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Purpose: We pursued genomic analysis of an exceptional responder with non–small cell lung cancer (NSCLC) through a multi-platform effort to discover novel oncogenic targets. Experimental Design: In this open-label, single-arm phase II study (NCT01829217), an enriched cohort of patients with advanced NSCLC was treated with the multi-kinase inhibitor sunitinib. The primary endpoint was objective response rate. Tissue was collected for multi-platform genomic analysis of responders, and a candidate oncogene was validated using in vitro models edited by CRISPR-Cas9. Results: Of 13 patients enrolled, 1 patient (8%), a never smoker, had a partial response lasting 33 months. Genomic analysis of the responder identified no oncogenic variant using multi-platform DNA analysis including hotspot allelotyping, massively parallel hybrid-capture next-generation sequencing, and whole-exome sequencing. However, bulk RNA-sequencing (RNA-seq) revealed a novel fusion, TMEM87A–RASGRF1, with high overexpression of the fusion partners. RASGRF1 encodes a guanine exchange factor which activates RAS from GDP-RAS to GTP-RAS. Oncogenicity was demonstrated in NIH/3T3 models with intrinsic TMEM87A–RASGRF1 fusion. In addition, activation of MAPK was shown in PC9 models edited to express this fusion, although sensitivity to MAPK inhibition was seen without apparent sensitivity to sunitinib. Conclusions: Sunitinib exhibited limited activity in this enriched cohort of patients with advanced NSCLC. Nonetheless, we find that RNA-seq of exceptional responders represents a potentially underutilized opportunity to identify novel oncogenic targets including oncogenic activation of RASGRF1.

Purpose: Evaluating drug responses using primary patient-derived cells ex vivo represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib combinations in HER2 mutant non–small cell lung cancer (NSCLC) patient xenograft-derived organotypic spheroids (XDOTS) using a short-term ex vivo system. Experimental Design: We generated two HER2-mutant NSCLC PDX models [DFCI359 (HER2 exon19 755_757LREdelinsRP) and DFCI315 (HER2 exon20 V777_G778insGSP)] and used the PDX tumors to generate XDOTS. Tumor spheroids were grown in a microfluidic device and treated ex vivo with neratinib-based drug combinations. Live/dead quantification was performed by dual-labeling deconvolution fluorescence microscopy. The most efficacious ex vivo combination was subsequently validated in vivo using the DFCI359 and DFCI315 PDXs and a HER2YVMA genetically engineered mouse model. Results: Both neratinib and afatinib, but not gefitinib, induced cell death in DFCI359 XDOTS. The combinations of neratinib/trastuzumab and neratinib/temsirolimus enhanced the therapeutic benefit of neratinib alone in DFCI315 and DFCI359. The combination of neratinib and trastuzumab in vivo was more effective compared with single-agent neratinib or trastuzumab and was associated with more robust inhibition of HER2 and downstream signaling. Conclusions: The XDOTS platform can be used to evaluate therapies and therapeutic combinations ex vivo using PDX tumors. This approach may accelerate the identification and clinical development of therapies for targets with no or few existing models and/or therapies.

PURPOSE Baseline use of corticosteroids is associated with poor outcomes in patients with non–small-cell lung cancer (NSCLC) treated with programmed cell death-1 axis inhibition. To approach the question of causation versus correlation for this association, we examined outcomes in patients treated with immunotherapy depending on whether corticosteroids were administered for cancer-related palliative reasons or cancer-unrelated indications. PATIENTS AND METHODS Clinical outcomes in patients with NSCLC treated with immunotherapy who received ≥ 10 mg prednisone were compared with outcomes in patients who received 0 to < 10 mg of prednisone. RESULTS Of 650 patients, the 93 patients (14.3%) who received ≥ 10 mg of prednisone at the time of immunotherapy initiation had shorter median progression-free survival (mPFS) and median overall survival (mOS) times than patients who received 0 to < 10 mg of prednisone (mPFS, 2.0 v 3.4 months, respectively; P = .01; mOS, 4.9 v 11.2 months, respectively; P < .001). When analyzed by reason for corticosteroid administration, mPFS and mOS were significantly shorter only among patients who received ≥ 10 mg prednisone for palliative indications compared with patients who received ≥ 10 mg prednisone for cancer-unrelated reasons and with patients receiving 0 to < 10 mg of prednisone (mPFS, 1.4 v 4.6 v 3.4 months, respectively; log-rank P < .001 across the three groups; mOS, 2.2 v 10.7 v 11.2 months, respectively; log-rank P < .001 across the three groups). There was no significant difference in mPFS or mOS in patients receiving ≥ 10 mg of prednisone for cancer-unrelated indications compared with patients receiving 0 to < 10 mg of prednisone. CONCLUSION Although patients with NSCLC treated with ≥ 10 mg of prednisone at the time of immunotherapy initiation have worse outcomes than patients who received 0 to < 10 mg of prednisone, this difference seems to be driven by a poor-prognosis subgroup of patients who receive corticosteroids for palliative indications.

Objectives The ECOG‐ACRIN Cancer Research Group trial E2511 recently demonstrated a potential benefit for the addition of veliparib to cisplatin‐etoposide (CE) in patients with extensive stage small cell lung cancer (ES‐SCLC) in a phase II randomized controlled trial. Secondary trial endpoints included comparison of the incidence and severity of neurotoxicity, hypothesized to be lower in the veliparib arm, and tolerability of the addition of veliparib to CE. Physician‐rated and patient‐reported neurotoxicity was also compared. Materials and Methods Patients randomized to veliparib plus CE (n = 64) or placebo plus CE (n = 64) completed the 11‐item Functional Assessment of Cancer Therapy Gynecologic Oncology Group Neurotoxicity (questionnaire pre‐treatment, end of cycle 4 [ie 3 months after randomization] and 3 months post‐treatment [ie 6‐months]). Adherence analysis was based on treatment forms. Results and Conclusion No significant differences in mean or magnitude of change in neurotoxicity scores were observed between treatment arms at any time point. However, patients in the placebo arm reported worsening neurotoxicity from baseline to 3‐months (M difference = −1.5, P = .045), compared to stable neurotoxicity in the veliparib arm (M difference = −0.2, P = .778). Weakness was the most common treatment‐emergent (>50%) and moderate to severe (>16%) symptom reported, but did not differ between treatment arms. The proportion of adherence to oral therapy in the overall sample was 75%. Three percent of patients reported clinically significant neurotoxicity that was not captured by physician assessment. Neurotoxicity scores were not different between treatment arms. The addition of veliparib to CE appeared tolerable, though weakness should be monitored. ClinicalTrials.gov Identifier NCT01642251., We examined patient‐reported tolerability of the addition of a PARP inhibitor, veliparib, to cisplatin‐etoposide for treatment of extensive stage small cell lung cancer in randomized controlled trial E2511. The addition of veliparib to cisplatin‐etoposide was tolerable according to a patient‐reported outcome and adherence. Future studies should assess whether veliparib may have a protective effect against chemotherapy‐induced peripheral neuropathy.

PURPOSE Heterogeneity in tumor mutational burden (TMB) quantification across sequencing platforms limits the application and further study of this potential biomarker of response to immune checkpoint inhibitors (ICIs). We hypothesized that harmonization of TMB across platforms would enable integration of distinct clinical data sets to better characterize the association between TMB and ICI response. METHODS Cohorts of patients with non–small-cell lung cancer sequenced by 1 of 3 targeted panels or by whole-exome sequencing (WES) were compared (N = 7,297). TMB was calculated uniformly and compared across cohorts. TMB distributions were harmonized by applying a normal transformation followed by standardization to z scores. In subcohorts of patients treated with ICIs (Dana-Farber Cancer Institute n = 272; Memorial Sloan Kettering Cancer Center n = 227), the association between TMB and outcome was assessed. Durable clinical benefit (DCB) was defined as responsive/stable disease lasting ≥ 6 months. RESULTS TMB values were higher in the panel cohorts than in the WES cohort. Average mutation rates per gene were highly concordant across cohorts (Pearson’s correlation coefficients, 0.842-0.866). Subsetting the WES cohort by gene panels only partially reproduced the observed differences in TMB. Standardization of TMB into z scores harmonized TMB distributions and enabled integration of the ICI-treated subcohorts. Simulations indicated that cohorts > 900 are necessary for this approach. TMB did not associate with response in never-smokers or patients who harbor targetable driver alterations, although these analyses were underpowered. An increase of TMB thresholds increased DCB rate, but DCB rates within deciles varied. Receiver operating characteristic curves yielded an area under the curve of 0.614, with no natural inflection point. CONCLUSION The z score conversion harmonizes TMB values and enables integration of data sets derived from different sequencing panels. Clinical and biologic features may provide context to the clinical application of TMB and warrant additional study.

