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Background The role of postoperative radiotherapy (PORT) in patients with clinical stage III-N2 (cIII-N2) non-small cell lung cancer (NSCLC) treated with induction chemotherapy and surgical resection with persistent ypN2 disease is not well established. Methods We retrospectively reviewed a prospectively maintained database for patients with cIII-N2 NSCLC who underwent induction chemotherapy followed by resection (2004–2016). Exclusion criteria included induction radiotherapy, non–biopsy-confirmed cN2 disease, incomplete resection, ypN0/1, and nonanatomic resection. The primary outcome was locoregional recurrence (LR); secondary outcomes were disease-free survival (DFS), lung cancer–specific death (LCSD), and overall survival (OS). Associations between variables and outcomes were assessed using Fine and Gray competing risk regression for LR/LCSD and Cox proportional hazard models for survival. Results Of the 501 patients identified with cIII-N2 disease, 99 met the inclusion criteria. Median follow-up was 25 months (range, 3-137 months). Sixty-nine patients (70%) received PORT. Sixty (61%) developed a recurrence: 3 (5%) with an initial isolated LR and 57 (95%) with an initial distant recurrence. On multivariable analysis, PORT was not associated with LR (HR, 0.51 [95% CI, 0.22-1.21], p = 0.13). PORT was also not associated with DFS (p = 0.6) or LCSD (p = 0.1). PORT was associated with improved 3-year OS (55% [95% CI, 42%-71%]) versus the no-PORT group (50% [95% CI, 34%-74%]) (p = 0.04). Conclusions PORT is not independently associated with decreased LR or improved DFS/LCSD in this patient population. Given that the predominant failure pattern was distant recurrence, future clinical trials should focus on adjuvant systemic therapies, which may decrease distant recurrences in ypN2 patients.

Objectives Reports of the prognostic significance of ALK-rearrangement in resected non-small cell lung cancer (NSCLC) have been contradictory. We aimed to determine the prognosis of early-stage ALK-positive lung cancers relative to KRAS- and EGFR-mutant lung cancers. Material and methods We reviewed medical records of patients with resected NSCLC harboring an ALK rearrangement (n = 29) or a driver mutation in EGFR (n = 255) or KRAS (n = 480). Recurrence-free survival (RFS) was estimated for each genotype with the differences reported as a hazard ratio (HR). Results Among the 764 patients, 555 (73%), 101 (13%), and 108 (14%) had stage I, II, and III NSCLC, respectively. ALK-positive patients were distributed across all stages: 10 (34%) stage I, 6 (21%) stage II, and 13 (45%) stage III. Median RFS was not reached for EGFR-mutant patients, 24.3 months (95%CI 11.4–65.3) for ALK-positive patients, and 72.9 months (95%CI 59.7 to undefined) for KRAS-mutant patients. When adjusted for stage, ALK-positive NSCLC remained associated with worse RFS compared to EGFR-mutant (HR 1.8, 95%CI: 1.1-3.1), but not when compared to KRAS-mutant (HR 1.3, 95%CI: 0.8-2.1) NSCLC. Conclusions In this large series of resected NSCLC, ALK rearrangements were associated with a trend toward inferior disease outcomes compared to other clinically relevant genomic subsets. These data support the need for clinical trials evaluating use of ALK inhibitors among ALK-positive patients with localized or locally-advanced disease.

Purpose To examine the significance of the proposed International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) histologic subtypes of lung adenocarcinoma for patterns of recurrence and, among patients who recur following resection of stage I lung adenocarcinoma, for postrecurrence survival (PRS). Patients and Methods We reviewed patients with stage I lung adenocarcinoma who had undergone complete surgical resection from 1999 to 2009 (N = 1,120). Tumors were subtyped by using the IASLC/ATS/ERS classification. The effects of the dominant subtype on recurrence and, among patients who recurred, on PRS were investigated. Results Of 1,120 patients identified, 188 had recurrent disease, 103 of whom died as a result of lung cancer. Among patients who recurred, 2-year PRS was 45%, and median PRS was 26.1 months. Compared with patients with nonsolid tumors, patients with solid predominant tumors had earlier (P = .007), more extrathoracic (P < .001), and more multisite (P = .011) recurrences. Multivariable analysis of primary tumor factors revealed that, among patients who recurred, solid predominant histologic pattern in the primary tumor (hazard ratio [HR], 1.76; P = .016), age older than 65 years (HR, 1.63; P = .01), and sublobar resection (HR, 1.6; P = .01) were significantly associated with worse PRS. Presence of extrathoracic metastasis (HR, 1.76; P = .013) and age older than 65 years at the time of recurrence (HR, 1.7; P = .014) were also significantly associated with worse PRS. Conclusion In patients with stage I primary lung adenocarcinoma, solid predominant subtype is an independent predictor of early recurrence and, among those patients who recur, of worse PRS. Our findings provide a rationale for investigating adjuvant therapy and identify novel therapeutic targets for patients with solid predominant lung adenocarcinoma.

Human epidermal growth factor 2 (HER2, ERBB2) mutations in lung cancers are oncogenic drivers that respond to HER2 targeted therapies. Little is known about the sensitivity of subtypes of HER2 mutant lung cancers to targeted agents. We present a patient with HER2 mutant lung cancer with a 12 base pair insertion YVMA (p.A775_G776insYVMA), who had a long natural history and durable partial response to afatinib. We demonstrate that afatinib has activity in patients with HER2 mutant lung cancers with exon 20 YVMA insertions, the most common variant.

