Preclinical models of glucocorticoid receptor (GR)-positive breast cancer (BC) and ovarian cancer (OC) suggest GR activity inhibits chemotherapy-induced apoptosis, and GR antagonism using mifepristone (Mif) enhances cytotoxicity. We performed a phase I trial combining mifepristone, carboplatin (C), gemcitabine (G). A standard "3 + 3" dose escalation scheme was used. Objectives were safety and to determine the maximum tolerated dose (MTD) of Mif + CG. CG was administered intravenously on days 1 and 8 of a 21-day cycle, and mifepristone was administered orally the day before and day of chemotherapy. Thirty-one patients enrolled with a median age of 54 years; the median prior metastatic regimens were one. Twenty-five patients were evaluable for dose-limiting toxicities (DLT) including 16 BC and 9 OC. Dose was de-escalated to dose level (DL) -1 due to 2/4 neutropenia-related DLT's. DLT definition was updated to exclude hematologic DLTs starting at DL-1. The dose was further de-escalated due to neutropenia, and 2/3, 1/4 and 0/6 patients experienced a DLT at DL-1, DL-2, and DL-3, respectively. At DL-1, prophylactic pegylated granulocyte colony-stimulating factor (G-CSF) was instituted. Dose levels -1 and -2 were expanded to add 3 and 6 patients, respectively, to evaluate tolerability in dose levels -1a and -2a. There were 3 major responses (1CR, 2PR) at DL1, and 1 CR at DL-1. No responses were observed at lower levels. The MTD was carboplatin AUC 2 + gemcitabine 600 mg/m2 on D1 and 8 with Mif 300 mg D-1 and D1 with pegylated G-CSF administered on day 9 of a 21-day cycle.

Checkmate 227 established ipilimumab and nivolumab (ipi/nivo) as a first line treatment option for stage IV non-small cell lung cancer (NSCLC), providing a median overall survival of 17.1 months. Stereotactic body radiotherapy (SBRT) provides high rates of metastasis control and may be additive to immunotherapy by providing direct cytoreduction and preventing early progression at existing sites of disease, leading to durable improved outcomes. We designed a phase I study to examine the safety and efficacy of SBRT and ipi/nivo in first line treatment of metastatic NSCLC.

•Liquid biopsy and next-generation sequencing of circulating tumor DNA is increasingly used at the time of diagnosis of non-small cell lung cancer. Its role at the time of progression—and whether it will complement or even supplant tissue biopsy-based methods of identifying targetable resistance mutations in lung adenocarcinoma—remains unclear.•In this brief report, we demonstrate using 138 paired tests that tissue-liquid concordance rates at diagnosis are similar to previously published findings (∼80%), followed by steep decline in concordance at the time of progression (∼40%).•These findings suggest ctDNA or tissue biopsy alone is therefore likely to be insufficient to identify resistance mutations at progression in the majority of patients. We encourage practitioners to pursue both methods of testing to maximize the likelihood of identifying a targetable mutation.

