Exploring published and novel pre-treatment CT and PET radiomics to stratify risk of progression among early-stage non-small cell lung cancer patients treated with stereotactic radiation.

PURPOSE: Disease progression after definitive stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) occurs in 20-40% of patients. Here, we explored published and novel pre-treatment CT and PET radiomics features to identify patients at risk of progression. MATERIALS/METHODS: Published CT and PET features were identified and explored along with 15 other CT and PET features in 408 consecutively treated early-stage NSCLC patients having CT and PET < 3 months pre-SBRT (training/set-aside validation subsets: n = 286/122). Features were associated with progression-free survival (PFS) using bootstrapped Cox regression (Bonferroni-corrected univariate predictor: p ≤ 0.002) and only non-strongly correlated predictors were retained (|Rs|<0.70) in forward-stepwise multivariate analysis. RESULTS: Tumor diameter and SUVmax were the two most frequently reported features associated with progression/survival (in 6/20 and 10/20 identified studies). These two features and 12 of the 15 additional features (CT: 6; PET: 6) were candidate PFS predictors. A re-fitted model including diameter and SUVmax presented with the best performance (c-index: 0.78; log-rank p-value < 0.0001). A model built with the two best additional features (CTspiculation1 and SUVentropy) had a c-index of 0.75 (log-rank p-value < 0.0001). CONCLUSIONS: A re-fitted pre-treatment model using the two most frequently published features - tumor diameter and SUVmax - successfully stratified early-stage NSCLC patients by PFS after receiving SBRT.

Standard-of-care systemic therapy with or without stereotactic body radiotherapy in patients with oligoprogressive breast cancer or non-small-cell lung cancer (Consolidative Use of Radiotherapy to Block [CURB] oligoprogression): an open-label, randomised, controlled, phase 2 study.

BACKGROUND: Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes. METHODS: We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03808662, and is complete. FINDINGS: From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0-4·5) for patients in the standard-of-care group versus 7·2 months (4·5-10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35-0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2-not reached] vs 2·2 months [95% CI 2·0-4·5]; HR 0·41, 95% CI 0·22-0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5-8·7] vs 4·2 months [1·8-5·5]; 0·78, 0·43-1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts. INTERPRETATION: The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted. FUNDING: National Cancer Institute.

Systemic Therapy for Small-Cell Lung Cancer: ASCO-Ontario Health (Cancer Care Ontario) Guideline.

PURPOSE: To provide evidence-based recommendations to practicing clinicians on the management of patients with small-cell lung cancer. METHODS: An Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, community oncology, research methodology, and advocacy experts were convened to conduct a literature search, which included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2022. Outcomes of interest included response rates, overall survival, disease-free survival or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 95 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS: Evidence-based recommendations were developed to address systemic therapy options, timing of therapy, treatment in patients who are older or with poor performance status, role of biomarkers, and use of myeloid-supporting agents in patients with small-cell lung cancer.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

Efficacy of PD-(L)1 blockade monotherapy compared with PD-(L)1 blockade plus chemotherapy in first-line PD-L1-positive advanced lung adenocarcinomas: a cohort study.

BACKGROUND: Single-agent PD-(L)1 blockade (IO) alone or in combination with chemotherapy (Chemotherapy-IO) is approved first-line therapies in patients with advanced lung adenocarcinomas (LUADs) with PD-L1 expression ≥1%. These regimens have not been compared prospectively. The primary objective was to compare first-line efficacies of single-agent IO to Chemotherapy-IO in patients with advanced LUADs. Secondary objectives were to explore if clinical, pathological, and genomic features were associated with differential response to Chemotherapy-IO versus IO. METHODS: This was a multicenter retrospective cohort study. Inclusion criteria were patients with advanced LUADs with tumor PD-L1 ≥1% treated with first-line Chemotherapy-IO or IO. To compare the first-line efficacies of single-agent IO to Chemotherapy-IO, we conducted inverse probability weighted Cox proportional hazards models using estimated propensity scores. RESULTS: The cohort analyzed included 866 patients. Relative to IO, Chemotherapy-IO was associated with improved objective response rate (ORR) (44% vs 35%, p=0.007) and progression-free survival (PFS) in patients with tumor PD-L1≥1% (HR 0.84, 95% CI 0.72 to 0.97, p=0.021) or PD-L1≥50% (ORR 55% vs 38%, p<0.001; PFS HR 0.68, 95% CI 0.53 to 0.87, p=0.002). Using propensity-adjusted analyses, only never-smokers in the PD-L1≥50% subgroup derived a differential survival benefit from Chemotherapy-IO vs IO (p=0.013). Among patients with very high tumor PD-L1 expression (≥90%), there were no differences in outcome between treatment groups. No genomic factors conferred differential survival benefit to Chemotherapy-IO versus IO. CONCLUSIONS: While the addition of chemotherapy to PD-(L)1 blockade increases the probability of initial response, never-smokers with tumor PD-L1≥50% comprise the only population identified that derived an apparent survival benefit with treatment intensification.