Purpose Although programmed death (PD)-1 pathway inhibitors are now used in nearly all patients with advanced non–small-cell lung cancer (NSCLC), the large number of patients with NSCLC and concurrent autoimmune disease (AID) have been universally excluded from immunotherapy clinical trials. Therefore, the safety of PD-1 and PD-ligand 1 (PD-L1) inhibitors in patients with NSCLC and underlying AID is currently unknown. Methods As part of a multi-institutional effort, we retrospectively collected clinicopathologic data from patients with NSCLC and a history of AID who received monotherapy with either a PD-1 or a PD-L1 (herein referred to as PD-[L]1) inhibitor. Qualifying AIDs included but were not limited to: rheumatologic, neurologic, endocrine, GI, and dermatologic conditions. Results We identified 56 patients with NSCLC and an AID who received a PD-(L)1 inhibitor. At the time of treatment initiation, 18% of patients had active AID symptoms and 20% were receiving immunomodulatory agents for their AID. A total of 55% of patients developed an AID flare and/or an immune-related adverse event (irAE). Exacerbation of the AID occurred in 13 patients (23% of the whole cohort), four of whom required systemic corticosteroids. Immune-related adverse events occurred in 21 patients (38%). Among irAEs, 74% were grade 1 or 2 and 26% were grade 3 or 4; eight patients required corticosteroids for irAE management. PD-(L)1 therapy was permanently discontinued in eight patients (14%) because of irAEs. The overall response rate to immunotherapy in this population was 22%. Conclusion In patients with NSCLC with AID treated with a PD-(L)1 inhibitor, exacerbation of AID occurred in a minority of patients. The incidence of irAEs was similar to reported rates in clinical trials where patients with AID were excluded. Adverse events were generally manageable and infrequently led to permanent discontinuation of immunotherapy.

Background Programmed cell death protein 1 inhibitors increasingly are being used to treat patients with advanced lung carcinomas. Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) in tumor cells (TCs) and tumor-infiltrating immune cells (ICs) is used to select patients for programmed cell death protein 1 inhibition, but few studies have evaluated PD-L1 IHC in cytology specimens. The objective of the current study was to compare PD-L1 IHC in cytology cell blocks and matched surgical specimens. Methods A total of 56 cytology specimens obtained between 2013 and 2016 with matching surgical specimens were stained with anti-PD-L1. Membranous positivity was scored as a percentage of the TCs and ICs by 2 pathologists. Results were compared between cytology and surgical specimens, and interobserver concordance was assessed. Results The average PD-L1 positivity rate was 28% in TCs and 5% in ICs in surgical specimens (standard deviations of 37% and 7%, respectively), and 21% in TCs and 8% in ICs in cytology specimens (standard deviations of 33% and 15%, respectively). Interobserver concordance was high for TCs in surgical and cytology specimens (intraclass correlation coefficients of 0.96 and 0.96, respectively), and was moderate for ICs in surgical and cytology specimens (intraclass correlation coefficients of 0.47 and 0.67, respectively). There was moderate to high correlation between PD-L1 positivity in TCs between surgical and cytology specimens (Spearman correlation coefficient [Spearman r], 0.69), particularly among fine-needle aspiration specimens (Spearman r, 0.78), but not between PD-L1 positivity in ICs in surgical and cytology specimens (Spearman r, 0.14), including among fine-needle aspiration specimens (Spearman r, 0.23). Conclusions Tumor PD-L1 IHC positivity in cytology specimens appears to correlate strongly with results obtained from matching surgical specimens. PD-L1 IHC in ICs within cytology specimens does not reflect results in matched surgical specimens and should not be used in clinical decision making. Cancer Cytopathol 2018;126:253-63. © 2018 American Cancer Society.

Purpose: Genotype-directed therapy is the standard of care for advanced non–small cell lung cancer (NSCLC), but obtaining tumor tissue for genotyping remains a challenge. Circulating tumor cell (CTC) or cell-free DNA (cfDNA) analysis may allow for noninvasive evaluation. This prospective trial evaluated CTCs and cfDNA in EGFR-mutant NSCLC patients treated with erlotinib until progression. Experimental Design: EGFR-mutant NSCLC patients were enrolled in a phase II trial of erlotinib. Blood was collected at baseline, every 2 months on study, and at disease progression. Plasma genotyping was performed by droplet digital PCR for EGFR19del, L858R, and T790M. CTCs were isolated by CellSave, enumerated, and analyzed by immunofluorescence for CD45 and pan-cytokeratin and EGFR and MET FISH were also performed. Rebiopsy was performed at disease progression. Results: Sixty patients were enrolled; 44 patients discontinued therapy for disease progression. Rebiopsy occurred in 35 of 44 patients (80%), with paired CTC/cfDNA analysis in 41 of 44 samples at baseline and 36 of 44 samples at progression. T790M was identified in 23 of 35 (66%) tissue biopsies and 9 of 39 (23%) cfDNA samples. CTC analysis at progression identified MET amplification in 3 samples in which tissue analysis could not be performed. cfDNA analysis identified T790M in 2 samples in which rebiopsy was not possible. At diagnosis, high levels of cfDNA but not high levels of CTCs correlated with progression-free survival. Conclusions: cfDNA and CTCs are complementary, noninvasive assays for evaluation of acquired resistance to first-line EGFR TKIs and may expand the number of patients in whom actionable genetic information can be obtained at acquired resistance. Serial cfDNA monitoring may offer greater clinical utility than serial monitoring of CTCs. Clin Cancer Res; 22(24); 6010–20. ©2016 AACR.

Phase I cancer trials increasingly incorporate dose-expansion cohorts (DECs), reflecting a growing demand to acquire more information about investigational drugs. Protocols commonly fail to provide a sample-size justification or analysis plan for the DEC. In this study, we develop a statistical framework for the design of DECs.We assume the maximum tolerated dose (MTD) for the investigational drug has been identified in the dose-escalation stage of the trial. We use the 80% lower confidence bound and the 90% upper confidence bound for the response and toxicity rates, respectively, as decision thresholds for the dose-expansion stage. We calculate the operating characteristics with reference to prespecified minimum effective response rates and maximum safe DLT rates.We apply our framework to specify a system of DEC plans. The design comprises three components: 1) the number of subjects enrolled at the MTD, 2) the minimum number of responses necessary to indicate provisional drug efficacy, and 3) the maximum number of dose-limiting toxicities (DLTs) permitted to indicate drug safety. We demonstrate our method in an application to a cancer immunotherapy trial.Our simple and practical tool enables creation of DEC designs that appropriately address the safety and efficacy objectives of the trial.

PURPOSE Pemetrexed or bevacizumab is used for maintenance therapy of advanced nonsquamous non–small-cell lung cancer (NSCLC). The combination of bevacizumab and pemetrexed has also demonstrated efficacy. We conducted a randomized study to determine the optimal maintenance therapy. PATIENTS AND METHODS Patients with advanced nonsquamous NSCLC and no prior systemic therapy received carboplatin (area under the curve, 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg) for up to four cycles. Patients without progression after four cycles were randomly assigned to maintenance therapy with bevacizumab (15 mg/kg), pemetrexed (500 mg/m2), or a combination of the two agents. The primary end point was overall survival, with bevacizumab serving as the control group. RESULTS Of the 1,516 patients enrolled, 874 (57%) were randomly assigned after induction therapy to one of the three maintenance therapy groups. With a median follow-up of 50.6 months, median survival with pemetrexed was 15.9 months, compared with 14.4 months with bevacizumab (hazard ratio [HR], 0.86; P = .12); median survival with pemetrexed and bevacizumab was 16.4 months (HR, 0.9; P = .28); median progression-free survival was 4.2, 5.1 (HR, 0.85; P = .06), and 7.5 months (HR, 0.67; P < .001) for the three groups, respectively. Incidence of worst grade 3 to 4 toxicity was 29%, 37%, and 51%, respectively, for bevacizumab, pemetrexed, and the combination regimen. CONCLUSION Single-agent bevacizumab or pemetrexed is efficacious as maintenance therapy for advanced nonsquamous NSCLC. Because of a lack of survival benefit and higher toxicity, the combination of bevacizumab and pemetrexed cannot be recommended.