Introduction: Previous studies have evaluated stereotactic body radiotherapy (SBRT) in oligometastatic patients with NSCLC, including multimodality treatment with anti- programmed cell death protein-1 monotherapy. Questions remain regarding the timing of SBRT and immunotherapy, safety with dual checkpoint blockade, and the utility in widely metastatic patients. This randomized phase 1 trial combined nivolumab and ipilimumab with sequential or concurrent multisite SBRT in patients with stage IV NSCLC to evaluate safety and obtain preliminary activity data. Methods: Treatment-naive patients with metastatic NSCLC were randomized to concurrent (SBRT with immuno-therapy) or sequential (SBRT followed by immunotherapy) treatment. A maximum of four treatment fields received SBRT. Nivolumab and ipilimumab were continued until clinical progression, development of toxicity, or after 2 years. Dose-limiting toxicity was defined as greater than or equal to grade 3 toxicity to the relevant organ system attributed to SBRT and immunotherapy occuring within 3 months. Results: A total of 37 patients were assessable. No dose-limiting toxicity occurred in the concurrent cohort (n 1/4 18). The sequential cohort required a dose reduction in the central lung group owing to two grade 4 pneumonitis events (2 of 19). Overall best response was as follows: 5.4% (2 of 37) complete response, 40.5% (15 of 37) partial response, 16.2% (6 of 37) stable disease, and 37.8% (14 of 37) progressive disease. Median progression-free survival was 5.8 months (95% confidence interval: 3.6-11.4 mo), with median follow-up of 17.0 months. Median overall survival was not reached. Conclusions: Concurrent nivolumab, ipilimumab, and SBRT were not more toxic than sequential therapy, and multisite SBRT was well tolerated in widely metastatic patients. Multimodality therapy resulted in durable metastasis con-trol and encouraging early overall survival. (c) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resistance. We analyzed 139 consecutive patients with advanced NSCLC who underwent NGS prior to ICB initiation to explore the association of CDKN2A LOF with clinical outcomes. 73% were PD-L1 positive (≥ 1%). 48% exhibited high TMB (≥ 10 mutations/megabase). CDKN2A LOF was present in 26% of patients and was associated with inferior PFS (multivariate hazard ratio [MVA-HR] 1.66, 95% CI 1.02–2.63, p = 0.041) and OS (MVA-HR 2.08, 95% CI 1.21–3.49, p = 0.0087) when compared to wild-type (WT) patients. These findings held in patients with high TMB (median OS, LOF vs. WT 10.5 vs. 22.3 months; p = 0.069) and PD-L1 ≥ 50% (median OS, LOF vs. WT 11.1 vs. 24.2 months; p = 0.020), as well as in an independent dataset. CDKN2A LOF vs. WT tumors were twice as likely to experience disease progression following ICB (46% vs. 21%; p = 0.021). CDKN2A LOF negatively impacts clinical outcomes in advanced NSCLC treated with ICB, even in high PD-L1 and high TMB tumors. This novel finding should be prospectively validated and presents a potential therapeutic target.

9616 Background: Stereotactic body radiotherapy (SBRT) provides high rates of treated metastasis control, stimulates innate and adaptive immune pathways, and is safe in patients treated with anti-PD1 monotherapy following SBRT. We hypothesize that SBRT may improve outcomes for patients receiving immunotherapy through both direct cytoreduction and increased immunogenicity. Within this context, we conducted a phase 1 trial designed to evaluate the safety of combination immune checkpoint blockade with nivolumab and ipilimumab(N/Ip) plus sequential (Seq) or concurrent (Con) multisite SBRT (mSBRT) in patients with stage IV NSCLC. Methods: Treatment naïve patients (EGFR/ALK WT) with advanced NSCLC received SBRT to 1 to 4 metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. Brain metastases were allowed on protocol, and those > 3mm were treated prior to enrollment. SBRT dose varied by anatomic site and ranged from 45 to 50 Gy in 3 to 5 fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Patients on Seq arm received N/Ip between 1-7 days after completion of SBRT. Patients in Con arm received N/Ip prior to completion of SBRT. N/Ip continued until progression, development of toxicity, or up to 2 years. Patients underwent pre- and post-treatment biopsy of one irradiated lesion. Results: A total of 35 patients (Seq/Con 19/16) were enrolled and evaluable for toxicity analysis (SBRT and at least 1 cycle N/Ip). Brain metastases were present in 27%. PD-L1 expression: 0% (16), 1-49% (10), >50% (9). Median number of metastases treated with SBRT was 3.2. 6 patients experienced DLT (4 pneumonitis), resulting in dose reduction in central lung Seq cohort of the organs at risk (OAR) by 20%. Median PFS by RECIST (total/Seq/Con) was 5.9 mo, 95% CI: 4.9-13.1/ 6.2 mo, 95% CI: 3.5-12.6/ 5.9 mo, 95% CI: 3.1-18.0. RECIST best response was 11% CR, 57% PR, 6% SD, and 26% PD. Treatment past first progression was allowed, and time to second line therapy (chemotherapy) by arm (Seq/Con) was NR/17.5 months. Median OS has not been reached with median follow up of 15mo. PDL1 status did not impact PFS (p = 0.64) nor OS (p = 0.77). Conclusions: Multisite SBRT and concurrent N/Ip was well tolerated. Responses appear durable as median OS was not reached. Multimodality therapy with mSBRT and dual checkpoint inhibitor therapy resulted in impressive tumor control and clinical benefit with promising efficacy. Clinical trial information: NCT03223155 .

Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool. Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m2/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint. Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea—DPYD*5 (odds ratio [OR] 4.9; P = 0.0005), a MTHFR missense SNP (OR 3.3; P = 0.02), and a SNP upstream of MTRR (OR 3.0; P = 0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P = 0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta = − 0.74; P = 1.46 × 10–23), representing a previously unidentified mechanism for HFS. This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.

Background: S1400D is a biomarker-driven therapeutic substudy of Lung-MAP evaluating the fibroblast growth factor (FGF) receptor (FGFR) inhibitor AZD4547 in patients with FGF pathway-activated squamous cell. This is the first phase II trial to evaluate AZD4547 as a targeted approach in patients with previously treated FGFR-altered squamous cell NSCLC and is the first demonstration of successful implementation and conduct of a national umbrella protocol in this disease setting. Methods: Eligible patients had tumoral FGFR alteration or mutation and had progressive disease after at least one line of platinum-based systemic therapy. Patients received AZD4547 80 mg twice daily orally. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival, and duration of response (DoR). Results: Ninety-two patients were assigned to S1400D, 43 were enrolled, and 27 AZD4547-treated patients were evaluable. Evaluable patients were predominantly white (n = 24, 89%), median age 66 years (range, 49-88 years old), and female (n = 7, 26%). FGFR alterations included FGFR1 amplification (n = 23; 85%), FGFR3 amplification (n = 2; 7%), FGFR3 S249C (n = 2; 7%), and FGFR3 fusion (n = 1; 4%). Treatment with ADZ4547 was well tolerated; grade 3 adverse events occurred in six patients, and one patient had grade 4 sepsis. Of 27 response-evaluable patients, 1 patient with FGFR3 S249C had unconfirmed partial response with a DoR of 1.5 months and 1 patient with FGFR1 amplification had a confirmed partial response with a DoR of 2.9 months (7%, 95% confidence interval [CI]: 0%-17%). Median progression-free survival and overall survival for the AZD4547-treated cohort were 2.7 months (95% CI: 1.4-4.5 months) and 7.5 months (95% CI: 3.7-9.3 months). Conclusions: AZD4547 had an acceptable safety profile but minimal activity in this predominantly FGFR1/FGFR3amplified cohort. Evaluation of other targeted agents in Lung-MAP is ongoing. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

