance analysis population. An Eastern Cooperative Oncology Group performance status of 0 and absence of liver metastases at baseline were identified as prognostic factors for reaching the maintenance phase. The positive treatment effect with atezolizumab remained after adjusting for baseline characteristics. Median OS and PFS from the start of maintenance therapy in the atezolizumab versus placebo arm were 12.5 versus 8.4 months (hazard ratio = 0.59, 95% confidence interval: 0.43–0.80) and 2.6 versus 1.8 months (hazard ratio = 0.63 [95% confidence interval: 0.49–0.80]), respectively. Treatment-related adverse events from the start of maintenance therapy occurred in 41% (n = 64 of 155) and 25% (n = 41 of 163) of safety-evaluable patients in the atezolizumab and placebo arms, respectively, and were grade 3 or 4 in 28% (n = 43 of 155) and 23% (n = 37 of 163) of the respective populations; no patient in the atezolizumab arm and one patient in the placebo arm had a grade 5 treatment-related adverse event.ConclusionsThese data in the context of other immunotherapy trials in ES-SCLC suggest that induction with atezolizumab plus CP/ET and maintenance treatment with atezolizumab are important components that contributed to the OS benefit observed in IMpower133. Safety results from randomization and from the start of maintenance therapy were similar between the treatment arms despite the continuation of atezolizumab in the maintenance phase.     

Updated Overall Survival Analysis From IMpower110: Atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1–Selected NSCLC

IntroductionIMpower110 previously revealed significant overall survival (OS) benefit with atezolizumab versus chemotherapy in patients with treatment-naive EGFR- and ALK-negative (wild type [WT]) metastatic NSCLC with high programmed death-ligand 1 (PD-L1) expression (≥50% on tumor cells [TCs] or ≥10% on tumor-infiltrating immune cells [ICs], per SP142 immunohistochemistry assay; p = 0.0106). We present primary OS analyses in lower PD-L1 expression groups and an updated, exploratory analysis in the high PD-L1 expression group.MethodsThis open-label, phase 3 trial randomized patients with PD-L1 expression on greater than or equal to 1% of TC or IC to receive atezolizumab or platinum-based chemotherapy. The primary end point was OS, hierarchically tested in PD-L1 expression WT subgroups: first the high PD-L1 expression subgroup, then the high-or-intermediate PD-L1 expression subgroup (≥5% on TC or IC), and then the any PD-L1 expression subgroup (≥1% on TC or IC).ResultsThe any PD-L1 expression WT population included 554 patients (excluded 18 EGFR- or ALK-positive patients). With 17 months’ additional follow-up, OS improvement in the atezolizumab versus chemotherapy arm was not statistically significant in high-or-intermediate PD-L1 expression WT patients (n = 328; hazard ratio = 0.87, 95% confidence interval: 0.66–1.14, p = 0.3091; median = 19.9 versus 16.1 mo), precluding formal OS testing in any PD-L1 expression WT patients. Exploratory analysis in high PD-L1 expression WT patients (n = 205) revealed maintained OS benefit in the atezolizumab arm (hazard ratio = 0.76, 95% confidence interval: 0.54–1.09; median = 20.2 versus 14.7 mo). Updated safety data continued to favor atezolizumab.ConclusionsStatistical significance for OS was not revealed in the high-or-intermediate expression WT group, and, as a result, OS in the any PD-L1 expression WT group was not formally tested. No new safety signals were found. This updated analysis of IMpower110 supports using atezolizumab in treatment-naive, metastatic WT NSCLC with high PD-L1 expression.     