Background Clinically-available biomarkers to identify the fraction of patients with small cell lung cancer (SCLC) who respond to immune-checkpoint inhibitors (ICIs) are lacking. High nonsynonymous tumor mutational burden (TMB), as assessed by whole exome sequencing, correlates with improved clinical outcomes for patients with SCLC treated with ICIs. Whether TMB as assessed by targeted next generation sequencing (NGS) is associated with improved efficacy of ICIs in patients with SCLC is currently unknown. Here we determined whether TMB by targeted NGS is associated with efficacy of ICIs in patients with SCLC. Methods We collected clinicopathologic data from patients with relapsed or refractory SCLC which underwent targeted NGS with TMB assessment by the Dana-Farber Cancer Institute OncoPanel platform. The relationship between TMB and clinical outcomes after treatment with ICIs was investigated. Results Among the 52 patients treated with ICIs, we found no significant difference in the objective response rate (ORR) between patients with a TMB above the 50th percentile (“TMB high”) and those with a TMB at or below the 50th percentile (“TMB low”). The median progression-free survival (mPFS) and median overall survival (mOS) were significantly longer in patients with a high TMB compared to those with a low TMB (mPFS: 3.3 versus 1.2 months, HR: 0.37 [95% CI: 0.20–0.69], P

Objectives Although dramatic responses to MET inhibitors have been reported in patients with MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC), the impact of these treatments on overall survival in this population is unknown. Methods We conducted a multicenter retrospective analysis of patients with METex14 NSCLC to determine if treatment with MET inhibitors impacts median overall survival (mOS). Event-time distributions were estimated using the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox models were fitted to estimate hazard ratios. Results We identified 148 patients with METex14 NSCLC; the median age was 72; 57% were women and 39% were never smokers. Of the 34 metastatic patients who never received a MET inhibitor, the mOS was 8.1 months; those in this group with concurrent MET amplification had a trend toward worse survival compared to cancers without MET amplification (5.2 months vs 10.5 months, P = 0.06). Of the 27 metastatic patients who received at least one MET inhibitor the mOS was 24.6 months. A model adjusting for receipt of a MET inhibitor as first- or second-line therapy as a time-dependent covariate demonstrated that treatment with a MET inhibitor was associated with a significant prolongation in survival (HR 0.11, 95% CI 0.01-0.92, P = 0.04) compared to patients who did not receive any MET inhibitor. Among 22 patients treated with crizotinib, the median progression-free survival was 7.4 months. Discussion For patients with METex14 NSCLC, treatment with a MET inhibitor is associated with an improvement in overall survival.

Purpose Veliparib, a poly (ADP ribose) polymerase inhibitor, potentiated standard chemotherapy against small-cell lung cancer (SCLC) in preclinical studies. We evaluated the combination of veliparib with cisplatin and etoposide (CE; CE+V) doublet in untreated, extensive-stage SCLC (ES-SCLC). Materials and Methods Patients with ES-SCLC, stratified by sex and serum lactate dehydrogenase levels, were randomly assigned to receive four 3-week cycles of CE (75 mg/m2 intravenously on day 1 and 100 mg/m2 on days 1 through 3) along with veliparib (100 mg orally twice per day on days 1 through 7) or placebo (CE+P). The primary end point was progression-free survival (PFS). Using an overall one-sided 0.10-level log-rank test, the study had 88% power to demonstrate a 37.5% reduction in the PFS hazard rate. Results A total of 128 eligible patients received treatment on protocol. The median age was 66 years, 52% of patients were men, and Eastern Cooperative Oncology Group performance status was 0 for 29% of patients and 1 for 71%. The respective median PFS for the CE+V arm versus the CE+P arm was 6.1 versus 5.5 months (unstratified hazard ratio [HR], 0.75 [one-sided P = .06]; stratified HR, 0.63 [one-sided P = .01]), favoring CE+V. The median overall survival was 10.3 versus 8.9 months (stratified HR, 0.83; 80% CI, 0.64 to 1.07; one-sided P = .17) for the CE+V and CE+P arms, respectively. The overall response rate was 71.9% versus 65.6% (two-sided P = .57) for CE+V and CE+P, respectively. There was a significant treatment-by-strata interaction in PFS: Male patients with high lactate dehydrogenase levels derived significant benefit (PFS HR, 0.34; 80% CI, 0.22 to 0.51) but there was no evidence of benefit among patients in other strata (PFS HR, 0.81; 80% CI, 0.60 to 1.09). The following grade ≥ 3 hematology toxicities were more frequent in the CE+V arm than the CE+P arm: CD4 lymphopenia (8% v 0%; P = .06) and neutropenia (49% v 32%; P = .08), but treatment delivery was comparable. Conclusion The addition of veliparib to frontline chemotherapy showed signal of efficacy in patients with ES-SCLC and the study met its prespecified end point.

BACKGROUND Erlotinib is a standard first-line therapy for patients who have metastatic nonsmall cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The recommended dose of 150 mg daily is the maximum tolerated dose (MTD). Few clinical data are available regarding its efficacy at doses less than the MTD. METHODS An institutional database was queried for patients with advanced NSCLC who were positive for EGFR L858R mutations or exon 19 deletions and had received treatment with erlotinib. The treatment course, including the erlotinib dose at initiation of treatment, at 4 months into therapy, and at disease progression, was retrospectively studied. Progression-free survival (PFS) was compared between patients who received the MTD (150 mg) and those who received reduced-dose erlotinib (≤100 mg). RESULTS In total, 198 eligible patients were identified. Thirty-one patients (16%) were initiated on reduced-dose erlotinib; they were older (P = .001) and had lower performance status (P = .01) compared with those who were initiated on erlotinib at the MTD. The response rate to reduced-dose erlotinib was 77%. The median PFS of patients initiated on reduced-dose erlotinib was 9.6 months versus 11.4 months for those initiated at the MTD, a difference that was not statistically significant (hazard ratio, 0.81; 95% confidence interval, 0.54-1.21; P = .30). There was a nonsignificant trend toward higher rates of progression within the central nervous system with reduced-dose erlotinib. CONCLUSIONS At doses below the MTD, erlotinib treatment results in a high response rate and a prolonged median PFS. Review of the literature indicates that 15 of 30 small-molecule inhibitors that are approved or in late-stage development for cancer therapy have recommended doses below the MTD. When the toxicities of MTD dosing are a concern, an investigation of small-molecule inhibitors at doses below the MTD is warranted. Cancer 2016;122:3456–63. © 2016 American Cancer Society.

BACKGROUND Preclinical targeting of the hedgehog pathway by vismodegib and of insulin-like growth factor 1 receptor by cixutumumab enhances the efficacy of chemotherapy and also demonstrates activity against the tumor cell fraction responsible for disease recurrence in small cell lung cancer. METHODS Patients with newly diagnosed extensive-stage small cell lung cancer (SCLC-ED) were randomized to receive four 21-day cycles of cisplatin and etoposide alone (cisplatin at 75 mg/m2 on day 1 and etoposide at 100 mg/m2 on days 1-3; arm A) or in combination with either vismodegib (150 mg/d by mouth; arm B) or cixutumumab (6 mg/kg/wk intravenously on day 1; arm C). The primary endpoint was progression-free survival (PFS). Circulating tumor cells (CTCs) were isolated/enumerated with the Veridex CellSearch platform at the baseline. RESULTS One hundred fifty-two eligible patients were treated. Patient demographics and disease characteristics were well balanced between the 3 arms except for the higher rate with a performance status of 0 in arm B (P = .03). The median PFS times in arms A, B, and C were 4.4, 4.4, and 4.6 months, respectively; the median overall survival (OS) times were 8.8, 9.8, and 10.1 months, respectively; and the response rates were 48%, 56%, and 50%, respectively. None of the comparisons of these outcomes were statistically significant. The median OS was 10.5 months for those with low CTC counts (≤100/7.5 mL) at baseline and 7.2 months for those with high CTC counts (hazard ratio, 1.74; P = .006). CONCLUSIONS There was no significant improvement in PFS or OS with the addition of either vismodegib or cixutumumab to chemotherapy in patients with SCLC-ED. A low baseline CTC count was associated with a favorable prognosis. Cancer 2016;122:2371–2378. © 2016 American Cancer Society.

Purpose Non–small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors. We sought to describe the clinical, pathologic, and genomic characteristics of patients with cancer with MET exon 14 mutations. Patients and Methods We interrogated next-generation sequencing results from 6,376 cancers to identify those harboring MET exon 14 mutations. Clinical characteristics of MET exon 14 mutated NSCLCs were compared with those of NSCLCs with activating mutations in KRAS and EGFR. Co-occurring genomic mutations and copy number alterations were identified. c-Met immunohistochemistry and real-time polymerase chain reaction to detect exon 14 skipping were performed where sufficient tissue was available. Results MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs (3.0%) and were not seen in other cancer types in this study. Patients with MET exon 14–mutated NSCLC were significantly older (median age, 72.5 years) than patients with EGFR-mutant (median age, 61 years; P < .001) or KRAS-mutant NSCLC (median age, 65 years; P < .001). Among patients with MET exon 14 mutations, 68% were women, and 36% were never-smokers. Stage IV MET exon 14–mutated NSCLCs were significantly more likely to have concurrent MET genomic amplification (mean ratio of MET to chromosome 7, 4.3) and strong c-Met immunohistochemical expression (mean H score, 253) than stage IA to IIIB MET exon 14–mutated NSCLCs (mean ratio of MET to chromosome 7, 1.4; P = .007; mean H score, 155; P = .002) and stage IV MET exon 14–wild-type NSCLCs (mean ratio of MET to chromosome 7, 1.2; P < .001; mean H score, 142; P < .001). A patient whose lung cancer harbored a MET exon 14 mutation with concurrent genomic amplification of the mutated MET allele experienced a major partial response to the c-Met inhibitor crizotinib. Conclusion MET exon 14 mutations represent a clinically unique molecular subtype of NSCLC. Prospective clinical trials with c-Met inhibitors will be necessary to validate MET exon 14 mutations as an important therapeutic target in NSCLC.