9055 Background: LungMAP is a National Clinical Trials Network umbrella trial for previously-treated SqNSCLC. S1400D is a phase II biomarker-driven therapeutic sub-study evaluating the FGFR inhibitor AZD4547 in patients (pts) with FGFR positive chemo-refractory SqNSCLC. Methods: Eligible pts had tumor FGFR alteration and/or mutation by next generation sequencing (Foundation Medicine), measurable disease, Zubrod PS 0-2, progression after 1 line of systemic therapy, and adequate end organ function. Receipt of prior immunotherapy was allowed. Eligible pts received AZD4547 80 mg bid orally. Primary endpoint was overall response rate (ORR) by RECIST; secondary endpoints included progression-free survival (PFS) and duration of response (DoR). Originally designed as a randomized trial of AZD4547 versus docetaxel, it was redesigned to be a single arm AZD4547 trial with the emergence of immunotherapy as standard 2ndline therapy. Forty pts were required to rule out an ORR of < = 15% if the true ORR was > 35% (90% power, alpha 0.05). Results: 93 pts (13% of pts screened on S1400) were assigned to S1400D; 43 were enrolled with 28 receiving AZD4547. Pt characteristics: median age 66.3 y (49-88), female (n = 8, 29%), & Caucasian (n = 25; 89%). Biomarker profile: FGFR1 amplification (n = 38; 86%); FGFR3 S249C (n = 4; 9%); FGFR3 amplification (n = 3; 7%); and FGFR3 fusion (n = 2; 5%). Nine pts (26%) had more than one biomarker alteration. The study was closed at interim analysis for futility in October 2016. Treatment related Grade 3 AEs were seen in 5 pts (dyspnea, fatigue, hyponatremia, lung infection & retinopathy); 1 pt had Grade 4 sepsis. There were no Grade 5 AEs. Median follow up among alive pts was 4.3 months (mos). Of 25 response evaluable pts, one with FGFR3 S249C had unconfirmed PR (4%, 95% CI 1-20%) with DoR of 1.5 mos. Median PFS was 2.7 mos (95% CI 1.4 - 4.3 mos). Conclusions: This is the first Phase II trial to evaluate AZD4547 as a targeted approach in pts with previously treated FGFR-altered SqNSCLC. AZD4547 had an acceptable safety profile but minimal activity in this biomarker-enriched cohort. Evaluation of other targeted agents in LUNG-MAP is currently ongoing. Clinical trial information: NCT02965378.

3061 Background: Immune checkpoint blockers have demonstrated durable response in many tumor types including lung cancer. This clinical benefit is however restricted to a subset of patients in whom longitudinal assessments of their tumor microenvironment have revealed increase CD8+ T cell infiltration. However detailed characterization of this T cell dynamics at clonal levels in a large population of patients is yet to be reported. Such analyses will provide vital insight into the mechanism of tumor eradication in responders. Methods: We performed next-generation sequencing of T cell receptor β chain in longitudinal tumor and peripheral blood samples obtained from lung cancer patients treated with immunotherapies. We first extracted RNA from these samples and synthesized cDNA with 5’RACE adapter using SMART library construction kit (Clontech). We then amplified TCR β gene products to prepare sequence libraries which were analyzed with MiSeq system (Illumina). Results: Here we report on TCR receptor β chain sequencing data for 29 patients in whom we had 3 or more serial samples. Thirteen (45%) of the selected patients in this cohort had durable response and seven (24%) had radiological complete response. We confirmed that there is concordance between the expanded T cell clone at tumor site and the peripheral blood. In one responder, we found expansion of a dominant T cell clone (20%) at a metastatic site where he had pathological complete response on day 17 of treatment and the same clone remained persistent in his peripheral blood (24%) at week 48 of therapy. Similarly in other responders, there were T cell clonal expansions detected as early as week 2 after only one cycle of treatment and such clones remained at high frequencies several months afterwards. Such pattern of early and sustained clonal expansions were absent among non-responders even while they remained on therapy. Conclusions: We found durable response to immune checkpoint blockade to correlate with early and sustained expansion of one to two dominant T cell clones in this selected patient cohort.