Clinical and Genomic Features of Response and Toxicity to Sotorasib in a Real-World Cohort of Patients With Advanced KRAS G12C-Mutant Non-Small Cell Lung Cancer.

PURPOSE: With the recent approval of the KRAS G12C inhibitor sotorasib for patients with advanced KRAS G12C-mutant non-small cell lung cancer (NSCLC), there is a new need to identify factors associated with activity and toxicity among patients treated in routine practice. MATERIALS AND METHODS: We conducted a multicenter retrospective study of patients treated with sotorasib outside of clinical trials to identify factors associated with real-world progression free survival (rwPFS), overall survival (OS), and toxicity. RESULTS: Among 105 patients with advanced KRAS G12C-mutant NSCLC treated with sotorasib, treatment led to a 5.3-month median rwPFS, 12.6-month median OS, and 28% real-world response rate. KEAP1 comutations were associated with shorter rwPFS and OS (rwPFS hazard ratio [HR], 3.19; P = .004; OS HR, 4.10; P = .003); no significant differences in rwPFS or OS were observed across TP53 (rwPFS HR, 1.10; P = .731; OS HR, 1.19; P = .631) or STK11 (rwPFS HR, 1.66; P = .098; OS HR, 1.73; P = .168) comutation status. Notably, almost all patients who developed grade 3 or higher treatment-related adverse events (G3+ TRAEs) had previously been treated with anti-PD-(L)1 therapy. Among these patients, anti-PD-(L)1 therapy exposure within 12 weeks of sotorasib was strongly associated with G3+ TRAEs (P < .001) and TRAE-related sotorasib discontinuation (P = .014). Twenty-eight percent of patients with recent anti-PD-(L)1 therapy exposure experienced G3+ TRAEs, most commonly hepatotoxicity. CONCLUSION: Among patients treated with sotorasib in routine practice, KEAP1 comutations were associated with resistance and recent anti-PD-(L)1 therapy exposure was associated with toxicity. These observations may help guide use of sotorasib in the clinic and may help inform the next generation of KRAS G12C-targeted clinical trials.

Brief Report: Combination of Osimertinib and Dacomitinib to Mitigate Primary and Acquired Resistance in EGFR-Mutant Lung Adenocarcinomas.

PURPOSE: Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance. PATIENTS AND METHODS: We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation. RESULTS: Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%-88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%-58%). CONCLUSIONS: We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.

Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.

Pre-treatment immune status predicts disease control in NSCLCs treated with chemoradiation and durvalumab.

BACKGROUND: The impact of peripheral blood immune measures and radiation-induced lymphopenia on outcomes in non-small cell lung cancer (NSCLC) patients treated with concurrent chemoradiation (cCRT) and immune check point inhibition (ICI) has yet to be fully defined. METHODS: Stage III NSCLC patients treated with cCRT and ≥1 dose of durvalumab across a cancer center were examined. Peripheral blood counts were assessed pre-cCRT, during cCRT and at the start of ICI. These measures and risk-scores from two published models estimating radiation dose to immune-bearing organs were tested for association with disease control. RESULTS: We assessed 113 patients treated with cCRT and a median of 8.5 months of durvalumab. Median PFS was 29 months (95% CI 18-35 months). A lower pre-cCRT ALC (HR: 0.51 (95% CI: 0.32-0.82), p = 0.02) and a higher pre-cCRT ANC (HR: 1.14 (1.06-1.23), p = 0.005) were associated with poor PFS. Neither ALC nadir, ALC at ICI start, ANC at ICI start or the normalized change in ALC from pre-cCRT to nadir were significantly associated with PFS (p = 0.07-0.49). Also, risk scores from the two radiation-dose models were not associated with PFS (p = 0.14, p = 0.21) but were so with the ALC Nadir (p = 0.001, p = 0.002). A higher pre-cCRT NLR was the strongest predictor for PFS (HR: 1.09 (1.05-1.14), p = 0.0001). The 12-month PFS in patients with the bottom vs. top NLR tertile was 84% vs 46% (p = 0.000004). CONCLUSIONS: Baseline differences in peripheral immune cell populations are associated with disease outcomes in NSCLC patients treated with cCRT and ICI.