TPS9077 Background: ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) is a clinical trial platform of the National Cancer Institute that offers biomarker analysis for high-risk resected non-small cell lung cancer (NSCLC) to support randomized trials of novel adjuvant therapies within the National Clinical Trials Network (NCTN). EA5142, a trial of adjuvant nivolumab for patients (pts) without EGFR / ALK alterations, has completed enrollment. Given the survival benefit seen with 1st-line chemo-immunotherapy (chemo-IO) for advanced NSCLC without EGFR / ALK alterations, there was compelling rationale for the launch of a trial offering concurrent immunotherapy with adjuvant chemo. Here we report updated enrollment to ALCHEMIST as of Jan 14, 2020. Methods: ALCHEMIST includes a screening trial (A151216, 5362 registered) that enrolls pts with completely resected clinical stage IB (≥4 cm)–IIIA (per AJCC 7) NSCLC. Tissue and blood are collected, biomarker testing includes EGFR sequencing, ALK FISH and PD-L1 IHC. 733 active sites are enrolling across the NCTN. Pts with EGFR mutations may enroll to adjuvant erlotinib vs observation (A081105, 352 randomized); those with ALK fusions may enroll to adjuvant crizotinib vs observation (E4512, 99 randomized). A trial offering adjuvant nivolumab vs observation regardless of PD-L1 status (EA5142, 935 randomized) recently completed enrollment. To support ongoing investigation of adjuvant immunotherapy, ALCHEMIST is adding A081801 (opens spring 2020). Pts will be randomized to one of 3 arms: chemo-IO with pembrolizumab during and after chemo vs sequential chemo followed by pembrolizumab vs chemo alone. Pts with pathological N2 nodes are eligible and can undergo postoperative radiotherapy after completing chemo. Pts are eligible if enrolled to A151216, negative for EGFR and ALK alterations, and with PD-L1 testing completed (required for stratification). Local testing for EGFR, ALK and PD-L1 will be accepted for enrollment; central testing will not delay randomization. Pts may not have received any therapy except surgery for the lung cancer and must be age >18, Eastern Cooperative Oncology Group performance status 0-1, have no active autoimmune disease requiring systemic treatment within 2 years, must not be pregnant or nursing, have no active second malignancy within 3 years and meet standard organ function values. By building off the ongoing ALCHEMIST platform, we hope to facilitate rapid enrollment to A081801 across participating NCTN sites. Clinical trial information: NCT02194738.

The 8th edition of TNM staging of lung cancer revised M staging and defined M1b disease with single extrathoracic metastasis, to be distinguished from M1c with multiple extrathoracic metastases in one or more organs. This new distinct category of M1b disease consists of patients with a single extrathoracic metastasis, thus consisting of a strictly defined oligometastatic disease. This article reports the prevalence of M1b disease among patients with stage IV non‐small cell lung cancer, focusing on the clinical characteristics and patterns of single extrathoracic metastasis and relationships with overall survival., Background. The 8th edition of TNM staging of non‐small cell lung cancer (NSCLC) has revised M classification and defined M1b disease with single extrathoracic metastasis, which is distinguished from M1c with multiple extrathoracic metastases. We investigated the prevalence, characteristics, and overall survival (OS) of M1b disease in patients with stage IV NSCLC. Methods. The study reviewed the medical records and imaging studies of 567 patients with stage IV NSCLC to determine M stage using the 8th edition of TNM staging. Clinical characteristics and OS were compared according to M stages. Results. Among 567 patients, 57 patients (10%) had M1b disease, whereas 119 patients (21%) had M1a disease and 391 patients (69%) had M1c disease. Squamous histology was more common in M1b (16%) than in M1a (6%) and M1c (6%; p = .03). The median OS of patients with M1b disease was 14.8 months, compared with 22.6 months for patients with M1a and 13.4 months for those with M1c disease (p

Allosteric kinase inhibitors offer a potentially complementary therapeutic strategy to ATP-competitive kinase inhibitors due to their distinct sites of target binding. In this study, we identify and study a mutant-selective EGFR allosteric inhibitor, JBJ-04-125-02, which as a single agent can inhibit cell proliferation and EGFRL858R/T790M/C797S signaling in vitro and in vivo. However, increased EGFR dimer formation limits treatment efficacy and leads to drug resistance. Remarkably, osimertinib, an ATP-competitive covalent EGFR inhibitor, uniquely and significantly enhances the binding of JBJ-04-125-02 for mutant EGFR. The combination of osimertinib and JBJ-04-125-02 results in an increase in apoptosis, a more effective inhibition of cellular growth, and an increased efficacy in vitro and in vivo compared with either single agent alone. Collectively, our findings suggest that the combination of a covalent mutant–selective ATP-competitive inhibitor and an allosteric EGFR inhibitor may be an effective therapeutic approach for patients with EGFR-mutant lung cancer. Significance: The clinical efficacy of EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutant lung cancer is limited by acquired drug resistance, thus highlighting the need for alternative strategies to inhibit EGFR. Here, we identify a mutant EGFR allosteric inhibitor that is effective as a single agent and in combination with the EGFR TKI osimertinib. This article is highlighted in the In This Issue feature, p. 813

Retrospective clinical data and laboratory studies point to metformin having a potential role in cancer treatment; however, the efficacy of this drug in cancer treatment therapy has not been validated in prospective trials. In particular, limited data evaluating the effects of metformin in lung cancer has been available. Responding to this need, a prospective phase II clinical trial was conducted, and this article evaluates response rate and progression‐free survival of platinum‐based doublet chemotherapy with or without metformin in chemotherapy‐naïive advanced or metastatic nonsquamous non‐small cell lung cancer., Background. In the absence of a targeted oncogenic driver mutation or high programmed death‐ligand 1 expression, systemic therapy with platinum‐based doublet chemotherapy with or without bevacizumab has been the standard treatment in advanced or metastatic non‐small cell lung cancer (NSCLC). Metformin has been shown to have antitumor effects via a variety of insulin‐dependent and insulin‐independent mechanisms and to be potentially synergistic with chemotherapy. Materials and Methods. This open‐label single‐center phase II study (NCT01578551) enrolled patients with chemotherapy‐naïve advanced or metastatic nonsquamous NSCLC and randomized them (3:1) to receive carboplatin, paclitaxel, and bevacizumab with (Arm A) or without (Arm B) concurrent metformin for four to six cycles followed by maintenance therapy with bevacizumab ± metformin continued until disease progression, intolerable toxicity, or study withdrawal. The primary outcome was 1‐year progression free survival (PFS). Secondary outcomes included overall survival, response to therapy, and toxicity. Results. A total of 25 patients were enrolled from August 2012 to April 2015, of whom 24 received at least one cycle of therapy administration. The study was stopped early due to slow accrual and changes in standard first‐line therapy of advanced NSCLC. The 1‐year PFS on Arm A (n = 18) was 47% (95% confidence interval [CI]: 25%–88%), which exceeded the historical control 1‐year PFS of 15%. Median overall survival of patients treated on Arm A was 15.9 months (95% CI: 8.4–not available [NA]) and 13.9 months (95% CI: 12.7–NA) on Arm B. There were no significant differences in toxicity between the study arms. Conclusion. To the authors' knowledge, this is the first study to show a significant benefit in PFS with the use of metformin in this patient population and is a signal of efficacy for metformin in advanced NSCLC. Implications for Practice. The anticancer effects of metformin continue to be elucidated. To the authors' knowledge, this is the first trial in nondiabetic advanced non‐small cell lung cancer patients to show a significant change in outcome with the addition of metformin to standard first‐line chemotherapy. Well tolerated and widely available, metformin is a drug that should be considered for further study in the lung cancer treatment landscape.

Veliparib (V) potentiated therapeutic efficacy of cisplatin (C) and etoposide (E) in preclinical models of SCLC. We conducted this phase 1 study to establish the safety of the combination in human subjects.The study employed the 3+3 dose escalation design to establish the safety and recommended phase 2 dose (RP2D) of V when combined with fixed doses of C (75 mg/m(2) on day 1) and E (100mg/m(2) on days 1-3) in a 21-day cycle. The starting dose of V was 60 mg (bid days 1-7) with plan to escalate to 100mg (days 1-7) or de-escalate to 40 mg (days 1-7) depending on the dose limiting toxicity (DLT) experience during cycle 1. Patients with treatment-naïve, extensive stage SCLC were included.The study enrolled 9 patients: M/F (4/5); median age (60); White/African American (8/1). V was tolerated at the 60 mg (DLT in 0 of 3 patients) and 100mg dose (DLT in 1 of 6 patients; grade 5 cardiac failure). Veliparib at 100mg in combination with standard doses of C and E was established as the RP2D. Grades 3-5 adverse events irrespective of attribution during cycle 1 included: dehydration (1), diarrhea (1), fatigue (1), febrile neutropenia (1), heart failure (1), leukopenia (6), lymphopenia (1), nausea (2), neutropenia (8), respiratory failure (1), and thrombocytopenia (2). Investigator-assessed efficacy outcome in 7 evaluable patients were stable disease in 2/7 (28.6%), partial response in 4/7 (57.1%), and complete response in 1/7 (14.3%) patients.This study demonstrated the safety of combining veliparib with cisplatin and etoposide in previously untreated SCLC patients.