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in select cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI.To examine this association more broadly, we analyzed the clinical and genomic data of 1662 advanced cancer patients treated with ICI, and 5371 non-ICI treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better OS (HR 0.52; p=1.6 ×10(−6)). For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.

OBJECTIVES: Thyroid transcription factor 1 (TTF-1) is routinely tested in the diagnostic evaluation of suspected lung cancers, is commonly expressed by lung adenocarcinomas, and may modulate lung cancer biology. We examined the role of TTF-1 as a predictive and prognostic marker in patients with advanced lung adenocarcinomas. MATERIALS AND METHODS: We analyzed clinical, pathologic, and molecular features, treatments received, and overall survival obtained from the medical records of 479 consecutive patients at a single site with stage IV lung adenocarcinomas and evaluable TTF-1 expression. TTF-1 expression was determined by immunohistochemistry using antibody 8G7G3/1. RESULTS AND CONCLUSION: TTF-1 expression was evaluable in 479 (75%) of all patients reviewed, and was positive in 383 (80%, 95% CI 76 to 83%). Clinicopathologic features were similar between TTF-1 positive and TTF-1 negative tumors, except EGFR mutations were more common in TTF-1 positive cases (24% vs 6%, p/= 80% (HR 0.62, p=0.0003) and receipt of first-line combination chemotherapy or targeted therapy (HR relative to single agent chemotherapy 0.59, p=0.05 and 0.51, p=0.05 respectively). Both patients with TTF-1 positive and TTF-1 negative cancers had longer durations of initial therapy when treated with pemetrexed-based chemotherapy. In patients with advanced lung adenocarcinomas, TTF-1 expression is associated with better survival but is not predictive of distinct benefit from pemetrexed-based chemotherapy.

Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced non–small-cell lung cancer (NSCLC) across lines of therapy. Patients were selected on the basis of PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior chemotherapy. Patients whose tumors expressed PD-L1 using the SP142 immunohistochemistry assay on ≥ 5% of TC or IC (TC2/3 or IC2/3 [TC or IC ≥ 5% PD-L1–expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659) comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n = 268); and third line or higher (cohort 3; n = 252). The primary end point was independent review facility–assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points included median duration of response, progression-free survival, and overall survival (OS). Results BIRCH met its primary objective of demonstrating a significant ORR versus historical controls. With a minimum of 12 months of follow-up, the independent review facility–assessed ORR was 18% to 22% for the three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The median OS from an updated survival analysis (minimum of 20 month follow up) for cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in patients with PD-L1–selected advanced NSCLC, with good tolerability. PD-L1 status may serve as a predictive biomarker for identifying patients most likely to benefit from atezolizumab.

Introduction Patients with early-stage lung cancer have a high risk of recurrence despite multimodality therapy. KRAS-mutant lung adenocarcinomas are the largest genetically defined subgroup, representing 25% of patients. GI-4000 is a heat-killed recombinant Saccharomyces cerevisiae yeast–derived vaccine expressing mutant KRAS proteins. The present phase II study assessed the feasibility, immunogenicity, and safety of the GI-4000 vaccine in patients with early-stage, KRAS-mutant lung cancer. Materials and Methods Patients with stage I-III KRAS-mutant lung cancer who completed curative therapy were enrolled. The patients received the genotype matched GI-4000 vaccine for ≤ 3 years or until intolerance, disease recurrence, or death. The KRAS antigen T-cell response was assessed using the interferon-gamma enzyme-linked immunospot assay in peripheral blood mononuclear cells. The study was powered to detect an immune response in ≥ 25% of patients. Results A total of 24 patients were enrolled over 28 months. No vaccine-related serious adverse events occurred. One patient withdrew consent because of pain at the injection site. The study met its primary endpoint, with 50% of patients developing an immune response to mutant KRAS. The median number of vaccinations received was 15 (range, 1-19). Ten patients experienced disease recurrence, and 6 died. Compared with the genotypically matched historical controls, the recurrence rates were equivalent but overall survival showed a favorable trend. Conclusion GI-4000 was well tolerated and immunogenic when used as consolidation therapy in patients with stage I-III KRAS-mutant lung cancer. The patterns of recurrence and death observed in the present study can be used to design a randomized study of GI-4000 with overall survival as the primary endpoint.

SummaryBrain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers.

Improvements in outcomes for patients with resectable lung cancers have plateaued. Clinical trials of resectable non-small-cell lung cancers with overall survival as the primary endpoint require a decade or longer to complete, are expensive, and limit innovation. A surrogate for survival, such as pathological response to neoadjuvant chemotherapy, has the potential to improve the efficiency of trials and expedite advances. 10% or less residual viable tumour after neoadjuvant chemotherapy, termed here major pathological response, meets criteria for a surrogate; major pathological response strongly associates with improved survival, is reflective of treatment effect, and captures the magnitude of the treatment benefit on survival. We support the incorporation of major pathological response as a surrogate endpoint for survival in future neoadjuvant trials of resectable lung cancers. Additional prospective studies are needed to confirm the validity and reproducibility of major pathological response within individual histological and molecular subgroups and with new drugs.