Pilot Study of Dacomitinib for Patients With Metastatic EGFR-Mutant Lung Cancers With Disease Progression After Initial Treatment With Osimertinib.

Patients with EGFR-mutant lung cancer have no approved targeted therapies after disease progression on first-line osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Preclinical studies suggest that tumors with both EGFR-sensitizing alteration and acquired second-site EGFR resistance alterations after treatment with osimertinib retain sensitivity to second-generation EGFR TKIs. We hypothesized that dacomitinib, a pan-human epidermal growth factor receptor TKI, may be effective in this setting. METHODS: In this phase II study, patients who had progressed on first-line osimertinib were treated with dacomitinib 45 mg orally daily until disease progression or intolerability. The primary end point was objective response rate. RESULTS: We enrolled 12 patients. Two partial responses were documented (17% objective response rate; 95% CI, 5 to 45). The median progression-free survival was 1.8 months (95% CI, 1.6 to not reached). One patient with an original sensitizing EGFR G719A mutation and one patient without molecular testing available had partial responses, whereas 0 of the 3 patients with second-site acquired EGFR resistance mutations (two C797S and one G724S) met the response criteria. The patient with EGFR G719A has an ongoing response at 17 months, which exceeds prior time on osimertinib (11 months). CONCLUSION: In the first trial evaluating a second-generation EGFR TKI after first-line third-generation osimertinib, we found that dacomitinib after disease progression on osimertinib has limited benefit.

Predicting immunotherapy outcomes under therapy in patients with advanced NSCLC using dNLR and its early dynamics.

BACKGROUND: dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non-small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance. PATIENTS AND METHODS: aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR≤3 = low]. B+C2 dNLR were combined in one score: good = low (B+C2), poor = high (B+C2), intermediate = other situations. In 57 patients, we prospectively explored the immunophenotype of circulating neutrophils, particularly the CD15+CD244-CD16lowcells (immature) by flow cytometry. RESULTS: About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (~1/3rd) associated with worse progression-free (PFS)/overall survival (OS) (HR 1.56/HR 2.02, P < 0.0001) but not with chemotherapy alone (N = 173). High dNLR at C2 was associated with worse PFS/OS (HR 1.64/HR 2.15, P < 0.0001). When dNLR at both time points were considered together, those with persistently high dNLR (23%) had poor survival (mOS = 5 months (mo)), compared with high dNLR at one time point (22%; mOS = 9.2mo) and persistently low dNLR (55%; mOS = 18.6mo) (P < 0.0001). The dNLR impact remained significant after PD-L1 adjustment. By cytometry, high rate of immature neutrophils (B) (30/57) correlated with poor PFS/OS (P = 0.04; P = 0.0007), with a 12-week death rate of 49%. CONCLUSION: The dNLR (B) and its dynamics (C2) under ICI associate with ICI outcomes in aNSCLC. Persistently high dNLR (B+C2) correlated with early ICI failure. Immature neutrophils may be a key subpopulation on ICI resistance.

Evaluating of HPV-DNA ISH as an adjunct to p16 testing in oropharyngeal cancer.

AIM: Current guidelines recommend p16 immunohistochemistry (IHC) for testing human papillomavirus (HPV) in oropharyngeal carcinoma (OPSCC). We evaluated the value of adding DNA in situ hybridization (ISH) to p16 IHC. METHODS: Fifty patients with OPSCC were analyzed. Concordance between HPV-DNA ISH and p16 IHC was measured by Gwet's agreement coefficient. RESULTS: p16 IHC was positive in 35/48 (72.9%), negative in 8/48 (16.7%) patients. Wide spectrum DNA-ISH was positive in 9/23 (39%) and negative in 14/23 (60.9%) patients. High-risk 16/18 (HR) HPV DNA-ISH was positive in 11/23 (47.8%) and negative in 12 (52.2%) patients. The agreement between HPV DNA-ISH and p16 IHC is fair (Gwet's AC1 = 0.318). CONCLUSION: The agreement between p16 IHC and HPV-DNA ISH was fair. However, ISH sensitivity was low. Our findings add to the current data that p16 IHC testing is reliable and may be enough as a stand-alone test for HPV detection in OPSCC.

Optimizing Tissue Use: A Step-wise Approach to Diagnosing Squamous Cell Lung Carcinoma on Small Biopsies.