Purpose: LKB1 loss is common in lung cancer, but no assay exists to efficiently evaluate the presence or absence of LKB1. We validated an IHC assay for LKB1 loss and determined the impact of LKB1 loss in KRAS-mutant non–small cell lung cancer (NSCLC). Experimental Design: We optimized and validated an IHC assay for LKB1 (clone Ley37D/G6) using a panel of lung cancer cell lines and tumors with known LKB1 mutations, including 2 patients with Peutz–Jeghers syndrome (PJS) who developed lung adenocarcinoma. We retrospectively analyzed tumors for LKB1 using IHC from 154 KRAS-mutant NSCLC patients, including 123 smokers and 31 never-smokers, and correlated the findings with patient and tumor characteristics and clinical outcome. Results: LKB1 expression was lost by IHC in 30% of KRAS-mutant NSCLC (smokers 35% vs. never-smokers 13%, P = 0.017). LKB1 loss did not correlate with a specific KRAS mutation but was more frequent in tumors with KRAS transversion mutations (P = 0.029). KRAS-mutant NSCLC patients with concurrent LKB1 loss had a higher number of metastatic sites at the time of diagnosis (median 2.5 vs. 2, P = 0.01), higher incidence of extrathoracic metastases (P = 0.01), and developed brain metastasis more frequently (48% vs. 25%, P = 0.02). There was a nonsignificant trend to worse survival in stage IV KRAS-mutant NSCLC patients with LKB1 loss. Conclusions: LKB1 IHC is a reliable and efficient assay to evaluate for loss of LKB1 in clinical samples of NSCLC. LKB1 loss is more common in smokers, and is associated with a more aggressive clinical phenotype in KRAS-mutant NSCLC patients, accordingly to preclinical models. Clin Cancer Res; 21(12); 2851–60. ©2015 AACR.

BACKGROUND Erlotinib is a highly active epidermal growth factor receptor (EGFR) kinase inhibitor that is approved for first-line use in lung cancers harboring EGFR mutations. Anecdotal experience suggests that this drug may provide continued disease control after patients develop objective progression of disease (PD), although this has not been systematically studied to date. METHODS Patients who had Response Evaluation Criteria In Solid Tumors-defined PD who were participating in 3 prospective trials of first-line erlotinib in advanced lung cancer were studied retrospectively, and the progression characteristics were compared between patients with and without EGFR-sensitizing mutations. Factors were studied that influenced the time until treatment change (TTC), defined as the time from PD to the start of a new systemic therapy or death. The rate of tumor progression was assessed by comparing tumor measurements between the computed tomography scan obtained at the time of PD and the preceding scan. RESULTS In total, 92 eligible patients were studied, including 42 with and 50 without an EGFR-sensitizing mutation. The EGFR-mutant cohort had a slower rate of progression (P = .003) and a longer TTC (P 3 months; only 2 patients received local debulking therapy during that period. Multivariate analysis of the patients with EGFR-mutant tumors demonstrated that a longer time to progression, a slower rate of progression, and a lack of new extrathoracic metastases were associated with a longer TTC. CONCLUSIONS A change in systemic therapy commonly can be delayed in patients with EGFR-mutant lung cancer who objectively progress on first-line erlotinib, particularly in those with a longer time to progression, a slow rate of progression, and a lack of new extrathoracic metastases. Cancer 2015;121:2570–2577. © 2015 American Cancer Society.

Brain metastases (BM) are common in non-small-cell lung cancer (NSCLC). However, the baseline incidence and evolution of BM over time in oncogene-driven NSCLCs are seldom reported. In this study, we evaluated the frequency of BM in patients with epidermal growth factor receptor (EGFR)-mutated or anaplastic lymphoma kinase (ALK)-rearranged NSCLC.The presence of BM, clinicopathologic data, and tumor genotype were retrospectively compiled and analyzed from a cohort of 381 patients.We identified 86 EGFR-mutated (90.7% with metastatic disease; 85.9% received an EGFR inhibitor) and 23 ALK-rearranged (91.3% with metastatic disease; 85.7% received an ALK inhibitor) NSCLCs. BM were present in 24.4% of EGFR-mutated and 23.8% of ALK-rearranged NSCLCs at the time of diagnosis of advanced disease. This study did not demonstrate a difference in the cumulative incidence of BM over time between the two cohorts (EGFR/ALK cohort competing risk regression [CRR] coefficient of 0.78 [95% CI 0.44-1.39], p=0.41). In still living patients with advanced EGFR-mutated NSCLC, 34.2% had BM at 1 year, 38.4% at 2 years, 46.7% at 3 years, 48.7% at 4 years, and 52.9% at 5 years. In still living patients with advanced ALK-rearranged NSCLC, 23.8% had BM at 1 year, 45.5% at 2 years, and 58.4% at 3 years.BM are frequent in advanced EGFR-mutated or ALK-rearranged NSCLCs, with an estimated45% of patients with CNS involvement by three years of survival with the use of targeted therapies. These data point toward the CNS as an important unmet clinical need in the evolving schema for personalized care in NSCLC.

On the basis of the data suggesting that adolescents and young adult patients with acute lymphoblastic leukemia (ALL) have improved outcomes when treated on pediatric protocols, we assessed the feasibility of treating adult patients aged 18-50 years with ALL with the DFCI Pediatric ALL Consortium regimen utilizing a 30-week course of pharmacokinetically dose-adjusted E. coli L-asparaginase during consolidation. Between 2002 and 2008, 92 eligible patients aged 18-50 years were enrolled at 13 participating centers. Seventy-eight patients (85%) achieved a complete remission (CR) after 1 month of intensive induction therapy. With a median follow-up of 4.5 years, the 4-year disease-free survival (DFS) for the patients achieving a CR was 69% (95% confidence interval (CI) 56-78%) and the 4-year overall survival (OS) for all eligible patients was 67% (95% CI 56-76%). The 4-year DFS for the 64 patients who achieved a CR and were Philadelphia chromosome negative (Ph-) was 71% (95% CI 58-81%), and for all 74 Ph- patients the 4-year OS was 70% (95% CI 58-79%). We conclude that a pediatric-like treatment strategy for young adults with de novo ALL is feasible, associated with tolerable toxicity, and results in improved outcomes compared with historical regimens in young adult patients with ALL.

Background Poly(ADP-ribose) polymerase (PARP)-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3 and olaparib, a PARP-inhibitor (NCT01116648). Methods Cediranib tablets once daily and olaparib capsules twice daily were administered orally in a standard 3+3 dose escalation design. Patients with recurrent ovarian or metastatic triple-negative breast cancer were eligible. Patients had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or met Gynecologic Cancer InterGroup (GCIG) CA125 criteria. No prior PARP-inhibitors or anti-angiogenics in the recurrent setting were allowed. Results 28 patients (20 ovarian, 8 breast) enrolled to 4 dose levels. 2 dose limiting toxicities (DLTs) (1 grade 4 neutropenia ⩾4 days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30 mg daily; olaparib 400 mg twice daily [BID]). The RP2D was cediranib 30 mg daily and olaparib 200 mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel obstruction occurred. The overall response rate (ORR) in the 18 RECIST-evaluable ovarian cancer patients was 44%, with a clinical benefit rate (ORR plus stable disease (SD) >24 weeks) of 61%. None of the seven evaluable breast cancer patients achieved clinical response; two patients had stable disease for >24 weeks. Interpretation The combination of cediranib and olaparib has haematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients.

Cervical cancer is the second leading cause of cancer deaths among women worldwide. The objective of this study was to describe the most common oncogenic mutations in cervical cancers and to explore genomic differences between the 2 most common histologic subtypes: adenocarcinoma and squamous cell carcinoma.A high-throughput genotyping platform, termed Oncomap, was used to interrogate 80 cervical tumors for 1250 known mutations in 139 cancer genes. Samples were analyzed using a mass spectrometry-based genotyping platform and were validated using orthogonal chemistry. Epidermal growth factor receptor (EGFR) mutations were further validated by massive parallel sequencing. Human papilloma virus (HPV) genotyping also was performed.Validated mutations were detected in 48 of 80 tumors (60%) examined. The highest mutation rates were in the genes phosphatidylinositol 3-kinase, catalytic subunit α (PIK3CA) (31.3%); Kirsten rat sarcoma viral oncogene homolog (KRAS) (8.8%); and EGFR (3.8%). PIK3CA mutation rates did not differ significantly between adenocarcinomas and squamous cell carcinomas (25% vs 37.5%, respectively; P = .33). In contrast, KRAS mutations were identified only in adenocarcinomas (17.5% vs 0%; P = .01), and a novel EGFR mutation was detected only in squamous cell carcinomas (0% vs 7.5%; P = .24). There were no associations between HPV-16 or HPV-18 and somatic mutations or overall survival. In adjusted analyses, PIK3CA mutations were associated with shorter survival (67.1 months vs 90.3 months; hazard ratio, 9.1; 95% confidence interval, 2.8-29.5 months; P.001).Cervical cancers harbor high rates of potentially targetable oncogenic mutations. In addition, cervical squamous cell carcinoma and adenocarcinoma have distinct molecular profiles, suggesting that clinical outcomes may be improved with the use of more tailored treatment strategies, including PI3K and MEK inhibitors.