8503 Background: Small pilot studies (e.g., N Engl J Med. 2018;378:1976) have shown that preoperative immune checkpoint inhibitor therapy may be of benefit in early-stage NSCLC. This large multicenter trial assesses the benefit of neoadjuvant treatment with atezolizumab (atezo; NCT02927301). Methods: Patients (pts) with stages IB to selected IIIB resectable NSCLC receive 2 cycles of atezo 1200 mg (days 1, 22) then undergo resection (day 40 ± 10). Primary tumor +/- node biopsies and blood samples are obtained before atezo and at surgery for biomarker studies. The primary endpoint is major pathological response (MPR), defined as ≤ 10% viable tumor cells in the resection specimen. Secondary endpoints include safety and correlation of response with PD-L1 expression, tumor mutation burden (TMB) and gene expression signatures. Results: For this interim efficacy analysis (5 Sep 2018 data cut), we report on the first 101 of 180 planned pts: 47 males, median age, 64 y; all ECOG PS 0-1; 23 current and 68 former smokers; 66 non-squamous NSCLC; clinical stages IB/IIA/IIB/IIIA/IIIB n = 11/16/28/39/7. There were 2 treatment-unrelated Gr 5 AEs (cardiac death post surgical resection; death due to disease progression), 29 Gr 3-4 AEs (6 [6%] treatment related). 90 pts had surgery. Excluding 8 pts who had driver mutations (7 EGFR, 1 ALK, no MPR), MPR rate was 15/82 (18%, 95% CI 11%-28%), 4 pts had pathological complete response (pCR). By RECIST, 6/82 pts had PR, 72 had SD and 4 had PD. Two of 26 (8%) PD-L1− (TC0 and IC0, clone SP142) and 10 of 35 (29%) PD-L1+ had MPR ( P= 0.055). Five of 44 (11%) TPS < 50 (PD-L1 clone 22C3) and 7 of 20 (35%) TPS > 50 had MPR ( P= 0.040). Exome sequencing data was available for 47/101 pts. Median TMB was 10.4 (range, 1.5-46.5) mutations per Mb and was not different in those with MPR compared with those without MPR. Further analysis of TMB, mutation signatures, and gene expression profiling is ongoing. Conclusions: Atezo in the neoadjuvant setting was well tolerated, and pCR and MPR rates are encouraging in this large multicenter trial. Efficacy interim analysis passed its futility boundary, and study enrollment continues. Safety, efficacy results and ongoing correlative analyses will be presented. Clinical trial information: NCT02927301.

8524 Background: Improved therapy is needed for patients (pts) with early-stage non-small cell lung cancer (NSCLC), as the majority relapse after curative resection. Our group reported the first trial of neoadjuvant PD-1 blockade in resectable NSCLC, finding therapy to be safe and feasible. Here we report extended clinical follow-up and long-term molecular response data from this trial. Methods: IV nivolumab 3 mg/kg was given every 2 weeks for 2 doses prior to surgery in 20 pts with resectable NSCLC at Johns Hopkins and MSKCC. Blood for correlative studies was taken prior to each dose of nivolumab, prior to surgery, 2-4 weeks post-surgery, and during long-term follow up. In a subgroup of pts, longitudinal molecular data was assessed in peripheral blood for circulating tumor DNA (ctDNA) and dynamics of tumor-infiltrating T-cell clonotypes. Results: At median follow up of 30 months (m), 15 of 20 pts are disease-free and alive. Two pts have died (one from relapsed disease). Median recurrence free survival (RFS) has not been reached. The 24m RFS rate is 69% (95% CI: 51-93). Thus far, presence of ctDNA at diagnosis and major pathologic response (MPR - ≤10% viable tumor in resected specimen) do not associate with RFS. One long-term immune-related adverse event has occurred (skin, G3). All pts who on pathologic review had ≥30% reduction in viable tumor in response to nivolumab demonstrated clearance of detectable ctDNA from blood prior to surgery. Pts with MPR experienced expansion of neoantigen-specific T-cells in peripheral blood. In one patient with ongoing disease free status, expansion of tumor-associated T-cells has persisted in peripheral blood beyond 15m from surgery. By contrast, in a patient who had detectable peri-operative ctDNA and 75% residual disease at surgery, minimal T-cell expansion was observed in peripheral blood, with a decreasing frequency of expanded T-cell clones over time that correlated with eventual cancer relapse. Conclusions: Long-term follow up reinforces the safety of neoadjuvant nivolumab in resectable NSCLC. Analysis of ctDNA and peripheral T-cell expansion in responders compared with non-responders suggests potential biomarkers for response and surveillance. While RFS data is encouraging, phase 3 trials are ongoing to evaluate efficacy of PD-(L)1 blockade in early-stage NSCLC. Clinical trial information: NCT02259621.