BACKGROUND: Histologic subtyping of lung cancer has significant implications for treatment planning. Accurate diagnosis based on cytology/small biopsy specimens is challenging and frequently determined by morphology, as material is often not sufficient for immunohistochemical studies (IHC). We investigated the concordance between the rates of diagnosis from cytology/small biopsies compared with surgical specimens in patients with squamous cell lung cancer (SCC) and the utility of IHC for diagnostic precision in lung cancer subtyping. METHODS: We conducted a 5-year retrospective analysis identifying cases of SCC diagnosed on cytology/small biopsies ± IHC and compared them with subsequent surgical specimens when available. The number of patients with SCC on surgical biopsy and the concordance between cytology ± IHC was determined. RESULTS: Over the 5-year period (2011-2015), 231 cases were identified. Surgery was performed on 66 cases (28.5%), of which 87.9% concurred with cytological diagnosis (95% exact binomial confidence interval [CI] = 77.5%-94.6%). There were 36 cases diagnosed in 2014 and 2015 with IHC data. Of those cytology cases with IHC (n = 12), SCC was confirmed by surgery in 91.7% (95% CI = 61.5%-99.8%). Of those without IHC (n = 24), 95.8% were confirmed SCC by surgery (95% CI = 78.9%-99.9%). These rates were not different (Fisher exact test). All cases with IHC were morphologically squamous. CONCLUSIONS: Our data demonstrate that diagnostic precision of identifying SCC by cytology/small biopsy is comparable with or without additional IHC studies. We recommend judicious use of IHC on cytology specimens, reserving it for cases where cytomorphology is equivocal. Tissue should be preserved for molecular analysis, which may have therapeutic implications.

Impact of PD-1 Blockade on Severity of COVID-19 in Patients with Lung Cancers.

The coronavirus disease 2019 (COVID-19) pandemic has led to dramatic changes in oncology practice. It is currently unknown whether programmed death 1 (PD-1) blockade therapy affects severity of illness from COVID-19 in patients with cancer. To address this uncertainty, we examined consecutive patients with lung cancers who were diagnosed with COVID-19 and examined severity on the basis of no or prior receipt of PD-1 blockade. Overall, the severity of COVID-19 in patients with lung cancer was high, including need for hospitalization in more than half of patients and death in nearly a quarter. Prior PD-1 blockade was, as expected, associated with smoking status. After adjustment for smoking status, PD-1 blockade exposure was not associated with increased risk of severity of COVID-19. PD-1 blockade does not appear to affect the severity of COVID-19 in patients with lung cancers. SIGNIFICANCE: A key question in oncology practice amidst the COVID-19 pandemic is whether PD-1 blockade therapy affects COVID-19 severity. Our analysis of patients with lung cancers supports the safety of PD-1 blockade treatment to achieve optimal cancer outcomes.This article is highlighted in the In This Issue feature, p. 1079.

Circulating Tumor DNA Analysis to Assess Risk of Progression after Long-term Response to PD-(L)1 Blockade in NSCLC.

PURPOSE: Treatment with PD-(L)1 blockade can produce remarkably durable responses in patients with non-small cell lung cancer (NSCLC). However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression. EXPERIMENTAL DESIGN: In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (progression-free survival ≥ 12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing. Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing (n = 18) or by targeted sequencing (n = 6). RESULTS: Thirty-one patients with NSCLC with long-term benefit to PD-(L)1 blockade were identified, and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; in contrast, all 4 patients with detectable ctDNA eventually progressed [Fisher P < 0.0001; positive predictive value = 1, 95% confidence interval (CI), 0.51-1; negative predictive value = 0.93 (95% CI, 0.80-0.99)]. CONCLUSIONS: ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 blockade and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression.

Simple parameters to solve a complex issue: predicting response to checkpoint inhibitor therapy in lung cancer.

BACKGROUND: Noninvasive biomarkers predicting immune checkpoint inhibitor (ICI) response are urgently needed. We evaluated the predictive value of pretreatment neutrophil-to-lymphocyte ratio (NLR), smoking history, smoking intensity, BMI and programmed death ligand 1 (PD-L1) expression in non-small-cell lung cancer (NSCLC) patients treated with ICIs. MATERIALS & METHODS: Single-center retrospective study included 137 patients from July 2015 to February 2018. Outcomes included 3-month disease control rate, progression-free survival, and overall survival. Predictive value of biomarkers was assessed independently and in a multivariable model. RESULTS: NLR was associated with all outcomes. Smoking history was predictive of progression-free survival and smoking intensity was predictive of disease control rate. BMI and PD-L1 were not associated with any outcome. High BMI was associated with low NLR. CONCLUSION: Simple clinical biomarkers can predict response to ICIs. A score incorporating both clinical factors and established tissue/serum biomarkers may be useful in identifying NSCLC patients who would benefit from ICIs.

Stage IV lung carcinoids: spectrum and evolution of proliferation rate, focusing on variants with elevated proliferation indices.