BACKGROUND The objective of this study was to define the volumetric tumor growth rate in patients who had advanced nonsmall cell lung cancer (NSCLC) with sensitizing epidermal growth factor receptor (EGFR) mutations and had initially received treatment with EGFR-tyrosine kinase inhibitor (TKI) therapy beyond progression. METHODS The study included 58 patients with advanced NSCLC who had sensitizing EGFR mutations treated with first-line gefitinib or erlotinib, had baseline computed tomography (CT) scans available that revealed a measurable lung lesion, had at least 2 follow-up CT scans during TKI therapy, and had experienced volumetric tumor growth. The tumor volume (in mm3) of the dominant lung lesion was measured on baseline and follow-up CT scans during therapy. In total, 405 volume measurements were analyzed in a linear mixed-effects model, fitting time as a random effect, to define the growth rate of the logarithm of tumor volume (logeV). RESULTS A linear mixed-effects model was fitted to predict the growth of logeV, adjusting for time in months from baseline. LogeV was estimated as a function of time in months among patients whose tumors started growing after the nadir: logeV = 0.12*time + 7.68. In this formula, the regression coefficient for time, 0.12/month, represents the growth rate of logeV (standard error, 0.015/month; P

7553 Background: EGFR mutated advanced NSCLC treated with EGFR TKIs typically progresses after initial response due to acquired resistance. TKI therapy is often continued beyond RECIST progression (PD). We investigated the frequency of this practice and patterns of RECIST PD via imaging findings, as well as the association between patient characteristics and discontinuation of TKI among patients (pts) who progressed while on TKI. Methods: Among a cohort of 101 advanced NSCLC pts with sensitizing EGFR mutations treated with first-line erlotinib or gefitinib at DFCI, 70 pts treated between 2002 and 2010 had at least two CT scans for retrospective radiographic assessments using RECIST1.1; 56 pts had experienced PD by the data closure date of June 2011. Results: Among 56 pts experiencing PD, 46 (82%) were female, median age was 63 (range 35-79), 28 (50%) were never-smokers, 32 (57%) had distant mets, 32(57%) had exon 19 deletion, and 50 (89%) received erlotinib. 49 pts (88%) continued TKI therapy for at least 2 mos beyond retrospectively assessed PD. 31/32 (97%) pts who progressed by increase of target lesions continued TKI. 13/16 (81%) pts who progressed by new lesion remained on TKI. Two pts with PD in non-target lesions discontinued therapy at PD. 5/6 (83%) pts with both increase of target lesions and new lesion at PD continued TKI. In 49 continuing pts, the median time from RECIST PD to termination of TKI was 10.1 mos (range: 2.2-64.2 mos). 15/49 (31%) pts who continued TKI received additional chemo compared to 0/7 pts who discontinued (Fisher’s p=0.17). Pts who discontinued therapy (n=7) were significantly younger (median 48 yrs) than those who continued TKI at PD (median 64 yrs, Wilcoxon p=0.003). Median OS beyond RECIST PD among those who continued TKI was 31.8 mos (95% CI 15.9- not reached) and though underpowered, this did not appear to be impacted by TTP when adjusted in a Cox model (p=0.84). Conclusions: 88% of EFGR-mutant NSCLC pts who progressed on first-line TKI continued therapy beyond RECIST PD, which is not the single determining factor for terminating TKI in EGFR-mutant NSCLC pts. Additional progression criteria specific to this population are needed to better guide therapeutic decision making.

Introduction Exon 20 insertions are the third most common family of epidermal growth factor receptor (EGFR) mutations found in non–small-cell lung cancer (NSCLC). Little is known about cancers harboring these mutations aside from their lack of response to EGFR tyrosine kinase inhibitors, impairing the development of effective targeted therapies. Methods NSCLC patients with EGFR genotyping were studied using a mechanism approved by the Institutional Review Board. Cancers with exon 20 insertions were indentified, sequences were characterized, and effectiveness of different treatment regimens was reviewed retrospectively. Clinical characteristics and survival were compared with cancers harboring common EGFR mutations and cancers with wild-type EGFR. Results One thousand eighty-six patients underwent EGFR genotyping from 2004 to 2012. Twenty seven (2.5%) harbored exon 20 insertions, making up 9.2% of all cancers with documented EGFR mutations. Compared with wild-type cancers, those with exon 20 insertions were more commonly found in never-smokers and Asian patients. Insertion sequences were highly variable, with the most common variant (V769_D770insASV) making up only 22% of cases. Median survival of patients with exon 20 insertions was 16 months, similar to the survival of wild-type cancers and shorter than the survival of cancers with common EGFR mutations. Conclusions Patients with EGFR exon 20 insertions have similar clinical characteristics to those with common EGFR mutations but a poorer prognosis. The prevalence of this subset of NSCLC is similar to that of other genotype-defined subsets of lung adenocarcinoma (e.g. those with BRAF mutations, HER2 insertions, ROS1 rearrangements) and is a population of interest for trials of new targeted therapies.

Importance Plasma genotyping of cell-free DNA has the potential to allow for rapid noninvasive genotyping while avoiding the inherent shortcomings of tissue genotyping and repeat biopsies. Objective To prospectively validate plasma droplet digital PCR (ddPCR) for the rapid detection of common epidermal growth factor receptor ( EGFR ) and KRAS mutations, as well as the EGFR T790M acquired resistance mutation. Design, Setting, and Participants Patients with advanced nonsquamous non–small-cell lung cancer (NSCLC) who either (1) had a new diagnosis and were planned for initial therapy or (2) had developed acquired resistance to an EGFR kinase inhibitor and were planned for rebiopsy underwent initial blood sampling and immediate plasma ddPCR for EGFR exon 19 del, L858R, T790M, and/or KRAS G12X between July 3, 2014, and June 30, 2015, at a National Cancer Institute–designated comprehensive cancer center. All patients underwent biopsy for tissue genotyping, which was used as the reference standard for comparison; rebiopsy was required for patients with acquired resistance to EGFR kinase inhibitors. Test turnaround time (TAT) was measured in business days from blood sampling until test reporting. Main Outcomes and Measures Plasma ddPCR assay sensitivity, specificity, and TAT. Results Of 180 patients with advanced NSCLC (62% female; median [range] age, 62 [37-93] years), 120 cases were newly diagnosed; 60 had acquired resistance. Tumor genotype included 80 EGFR exon 19/L858R mutants, 35 EGFR T790M, and 25 KRAS G12X mutants. Median (range) TAT for plasma ddPCR was 3 (1-7) days. Tissue genotyping median (range) TAT was 12 (1-54) days for patients with newly diagnosed NSCLC and 27 (1-146) days for patients with acquired resistance. Plasma ddPCR exhibited a positive predictive value of 100% (95% CI, 91%-100%) for EGFR 19 del, 100% (95% CI, 85%-100%) for L858R, and 100% (95% CI, 79%-100%) for KRAS , but lower for T790M at 79% (95% CI, 62%-91%). The sensitivity of plasma ddPCR was 82% (95% CI, 69%-91%) for EGFR 19 del, 74% (95% CI, 55%-88%) for L858R, and 77% (95% CI, 60%-90%) for T790M, but lower for KRAS at 64% (95% CI, 43%-82%). Sensitivity for EGFR or KRAS was higher in patients with multiple metastatic sites and those with hepatic or bone metastases, specifically. Conclusions and Relevance Plasma ddPCR detected EGFR and KRAS mutations rapidly with the high specificity needed to select therapy and avoid repeat biopsies. This assay may also detect EGFR T790M missed by tissue genotyping due to tumor heterogeneity in resistant disease.

Purpose: NF1 is a tumor suppressor that negatively regulates Ras signaling. NF1 mutations occur in lung cancer, but their clinical significance is unknown. We evaluated clinical and molecular characteristics of NF1 mutant lung cancers with comparison to tumors with KRAS mutations. Experimental Design: Between July 2013 and October 2014, 591 non–small cell lung cancer (NSCLC) tumors underwent targeted next-generation sequencing in a 275 gene panel that evaluates gene mutations and genomic rearrangements. NF1 and KRAS cohorts were identified, with subsequent clinical and genomic analysis. Results: Among 591 patients, 60 had NF1 mutations (10%) and 141 (24%) had KRAS mutations. 15 NF1 mutations (25%) occurred with other oncogenic mutations [BRAF (2); ERBB2 (2); KRAS (9); HRAS (1); NRAS (1)]. There were 72 unique NF1 variants. NF1 tumor pathology was diverse, including both adenocarcinoma (36, 60%) and squamous cell carcinoma (10, 17%). In contrast, KRAS mutations occurred predominantly in adenocarcinoma (136, 96%). Both mutations were common in former/current smokers. Among NF1 tumors without concurrent oncogenic alterations, TP53 mutations/2-copy deletions occurred more often (33, 65%) than with KRAS mutation (46, 35%; P < 0.001). No difference between cohorts was seen with other tumor suppressors. Conclusions: NF1 mutations define a unique population of NSCLC. NF1 and KRAS mutations present in similar patient populations, but NF1 mutations occur more often with other oncogenic alterations and TP53 mutations. Therapeutic strategies targeting KRAS activation, including inhibitors of MAP kinase signaling, may warrant investigation in NF1 mutant tumors. Tumor-suppressor inactivation patterns may help further define novel treatment strategies. Clin Cancer Res; 22(13); 3148–56. ©2016 AACR.