8507 Background: EGFR tyrosine kinase inhibitors are superior to chemotherapy in patients with advanced EGFR+ lung cancers. In the adjuvant setting, erlotinib for two years improves recurrence free survival (RFS) compared to historical controls. The optimal duration of adjuvant TKI is unknown. Methods: Patients with completely resected Stage I-III NSCLC with a sensitizing EGFR mutation were enrolled after standard adjuvant therapy. Pts were randomly assigned to 3 months (3m) or 2 years (2y) of adjuvant afatinib. Afatinib was started at 30 mg by mouth daily. Patients without toxicity after 28 days were allowed to escalate to 40 mg daily. Patients were imaged with CT every 6 months for 3 years and then annually or as clinically indicated. RFS was measured from the date of randomization. The primary study endpoint was recurrence rate at 2 years. 60 randomized patients would provide 82.5% power to detect a 26% difference in 2y-recurrence rate. Results: Patient characteristics are in the Table. The study was terminated for slow accrual after 46 of the planned 60 patients. Planned treatment was completed by 92% (22/24) pts in the 3m arm and 41% (9/22) of pt in the 2y arm. 22 patients required ≥1 dose modification due to toxicity including expected GI, mucosal, and skin AEs. With a median follow-up of ≥38 months there were 10 recurrences and 3 deaths in the 3m arm and there were 5 recurrences (2 on treatment) and 2 deaths in the 2y arm. Median RFS has not been reached in either arm, but recurrence was more common in the 3m arm at every landmark. 2y-recurrence rates were 29% for 3m and 15% for 2y. Conclusions: Recurrences at 2 years were 14% less common with 2y versus 3m of adjuvant afatinib. This difference did not meet the primary study endpoint. The RFS curves show a durable and clinically meaningful separation with substantial follow-up. Failure to meet significance was likely influenced by under-accrual and early drug discontinuation on the 2y arm. In the era of TKIs with improved tolerance, duration of adjuvant therapy remains an important question. Clinical trial information: NCT01746251. [Table: see text]

2546 Background: Early on-treatment changes in ctDNA may identify responders to immunotherapy and complement radiologic assessment of benefit. Here we investigate how early changes in ctDNA associate with long-term survival following treatment with immunotherapy, and if differential patterns in molecular ctDNA response (MCR) among patients with radiologic stable disease (SD) at first on-treatment scan could identify patients deriving benefit from treatment. Methods: Paired pre- and on-treatment (week 6-8) plasma samples from 3 cohorts of patients treated with durvalumab (D) +/- tremelimumab (D+T) were evaluated (NCT01693562, NCT02087423, NCT02261220). CtDNA was profiled with the 73-gene Guardant 360 assay. Nonsynonymous variants were summarized per patient to calculate variant allelic frequency changes (dVAF) and on-treatment variant allele frequency (pVAF). A combination of dVAF and pVAF was used to define MCR. Results: The reduction of ctDNA (dVAF

For patients with resected stage II–III non-small cell lung cancers (NSCLCs), adjuvant cisplatin-based chemotherapy improves survival over surgery alone. For cisplatin ineligible patients, there is no standard adjuvant option. We evaluated drug delivery and toxicity of docetaxel and vinorelbine in patients who could not receive cisplatin. Patients with completely resected stage IB–III NSCLCs were treated with up to 4 cycles of docetaxel and vinorelbine at the recommended phase II dose. The primary endpoint was drug delivery compared to historical delivery of adjuvant cisplatin plus vinorelbine. Secondary endpoints were toxicity and feasibility. Twenty-five patients were enrolled. Overall, 13/25 (52 %, 95 % CI 34–70) completed 4 cycles, and 19/25 (76 %, 95 % CI 60–87) completed ≥3 cycles. Twenty of 25 patients (80 %) experienced a Grade 3 or 4 adverse event. Delivery of this dose and schedule of docetaxel and vinorelbine was difficult with a dose delivery comparable to cisplatin plus vinorelbine, and cisplatin plus docetaxel, used in this setting.

Introduction: Bevacizumab improves survival in patients with advanced non–small-cell lung cancer (NSCLC). This phase II clinical trial assessed the effects of the addition of bevacizumab to neoadjuvant chemotherapy in resectable nonsquamous NSCLC. Methods: Patients with resectable stage IB–IIIA nonsquamous NSCLC were treated with bevacizumab followed by imaging 2 weeks later to assess single-agent effect. After this they received two cycles of bevacizumab with four cycles of cisplatin and docetaxel followed by surgical resection. Resected patients were eligible for adjuvant bevacizumab. The primary endpoint was the rate of pathological downstaging (decrease from pretreatment clinical stage to post-treatment pathological stage). Secondary endpoints included overall survival, safety, and radiologic response. Results: Fifty patients were enrolled. Thirty-four (68%) were clinical stage IIIA. All three doses of neoadjuvant bevacizumab were delivered to 40 of 50 patients. Six patients (12%) discontinued because of bevacizumab-related adverse events. The rate of downstaging (38%), response to chemotherapy (45%), and perioperative complications (12%) were comparable with historical data. No partial responses were observed to single-agent bevacizumab, but 18% of the patients developed new intratumoral cavitation, with a trend toward improved pathologic response (57% versus 21%; p = 0.07). A major pathologic response (≥90% treatment effect) was associated with survival at 3 years (100% versus 49%; p = 0.01). No patients with KRAS -mutant NSCLC (0 of 10) had a pathologic response as compared with 11 of 31 with wild-type KRAS . Conclusion: Although preoperative bevacizumab plus chemotherapy was feasible, it did not improve downstaging in unselected patients. New cavitation after single-agent bevacizumab is a potential biomarker. Alternative strategies are needed for KRAS -mutant tumors.