The U.S. Food and Drug Administration approved pembrolizumab in combination with carboplatin/pemetrexed for patients with untreated, metastatic, non-squamous, non-small cell lung cancer based on KEYNOTE 021G. This trial randomized 123 patients to carboplatin/pemetrexed versus carboplatin/pemetrexed/pembrolizumab with maintenance pembrolizumab. Maintenance pemetrexed was optional in both arms. Progression-free survival (PFS) was longer for carboplatin/pemetrexed/pembrolizumab (not reached vs. 8.9 months, HR 0.49, 95% CI 0.29-0.83, p=0.0035). No statistically significant improvement in overall survival (OS) has yet been demonstrated (HR 0.69, 95% CI 0.36-1.31, p=0.13), with neither arm reaching median OS. Frontline pembrolizumab improves PFS and OS in comparison to chemotherapy in patients with high PD-L1 expression. Drug cost information should be available to providers to better inform decision-making and assess value. Dose calculations were based on the following: GFR 125, BSA 2.00 m2, carboplatin AUC 5, pemetrexed 500mg/m2, and pembrolizumab 200mg. Drug costs were obtained via the Centers for Medicare & Medicaid Services Pricing File. Four cycles of carboplatin/pemetrexed/pembrolizumab followed by maintenance pembrolizumab and pemetrexed cost $618,889. Four cycles of carboplatin/pemetrexed followed by pemetrexed maintenance cost $249,972. Pembrolizumab alone for an equivalent number of cycles cost $368,917. While the addition of pembrolizumab to front-line therapy resulted in an improvement in PFS in a phase II study of 123 patients, it increased medication costs 2.4 fold, from $249,972 to $618,889. Phase III trials are underway to more definitively assess the benefit of immunotherapy administered with chemotherapy in a broad population of patients. Treatment with carboplatin/pemetrexed/pembrolizumab cost 1.7 times that of pembrolizumab alone, and the addition of chemotherapy is of unclear benefit for patients with high PD-L1 expression. Further defining patient subsets who will benefit the most from this costly regimen should be undertaken. It is crucial healthcare professionals and patients understand the cost implications of front line therapy options.

1083 Background: Glucocorticoid receptor (GR) activity inhibits chemotherapy-induced apoptosis, and GR antagonism with m enhances chemotherapy sensitivity in GR+ breast (B) and ovarian cancer (OC) cells. C+G is a commonly used regimen for B and OC. We report the results of a phase I trial of the GR antagonist m plus C+G in patients with advanced B and OC. Methods: A standard “3+3” dose escalation phase I study was performed. Objectives were to assess the safety and tolerability of the regimen, and to determine the recommended phase 2 (RP2D) dose of M+C+G. C+G was administered on days 1 and 8 of a 21 day cycle, and m was administered the day prior to and the day of chemotherapy. The starting dose level (DL) was 1, with additional DLs as follows in the table. Results: 31 patients (pts) with a median age of 54 years (range 32-76) were enrolled. 18 pts had BC (3 ER+, 15 triple-negative), and 13 had high grade serous OC (11 platinum-sensitive, 2 platinum-resistant). The median number of prior therapies for advanced BC was 1 (range 0-5) and for OC was 2 (range 1-3). Dose de-escalation was necessary due to the DLT of neutropenia. After DL -3, prophylactic G-CSF (PGF) was instituted. The RP2D was C AUC 2, G 600 mg/m2, m 300 mg with PGF administered on day 9. Of the BC pts, 2 had a complete response (CR), 2 had a partial response (PR), 8 had stable disease (SD), 4 had progressive disease (PD). Of the OC pts, there was 1 CR (CR2 lasted > 27 mos; CR1 lasted only 8 mos), 1 PR, 6 SD, and 3 PD. 4 pts were inevaluable for response. Conclusions: These data suggest that M+C+G is safe and tolerable, and the most common DLT is neutropenia. This was easily managed with the institution of PGF. Studies correlating tumor GR expression with response are ongoing, and may help identify patients who are most likely to benefit from this combination. Clinical trial information: NCT02046421. [Table: see text]

