bluuebunny/crossref_metadata_2025 huggingface dataset:
miRNA profiling in resectable NSCLC by multiplex next-generation sequencing.
Authors: Gallach Sandra , Jantus-Lewintre Eloisa , Montaner David , Usó Marta , Sanmartin Elena , Sirera Rafael , Blasco Ana , Guijarro Ricardo , Martorell Miguel , Camps Carlos
Published: March 2020

7060

Background: Early-stage NSCLC has a relapse rate around 40% within 5 years. With the advent of microRNA (miRNA), which seems to regulate many genes critical for tumorigenesis, there is a growing interest in the characterization of miRNAome in NSCLC specimens and to correlate them with prognosis. Next generation sequencing is a useful tool to study the miRNA content of solid tumors. Here, we applied high-throughput SOLiD transcriptome sequencing to study miRNAs expression in a cohort of early-stage NSCLC patients (tumor vs normal lung). Methods: RNA was isolated from frozen lung specimens (tumor and normal lung) from resectable NSCLC patients (n=35). Samples with a RIN ≥ 7 were analyzed and enriched in the miRNA fraction. miRNAs were sequencing using a bar-code multiplex SOLiD protocol. Data normalization was carried out by rescaling all data according to their counts. Readings were mapped against mature and no-mature miRNAs using miRBase. Statistical analysis was performed with CLCbio software and considered significant when p-adj<0.005. Results: Using the SOLiD high throughput sequencing, we performed a systemic miRNA expression profiling analysis of paired samples (tumor vs normal lung). A total of 1268 miRNAs (mature and no-mature) have been detected in at least one sample. The differential expression between normal and tumor samples shown that 6 miRNAs (miR-193b, miR-182, miR-96, miR-148a, miR-299, miR-590) were upregulated and 7 (miR-145, miR-133a, miR-218, miR-125a, miR-30a, miR-126 and miR-139) were down-regulated significantly in tumor samples compared with normal lung tissues. We are performing studies using qRT-PCR in an independent cohort to further validate these findings. Conclusions: The deep sequencing technology used for differential miRNA expression is useful and novel. The use of barcoding allows multiplexing and lowers cost per sample. Several miRNAs were differentially expressed between tumor and normal tissue, but this point needs to be further validated in an independent cohort. Supported by grants TRA09-0132 (MICINN) and RD06/0020/1024 (ISCIII).
Phase II study of concurrent cetuximab (C225) plus definitive thoracic radiotherapy (XRT) followed by adjuvant docetaxel in poor prognosis patients with locally advanced non-small cell lung cancer (LA-NSCLC).
Authors: Dilling Thomas J. , Extermann Martine , Kim Jongphil , Thompson Lora , Yue Binglin , Stevens Craig William , Antonia Scott , Gray Jhanelle Elaine , Williams Charles C. , Haura Eric B. , Pinder Mary Colleen , Tanvetyanon Tawee , Chiappori Alberto
Published: March 2020

7065

Background: Recursive partitioning analysis has shown that ECOG PS ≥ 2, male gender, or age > 70 are prognostic of poor outcome in LA-NSCLC pts. Concurrent chemoradiotherapy improves survival, but toxicity is concerning in this frail pt cohort. We therefore opened this trial of concurrent definitive-dose XRT (70 Gy in 35 fractions) and C225 (250 mg/m2/dose), followed by adjuvant C225 and docetaxel (60 mg/m2 q3weeks x 3 cycles). Methods: Eligible patients had pathologically-proven LA-NSCLC (stage IIA – “dry” IIIB), not surgically resectable. They had ECOG PS 2 OR weight loss ≥5% in 3 months OR age >70. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS) and overall response rate (ORR). Results: From 5/2008 to 11/2010, 32 pts were evaluated for our single-institution, IRB-approved prospective clinical trial. 3 pts were screen-failures and 2 more withdrew consent prior to treatment, leaving 27 evaluable patients. 1 was removed due to poor therapy compliance and 2 were taken off trial due to grade 3 toxicity from the C225 loading dose, but were followed under intent-to-treat analysis. Median follow-up and OS was 10.5 months. Median PFS was 7.8 months. ORR = 59.3%. 8 early/sudden deaths were reported, so the trial closed early: radiation pneumonitis (RP) was the apparent cause in 1 and probably/possibly in 4 others, with insufficient information in 2 additional pts; 1 pt died of failure to thrive. Of the remaining pts, 3 developed grade 3+ RP and 2 had grade 2 RP. Conclusions: Pts enrolled on this trial had improved OS compared with poor-PS historical controls (10.5 vs 6.3 months) and comparable OS compared with good-PS historical controls (10.5 vs 11.9 months) treated with RT (Werner-Wasik M et al. Int J Radiat Oncol Biol Phys. 2000;48:1475-82). However, pulmonary toxicity is a concern. Analysis of RP events is ongoing. Updated results will be presented at the meeting.
Preoperative survivin, ERCC1, and PTEN expression in stage III non-small cell lung cancer (NSCLC) patients (pts) treated with neoadjuvant and definitive chemoradiation and association with overall survival (OS).
Authors: Batus Marta , Fidler Mary J. , Walters Kelly Kaiser , Pool Mark , Mahon Brett , Basu Sanjib , Borgia Jeffrey Allen , Sher David , Bonomi Philip D.
Published: March 2020