Pulmonary large cell carcinoma - a diagnostically and clinically controversial entity - is defined as a non-small cell carcinoma lacking morphologic differentiation as either adenocarcinoma or squamous cell carcinoma, but suspected to represent an end-stage of poor differentiation of these tumor types. Given the recent advances in immunohistochemistry to distinguish adenocarcinoma and squamous cell carcinoma, and the recent insights that several therapeutically-relevant genetic alterations are distributed differentially in these tumors, we hypothesized that immunophenotyping may stratify large cell carcinomas into subsets with distinct profiles of targetable driver mutations. We therefore analyzed 102 large cell carcinomas by immunohistochemistry for TTF-1 and ΔNp63/p40 as classifiers for adenocarcinoma and squamous cell carcinoma, respectively, and correlated the resulting subtypes with 9 therapeutically-relevant genetic alterations characteristic of adenocarcinoma (EGFR, KRAS, BRAF, MAP2K1/MEK1, NRAS, ERBB2/HER2 mutations and ALK rearrangements) or more common in squamous cell carcinoma (PIK3CA and AKT1 mutations). The immunomarkers classified large cell carcinomas as variants of adenocarcinoma (n=62; 60%), squamous cell carcinoma (n=20; 20%), or marker-null (n=20; 20%). Genetic alterations were found in 38 cases (37%), including EGFR (n=1), KRAS (n=30), BRAF (n=2), MAP2K1 (n=1), ALK (n=3) and PIK3CA (n=1). All molecular alterations characteristic of adenocarcinoma occurred in tumors with immunoprofiles of adenocarcinoma or marker-null, but not in tumors with squamous immunoprofiles (combined mutation rate 50% vs 30% vs 0%, respectively; P

Purpose Pneumonitis is an uncommon but potentially fatal toxicity of anti–programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. Methods Patients who received anti–PD-1/PD-L1 monotherapy or in combination with anti–cytotoxic T-cell lymphocyte associated antigen-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlying malignancy were examined with Fisher’s exact test as were associations between pneumonitis features and outcomes. Results Of 915 patients who received anti–PD-1/PD-L1 mAbs, pneumonitis developed in 43 (5%; 95% CI, 3% to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 [5%]; Melanoma Institute of Australia, 16 of 337 [5%]). Time to onset of pneumonitis ranged from 9 days to 19.2 months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 [10%] v 24 of 716 [3%]; P < .01). Incidence was similar in patients with melanoma and non–small-cell lung cancer (overall, 26 of 532 [5%] v nine of 209 [4%]; monotherapy, 15 of 417 v five of 152 [ P = 1.0]; combination, 11 of 115 v four of 57 [ P = .78]). Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. Conclusion Pneumonitis associated with anti–PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti–PD-1/PD-L1 mAbs are combined with anti–cytotoxic T-cell lymphocyte associated antigen-4 mAb. Most events are low grade and improve/resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.

// Takashi Eguchi 1, 2 , Kyuichi Kadota 3, 4 , Jamie Chaft 5 , Brent Evans 6 , John Kidd 6 , Kay See Tan 7 , Joe Dycoco 1 , Kathryn Kolquist 6 , Thaylon Davis 6 , Stephanie A. Hamilton 6 , Kraig Yager 6 , Joshua T. Jones 6 , William D. Travis 3 , David R. Jones 1 , Anne-Renee Hartman 6 , Prasad S. Adusumilli 1, 8 1 Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA 2 Division of Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan 3 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 4 Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan 5 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 6 Myriad Genetic Laboratories, Inc., Salt Lake City, UT, USA 7 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA 8 Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA Correspondence to: Prasad S. Adusumilli, email: adusumip@mskcc.org Keywords: molecular prognostic score, CCP score, chemotherapy, adjuvant therapy, overall survival Received: February 08, 2016 Accepted: April 16, 2016 Published: May 2, 2016 ABSTRACT Purpose: The goals of our study were (a) to validate a molecular expression signature (cell cycle progression [CCP] score and molecular prognostic score [mPS; combination of CCP and pathological stage {IA or IB}]) that identifies stage I lung adenocarcinoma (ADC) patients with a higher risk of cancer-specific death following curative-intent surgical resection, and (b) to determine whether mPS stratifies prognosis within stage I lung ADC histological subtypes. Methods: Formalin-fixed, paraffin-embedded stage I lung ADC tumor samples from 1200 patients were analyzed for 31 proliferation genes by quantitative RT-PCR. Prognostic discrimination of CCP score and mPS was assessed by Cox proportional hazards regression, using 5-year lung cancer–specific mortality as the primary outcome. Results: In multivariable analysis, CCP score was a prognostic marker for 5-year lung cancer–specific mortality (HR=1.6 per interquartile range; 95% CI, 1.14–2.24; P =0.006). In a multivariable model that included mPS instead of CCP, mPS was a significant prognostic marker for 5-year lung cancer–specific mortality (HR=1.77; 95% CI, 1.18–2.66; P =0.006). Five-year lung cancer–specific survival differed between low-risk and high-risk mPS groups (96% vs 81%; P