Purpose In lung cancer, randomized trials assessing hyperfractionated or accelerated radiotherapy seem to yield conflicting results regarding the effects on overall (OS) or progression-free survival (PFS). The Meta-Analysis of Radiotherapy in Lung Cancer Collaborative Group decided to address the role of modified radiotherapy fractionation. Material and Methods We performed an individual patient data meta-analysis in patients with nonmetastatic lung cancer, which included trials comparing modified radiotherapy with conventional radiotherapy. Results In non–small-cell lung cancer (NSCLC; 10 trials, 2,000 patients), modified fractionation improved OS as compared with conventional schedules (hazard ratio [HR] = 0.88, 95% CI, 0.80 to 0.97; P = .009), resulting in an absolute benefit of 2.5% (8.3% to 10.8%) at 5 years. No evidence of heterogeneity between trials was found. There was no evidence of a benefit on PFS (HR = 0.94; 95% CI, 0.86 to 1.03; P = .19). Modified radiotherapy reduced deaths resulting from lung cancer (HR = 0.89; 95% CI, 0.81 to 0.98; P = .02), and there was a nonsignificant reduction of non–lung cancer deaths (HR = 0.87; 95% CI, 0.66 to 1.15; P = .33). In small-cell lung cancer (SCLC; two trials, 685 patients), similar results were found: OS, HR = 0.87, 95% CI, 0.74 to 1.02, P = .08; PFS, HR = 0.88, 95% CI, 0.75 to 1.03, P = .11. In both NSCLC and SCLC, the use of modified radiotherapy increased the risk of acute esophageal toxicity (odds ratio [OR] = 2.44 in NSCLC and OR = 2.41 in SCLC; P < .001) but did not have an impact on the risk of other acute toxicities. Conclusion Patients with nonmetastatic NSCLC derived a significant OS benefit from accelerated or hyperfractionated radiotherapy; a similar but nonsignificant trend was observed for SCLC. As expected, there was increased acute esophageal toxicity.

Although the treatment of acute myeloid leukemia (AML) has improved substantially in the past three decades, more than half of all patients develop disease that is refractory to intensive chemotherapy(1,2). Functional genomics approaches offer a means to discover specific molecules mediating the aberrant growth and survival of cancer cells(3-8). Thus, using a loss-of-function RNA interference genomic screen, we identified the aberrant expression of hepatocyte growth factor (HGF) as a crucial element in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples we studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance resulting from compensatory upregulation of HGF expression, leading to the restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1)(9), concomitant inhibition of FGFR1 and MET blocked this compensatory HGF upregulation, resulting in sustained logarithmic cell killing both in vitro and in xenograft models in vivo. Our results show a widespread dependence of AML cells on autocrine activation of MET, as well as the key role of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers.

The impact of age on prognosis in advanced stage non-small cell lung cancer (NSCLC) may differ by sex.Eligible patients (N=1590) from E1594, a 4-arm platinum-based chemotherapy trial, and E4599 (carboplatin/paclitaxel ± bevacizumab) chemotherapy arm were divided into male and female cohorts and separated into age groups of60 or ≥60 years old. Eligible E4599 patients (N=850) were similarly separated by age and sex and by treatment (± bevacizumab). Survival was calculated separately for each cohort.The median survival time (MST) for women ≥60 years old treated with chemotherapy alone on E1594 and E4599 was 11.6 months versus 9.0 months for women60 (p=0.03). MST was 7.4 and 8.3 months for men ≥60 and60 years old respectively (NS). In E4599 the age60 by bevacizumab treatment interaction was statistically significant (p=0.03) for women (younger had greater benefit), with no age effect in men.In this unplanned, exploratory subgroup analysis of advanced stage NSCLC ECOG trials, women ≥60 years old treated with chemotherapy live longer than men and younger women. In contrast, bevacizumab survival benefit was more pronounced in men of any age and in younger women on E4599.

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.

The heparan sulfate 6-O-endosulfatase (SULF2) promotes growth and metastasis of solid tumors. We recently identified that cytosine methylation of the SULF2 promoter is associated with better survival of resected lung adenocarcinoma patients, and now also demonstrates a marginal improvement in survival of advanced non-small cell lung cancer (NSCLC) patients receiving standard chemotherapy (hazard ratio=0.63, P=0.07). Subsequent studies focused on investigating the effect of methylation on SULF2 expression and its genome-wide impact. The genes and pathways modulated by epigenetic inactivation of SULF2 and the effects on sensitivity to chemotherapy were characterized in vitro and in vivo. Silencing SULF2 through small interfering RNA or methylation primarily increased expression of interferon-inducible genes including ISG15, a marker for increased sensitivity to topoisomerase-1 inhibitors such as camptothecin (CPT). NSCLC cell lines with methylated SULF2 (SULF2M) express 60-fold higher ISG15 compared with SULF2 unmethylated (SULF2U) NSCLC cell lines and normal human bronchial epithelial cells. In vitro, SULF2M and high ISG15 (ISG15H)-expressing NSCLC cell lines were 134-fold more sensitive to CPT than SULF2U and low ISG15 (ISG15L)-expressing cell lines. Topotecan, a soluble analog of CPT and FDA-approved anticancer drug, dramatically arrested the growth of SULF2M-ISG15H, but not SULF2U-ISG15L lung tumors in nude mice (P

IMPORTANCE: Osimertinib mesylate is used globally to treat EGFR-mutant non–small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood. OBJECTIVE: To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior. DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017. MAIN OUTCOMES AND MEASURES: Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib. RESULTS: Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01). CONCLUSIONS AND RELEVANCE: Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.

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...

Purpose Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) with demonstrated efficacy in combination with carboplatin and paclitaxel (PCB) for the treatment of advanced non–small-cell lung cancer (NSCLC). Administration of bevacizumab is postulated to decrease nitric oxide synthesis and lead to hypertension, which may be a physiological sign that the VEGF pathway is more actively being blocked and could result in improved outcomes. Patients and Methods Eastern Cooperative Oncology Group (ECOG) 4599 randomly assigned patients with nonsquamous NSCLC to carboplatin and paclitaxel (PC) versus PCB. Hypertensive patients were compared with nonhypertensive patients with respect to overall survival (OS) and progression-free survival (PFS) using blood pressure data and adverse event data separately. High blood pressure (HBP) by the end of cycle 1 was defined as blood pressure > 150/100 at any previous time or at least a 20-mmHg increase in diastolic blood pressure from baseline. Results In a multivariable Cox model adjusting for HBP as a time-varying covariate, comparing those on PCB with HBP with those on PC gave an OS hazard ratio (HR) of 0.60 (95% CI, 0.43 to 0.81; P = .001); comparing those on PCB without HBP with those on PC alone, the OS HR was 0.86 (95% CI, 0.74 to 1.00; P = .05). Comparing the PCB HBP group with PC gave an adjusted PFS HR of 0.54 (95% CI, 0.41 to 0.73; P < .0001) and comparing those on PCB without HBP to those on PC, the HR was 0.72 (95% CI, 0.62 to 0.84; P < .0001). The 6-month cumulative incidence of hypertension was 6.2% (95% CI, 3.9% to 8.6%). Conclusion Data from ECOG 4599 suggest that onset of HBP during treatment with PCB may be associated with improved outcomes, and additional studies of the downstream effects of VEGF suppression and hypertension are needed.

8539 Background: ECOG-ACRIN E1505 was a phase III randomized trial of adjuvant chemotherapy with or without bevacizumab for patients with completely-resected Stage IB (>4CM) – IIIA non-small cell lung cancer. Prior studies have shown that the risk of brain recurrence in patients after definitive surgical resection is approximately 10%; however, covariates associated with development of brain recurrence have varied across these studies. We sought to estimate the incidence of and risk factors for brain recurrence. Methods: Among the 1501 patients enrolled to ECOG-ACRIN E1505, 121 patients developed brain metastases as their first site of recurrence and are the subject of this investigation. All 1501 patients underwent a pneumonectomy (N = 192) or (bi)lobectomy and had an R0 resection. The cumulative incidence of brain recurrence was estimated after adjusting for recurrence at other sites and death as competing events. A multivariable regression model was fitted using the methodology of Fine and Gray to evaluate the effect of covariates on the subdistribution of brain recurrence. Results: With a median follow-up of 50.3 months, a total of 121 brain metastases had been reported as the first site of recurrence. The incidence of brain recurrence at 12 months post-randomization was 3.7% (95% CI: 2.8% – 4.7%), and it increased to 8.5% (95% CI: 7.0% - 10.0%) at 3 years, and to 9.9% (95% CI: 8.0% - 11.7%) at 6 years. Risk factors for brain metastases included pneumonectomy(HR=1.8; p=0.01), and nonsquamous histology(HR=2.04; p=0.003), but bevacizumab(HR=0.64; p=0.02) was associated with potentially protective effect. Conclusions: The cumulative incidence of brain recurrence increased over time to 9.9% at 6 years in this population of patients with surgically-resected non-small cell lung cancer. Treatment, tumor histology, and type of resection appear to be associated with the risk of brain recurrence. Clinical trial information: NCT00324805.