7067

Background: Thoracic radiation and concurrent chemotherapy consisting of platinum based doublets has produced modest improvement in long term survival for patient with locally advanced (LA) NSCLC. There is relatively little information regarding molecular profiles and outcome in LA-NSCLC patients (pts) treated with chemoradiation. The objective of this retrospective study is to evaluate potential relationships between expression of DNA repair enzyme ERCC1 and enzymes involved in cell survival – survivin and PTEN. Methods: Stage III NSCLC pts who were treated with chest radiation (40-60Gy) and concurrently with platinum doublet and who had sufficient pretreatment tissue were included in this study. Immunohistochemistry was used to detect nuclear and cytoplasmic expression (frequency 0-4 and intensity 0-4) of survivin, and PTEN, and for nuclear expression of ERCC1. Product of intensity and frequency was calculated for all markers and correlated with overall survival (OS). Results: 97 pts had adequate tumor samples for analysis. 53 women, median age 67. 48 pts with ERCC1 prod <=6 had longer OS than 41 pts with ERCC1 prod >6 (19.6 vs 1.0 months, p=0.034). 16 pts with ERCC1 prod >6, PETN prod <=6 and survivin prod >4 had significantly lower OS than 68 pts with ERCC1<=6, PETN >6 and survivin <=4 (17.2 vs 40.2 months, p<0.001). Conclusions: The association of inferior survival in LA-NSCLC pts whose tumors express high survivin, low PTEN, and high ERCC1, suggests that combining inhibitors of survivin and or of PI3KCA with chemoradiation and developing strategies to inhibit DNA repair might improve outcomes in this group of pts.
Phase II trial: Concurrent chemotherapy and radiotherapy with nitroglycerin in locally advanced non-small cell lung cancer patients.
Authors: De la Mata Dolores , Blake Monika , Moreno Jesus Zamora , Pena Omar , Flores-Estrada Diana , Turcott Jenny , Arrieta Oscar
Published: March 2020

7068

Background: The treatment of choice for locally advanced non small cell lung cancer (NSCLC) is concurrent chemoradiation (CRT). However, efforts to improve treatment results include targeted therapy and the use of radiosensitizers. Nitroglycerin (NTG), a nitric oxide (NO) donor agent, reduces expression of Hypoxia-Induced Factor, which is associated to both chemo and radio resistance. Methods: This is phase II trial in patients with locally advanced NSCLC treated with chemotherapy (CT) based on cisplatin and vinorelbin with NTG concurrent with radiation therapy. A 25 mg NTG patch was administered to the patients during the first 5 days of each induction treatment cycle and during chemo-radiotherapy. Blood samples of VEGF were taken before any treatment and after two cycles of CT. The protocol is registered with ClinicalTrials.gov, number NCT00886405. Results: 35 patients were enrolled in this trial. Median Follow up was 16.6 months (SD ±13.6). Mean age was of 59.9 years (±10.8), 68.6% of the patients were smokers. ECOG status was 0 in 22.9%, 1 in 65.7% and 2 in 11.5%, respectively. Histopathology was adenocarcinoma in 68.6%, epidermoid in 17.1% and undifferentiated in 14.3%. Stage distribution was: IIIa, 57.6% and IIIb, 42.5%. All patients completed CRT treatment and four underwent surgical treatment. Toxicity profile related to NTG was grade 1 and 2 headache in 17.1%. Grade 3 and 4 toxicities were esophagitis (17.1%), neutropenia (62.9%), and nausea (5.7%). Sixty-four per cent of patients achieved partial response after CT and 75.8% after CRT. PFS was 11.8 months (95%, IC 7.8-15.6) and OS was 42.9 months (95%IC 31.3-52.1). After two cycles of CT, plasma VEGF levels were significantly lower (Median 132±79 vs. 53±78 pg/ml, p<0.001). No differences on PFS and OS were found between patients with a reduction ≥ 93 pg/ml (median of differences between VEGFR before and after chemotherapy). Conclusions: The addition of NTG to induction CT, and concurrent CRT on locally advanced NSCLC patients seems to increase the response rate, PFS and OS with an acceptable toxicity profile. A prospective trial is warranted to confirm these findings.
Phase II trial of anti-transforming growth factor-beta (TGFß) monoclonal antibody GC1008 in relapsed malignant pleural mesothelioma (MPM).
Authors: Stevenson James , Kindler Hedy Lee , Schwed Daniel , Ranganathan Anjana , Jacobs-Small Mona , Shouldis Jennfier , Marshall Amy , Heitjan Daniel , Langer Corey J. , Hsu Frank James , Albelda Steven
Published: March 2020

7077

Background: TGFβ is a pleiotropic cytokine overexpressed by MPM. Based on preclinical data documenting a key role for TGFβ in promoting growth and progression of MPM, we are conducting a phase II trial of GC1008 in patients (pts) with progressive MPM. Methods: Pts with progressive MPM by modified RECIST criteria and PS 0-1 with 1-2 prior systemic therapies (at least 1 pemetrexed-based) are eligible. Treatment plan: GC1008 3mg/kg IV over 90 minutes every 21 days. Responses are assessed by modified RECIST every 6 weeks. The primary endpoint is progression-free survival (PFS) rate at 3 months; secondary objectives include safety with GC1008, response rate by modified RECIST, time to progression (TTP), and overall survival (OS). Results: The modified Gehan stage 1 stopping criterion of 1/13 pts with 3 month PFS has been exceeded. To date, 13 pts (10 PS 0; 3 PS 1) with MPM (median age 69; 2F, 11M; 11 epithelial, 1 sarcomatoid, 1 biphasic) enrolled. Treatment-related toxicities include G1/2 fatigue (3 pts), nausea (1 pt) and xerosis (1 pt). Other adverse events possibly related to GC1008 were rapid disease progression in 1 pt after 2 cycles, and G2 skin keratoacanthoma in 1 pt after 5 cycles. Three pts met the primary objective of 3 month PFS at 4.1, 4.2 and 9 months each. Stable disease (SD) was seen in 3 pts (23%). Median TTP is 1.4 months (95% CI 1.2-∞); median OS is 13 months (95% CI 6-∞). Increased serum mesothelin levels have closely tracked disease progression. Serum from 6/13 pts showed new antibodies against MPM tumor lysates as measured by immunoblotting. Two of 3 pts with SD had anti-tumor antibody responses. Mean baseline plasma level of TGFβ was 2447 pg/ml but did not correlate with baseline plasma TGFβ or TTP. Conclusions: GC1008 was well tolerated in pretreated MPM patients. SD occurred in 3 pts, all with prior disease progression. Evidence for humoral anti-tumor immunity was seen in nearly half of enrollees and in 2 of 3 pts with SD. OS compares favorably to prior single-agent studies in pretreated MPM.
Elevated PDGFRB gene copy number gain as prognostic in resected malignant pleural mesothelioma.
Authors: Tsao Anne S. , Harun Nusrat , Fujimoto Junya , Devito Vikki , Lee J. Jack , Mehran Reza J. , Hong Waun Ki , Suraokar Milind B. , Wistuba Ignacio I.
Published: March 2020