Introduction In patients with resected lung cancer, sarcomatoid carcinomas are reputed to carry a worse prognosis. Although generally felt to be chemo-refractory, little data are available about chemotherapy in these patients. We sought to determine the effect of perioperative chemotherapy in patients with completely resected sarcomatoid carcinomas of the lung. Methods We reviewed the pathology reports of 4675 patients consecutively resected at Memorial Sloan-Kettering between 2000 and 2010. Charts and images were reviewed for patients with a histologic diagnosis of sarcomatoid carcinoma. Response to neoadjuvant chemotherapy was assessed radiographically. Kaplan-Meier disease-free probability (DFP) curves were compared for patients who did and did not receive perioperative chemotherapy, stratified by pathological stage. Results Of the 4675 patients who underwent an R0 lung cancer resection, 56 (1%) were diagnosed with sarcomatoid carcinomas. Twenty received neoadjuvant and/or adjuvant chemotherapy. Overall radiographic response rate (minor + major) to neoadjuvant chemotherapy was 73% (95% confidence interval 48-90%) in the 15 evaluable patients. The median DFP of patients who received chemotherapy was 34 months versus 12 months in those who did not (p = 0.37). Subset analysis did not reveal a benefit to perioperative chemotherapy in patients with stage Ib-IIa, whereas a benefit was seen in patients with IIb-IIIa disease (p = 0.02). Conclusions Although sarcomatoid carcinomas are felt to be chemo-refractory, our results demonstrate radiographic responses to neoadjuvant chemotherapy and an improvement in DFP in patients with stage IIb-IIIa disease. The use of pathological stage in this analysis may underestimate this benefit. Perioperative chemotherapy should be considered in these patients.

Background Lung adenocarcinomas can be distinguished by identifying mutated driver oncogenes, including epidermal growth factor receptor (EGFR) and KRAS. Mutations in EGFR are associated with both improved survival as well as response to treatment with erlotinib and gefitinib. However, the prognostic significance of KRAS has not been evaluated in large numbers of patients and remains controversial. For the current report, the authors examined the association of EGFR and KRAS mutations with survival among patients with advanced lung adenocarcinomas. Methods Data were analyzed from patients with advanced lung adenocarcinomas who had known EGFR and KRAS mutation status evaluated between 2002 and 2009. The collected clinical variables included age, sex, Karnofsky performance status, smoking history, and treatment history. Overall survival from the diagnosis of advanced disease was analyzed using Kaplan-Meier and Cox proportional hazard methods. Results In total, 1036 patients were evaluated, including 610 women (59%) and 344 never-smokers (33%). The median patient age was 65 years (range, 25-92 years), and the majority of patients (81%) had a Karnofsky performance status ≥80%. In multivariate analysis, EGFR mutations were associated with longer overall survival (hazard ratio, 0.6; P Conclusions KRAS mutations predicted shorter survival for patients with advanced lung adenocarcinomas. The presence of EGFR and KRAS mutations define distinct subsets of patients with lung adenocarcinomas and should be determined in patients when they are diagnosed with advanced disease. Clinical trial reports should include EGFR and KRAS mutation status along with other prognostic factors.

Phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3CA) encodes the p110α subunit of the mitogenic signaling protein phosphoinositide 3-kinase (PI3K). PIK3CA mutations in the helical binding domain and the catalytic subunit of the protein have been associated with tumorigenesis and treatment resistance in various malignancies. Characteristics of patients with PIK3CA-mutant lung adenocarcinomas have not been reported. We examined epidermal growth factor receptor (EGFR), Kirsten rate sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), human epidermal growth factor receptor 2 (HER2), PIK3CA, v-akt murine thymoma vial oncogene homolog 1 (AKT1), v-ras neuroblastoma viral oncogene homolog (NRAS), dual specificity mitogen-activated protein kinase kinase 1 (MEK1), and anaplastic lymphoma kinase (ALK) in patients with adenocarcinoma of the lung to identify driver mutations. Clinical data were obtained from the medical records of individuals with mutations in PIK3CA. Twenty-three of 1,125 (2%, 95% CI: 1–3) patients had a mutation in PIK3CA, 12 in exon 9 (10 E545K and 2 E542K), and 11 in exon 20 (3 H1047L and 8 H1047R). The patients (57% women) had a median age of 66 at diagnosis (range: 34–78). Eight patients (35%) were never smokers. Sixteen of 23 (70%, 95% CI: 49–86) had coexisting mutations in other oncogenes—10 KRAS, 1 MEK1, 1 BRAF, 1 ALK rearrangement, and 3 EGFR exon 19 deletions. We conclude that PIK3CA mutations occur in lung adenocarcinomas, usually concurrently with EGFR, KRAS, and ALK. The impact of PIK3CA mutations on the efficacy of targeted therapies such as erlotinib and crizotinib is unknown. Given the high frequency of overlapping mutations, comprehensive genotyping should be carried out on tumor specimens from patients enrolling in clinical trials of PI3K and other targeted therapies. Mol Cancer Ther; 11(2); 485–91. ©2011 AACR.