Purpose: Antibodies that target immune checkpoint molecules have demonstrated significant and durable clinical benefit through re-activation and proliferation of pre-existing tumor-infiltrating CD8+ T cells in a broad range of tumor types including lung cancer. Detailed characterization of T cell dynamics at clonal levels using nextgeneration T cell receptor (TCR) sequencing in large cohorts of lung cancer patients is yet reported.Methods: We performed TCR sequencing of peripheral blood samples (and some tumors) obtained from 27 lung cancer patients undergoing single/combined immune checkpoint blockade therapies.Results: In one responder, we found expansion of a single T cell clone (approximately 20% of the all TCR reads) in a metastatic subcutaneous lesion that showed pathologic complete response on day 17 of treatment. The same TCR CDR3 sequence was detected in 6.1% of TCR reads in the peripheral blood prior to treatment initiation and the expansion remained persistent in peripheral blood at 21.0% at week 10 and 24.3% at week 48. In other patients who showed durable response, we also found persistent oligoclonal T cell expansion in their peripheral blood which was not observed in non-responders even while they remained on therapy.Conclusion: We found sustained expansion of oligoclonal T cell clones in lung cancer patients who had durable response to immune checkpoint blockade. This suggests possible use of longitudinal TCR sequencing to assist clinical decision-making, assess synergism with other agents, and most importantly facilitate rational development of alternative treatment strategies for non-responders.

Purpose Glucocorticoid receptor (GR) overexpression is associated with poor prognosis ER-negative breast cancer. GR antagonism with mifepristone increases chemotherapy-induced breast cancer cell death, therefore we conducted a phase I clinical trial of mifepristone and nab-paclitaxel in advanced breast cancer. Methods A novel randomized phase I design was used to assess the effect of mifepristone on nab-paclitaxel pharmacokinetics and toxicity. Patients were randomized to placebo or mifepristone for the first cycle; mifepristone was given to all for subsequent cycles. Results Nine patients were enrolled. All were found to have a twofold or greater increase in serum cortisol after mifepristone administration, reflecting effective GR inhibition. Neutropenia occurred at both nab-paclitaxel dose levels studied (100 and 80 mg/m 2 ), and was easily managed with dose reduction and/or growth factor administration. Pharmacokinetic data suggest an interaction between nab-paclitaxel and mifepristone in some patients. Two patients had complete responses (CR), three partial responses (PR), one stable disease (SD), and three progressive disease (PD). Immunohistochemical staining for GR found six of nine tumors were GR-positive. All six GR-positive tumors were triple-negative at the time of recurrence. Of these six patients, two had CRs, two PRs, one SD, and one PD. Conclusions GR appears to be a promising target in TNBC, and GR inhibition plus chemotherapy produces manageable toxicity. While neutropenia was observed in some, a nab-paclitaxel dose of 100 mg/m 2 plus mifepristone 300 mg was found to be tolerable, and a randomized phase II trial of nab-paclitaxel with/without mifepristone is planned in GR-positive advanced TNBC.

Anti-PD1 therapies are known to induce T cell proliferation within the tumor microenvironment leading to eradication of cancer cells. There is lack of detailed characterization of these T cells in terms of their clonality, dynamics during the course of treatment and how these correlate with durable response. Such can be used as a tool to explore the number of cancer-antigen specific T cell clone(s) that mediate tumor eradication, serve as a biomarker to detect early response and also guide the determination of optimal duration of therapy. We performed next-generation T cell receptor alpha/beta chain sequencing of serially obtained tumor and PBMC samples from 54 NSCLC patients undergoing anti-PD1 therapy. The T cell receptor repertoires were compared between baseline and/or different time points during the course of treatment. We detected rapid T cell clonal expansion after one dose of immunotherapy with further expansion after 4 doses both within the tumor and in peripheral blood. Many responders had only one dominant expanded clone in their peripheral blood and this was found to be concordant with the dominant clone within the tumor. One patient had pathologic complete response at a metastatic site after two cycles of therapy and the dominant clone continue to remain prevalent within peripheral blood for several months as he remains on therapy. We identified early and persistent oligoclonal T cell expansion within tumor and peripheral blood of NSCLC patients who had pathologic complete response and/or radiologic significant tumor shrinkage while on anti-PD1 therapy.