9087 Background: PD-1 inhibitors have shown promising activity in advanced NSCLC, with increasing clinical use. We evaluated tumor burden dynamics in advanced NSCLC pts treated with commercial PD-1 inhibitors to identify imaging markers for clinical benefit. Methods: The study included 160 advanced NSCLC pts (79 males; median age: 65) treated with commercial nivolumab or pembrolizumab monotherapy at DFCI as a part of routine clinical care. Tumor burden dynamics were assessed on serial CT scans during therapy by irRECIST1.1, which uses unidimensional measures and includes new lesions in tumor burden [Clin Cancer Res. 2013;19:3936-43]. Results: Tumor burden change at best overall response (BOR) ranged from -100% to +278% (median: +3.5%). Objective response rate (ORR) was 18% (29/160). Current and former smokers had higher ORR than never smokers (ORR:14% (8/58), 25% (20/79), 4% (1/23); Fisher p = 0.04). Durable disease control with tumor burden < 20% increase from baseline for at least 6 months was noted in 27 pts (17%), which included 11 pts with stable disease as their irBOR. Using an 8-week landmark analysis, pts with < 20% tumor burden increase from baseline at 8 weeks had longer OS than pts with ≥20% increase (median OS:12.4 vs. 4.6 months, p < 0.001). In Cox models using a time varying covariate, pts with < 20% tumor burden increase during therapy had significantly reduced hazards of death (HR = 0.24, p < 0.0001) after adjusting for smoking (HR = 1.77, p = 0.016) and baseline tumor burden (HR = 1.66, p = 0.032). Two pts (1.3%) had atypical response pattern or “pseudoprogression”, where tumor burden showed initial increase and subsequent decrease, which was noted after confirmed irPD on consecutive scans in both pts. Conclusions: An objective response or durable disease control was noted in 25% of advanced NSCLC pts treated with PD-1 inhibitors in the clinical setting. Tumor burden increase of < 20% from the baseline during therapy was associated with longer OS, proposing a practical marker of clinical benefit. Pseudoprogression was uncommon, with tumor decrease noted after confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluation.

9051 Background: Up to 50% of advanced NSCLC patients receive radiation therapy at some point in their course. We sought to determine whether patients with prior radiation demonstrate altered outcomes on subsequent metastatic clinical trials. Methods: We reviewed 8 ECOG-ACRIN advanced non-small cell lung cancer studies conducted between 1993 and 2011 in which information was collected about receipt of prior radiation. Whether radiotherapy was given with curative or palliative intent, or to specific sites was not recorded. Median follow-up among all trials was 66 months. We used the log-rank, Wilcoxon and Fisher’s exact tests to compare patients, and Cox Model and Kaplan-Meier method to calculate survival. Results: 574/3041 (18.9%) patients had received prior radiation. These patients were more likely to be male (64% vs 58%), have squamous histology (20% vs 14%) and have had prior surgery (48% vs 33%) compared to those with no prior radiation. At registration, prior radiation patients were more likely to have an ECOG PS of 1 (66% vs 58%), while they were less likely to have a PS of 0 (24% vs 36%) or have a pleural effusion (23% vs 37%). Patients who received radiation were more likely to have been registered on to studies between 1993-1999 than 2000-2011 (69% vs 31%) (all p < 0.001). Median Overall Survival (OS) for patients with prior radiation was 7.6 months (range 7-8.3) vs 9.5 (9.1-9.8) for those without (p < 0.001). Median Progression Free Survival (PFS) for those with prior radiation was 3.5 months (3-3.9) vs 4.2 (4.1-4.4) for those without (p < 0.001). In multivariable analysis controlling for stage IIIB/IV, sex, PS, histology, and prior surgery, the impact of prior radiation on overall survival remained significant (p = 0.042, HR (95% CI) = 1.11 (1.00, 1.22)). Conclusions: Almost one-fifth of lung cancer patients on systemic therapy trials for advanced disease previously received radiation. They are more likely to be male, have squamous histology, have an ECOG PS of 1 and have had prior surgery. Prior radiation is significantly associated with inferior OS and PFS. For advanced NSCLC clinical trials, documentation of whether curative intent/palliative intent radiation was given and stratification by prior radiation exposure should be considered.

TPS8575 Background: There have been no advances in the systemic treatment of resected lung cancers in the last decade. This is in contrast to advanced disease where molecularly targeted therapies for patients with oncogene-driven tumors have replaced and/or delayed chemotherapy and where immunotherapy drugs that target the programmed death receptor pathway (PD-1 or PD-L1) are now utilized in first and second line. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is a National Cancer Institute (NCI) sponsored National Clinical Trials Network (NCTN) initiative to address the role of genomic testing and personalized therapies in the adjuvant treatment of non-small cell lung cancers. EA5142 is the newest of the ALCHEMIST studies, investigating adjuvant nivolumab in patients not eligible for the EGFR or ALK directed trials. Methods: ALCHEMIST is a clinical trial platform that consists of integrated protocols: ALCHEMIST Screening (A151216; NCT02194738), ALCHEMIST-EGFR (A081105; NCT02193282), ALCHEMIST-ALK (E4512; NCT02201992), and ALCHEMIST-nivo (EA5142; NCT02595944). In ALCHEMIST-Screening, up to 8,000 patients with pathologically confirmed stage IB (≥ 4 cm)-IIIA NSCLC will be enrolled either before or after surgical resection. Tumors that are non-squamous histology will be centrally genotyped for EGFR mutations and ALK rearrangements. Patients with EGFR or ALK-positive tumors are offered enrollment in trials evaluating adjuvant erlotinib or crizotinib, respectively. In the ~80% of patients enrolled with tumors that have wildtype EGFR and ALK or those with squamous histology central testing will be performed for PD-L1 utilizing immunohistochemistry (DAKO 28-8). Adjuvant therapy is allowed but not required. Patients are randomized to nivolumab 240 mg IV over 3 minutes every 2 weeks for up to 1 year versus standard of care observation, stratified by stage, histology, prior adjuvant treatment, and PD-L1 status ( > / = 1% or < 1%). ANVIL has enrolled 52 of 714 planned patients to detect co-primary endpoints of a 30% improvement in overall survival and/or a 33% reduction in disease free survival favoring nivolumab. EA5142 is currently open at over 400 centers nationwide. Clinical trial information: NCT02595944.

8511 Background: Dramatic responses to MET inhibitors have been reported in patients with NSCLC harboring activating mutations that cause MET exon 14 ( METdel14) skipping. We conducted a multicenter retrospective analysis of pts with METdel14 NSCLC to determine if treatment with MET inhibitors impacts survival. Methods: We collected clinicopathologic data on pts with METdel14 NSCLC. Event-time distributions were estimated using Kaplan-Meier and compared with the log-rank test. Multivariable Cox models were fitted to estimate hazard ratios. Results: Of the 148 pts with METdel14 mutant NSCLC, the median age was 72 (range 43-88); 57% were women, and 41% were never smokers. The most common histologies were adenocarcinoma (77%) and pulmonary sarcomatoid carcinoma (14%). Overlap with oncogenic driver mutations in other genes was rare. At the time of diagnosis, 70% of pts had stage I-III disease, and 30% had stage IV disease. Of the 34 pts with metastastic disease who never received a MET inhibitor, the median overall survival (mOS) was 8.1 months. In this cohort, cancers that also had concurrent MET amplification had a trend toward worse survival compared to cancers without MET amplification (5.2 months vs 10.5 months, P = 0.06). Of the 27 pts with metastatic disease who received at least one MET inhibitor (including crizotinib, glesatinib, capmatinib, and ABBV-399), the mOS was 24.6 months. A model adjusting for receipt of a MET inhibitor as first- or second-line therapy as a time-dependent covariate demonstrated that treatment with a MET inhibitor was associated with a significant prolongation in survival (HR 0.11, 95% CI 0.01-0.92, P = 0.04). Among 22 patients treated with crizotinib, the median progression-free survival (PFS) was 7.36 months. Conclusions: Forpts with METdel14 NSCLC, treatment with a MET inhibitor is associated with an improvement in overall survival. The prognosis of pts who never received treatment with a MET inhibitor appears to be poor, particularly among METdel14 cancers with concurrent MET amplification.