Prognostic Impact of the Findings on Thin-Section Computed Tomography in Patients with Subcentimeter Non–Small Cell Lung Cancer

IntroductionSubcentimeter NSCLC is not always an early-stage disease despite its small tumor size. We investigated the prognostic impact of such cancers on the basis of the findings of thin-section computed tomography (CT).MethodsWe evaluated the clinicopathological features and prognosis of 328 surgically resected clinical-N0 NSCLCs 1.0 cm or less in size. Consolidation-to-tumor ratio (CTR) was evaluated for all, and tumors were classified into three groups, namely, pure ground glass opacity (GGO) (CTR = 0 [n = 139]), part solid (0 < CTR < 1.0 [n = 123]), and pure solid (CTR = 1.0 [n = 66]).ResultsPathological nodal involvement was observed in seven patients, with all cases found exclusively in pure solid subcentimeter NSCLC (10.9%). Furthermore, a multivariate analysis revealed that the presence of GGO was an independently significant clinical factor in overall survival (OS) and recurrence-free survival (RFS) (OS: p = 0.0340; RFS: p = 0.0018). Histological examination revealed that 134 of the 139 cases of pure GGO (97%), 99 of the 123 cases of part solid tumor (81%), and 16 of the 66 cases of pure solid tumor (25%) were lepidic predominant lung adenocarcinoma. Evaluation of the oncological outcomes on the basis of CTR revealed that 5-year OS and RFS rates were significantly better in patients with nonsolid tumors (OS and RFS = 100%) or part solid tumors (OS = 97.5% and RFS=94.9%), whereas the OS and RFS rates of patients with pure solid subcentimeter NSCLC were 87.6% and 79.3%, respectively (OS: p = 0.0015; RFS: p < 0.0001).ConclusionsThe findings of thin-section CT are extremely important when considering the prognosis of subcentimeter NSCLC. Radiologically determined solid subcentimeter NSCLCs should be treated as invasive tumors regardless of their small size.     

S100A2 is a predictive biomarker of adjuvant therapy benefit in pancreatic adenocarcinoma

BackgroundPrognosis of patients with pancreatic adenocarcinoma (PAC) remains poor. S100A2 has been recently suggested as a negative prognostic biomarker in PAC. We aimed to investigate its prognostic and/or predictive value in a large independent multicentric cohort of patients with resected PAC.MethodsSequential samples of 471 patients were retrospectively collected; 142 patients did not receive adjuvant treatment (30%) and 329 (70%) received an adjuvant treatment. We measured protein levels of S100A2 by semiquantitative immunohistochemistry with tissue microarrays and correlated with patients’ overall survival (OS) and disease-free survival (DFS).ResultsS100A2 protein status was obtained in 462 (98%) patients. Its expression was low, moderate or high in 59%, 12% and 2% of cases, respectively. It was not correlated with DFS or OS in the whole population, neither in the subgroup of patients who did not receive adjuvant treatment. However among patients who received an adjuvant therapy, moderate/high levels of S100A2 were significantly associated with longer OS and DFS in multivariate analysis (hazard ratios of 0.63, p = 0.022 and 0.67, p = 0.017, respectively), whereas low S100A2 was not. Interaction tests for adjuvant therapy were statistically significant both for the OS and the DFS (p = 0.001 and p = 0.023, respectively). On multivariate analysis, S100A2 retained independent predictive values (OS: p < 0.001, DFS: p = 0.003) with a significant benefit of adjuvant therapy for those patients with moderate/high S100A2.ConclusionsS100A2 expression predicts longer DFS and OS in patients treated with adjuvant therapy and should be evaluated as a predictive biomarker.     

Predictive Value of Combining Biomarkers for Clinical Outcomes in Advanced Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors

IntroductionA high tumor mutational burden (TMB) (≥10 mut/Mb) has been associated with improved clinical benefit in non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI) and is a tumor agnostic indication for pembrolizumab across tumor types. We explored whether combining TMB with programmed cell death ligand 1 (PD-L1) and pretreatment neutrophil-lymphocyte ratio (NLR) was associated with improved outcomes in ICI-treated NSCLC.MethodsWe retrospectively analyzed patients treated with ICI with Foundation One genomic testing, including TMB. Optimal cutoff for prediction of response by TMB was determined by receiver operating characteristic analysis, and area under the curve (AUC) was calculated for all 3 biomarkers and combinations. Cox model was used to assess prognostic factors of overall survival (OS) and time to progression (TTP). Survival cutoffs calculated with Kaplan-Meier survival curves were TMB ≥10 mut/Mb, PD-L1 ≥50%, NLR <5, and combined biomarkers.ResultsData from 88 patients treated were analyzed. The optimal TMB cutoff was 9.24 mut/Mb (AUC, 0.62), improving to 0.74 combining all 3 biomarkers. Adjusted Cox model showed that TMB ≥10 mut/Mb was an independent factor of OS (hazard ratio [HR], 0.31; 95% confidence interval; 0.14-0.69; P = .004) and TTP (HR, 0.46; 95% CI, 0.27-0.77; P = .003). The combination of high TMB with positive PD-L1 and low NLR was significantly associated with OS (P = .038) but not TTP.ConclusionsTMB has modest predictive and prognostic power for clinical outcomes after ICI treatment. The combination of TMB, PD-L1, and NLR status improves this power.     