This study reviews extensive genetic analysis in advanced non-small cell lung cancer (NSCLC) patients in order to: describe how targetable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially targetable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. Thoracic Oncology Research Program Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. 364 patients including 289 adenocarcinoma underwent genotype testing by various platforms such as FoundationOne, Caris Molecular Intelligence, and Response Genetics Inc. For the entire adenocarcinoma cohort, 25% of patients were African Americans; 90% of KRAS mutations were detected in smokers, including current and former smokers; 46% of EGFR and 61% of ALK alterations were detected in never smokers. 99.4% of patients, whose samples were analyzed by next-generation sequencing (NGS), had genetic alterations identified with an average of 10.8 alterations/tumor throughout different tumor subtypes. However, mutations were not mutually exclusive. NGS in this study identified potentially targetable genetic alterations in the majority of patients tested, detected concurrent alterations and provided information on variants of unknown significance at this time but potentially targetable in the future.

7540 Background: Adjuvant chemotherapy for NSCLC has reached a plateau. The use of the tyrosine kinase inhibitor (TKI), E, was explored in the adjuvant setting given success in advanced setting.We report final f/u from RADIANT. Methods: Completely resected IB–IIIA NSCLC pts were randomized 2:1 to receive E 150 mg daily or P for 2 years. The primary endpoint was disease free survival (DFS) in the full analysis set (FAS). Secondary endpoints included overall survival (OS) in the FAS and DFS and OS in EGFR mutation (M+) subset (del19/L858R). 973 pts were randomized and the planned final analysis was performed after 410 DFS events (April 2013 data cutoff, ASCO14 #7501). A subsequent exploratory analysis occurred after final f/u (June 2014 cutoff). Results: The median f/u is 59.6m (95% CI 56.7–61.2). There was no statistically significant difference in DFS or OS overall or in the EGFR M+ group. The OS data remain immature with 33.5% deaths in the E arm and 31.4% in the P arm. The most common site of relapse (>15% pts) overall and in EGFR M+ were lung and brain in E treated pts and lung, bone and brain in P pts. Among the 13 pts in the EGFRM+ subgroup with brain as site of relapse, 11 of these patients relapsed after E cessation. There were no new safety concerns. Conclusions: Overall adjuvant E did not prolong DFS; a trend for E benefit previously observed (ASCO14 #7513) in EGFR M+ subgroup is no longer apparent. EGFR mutation status was not a stratification factor in this trial and was not a prognostic factor (ESMO14 #1177PD). Further results from ongoing trials are awaited to determine the role of TKI in EGFR M+ early stage lung cancer. Clinical trial information: NCT00373425. Full Analysis Set HR (95% CI) P-Value E (N=623) P (N=350) DFS Median 55 56.2 0.94 (0.78–1.144) 0.5620 # Events (%) 280 (44.9) 168 (48.0) OS Median NR NR 1.12 (0.890–1.413) 0.3306 # Events (%) 209 (33.5) 110 (31.4) EGFR M+ Subset HR (95% CI) P-Value E (N=102) P (N=59) DFS Median 47.8 28.5 0.75 (0.482–1.158) 0.1906 # Events (%) 49 (48.0) 34 (57.6) OS Median NR NR 1.19 (0.609–2.310) 0.6142 # Events (%) 26 (25.5) 13 (22.0) HR: Hazard Ratio; NR: Not Reached.

PURPOSE Epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitors have proven efficacy in advanced non-small-cell lung cancer (NSCLC). We hypothesized that erlotinib would be efficacious in the adjuvant setting. PATIENTS AND METHODS An international randomized, double-blind, placebo-controlled study was conducted in patients with completely resected IB to IIIA NSCLC whose tumors expressed EGFR protein by immunohistochemistry or EGFR amplification by fluorescence in situ hybridization. Patients were assigned 2:1 to erlotinib 150 mg once per day or placebo for 2 years. Stratification factors were stage, histology, previous adjuvant chemotherapy, smoking status, EGFR amplification status, and country. The primary end point was disease-free survival (DFS); key secondary end points were overall survival (OS) and DFS and OS in patients whose tumors had EGFR-activating mutations (EGFRm-positive). RESULTS A total of 973 patients were randomly assigned (November 26, 2007, to July 7, 2010). There was no statistically significant difference in DFS (median, 50.5 months for erlotinib and 48.2 months for placebo; hazard ratio, 0.90; 95% CI, 0.74 to 1.10; P = .324). Among the 161 patients (16.5%) in the EGFRm-positive subgroup, DFS favored erlotinib (median, 46.4 v 28.5 months; hazard ratio, 0.61; 95% CI, 0.38 to 0.98; P = .039), but this was not statistically significant because of the hierarchical testing procedure. OS data are immature. Rash and diarrhea were common adverse events occurring in 528 (86.4%) and 319 (52.2%) patients treated with erlotinib, respectively, versus 110 (32.1%) and 54 (15.7%) patients receiving placebo. The most common grade 3 adverse events in patients treated with erlotinib were rash (22.3%) and diarrhea (6.2%). CONCLUSION Adjuvant erlotinib did not prolong DFS in patients with EGFR-expressing NSCLC or in the EGFRm-positive subgroup. Further evaluation of erlotinib is warranted in the EGFRm-positive subgroup.

7513 Background: E, anEGFR TKI, prolongs survival in pts with advanced NSCLC. Pts with tumors carrying EGFR exon 19 del or 21 L858R mutations are particularly sensitive to EGFR TKIs. Methods: RADIANT was a randomized trial of postoperative E v P in pts with completely resected stage IB-IIIA NSCLC. Pts were stratified by histology (adenocarcinoma, other), stage (IB, II, IIIA), adjuvant chemotherapy (yes, no), smoking history (never, current/former), EGFR FISH (positive, negative/undetermined) and country. Pts were randomized 2:1 to receive E 150mg/day or P for up to 2 yr. Among 973 randomized pts, EGFR mutation status was determined for 921 (95%); 161 (17%) had mutations (55% exon 19 del, 45% exon 21 L858R). These pts form the basis of this report. Results: Pts with mutations were more frequently female (65%) and non-smokers (63%); 47% had stage IB, 29% stage II, 22% stage IIIA; 49% received adjuvant chemotherapy; 47% were Asian. Some imbalances were observed (E: less chemo and lower stage; P: smaller tumor size). There were 102 pts randomized to E and 59 to P. Median duration (range) of treatment was 21.2 (0.16-22.93) m for E and 21.9 (2.43-22.93) m for P; 34 (34%) and 24 (41%) pts completed >22 m of E and P, respectively. DFS events occurred in 71 (44%) pts. Pts on E had longer disease-free survival (DFS) v P (median 46.4 v 28.5 m; HR 0.61, 95% CI 0.38-0.98, p=0.039); however, this result is not statistically significant due to the hierarchical testing procedure. The effect on DFS remained consistent after adjusting for other prognostic variables via an exploratory multivariate Cox model (HR 0.60, 95% CI 0.36-0.98, p=0.046). There were more brain relapses on E (40%) v P (13%), and fewer bone relapses 14% v 29%. Deaths occurred in 35 (21.7%) pts. There was no significant difference in overall survival (OS median not reached in either arm; HR 1.09, 95% CI 0.56-2.16, p=0.815). For drug-related events, AE, serious AE and discontinuations for AE were higher with E compared to P (98% v 61%; 4% v 0%; 25% v 0%, respectively). Conclusions: Although not statistically significant, these data suggest adjuvant E prolongs DFS in pts with completely resected EGFR mutated NSCLC. OS interpretation is limited. Clinical trial information: NCT00373425.