The spectrum and evolution of proliferation rates in stage IV lung carcinoids is poorly defined. In particular, there are limited data on the prevalence and characteristics of tumors exceeding the standard upper proliferative criteria-as defined largely based on early-stage carcinoids-in metastatic setting. Sixty-six patients with stage IV lung carcinoids were identified, and all evaluable samples (n = 132; mean 2 samples per patient) were analyzed for mitotic counts and Ki-67 rate. Clinicopathologic and genomic features associated with elevated proliferation rates (>10 mitoses per 2 mm2 and/or >20% hot-spot Ki-67), and evolution of proliferation rates in serial specimens were analyzed. We found that mitoses and/or Ki-67 exceeded the standard criteria in 35 of 132 (27%) samples, primarily (31/35 cases) at  metastatic sites. Although neuroendocrine neoplasms with >10 mitoses per 2 mm2 are currently regarded as de facto neuroendocrine carcinomas, the notion that these cases are part of the spectrum of carcinoids was supported by (1) well-differentiated morphology, (2) conventional proliferation rates in other samples from same patient, (3) genetic characteristics, including the lack of RB1/TP53 alterations in all tested samples (n = 19), and (4) median overall survival of 2.7 years, compared to <1 year survival of stage IV neuroendocrine carcinomas in the historic cohorts. In patients with matched primary/metastatic specimens (48 pairs), escalation of mitoses or Ki-67 by ≥10 points was observed in 35% of metastatic samples; clonal relationship in one pair with marked proliferative progression was confirmed by next-generation sequencing. Notably, escalation of proliferation rate was documented in a subset of metastases arising from resected typical carcinoids, emphasizing that the diagnosis of typical carcinoid in primary tumor does not assure low proliferation rate at metastatic sites. In conclusion, stage IV lung carcinoids frequently exceed the standard proliferative criteria established for primary tumors, and commonly exhibit proliferative escalation at metastatic sites. Despite the overlap of proliferation rates, these tumors show fundamental morphologic, genomic and clinical differences from neuroendocrine carcinomas, and should be classified separately from those tumors. Awareness of the increased proliferative spectrum in metastatic carcinoids is critical for their accurate diagnosis. Further studies are warranted to explore the impact of proliferation indices on prognosis and therapeutic responses of patients with metastatic carcinoids.

New PD-L1 inhibitors in non-small cell lung cancer - impact of atezolizumab.

The era of immunotherapy has changed the face of how we approach treatment for many oncologic and hematologic malignancies. Lung cancer has been in the forefront of checkpoint inhibition for the past 2 years and has paved the path for other subspecialties. While PD-1 inhibitors nivolumab and pembrolizumab have been approved for non-small cell lung cancer (NSCLC), this review focuses on atezolizumab, its landmark studies, and ongoing trials. Atezolizumab is the first programmed death ligand 1 (PD-L1) inhibitor to receive US Food and Drug Administration (FDA) approval for metastatic NSCLC patients who have progressed on frontline chemotherapy. This approval was based on two open-label Phase II multicenter trials, POPLAR (NCT01903993) and BIRCH (NCT02031458). Both studies revealed a benefit in overall survival (OS), progression-free survival, and response rate in the atezolizumab arm when compared to single-agent docetaxol. There were also fewest Grade 3-5 treatment-related adverse events (TRAEs) in the atezolizumab cohort. The open-label randomized Phase III OAK trial (NCT02008227) further established the role of atezolizumab in previously treated NSCLC. This study compared atezolizumab with docetaxel in patients with advanced NSCLC (squamous or nonsquamous histologies) who had progressed on one to two prior chemotherapy regimens. OS in the PD-L1-enriched population was superior in the atezolizumab arm (n=241) at 15.7 months compared with docetaxel (n=222) at 10.3 months (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.58-0.93; p=0.0102). Patients lacking PD-L1 also had survival benefit with atezolizumab with a median OS (mOS) of 12.6 months versus 8.9 months with chemotherapy (HR 0.75, 95% CI 0.59-0.96). Benefit was noted in both squamous and nonsquamous NSCLC subsets and regardless of PD-L1 expressivity. As seen in the POPLAR and BIRCH studies, the toxicity profile was significantly better with immunotherapy. The future is unfolding rapidly as new checkpoint inhibitors are gaining FDA approval. It is still not known if these agents will be used in combination with chemotherapy, with other immune-modulating agents, radiation therapy, or all of the above. The results of these studies investigating their use in combination with chemotherapy agents, with other immunotherapy agents such as CTLA-4 inhibitors, and with radiation therapy, are eagerly awaited.