The treatment of patients with metastatic non–small cell lung cancer (NSCLC) is slowly evolving from empirical cytotoxic chemotherapy to personalized treatment based on specific molecular alterations. Despite this 10-year evolution, targeted therapies have not been studied adequately in patients with resected NSCLC who have clearly defined actionable mutations. The advent of next-generation sequencing has now made it possible to characterize genomic alterations in unprecedented detail. The efforts begun by The Cancer Genome Atlas project to understand the complexities of the genomic landscape of lung cancer will be supplemented further by studying a large number of tumor specimens. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is an NCI-sponsored national clinical trials network (NCTN) initiative to address the needs to refine therapy for early-stage NSCLC. This program will screen several thousand patients with operable lung adenocarcinoma to determine whether their tumors contain specific molecular alterations [epidermal growth factor receptor mutation (EGFR) and anaplastic lymphoma kinase rearrangement (ALK)], making them eligible for treatment trials that target these alterations. Patients with EGFR mutation or ALK gene rearrangement in their tumor will be randomized to placebo versus erlotinib or crizotinib, respectively, after completion of their standard adjuvant therapy. ALCHEMIST will also contain a large discovery component that will provide an opportunity to incorporate genomic studies to fully understand the clonal architecture, clonal evolution, and mechanisms of resistance to therapy. In this review, we describe the concept, rationale, and outline of ALCHEMIST and the plan for genomic studies in patients with lung adenocarcinoma. Clin Cancer Res; 21(24); 5439–44. ©2015 AACR.

T cell checkpoint inhibitors targeting the programmed death receptor-1 (PD-1) and its ligand (PDL-1) have recently been approved for the treatment of metastatic non-small cell lung cancer (NSCLC), but their safety and efficacy as neoadjuvant therapy are still undefined. Autoimmune toxicities, notably pneumonitis, are a particular concern in the perioperative setting. This series of 5 cases describes for the first time the safety and technical issues relating to pulmonary resection after checkpoint inhibitor therapy.

Purpose: Treatment of patients with oncogene-addicted cancers with tyrosine kinase inhibitors (TKI) is biologically and clinically different than with cytotoxic chemotherapy. We have observed that some patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib (RECIST progression after initial benefit) have accelerated progression of disease after discontinuation of TKI. To examine this observation and define the course of patients following TKI discontinuation, we systematically evaluated patients enrolled on clinical trials of agents to treat acquired resistance to erlotinib or gefitinib. Methods: We evaluated patients with EGFR-mutant lung cancer who participated in trials for patients with acquired resistance that mandated TKI discontinuation before administration of study therapy. Disease flare was defined as hospitalization or death attributable to disease progression during the washout period. Results: Fourteen of 61 patients (23%; 95% CI: 14–35) experienced a disease flare. The median time to disease flare after TKI discontinuation was 8 days (range 3–21). Factors associated with disease flare included shorter time to progression on initial TKI (P = 0.002) and the presence of pleural (P = 0.03) or CNS disease (P = 0.01). There was no association between disease flare and the presence of T790M at the time of acquired resistance. Conclusions: In patients with EGFR-mutant lung cancer and acquired resistance to epidermal growth factor receptor TKIs, discontinuation of erlotinib or gefitinib before initiation of study treatment is associated with a clinically significant risk of accelerated disease progression. Clinical trials in this patient population must minimize protocol-mandated washout periods. Clin Cancer Res; 17(19); 6298–303. ©2011 AACR.

Purpose: To determine if tumor regression following treatment with gefitinib correlates with the presence of sensitizing mutations in epidermal growth factor receptor (EGFR). Patients and Methods: Patients with resectable stage I and II non–small cell lung cancer (NSCLC) enriched for the likelihood of EGFR mutation (≤15 pack-year cigarette smoking history and/or a component of bronchioloalveolar carcinoma) received preoperative gefitinib for 21 days. Tumor specimens were analyzed for EGFR and KRAS mutations and EGFR protein expression and amplification. Patients with 25% or more reduction in tumor size measured bidimensionally at 3 weeks and/or patients with an EGFR mutation received adjuvant gefitinib for 2 years postoperatively. Results: Fifty patients with stage I/II NSCLC were treated. After 21 days of preoperative gefitinib a response of 25% or more was observed in 21 of 50 (42%) patients. Seventeen of 21 patients with a response had an EGFR mutation and 4 of 21 patients with a response did not (P = 0.0001). Twenty-five of 50 patients were eligible to receive adjuvant gefitinib. With a median follow-up of 44.1 months, 2-year disease free survival for EGFR mutant patients and for those who received adjuvant gefitinib was not statistically different than those who were EGFR wild-type and those who did not receive adjuvant gefitinib. The median disease free and overall survivals have not been reached. Conclusions: The presence of sensitizing EGFR mutations correlates with radiographic response. A short course of preoperative treatment serves a platform for evaluating activity of new agents and assures sufficient tumor availability for correlative analyses. Clin Cancer Res; 17(10); 3500–6. ©2011 AACR.