Haemorrhagic soft-tissue sarcoma: Oncological outcomes and prognostic factors for survival

IntroductionHaemorrhagic soft-tissue sarcomas (HSTS) are characterised by aggressive local growth and highly metastatic behaviour. We aimed to describe oncological outcomes and prognostic factors.Materials and methodsRetrospective review including 64 patients treated with palliation (n = 7), with limb salvage surgery (LSS) (n = 9), with neoadjuvant radiotherapy (RT) + LSS (n = 12), with LSS + adjuvant RT (n = 30) or amputation (n = 6). Kaplan-Meier survival analysis estimated overall survival (OS), metastasis-free survival (MFS) and local recurrence-free survival (LRFS). After uni- and multivariate analysis, prognostic factors affecting OS, MFS and LRFS were identified.ResultsMedian age was 67 years (IQR 23 years) with median follow-up of 11 months (IQR 28 months). All cases were high grade. Eight (13%) had pulmonary metastases at presentation and another 40 (63%) developed metastases after median 9 months (IQR 19 months). Median OS was 12 months (IQR 38 months), and estimated OS after two-years was 15.9% and 52.9% for patients with and without metastatic disease at presentation, respectively. Improved OS was associated with negative resection margins (p = 0.031), RT (p = 0.045), neoadjuvant RT (versus adjuvant RT, p = 0.044) and amputation (versus LSS, p < 0.001). MFS was 35.1% after two-years. LR occurred in 18 of 51 (35.3%) patients with surgically treated localised disease. LRFS was 63.4% after two-years and significantly affected by a negative margin (p = 0.042) and RT (p = 0.001).ConclusionHaemorrhagic soft-tissue sarcomas should be excised, either with amputation or LSS with a clear resection margin. If LSS is attempted, neoadjuvant RT reduces the risk of tumour spillage and early LR, enhances the feasibility of achieving clear resection margins, and offers superior overall survival compared to adjuvant RT.     

Outcome after surgical resection of multiple recurrent retroperitoneal soft tissue sarcoma

IntroductionLocal recurrences (LR) and distant metastases (DM) are common in retroperitoneal soft tissue sarcoma (RPS). Longer time to recurrence and resection of the recurrent lesion have been identified as beneficial prognostic factors for overall survival (OS) upon first tumor relapse. However, prognostic factors concerning OS upon subsequent recurrences are scarcely defined. In this study, we aimed to identify prognostic factors for post-relapse outcome in multiple recurrent RPS.MethodsPatients undergoing resection of primary and recurrent RPS at the University Hospital Heidelberg were retrospectively analyzed. Multivariable Cox regression analyses were performed to identify predictors of overall, LR- and DM-free survival. Subgroup analyses were performed for liposarcoma and leiomyosarcoma patients.Results201 patients with primary disease, 101 patients with first, 66 patients with second and 43 patients with third LR as well as 75 patients with DM were analyzed. More than 12 months to recurrence and resection of recurrence were associated with improved OS after resection of first and second LR (5-year OS for first/second LR; resection: 64%/62%, no resection: 20%/46%). Gross macroscopic incomplete resection of first (p < 0.001), second (p = 0.001), and third recurrences (p < 0.001) was an independent prognostic factor for poor OS.ConclusionDevelopment of LR and DM is frequent in RPS. Once a tumor relapsed, patients benefit from tumor resection not only in case of first, but also in case of subsequent recurrences.