7078

Background: PDGF/PDGFR pathway has been implicated in malignant pleural mesothelioma (MPM) carcinogenesis. We sought to evaluate the incidence of PDGFRB gene copy number gain (CNG) and PDGFR pathway protein expression by immunohistochemistry (IHC) in the tumor cell cytoplasm, membrane, nucleus, and stroma, and correlate it to patient clinical outcome. Methods: 88 archived tumor blocks from resected MPM with full clinical information were used to perform the analyses. IHC biomarkers for PDGFRα,β and p-PDGFRβ, and fluorescence in situ hybridization were performed for analysis of PDGFRB gene CNG. Spearman’s rank correlation, Wilcoxon rank-sum test or Kruskal-Wallis test, BLiP plots, and Kaplan-Meier method were used to assess the biomarkers and their correlation to clinical outcome. Results: There were several correlations identified between the IHC biomarkers; however, none associated with patient demographics or histology subtype, with the exception of high cytoplasmic PDGFRα occurring in patients with no prior known asbestos exposure (p=0.029). In the CNG analysis, PDGFRB gene CNG in > 10% of tumor cells had lower cytoplasmic p-PDGFRβ (p=0.029), while PDGFRB gene CNG in > 40% of tumor cells had a higher cytoplasmic PDGFRβ (p=0.04). PDGFRB gene CNG status did not associate with patient demographics or tumor characteristics. Patients with PDGFRB CNG > 40% of tumor cells had an improved relapse-free survival (RFS) [HR 0.25 (95% CI 0.09, 0.72), p=0.0096]. In the patients with PDGFRB CNG > 40% of cells, the addition of chemotherapy appeared to also improve RFS (p=0.017). In the multi-covariate analyses for RFS, there was no association with any IHC biomarker. In the overall survival (OS) analysis, having PDGFRB gene CNG > 40% of tumor cells correlated with an improved OS [HR 0.32 (95% CI 0.11, 0.89), p=0.029] and the addition of peri-operative chemotherapy led to a trend towards improved OS (p=0.089). Conclusions: PDGFRB CNG > 40% of tumor cells is a potential prognostic biomarker in surgically resected MPM tumors. Adding chemotherapy to patients with PDGFRB CNG > 40% of cells improved RFS and led to a trend towards improved OS. Future validation of this biomarker in prospective trials is needed.
SWOG 0722: A phase II study of mTOR inhibitor everolimus (RAD001) in malignant pleural mesothelioma (MPM).
Authors: Garland Linda L. , Ou Sai-Hong , Moon James , Mack Philip C , Testa Joseph , Tsao Anne S. , Wozniak Antoinette J. , Gandara David R.
Published: March 2020

7083

Background: MPM preclinical studies demonstrate activation of AKT pathway proteins, including mTOR, and provide the rationale to test everolimus, an mTOR inhibitor, in MPM. Methods: Unresectable MPM patients (pts) after 1-2 systemic regimens (including a platinum-based regimen), with PS 0-1, measurable disease and adequate organ function were treated with daily oral everolimus 10 mg. Study endpoints were progression-free survival (PFS) at 4 months, response rate,overall survival (OS), and frequency/severity of toxicities. Results: 61 pts were registered between 12/2008 and 9/2011; there were 57 evaluable pts for the primary endpoint of 4-month PFS. Median age was 65.9 yrs; M/F 43/14; prior regimens (1/2: 58%/42%); PS 0/1 (21%/79%); epithelial subtype 61%; biphasic 7%; NOS 28%; pending 4%. 5 pts remain on treatment. Preliminary data for 35 of 57 pts are as follows: RR 0% by standard RECIST and DCR of 14/35 (40%); data by mod RECIST are not yet available. Estimated 4-month PFS was 34% with an estimated median PFS of 3 months. The null hypothesis of 4-month PFS = 30% could not be rejected (p=0.28). 41 pts have died; median OS is estimated at 5 months. Frequent grade 1-3 toxicities were fatigue (55.4%), hypertriglyceridemia (41.1%), anemia (39.3%), nausea (33.9%), oral mucositis (32.1%), anorexia (32.1%), diarrhea (26.8%), and hyperglycemia (26.8%). One pt each had grade 4 and grade 5 dyspnea. Conclusions: The trial did not achieve the primary endpoint of an improvement of PFS at 4 months from 30% to 50%. Inhibition of mTOR using single agent everolimus is not active in unselected MPM patients. Other strategies for targeting the activated AKT pathway in MPM remain of interest.
A phase II study of second-line bendamustine in relapsed or refractory small cell lung cancer (SCLC).
Authors: Lovly Christine Marie , Li Chung-I , Hutchison Anne Smith , Carbone David Paul , Johnson David H. , Keedy Vicki Leigh , Pao William , Sandler Alan , Horn Leora
Published: March 2020

7094

Background: Bendamustine is an alkylating agent with a nitrogen mustard group and purine-like benzimidazole group. Bendamustine in combination with carboplatin has shown efficacy as first line therapy in extensive stage SCLC with RR 73%, TTP 5.2 months and OS 8.3 months [Köster, et al, JCO 2007]. This study aims to investigate the efficacy and safety of single agent bendamustine as 2nd or 3rd line therapy in patients with extensive-stage disease, small-cell lung cancer (ED-SCLC). Methods: This is an open-label, single-arm, multicenter phase II trial. Eligible patients had previously treated ED-SCLC, up to 2 prior regimens, ECOG performance status 0-2, evaluable/measurable disease, and adequate marrow, renal and hepatic function. Patients with stable treated brain metastases were allowed. Patients were treated with bendamustine (120mg/m2 IV days 1 and 2 every 3 weeks) for up to 6 cycles. Evaluation occurred every 2 cycles. Primary endpoint was TTP; secondary endpoints include RR, PFS, OS, and toxicity. Results: 48 patients were enrolled; 56% were male and 96% were Caucasian. 33 patients were evaluable for response. There was 1 CR, 9 PR, 13 SD (48% disease control rate) and 10 PD. Median TTP was 3.37 months (95% CI 2.30 to 4.47 months). At the time of analysis, 13 patients were alive and with a median overall survival of 4.77 months (95% CI 3.67 to 6.07 months). 5 patients (10.4%) required dose reductions due to AEs, 2 due to fatigue, 1 due to neutropenia, 1 due to pancytopenia and 1 due to pneumonia. Grade 3/4 AEs included fatigue (18.8%), dyspnea (14.5%), infection without neutropenia (12.5%), anemia (8.3%), neutropenia (8.3%), and diarrhea (8.3%). Conclusions: These data indicate that single agent bendamustine appears to be well tolerated and effective in the second or third line setting for patients with SCLC.
A phase II trial of pazopanib in relapsed/refractory small cell lung cancer (SCLC).
Authors: Gandhi Leena , Heist Rebecca Suk , Lucca Joan Vern , Temel Jennifer S. , Fidias Panos , Morse Linda K. , Johnson Bruce E
Published: March 2020

7099

Background: Despite response to initial therapy, SCLC has high rates of relapse or distant metastasis and limited 2nd-line therapeutic options. Angiogenesis is an essential part of cell invasion, dissemination, and outgrowth of distant metastases and therefore is a potential therapeutic target in SCLC. Pazopanib (Votrient, GSK) is a potent, competitive inhibitor of the tyrosine kinase activity of VEGFR-1, VEGFR-2, VEGFR-3, PDGF, and c-kit. We initiated a phase II single-arm trial of pazopanib in relapsed or refractory SCLC to determine impact on disease progression. Methods: Patients were eligible if they had progressive disease following up to two lines of prior therapy. Patients were treated at the FDA-approved dose of 800 mg pazopanib once daily. The primary endpoint was progression-free rate (PFR) at 8 weeks. Secondary endpoints included median progression-free survival, overall survival, and safety. The trial followed a Simon 2-stage design to limit accrual if no therapeutic benefit was observed. Results: To date, 27 of 30 planned subjects have been enrolled since October 2010. Two did not complete cycle 1 and were considered inevaluable for response. Major toxicities (mostly grade 1/2) were those previously described including nausea, fatigue, hypertension, electrolyte abnormalities, and AST/ALT elevations (grade 3 in 4 subjects). Three subjects were removed from study due to toxicity: 1 with grade 3 nausea, 1 with grade 3 drop in the cardiac ejection fraction, and 1 with multiple grade 2 toxicities including diarrhea, fatigue, and nausea. A fourth was removed due to grade 1 hemoptysis despite clinical response. The PFR at 8 weeks of 21 subjects evaluable for response to date was 52%; 4 of these 11 subjects had chemo-refractory disease. There were no confirmed responses, but tumor regressions ranged from 2-20%. Median progression-free survival is 14.1 weeks. Conclusions: In patients with SCLC, single-agent pazopanib demonstrated a notable rate of stable disease (including among chemo-refractory patients) and a median PFS that exceeds that of historical PFS rates of < 2 months on ineffective 2nd-line therapies. These data suggest that the potential for pazopanib in SCLC treatment should be further investigated.
Randomized phase II study of carboplatin and paclitaxel with either linifanib or placebo for advanced nonsquamous NSCLC.
Authors: Ramalingam Suresh S. , Shtivelband Mikhail , Soo Ross A. , Barrios Carlos H. , Makhson Anatoly , Segalla J.G.M. , Pittman Kenneth B. , Kolman Petr , Pereira Jose Rodrigues , Srkalovic Gordan , Belani Chandra Prakash , Axelrod Rita , Owonikoko Taofeek Kunle , Qian Jiang , McKee Mark D. , Ricker Justin L. , Carlson Dawn M. , Gorbunova Vera A.
Published: March 2020

7512

Background: Linifanib is a potent and selective inhibitor of VEGF and PDGF receptors with modest single-agent activity in NSCLC. We evaluated the combination of linifanib with carboplatin (C) and paclitaxel (P) for first-line therapy of advanced non-squamous NSCLC. Methods: Patients (pts) with stage IIIB/IV, non-squamous NSCLC, stratified by ECOG PS and gender, were randomized to receive up to six 3-wk cycles of C (AUC 6 mg/ml/min) and P (200 mg/m2) with daily placebo (Arm A), linifanib 7.5 mg (Arm B), or linifanib 12.5 mg (Arm C). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), 12 m survival rate, and objective response rate (ORR). Safety was assessed by NCI-CTCAE v3.0. Results: 138 pts were randomized at 37 sites in 6 countries. Baseline characteristics were: median age, 61 y; men, 57%; smoker, 84%. Efficacy results are shown in the table. Thrombocytopenia was the only Grade 3/4 AE significantly higher on linifanib (Arm B: 16.7%; Arm C: 29.8%) vs. placebo (2.1%). Other adverse events (AEs) related to the dose of linifanib were diarrhea, thrombocytopenia, hypertension, weight loss, palmar-plantar erythrodysaesthesia syndrome, and hypothyroidism. Analysis of samples for predictive biomarkers including serum VEGF and placental growth factor are underway. Conclusions: The addition of linifanib to chemotherapy was tolerable at the doses tested and resulted in a significant improvement in PFS, with a modest survival improvement for Arm C in first-line therapy of advanced non-squamous NSCLC. [Table: see text]
CALGB 30704: A randomized phase II study to assess the efficacy of pemetrexed or sunitinib or pemetrexed plus sunitinib in the second-line treatment of advanced non-small cell lung cancer (NSCLC).
Authors: Heist Rebecca Suk , Wang Xiaofei F. , Hodgson Lydia , Otterson Gregory Alan , Stinchcombe Tom , Vokes Everett E. , Socinski Mark A.
Published: March 2020

7513

Background: Second line chemotherapy improves survival modestly and new strategies are needed. This trial was designed to evaluate the paradigm of an anti-VEGF strategy with or without standard chemotherapy in previously treated NSCLC. Methods: Patients with Stage IIIB/IV NSCLC, PS 0-1 progressive after first-line chemotherapy were eligible for randomization to P (pemetrexed 500 mg/m2 d1), S (sunitinib 37.5 mg d1-21), or P+S (pemetrexed 500 mg/m2 d1 + sunitinib 37.5 mg d1-21). Pts were stratified by PS (0/1), stage (IIIB/IV), and gender (M/F). Primary objective was 18-week PFS rate; secondary objectives were response, OS, and toxicity. Target accrual was 225. The study was terminated early due to decreasing accrual rates. Results: Between 4/08 and 9/11, 130 pts registered; 128 pts treated (P=41, S=46, P+S=41). Median follow-up 99 weeks. Baseline characteristics in the three arms (P/S/P+S) were well balanced: Male (54%/54%/54%); PS 0 (32%/35%/34%); Stage IV (88%/83%/93%). Histology was predominantly adenocarcinoma (66%/57%/66%); squamous was allowed (10%/15%/15%). Toxicity was higher in the S-containing arms: Grade 3/4/5 hematologic toxicity: P 5/0/0 (12%), S 8/1/0 (21%), P+S 5/9/0 (36%); Grade 3/4/5 non-hematologic toxicity (excluding disease related deaths): P 6/2/0 (20%), S 21/3/1 (58%), P+S 21/3/1 (63%). The 18-week PFS rate in the three arms was: P 51% (38-69), S 36% (24-54), P+S 47% (34-65). There is an overall statistically significant difference in OS between the three arms (2-sided p=0.0179) with HR 0.65 (95%CI: 0.38-1.13) for P/S; HR 0.47 (95%CI: 0.27- 0.82) for P/P+S. Median OS was 10.5 mo (8.3-22.5) for P, 7.0 mo (6.0-13.0) for S, 6.7 (4.1-10.4) mo for P+S. Median PFS was 4.4 mo (1.7-8.8) for P, 3.3 mo (2.7-4.3) for S, 3.7 mo (2.5-4.3) for P+S (p=0.3). Fewer patients in the P+S arm received any subsequent therapy (29%) than either P (54%) or S (57%). Conclusions: Pemetrexed had a superior toxicity profile to either sunitinib or the combination of pemetrexed and sunitinib. OS was significantly better with P alone compared to the two S-containing arms, with P+S performing worst for OS.
Activity of cabozantinib (XL184) in metastatic NSCLC: Results from a phase II randomized discontinuation trial (RDT).
Authors: Hellerstedt Beth A. , Edelman Gerald , Vogelzang Nicholas J. , Kluger Harriet M. , Yasenchak Christopher A. , Shen Xiaodong , Ramies David A. , Gordon Michael S. , Lara Primo
Published: March 2020

7514

Background: Dysregulation of MET and VEGFR2 signaling has been observed in NSCLC and MET upregulation has been implicated in resistance to EGFR inhibitors. Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. A RDT evaluated activity and safety in 9 tumor types. Here we report on the metastatic NSCLC cohort which included patients who received prior EGFR and VEGF pathway targeted therapy. Methods: All eligible patients (pts) were required to have measurable disease at baseline. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Results: Enrollment to this cohort is complete (n = 60); all pts are unblinded. Baseline characteristics: median age 67 years; adenocarcinoma 72% and squamous cell 28%; 6 pts with known EGFR mutation (of 28 tested), all having received prior erlotinib; bone metastases 20%; median prior lines of therapy 3 (range 0 - 6); prior exposure to anti-EGFR therapy 50%, prior exposure to anti-VEGF pathway therapy 32%. Median follow-up was 2 months (range 0.4 - 22.3 months). At Wk 12, ORR per RECIST was 10% and overall disease control rate (PR+SD) was 40%. Objective tumor regression was observed in 30/47 pts (64%) with post-baseline tumor assessments, some of whom had known driver mutations in KRAS (3 pts) or EGFR (4 pts). 24 pts (40%) completed Lead-in stage with 15 randomized to continue cabo (N = 8) or to placebo (N = 7). No differences with respect to PFS were observed between treatment arms in the randomized phase of the study. Median PFS from study day 1 for all pts was 4.2 months. Most common Grade 3/4 AEs were fatigue (13%), Palmar-plantar erythrodyesthesia (8%), diarrhea (7%) and asthenia (7%); one related Grade 5 AE of hemorrhage was reported during Lead-in stage. Conclusions: Cabo treatment demonstrates activity in heavily pretreated metastatic NSCLC pts with 4.2 months median PFS, 10% RECIST response, and 64% rate of objective tumor regression. The safety profile of cabo was comparable to that seen with other VEGFR TKIs. Future studies are warranted in NSCLC.
Randomized phase III trial of S-1 plus cisplatin versus docetaxel plus cisplatin for advanced non-small-cell lung cancer (TCOG0701).
Authors: Katakami Nobuyuki , Gemma Akihiko , Sakai Hiroshi , Kubota Kaoru , Nishio Makoto , Inoue Akira , Okamoto Hiroaki , Isobe Hiroshi , Kunitoh Hideo , Takiguchi Yuichi , Kobayashi Kunihiko , Nakamura Yoichi , Ohmatsu Hironobu , Sugawara Shunichi , Minato Koichi , Fukuda Masaaki , Yokoyama Akira , Takeuchi Masahiro , Michimae Hirofumi , Kudoh Shoji ,   Tokyo Coopetative Oncology Group
Published: March 2020

7515

Background: Although molecularly targeted therapy improves outcome of selected patients with advanced non-small-cell lung cancer (NSCLC), most of the patients ultimately become candidates of cytotoxic chemotherapy, which is the cornerstone of patient management. S-1 plus cisplatin (SP) has shown activity and good tolerability in phase II settings. Docetaxel plus cisplatin (DP) is the only third-generation regimen that demonstrated statistically significant improvement of overall survival and quality of life by head to head comparison with a second-generation regimen, vindesine plus cisplatin, in patients with advanced NSCLC. Methods: Patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and adequate organ functions were randomized to receive either oral S-1 80 mg/m2/day (40 mg/m2 b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m2 on day 8 every 5 weeks or docetaxel 60mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 1 every 3 weeks, both up to 6 cycles. The primary endpoint is overall survival (OS). Non-inferiority study design was employed as upper confidence interval (CI) limit for HR<1.322. Secondary endpoints include progression-free survival (PFS), response, safety, and quality of life (QOL). Results: From April 2007 to December 2008, 608 patients from 66 sites in Japan were randomized to SP (n=303) or DP (n=305). Patient demographics were well balanced between the two groups. Two interim analyses were preplanned. At the final analysis, total of 480 death events were observed. The primary endpoint was met. OS for SP was non inferior to DP (median survival, 16.1 v 17.1 months, respectively; HR=1.013; 96.4% CI, 0.837-1.227). PFS was 4.9 months in the SP arm and 5.2 months in the DP arm. Statistically significantly lower rate of febrile neutropenia (7.4% v 1.0%), grade 3/4 neutropenia (73.4% v 22.9%), grade 3/4 infection (14.5% v 5.3%), grade 1/2 alopecia (59.3% v 12.3%) were observed in the SP arm than in the DP arm. QOL data investigated by EORTC QLQ-C30 and LC-13 favored for the SP arm. Conclusions: S-1 plus cisplatin is a standard first-line chemotherapy regimen for advanced NSCLC.
A randomized placebo-controlled phase III study of intercalated erlotinib with gemcitabine/platinum in first-line advanced non-small cell lung cancer (NSCLC): FASTACT-II.
Authors: Mok Tony , Wu Yi Long , Thongprasert Sumitra , Yu Chong-Jen , Zhang Li , Ladrera Guia Elena , Srimuninnimit Vichien , Sriuranpong Virote , Sandoval-Tan Jennifer , Zhu Yunzhong , Liao Meilin , Zhou Caicun , Pan Hongming , Lee Victor , Chen Yuh-Min , Sun Yan , Margono Benjamin , Jin Kate , Truman Matt , Lee Jin Soo
Published: March 2020

7519^

Background: FASTACT, a randomized, phase 2 study in advanced NSCLC, found that intercalated erlotinib with 1st-line platinum-based chemotherapy (CT) significantly prolongs progression-free survival (PFS) (HR 0.47, p=0.0002) versus CT alone (Mok et al. JCO 2009). FASTACT-II is a confirmatory, randomized, phase 3, placebo-controlled, double-blind study in a large patient population Methods: Patients with untreated stage IIIB/IV NSCLC and ECOG PS 0/1 were randomized (1:1) to receive up to 6 cycles of gemcitabine (1,250 mg/m2 on d1 and 8) plus platinum (carboplatin 5×AUC or cisplatin 75 mg/m2 on d1) q4w, with either intercalated erlotinib (150 mg/day on d15–28) or placebo. Non-progressing patients received maintenance erlotinib or placebo until progression, unacceptable toxicity or death. Stratification was by disease stage, histology, smoking status and CT regimen. Primary endpoint was PFS; secondary endpoints included overall response rate (ORR), overall survival (OS), safety, QoL and biomarker analyses. Results: From Apr 2009 to Sep 2010, 451 patients were randomized to receive erlotinib (n=226) or placebo (n=225). Baseline demographics were well balanced across the arms; overall, 49% were never smokers, 40% were female and 76% had adenocarcinoma. PFS was significantly prolonged with erlotinib vs placebo: median 7.6 vs 6.0 months, respectively; HR 0.57 (95% CI 0.46–0.70); p<0.0001. ORR was significantly improved with erlotinib vs placebo: 42.9% vs 17.8%; p<0.0001. A non-significant trend towards longer OS was seen with erlotinib vs placebo (median 18.3 vs 14.9 months; HR 0.78 [95% CI 0.60–1.02]; p=0.069); 73% of placebo patients received a 2nd-line EGFR TKI. Except for skin rash with erlotinib, there was no clinically significant difference in toxicity between arms. A total of 283 patients (62.7%) provided samples for biomarker analyses, including EGFR mutation status, results of which will be presented. Conclusions: Intercalation of erlotinib with CT significantly prolonged PFS in 1st-line advanced NSCLC. Biomarker analysis will determine the significance of this regimen in patients with or without activating EGFR mutations.
Results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC).
Authors: Kim Dong-Wan , Ahn Myung-Ju , Shi Yuankai , De Pas Tommaso Martino , Yang Pan-Chyr , Riely Gregory J. , Crinò Lucio , Evans Tracey L. , Liu Xiaoqing , Han Ji-Youn , Salgia Ravi , Moro-Sibilot Denis , Ou Sai-Hong Ignatius , Gettinger Scott N. , Wu Yi Long , Lanzalone Silvana , Polli Anna , Iyer Shrividya , Shaw Alice Tsang
Published: March 2020

7533

Background: Approximately 3–5% of NSCLC harbors ALK gene rearrangements. Crizotinib is a first-in-class, oral, small-molecule competitive ALK inhibitor with anti-MET activity. Methods: PROFILE 1005 is an ongoing global, multicenter, open-label, single-arm, phase II study evaluating the safety and efficacy of crizotinib (250 mg BID in 3-week cycles) in patients with advanced ALK-positive NSCLC who progressed after ≥1 chemotherapy for recurrent/advanced/metastatic disease. Tumor response was evaluated by RECIST 1.1 every 6 weeks. Patient-reported symptoms and global quality of life (QOL) were assessed using the EORTC QLQ-C30 and LC-13 at baseline, day 1 each cycle and at end of treatment. Results: As of June 2011, 439 patients were evaluable for safety and 255 patients for tumor response. Median age was 53 years. The majority of patients were female (53%), never smokers (65%), and had adenocarcinoma (92%), ECOG PS 0–1 (83%) and ≥2 prior chemotherapy regimens (85%). Among patients evaluable for efficacy, median treatment duration was 25 weeks (77% of patients still ongoing). ORR was 53% (95% CI: 47–60), disease control rate at 12 weeks was 85% (95% CI: 80–89), median duration of response was 43 weeks (96% CI 36–50) and median PFS was 8.5 months (95% CI: 6.2–9.9). The most frequent treatment-related AEs were visual effects (50%), nausea (46%), vomiting (39%), and diarrhea (35%), mostly grade 1–2. 29 patients (6.6%) had treatment-related SAEs, including dyspnea and pneumonitis (4 patients each; 0.9%), and febrile neutropenia and renal cyst (2 patients each; 0.5%). A statistically significant (p<0.05) and clinically meaningful (≥ 10 points) improvement from baseline was observed for patient-reported overall pain, pain in chest, cough, dyspnea, insomnia, fatigue and global QOL. Conclusions: Crizotinib demonstrated a high response rate and PFS, favorable tolerability profile and improvement in patient-reported symptoms. These results provide strong evidence for crizotinib as a standard of care for advanced ALK-positive NSCLC.
A novel targeted oral insulin-like growth factor-1 receptor (IGF-1R) inhibitor and its implications for patients with non-small cell lung cancer (NSCLC): A phase I clinical trial.
Authors: Ekman Simon , Harmenberg Johan , Frödin Jan-Erik , Bergström Stefan , Wassberg Cecilia , Eksborg Staffan , Larsson Olle , Axelson Magnus , Hedlund Åsa , Alvfors Carina , Ståhl Birgitta , Bergqvist Michael
Published: March 2020

7539

Background: The small-molecule IGF-1R inhibitor picropodophyllin (PPP) is the active compound in the oral suspension AXL1717. PPP has shown extensive preclinical antitumor effects against a wide range of cancers supporting its use as a single agent treatment. Methods: The clinical phase Ia/b study on advanced progressive cancer patients with various solid tumors and without remaining treatment options aimed at establishing the recommended phase II dose (RPTD) and the maximum tolerated dose (MTD) of AXL1717. Phase Ia consisted of single day dosing and phase Ib multiday dosing (to an accumulated total of 28 days of treatment; 2*28 days following amendment) with 3 weeks intermission between treatments. Non-progressing patients could continue treatment in the extension study without time limitation (treated 119 weeks). PK samples were obtained at 10 different time-points after the morning dose when appropriate. Results: Phase Ia included 16 patients treated with 78 BID doses ranging from 5-2900 mg AXL1717 BID without any dose-limiting toxicity. Phase Ib included 39 patients treated with doses between 290-930 mg BID in periods between 7-28 days, totally for 147 weeks. Phase Ib showed that AXL1717 was well tolerated and neutropenia was the only detected dose-related, reversible, dose-limiting toxicity (DLT). RPTD dose was set at 390 mg BID to minimize neutropenia. Although the study was not designed for efficacy assessment, some patients, mainly with NSCLC, showed signs of clinical benefit, including 3 partial responses and 12 patients with stable disease. The 15 patients with NSCLC and treatment duration of more than 2 weeks with single agent AXL1717 in 3rd or 4th line showed a median time to progression of 31 weeks and a survival time of 60 weeks with 4 patients being alive at cut-off. Down-regulation of IGF-1R on granulocytes and increases of serum IGF-1 were seen. The systemic exposure of AXL1717 was dose-dependent and sufficient for antitumor effects. Conclusions: AXL1717 has a good safety profile and demonstrated promising clinical benefits in this severely ill and heavily pretreated patient cohort, especially in patients with NSCLC.
Skin toxicity associated with outcome to erlotinib in non-small cell lung cancer (NSCLC) patients (p) with EGFR mutations in the EURTAC study.
Authors: Buges Cristina , Martinez Marti Alex , Rosell Rafael , Vergnenegre Alain , De Marinis Filippo , Massuti Bartomeu , De Castro Javier , Gervais Radj , Carcereny Costa Enric , Moran Teresa , Santarpia Mariacarmela , Felip Enriqueta , Majem Margarita , Porta Rut , Palmero Ramon , Drozdowskyj Ana , Heidecke Cordula , Gasco Amaya , Taron Miquel , Paz-Ares Luis G.
Published: March 2020

7542

Background: Rash is reported in 75% of p treated with erlotinib and has been associated with improved overall and progression-free survival (PFS) in unselected p although not specifically in p with EGFR mutations. Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) randomized 174 p with EGFR exon 19 deletions or L858R mutations to receive erlotinib or chemotherapy. Overall PFS was 9.7 months (m) vs 5.2 m, respectively (P<0.0001). Rash was defined according to NCI CTC v3.0 and dichotomized by grades 0-1 vs 2+. Grade 2 is macular or popular eruption or erythema with pruritus or other associated symptoms, localized desquamation or other lesions covering <50% of body surface area. We examined outcome in the erlotinib arm according to rash grade. Results: 16 p in the erlotinib arm had no rash (grade 0), 30 had grade 1, and 40 had grade 2+. 80% of cases of rash grade 2+ occurred in p with exon 19 deletions, while only 20% were in p with L858R mutations (P=0.039). There were no differences in rash grade according to sex, age or smoking status. PFS was 11.2 m in p with rash grade 2+ and 8.4 m in p with grade 0-1 (HR, 0.52; P=0.018). There was no correlation between rash grade 0-1 vs 2+ and response or overall survival (OS). Interestingly, when p were divided into those with no rash (16 p) and those with grade 2+ (40 p), PFS was 11.2 m for p with grade 2+ vs 2.7 m for p with no rash (P=0.031), and OS was 24.9 m for p with grade 2+ vs 16.1 m for p with no rash (P=0.033). Conclusions: Although the biological reasons for the association of skin rash with better outcome to erlotinib have not been elucidated, this sub-analysis of the EURTAC trial has enabled us to confirm for the first time that skin rash – especially grade 2+ - can predict better outcome to erlotinib in p with EGFR mutations. In addition, the correlation between rash and type of EGFR mutation warrants further investigation.
A phase II, multicenter, placebo-controlled trial of apatinib in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after two previous treatment regimens.
Authors: Zhang Li , SHI Meiqi , Huang Cheng , Liu Xiaoqing , Xiong Jian ping , Chen Gongyan , Liu Wei , Liu Wenchao , Zhang Yiping , LI Kai , Yu Hao , Jiang Haoyuan
Published: March 2020

7548

Background: Apatinib is an oral, small molecular tyrosine-kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR). Phase II study has showed that apatinib significantly improved the outcome of patients with advanced or metastatic gastric cancer (Li J, et al. ASCO 2011). The primary object of this study is to determine whether apatinib can improve progression free survival (PFS) compared with placebo in patients with advanced non-squamous NSCLC who failed two lines of treatment. Methods: This study recruited histologically diagnosed advanced non-squamous NSCLC patients who failed more than two lines of treatment including EGFR TKIs. Other eligible criteria included ECOG ≤1, adequate organ function and no prior exposure to VEGFR-TKI. The patients were randomized to receive apatinib at a dose of 750 mg or placebo (at allocation ratio of 2:1) orally once daily until the disease progression or unacceptable toxicity. Results: 135 patients (90 in apatinib arm, 45 in placebo arm) were included at 20 centers in China until Aug 2011. Median PFS was 4.7 months for apatinib group versus 1.9 months for placebo group, hazard ratio (HR) was 0.278 (95% CI 0.170, 0.455) (p<0.0001). The response rate (RR) and disease control rate (DCR) were also significantly better in study arm (12.2% and 68.9%) than in placebo arm (0% and 24.4%)(P=0.0158 and P<0.0001). The most frequently observed AEs were hypertension, proteinuria, and hand-foot syndrome (HFS). These AEs were generally mild or moderate in severity and were manageable. Conclusions: This randomized phase II trial shows that apatinib has substantial clinical activity without significant additional toxicity in patients with advanced non-squamous and non-small cell lung cancer. Continued investigation of apatinib is warranted in future clinical studies.
Phase II study of pemetrexed (Pem) and cisplatin (Cis) plus cetuximab (Cet) followed by Pem and Cet maintenance therapy in patients (Pts) with advanced nonsquamous non-small cell lung cancer (NSCLC).
Authors: Schmid-Bindert Gerald , Gebbia Vittorio , Mayer Frank , Arriola Edurne , Marquez-Medina Diego , Syrigos Konstantinos N. , Biesma Bonne , Leschinger Monika Iris , Visseren Grul Carla M. , Frimodt-Moller Bente , Ripoche Veronique , Myrand Scott , Nguyen Tuan , Zimmermann Annamaria , Schuette Wolfgang
Published: March 2020

7554

Background: A prospective, nonrandomized, multicenter study was conducted to assess the effect of adding cet to pem and cis in pts with advanced nonsquamous NSCLC. Methods: 113 Caucasian performance status 0-1 pts received 1st line pem (500 mg/m2) and cis (75 mg/m2) on day 1 (21d cycle) for 4-6 cycles and cet (400 mg/m2 loading dose followed by 250 mg/m2) weekly. Non-progressive pts received pem 500 mg/m2 on day 1 (21d cycle) plus cet (250mg/m2 weekly) until progression. Pts received vitamin B12/folic acid and dexamethasone. Primary endpoint was objective response rate (ORR) (RECIST 1.0). Secondary endpoints were progression free survival (PFS), 1 year survival rate, translational research (TR) and safety. Results: Pts’ characteristics: median age 59.7 years, 64% male, 50% PS 0, 92% stage IV, and 78% adenocarcinoma. All pts completed ≥ 1 cycle of induction therapy and 45% and 43% completed ≥ 1 cycle of maintenance with pem and cet, respectively. ORR (n=109) was 38.5% (80% CI 32.2-45.1), all partial responses. Disease control rate (response/stable disease) was 59.6% (80% CI: 53.1-65.9). Median PFS was 5.82 months (80% CI: 4.40-6.70). One year survival rate was 0.45 (80% CI: 0.39-0.51). Significant associations were seen between high EGFR by IHC and increased PFS (cytoplasm: HR=0.46, p=0.035; membrane: HR=0.41, p=0.008), and between high nuclear TTF-1 and increased ORR (OR=7.73, p=0.021) / PFS (HR=0.21, p<0.001) / OS (HR=0.25, p=0.035). Of 113 pts evaluated for safety, 73 (64.6%) pts had drug related CTC Grade 3/4 adverse events (AE): most frequent were neutropenia (14.2%), rash (15%), and vomiting (8.8%). Drug related serious AEs were reported in 27.4% pts: most frequent were anemia (5.3%), neutropenia (5.3%), vomiting (3.5%), and rash, renal failure, diarrhea and fatigue (1.8% each). There were 2 potential on-study drug related deaths (sudden death and large intestinal perforation). Conclusions: Pem, cis and cet appeared efficacious and tolerable. These results support further evaluation in a randomized trial. The TR outcomes are hypothesis generating given the study’s size and nonrandomized nature.
Interim analysis of afatinib monotherapy in patients with metastatic NSCLC progressing after chemotherapy and erlotinib/gefitinib (E/G) in a trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy following progression on afatinib monotherapy.
Authors: Schuler Martin H. , Planchard David , Yang James Chih-Hsin , Kim Joo-Hang , De Marinis Filippo , Chen Yuh-Min , Zhou Caicun , Bennouna Jaafar , Liu Xiaoqing , Feng Ji Feng , Bidoli Paolo , Strausz Janos , Ou Sai-Hong Ignatius , Chand Vikram K. , Wang Bushi , Munzert Gerd Michael , Park Keunchil
Published: March 2020

7557

Background: The benefit of sustained ErbB family blockade in NSCLC patients with acquired resistance (AR) to EGFR TKIs is unknown. We investigated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC, who had failed chemotherapy and E/G. Methods: This was a Phase III, randomized, open-label, multi-center trial. Patients with pathologically confirmed Stage IIIB/IV metastatic NSCLC after ≥1 line of chemotherapy who failed E/G received oral afatinib 50 mg until disease progression (Part A). After progression, patients with clinical benefit (≥12 wks) were eligible to continue afatinib 40 mg plus paclitaxel or receive investigator’s choice chemotherapy (Part B). Primary endpoint for Part A was PFS (RECIST 1.1; CT scan every 6 wks). Available tumor samples were collected for central EGFR mutation testing; local mutation data were also collected. An interim analysis of Part A, assessing afatinib monotherapy, is reported. Results: Part A enrolled April 2010 through to May 2011; 1154 patients received afatinib monotherapy. The majority had adenocarcinoma (85%), 57% were female, 43% were Asian, 54% were never smokers. Best response to prior E/G was CR (2%), PR (31%), SD (42%) and PD (20%). Median PFS for afatinib was 3.3 mths; 88 patients (8%) achieved an objective tumor response, 648 (56%) had SD. For EGFR mutation positive patients (n=49, centrally confirmed), PFS was 4.2 vs. 2.6 mths for EGFR mutation negative patients (n=35). When applying clinical enrichment criteria for AR, PFS was 4.2 mths for those with enrichment (n=597) vs. 2.8 mths for those without (n= 557; logrank test p<0.0001). The most common grade 3/4 adverse events were diarrhea (17%) and rash/acne (11%). In Part A, 99 patients remain on treatment. Conclusions: Afatinib monotherapy provided a clinically meaningful benefit in this large, treatment-refractory NSCLC trial, similar to LUX-Lung 1. Those clinically enriched for AR to EGFR TKIs achieved prolonged disease control upon continued ErbB blockade.