Background: The anti-PD-L1 antibody durvalumab (D) has shown manageable safety and encouraging clinical activity in patients with advanced NSCLC. Combination of D with anti-CTLA-4 antibody tremelimumab (T) may amplify T-cell responses against tumors through non-redundant immune checkpoint blockade and provide synergistic antitumor activity. We previously reported that D+T showed antitumor activity and manageable tolerability in the dose-escalation part of a phase 1b study (NCT02000947) of patients with advanced NSCLC. Here we present safety, clinical activity, and long-term follow-up for one of 3 expansion cohorts. Methods: Immunotherapy-naive patients with non-squamous NSCLC who progressed after 1 prior platinum-based therapy, ECOG PS 0-1, received D IV 20 mg/kg every 4 weeks (Q4W) for up to 12 months and T IV 1 mg/kg Q4W with the first 4 cycles of D. Tumor PD-L1 expression (fresh biopsy or archival sample within 3 mo) was assessed with the Ventana PD-L1 (SP263) assay, PD-L1 cutoff: ≥25% of tumor cells with membrane staining. Results: As of 20 Oct 2017, 213 patients (71% ECOG PS 1) received therapy and were followed for a median of 13.3 (0.5-21.0) mo. Treatment-related adverse events (AEs) were reported in 76% of patients; the most common were fatigue (19%), pruritus (17%), diarrhea (15%), decreased appetite (14%), and rash (14%). 14 patients (7%) had a treatment-related AE leading to discontinuation, with colitis (1%), diarrhea (1%), and pneumonitis (1%) reported in more than 1 patient. Grade 3/4 treatment-related AEs occurred in 23% of patients; the most common were increased lipase (5%), colitis (3%), and increased amylase (3%). There was 1 treatment-related death (multifactorial hypoxia). The 12-month OS rate was 53.8% (95% CI, 46.4-60.6). The Table shows antitumor activity and survival by PD-L1 status. Conclusions: Second-line D+T had a manageable safety profile in patients with non-squamous NSCLC. Clinical activity was seen in both PD-L1 ≥25% and Response and survivalPD-L1 ≥25% n=57PD-L1 Citation Format: Jamie Chaft, Byoung Chul Cho, Myung-Ju Ahn, Sylvestre Le Moulec, Eun Kyung Cho, Vassiliki Papadimitrakopoulou, Edward Garon, Sylvia Lee, Santiago Ponce Aix, Patrick C. Ma, Gregory Otterson, Rajesh Narwal, Guozhi Gao, Jennifer McDevitt, Judson Englert, Scott Antonia. Safety and activity of second-line durvalumab + tremelimumab in non-squamous advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT113.

There is great interest in using PD-(L)1 blockading drugs as neoadjuvant therapy for patients with resectable NSCLC. Early results demonstrated a 45% (9/20) major pathologic response (MPR) rate in patients with Stage I-III NSCLC after receiving nivolumab (NCT02259621). Major pathologic response (MPR) criteria were developed in the context of cytotoxic chemotherapy, defined as ≤10% residual viable tumor cells (RVT). The features of immune-mediated tumor regression following anti-PD-1 have yet to be described. We reviewed H&E-stained slides from resection specimens in 19 patients treated with neoadjuvant nivolumab [n=9 MPR, n=3 partial responders, n=7 non-responders (>70% RVT)] to identify histopathologic features of immune-mediated tumor regression. Specimens were assessed for immune characteristics (tumor infiltrating lymphocyte (TIL) and macrophage density, and presence/absence of, lymphoid aggregates, tertiary lymphoid structures (TLS), dense plasma cell infiltrates, neutrophils, giant cells, etc.) and non-immune features (necrosis, hemosiderin, hyalinized and proliferative fibrosis). We found that immune-mediated tumor regression is characterized by a fibroinflammatory stroma with features of (1) immune activation, including dense TIL and macrophages, TLS, and granulomas; (2) massive [tumor] cell death, including cholesterol clefts and giant cells; and (3) tissue repair, including neovascularization and proliferative fibrosis (each enriched in MPR vs. non-responders, Fisher's exact test p Citation Format: Tricia R. Cottrell, Julie E. Stein, Jamie E. Chaft, Elizabeth D. Thompson, Natasha Rekhtman, Valsamo Anagnostou, Kellie N. Smith, Amy S. Duffield, Robert A. Anders, James M. Isbell, David R. Jones, Jonathan D. Cuda, Richard Battafarano, Stephen C. Yang, Peter B. Illei, Edward Gabrielson, Frederic Askin, Moises Velez, Matthew D. Hellmann, Jennifer L. Sauter, Ludmila Danilova, Victor E. Velculescu, Jedd D. Wolchok, Suzanne L. Topalian, Julie R. Brahmer, Drew M. Pardoll, Ashley Cimino-Mathews, Patrick M. Forde, Janis M. Taube. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small cell lung carcinoma (NSCLC): A proposal for quantitative immune-related pathologic response criteria (irPRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-154.

TPS8581Background: There have been no advances in the systemic treatment of resected lung cancers in the last decade. In contrast, targeted therapies and immunotherapies have demonstrated benefit i...

9022Background: The transcendent feature of response to anti-PD-(L)1 therapy is durable, long-term responses, which can last up to years. Much effort in biomarkers has focused exclusively on initia...

9003Background: Treatment with PD-(L)1 inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of steroids may reduce efficacy of PD-(L)1 blockade. On-treatme...

8541Background: Platinum-based chemotherapy, before or after surgery, provides only a 5% benefit in 5yr. OS in locally advanced NSCLC. A recent pilot study (JCO 2017 35:15suppl, 8508) showed that p...

9041Background: The combination of anti-PD-L1 antibody durvalumab (D) with anti-CTLA-4 antibody tremelimumab (T) showed antitumor activity and manageable tolerability in IMT-naive patients with adv...

Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC.