bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized phase II trial of S-1 plus cisplatin or docetaxel plus cisplatin with concurrent thoracic radiotherapy for inoperable stage III non-small cell lung cancer (TORG1018).
Authors: Kubota Kaoru , Shimokawa Tsuneo , Yamada Kazuhiko , Tanaka Hiroshi , Kishi Kazuma , Saito Haruhiro , Takiguchi Yuichi , Hosomi Yukio , Kato Terufumi , Nogami Naoyuki , Yamanaka Takeharu , Masuda Noriyuki , Watanabe Koshiro
Published: September 2018

8534

Background: Concurrent chemoradiotherapy (CCRT) is standard of care in patients with inoperable stage III non-small cell lung cancer (NSCLC), however the best chemotherapy regimen has not been identified. The study was conducted to evaluate cisplatin plus S-1 (SP) or cisplatin plus docetaxel (DP) both with concurrent thoracic radiotherapy in patients with inoperable stage III NSCLC. Methods: Patients with inoperable stage III NSCLC were randomized to SP (S-1 40 mg/m2 twice a day on days 1-14 and 29-42 plus cisplatin 60 mg/m2 on days 1 and 29) or DP (docetaxel 50 mg/m2 and cisplatin 80 mg/m2 on days 1 and 29), stratified by institution, gender, histology, and stage. In both arms, concurrent radiotherapy began on day 1 (60 Gy/30 fr). After CCRT, patients in each group received two additional cycles of the consolidation chemotherapy. Primary endpoint was 2-year overall survival (OS), and secondary endpoints were OS, progression-free survival (PFS), toxicity profile, dose intensity and objective response rate (ORR). Results: From May 2011 to August 2014, 110 patients were enrolled from 19 institutions. Four patients (one in SP and 3 in DP) were ineligible, and 106 patients (53 in each arm) were evaluable for efficacy and safety. Patient characteristics were: male/female 83/23; median age 65 (range 42-74); performance status 0/1 59/47; IIIA/IIIB 59/47. With a median follow-up of 39.3 months, 2-year survival and median OS were 79% (95% CI: 66-88%) and 55.2 months in the SP arm and 69% (95% CI: 55-80%) and 50.8 months in the DP arm, respectively. ORR and median PFS in SP arm were 71.7% and 11.6 months, and ones in the DP arm were 67.9% and 19.9 months. Grade 3/4 leukopenia (62.3/34.0%) and neutropenia (56.6/28.3%) were significantly more frequent in DP arm than SP arm. Incidences of non-hematological toxicities including febrile neutropenia, anorexia, nausea, diarrhea, radiation pneumonitis and esophagitis tended to be higher in DP arm. No treatment-related death occurred. Conclusions: The 2-year OS favored for SP arm with less toxicity. We choose SP with concurrent thoracic radiotherapy as a future reference regimen. Clinical trial information: UMIN000005993.
Intratumor heterogeneity of stage IA lung adenocarcinoma by multiregion whole exome sequencing and association with survival.
Authors: Quek Kelly , Li Jun , Fujimoto Junya , Zhang Jianhua , Wang Jinliang , Chow Chi-Wan , Behrens Carmen , Little Latasha , Gumbs Curtis , Antonoff Mara , Kalhor Neda , Weissferdt Annikka , William William N. , Swisher Stephen , Lee J. Jack , Heymach John , Wistuba Ignacio Ivan , Futreal Andrew , Zhang Jianjun ,   Early NSCLC ITH Group
Published: September 2018

8545

Background: Our previous study has suggested that complex genomic intratumor heterogeneity (gITH) was associated with an increased risk of relapse in patients with localized lung adenocarcinomas (LUAD). We have launched a study to investigate molecular and immune profile ITH of Stage IA NSCLC (a patient population with no optimal biomarker to guide postsurgical therapy) to understand the molecular evolution during early carcinogenesis and to identify biomarkers for early detection and intervention. Here, we report the preliminary analysis on gITH. Methods: We performed multiregion whole exome sequencing on 30 Stage IA LUAD and matched normal lung tissue to a median sequencing depth of 494x. 15 patients have relapsed within 3 years post-surgery (cases) and 15 patients have not relapsed with a minimum of 5-year postsurgical follow up (controls). Cases and controls are 1:1 matched for the key prognostic factors including tumor size, smoking status, age, gender, ethnicity and lobectomy or wedge resection. Shannon diversity index (SDI) was used to quantify ITH in each individual tumor. Kaplan-Meier method was used to evaluate the relationship between ITH and disease-free survival (DFS) as well as overall survival (OS). Results: Consistent with our previous study, 108 of 110 (98.2%) canonical cancer gene mutations were shared events by all regions of individual tumor. Compared to non-relapsed controls, tumors from relapsed cases demonstrated significantly higher degree of ITH (SDI of 1.78 in cases vs 1.58 for controls, p = 0.016). Higher degree of gITH was associated with shorter DFS (p = 0.008) and shorter OS (p = 0.0153). Significantly higher mutation burden was observed in tumors from relapsed patients (median of 10.86 mutations per MB in cases vs 7.45 mutations per MB in controls, p = 0.03). Analysis of gITH on a larger cohort and on predicted neoantigen, methylation, gene expression and immune profiles are in progress. Conclusions: Majority of cancer gene mutations are clonal events during early carcinogenesis of LUAD. Complex gITH may be associated with more aggressive biology and inferior clinical outcome in patients with Stage IA LUAD, therefore, may be evaluated as a potential biomarker.
A nonrandomized confirmatory phase III study of sublobar surgical resection for peripheral ground glass opacity dominant lung cancer defined with thoracic thin-section computed tomography (JCOG0804/WJOG4507L).
Authors: Suzuki Kenji , Watanabe Shunichi , Wakabayashi Masashi , Moriya Yasumitsu , Yoshino Ichiro , Tsuboi Masahiro , Mitsudomi Tetsuya , Asamura Hisao
Published: September 2018

8561

Background: The optimal mode of surgery for peripheral ground glass opacity (GGO) dominant lung cancer (LC) defined with thoracic thin-section computed tomography (TSCT) remains unknown. Methods: We conducted multi-institutional confirmatory phase III trial to evaluate the efficacy and safety of sublobar resection for peripheral GGO dominant LC. Mode of surgery is basically wedge resection, and segmentectomy is allowed when surgical margin is insufficient ( < 5 mm) or histological invasiveness. LC with maximum tumor diameter (MTD) ≤ 2.0 cm and with consolidation tumor ratio ≤ 0.25 based on TSCT were registered. The primary endpoint was 5-year relapse-free survival (RFS). The planned sample size was 330, with the expected 5-year RFS of 98%, threshold of 95%, one-sided α of 5% and power of 90%. Survival analyses were performed using the Kaplan-Meier method and their confidence intervals were estimated by Greenwood’s formula. Results: Between May 2009 and April 2011, 333 pts were enrolled from 51 institutions. The primary endpoint, RFS was estimated on 314 pts who underwent sublobar resection. Median age was 62 (range 24 - 79) and 104 were smokers. Median MTD on lung window was 1.20 cm (0.53 - 2.00). Median MTD of consolidation was 0 (0.00 - 0.48). Operative modes were 258 wedge resection and 56 segmentectomy. Histological diagnosis were 310 adenocarcinomas, 27 precancerous lesions, and 14 non-neoplastic lesions. Median pathological surgical margin was 15 mm (0 - 55). Grade 2 or higher postoperative complications based on CTCAE v3.0 were observed in 119 (37.9%), and Grade 3 in 17 (5.4%), without any Grade 4 or 5. The 5-year RFS was 99.7% (95% CI, 97.7 - 100.0%), which met the primary endpoint. There was no local relapse. The ratio of FEV1.0 change between preoperative and one year after surgery over preoperative value ranged -37% to +49% with a median of -5%. Conclusions: Sublobar resection, mainly wedge resection, offered sufficient local control and RFS for peripheral GGO dominant LC on TSCT. Sublobar resection should be the first choice of mode of surgery if surgical margin is enough preserved. Clinical trial information: 000002008.
CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: Data from a randomized phase III trial (AURA3).
Authors: Mok Tony , Ahn Myung-Ju , Han Ji-Youn , Kang Jin Hyoung , Katakami Nobuyuki , Kim HyeRyun , Hodge Rachel , Ghiorghiu Dana C. , Cantarini Mireille , Wu Yi-Long , Papadimitrakopoulou Vassiliki , Garassino Marina C
Published: September 2018

9005

Background: CNS metastases (mets) are common in pts with advanced NSCLC. Preclinical studies have shown CNS penetration of osimertinib, and clinical data from a pooled analysis of 2 Phase II trials (AURA extension: NCT01802632, AURA2: NCT02094261) showed activity in the CNS. We report the first evidence of osimertinib efficacy in CNS mets from a randomized Phase III study (AURA3; NCT02151981) in pts with T790M-positive advanced NSCLC who have progressed on or after prior EGFR-TKI therapy. Methods: Pts were randomized 2:1 to osimertinib 80 mg once daily or platinum-based doublet chemotherapy every 3 wks for up to 6 cycles; maintenance pemetrexed was allowed. Pts with stable, asymptomatic CNS mets were eligible for enrolment. A prespecified subgroup analysis was conducted in pts with CNS mets present on baseline brain scan, as assessed by blinded independent central neuroradiology review (BICR), to define CNS objective response rate (ORR), duration of response (DoR) and progression-free survival (PFS) by RECIST v1.1. The CNS full analysis set (cFAS) included pts with ≥1 measurable and/or non-measurable CNS mets present on baseline brain scan by BICR; the CNS evaluable for response set (cEFR) included only pts with ≥1 measurable CNS mets. Results: As of 15 April 2016, 116/419 (28%) pts were included in the cFAS. In the cEFR (n = 46), CNS ORR was 70% (21/30; 95% CI 51, 85) with osimertinib and 31% (5/16; 95% CI 11, 59) with chemotherapy (OR, 5.13; 95% CI 1.44, 20.64; p = 0.015). In the cFAS, CNS ORR was 40% (30/75; 95% CI 29, 52) with osimertinib and 17% (7/41; 95% CI 7, 32) with chemotherapy (OR, 3.24; 95% CI 1.33, 8.81; p = 0.014). In the cEFR and cFAS, median CNS DoR was 8.9 months (m) (95% CI 4.3, NC and 4.3, NC) for osimertinib and 5.7 m (95% CI NC, NC and 4.4, 5.7; respectively) for chemotherapy. Median CNS PFS in the cFAS was significantly longer with osimertinib than with chemotherapy (11.7 vs 5.6 m; HR 0.32; 95% CI 0.15, 0.69; p = 0.004). Conclusions: Consistent with the overall response to osimertinib reported in pts with T790M-positive advanced NSCLC, osimertinib was superior to chemotherapy in the treatment of pts with CNS mets; CNS response rate was higher, responses were more durable and CNS PFS was longer. Clinical trial information: NCT02151981.
Molecular determinants of response and resistance to anti-PD-(L)1 blockade in patients with NSCLC profiled with targeted next-generation sequencing (NGS).
Authors: Hellmann Matthew David , Sanchez-Vega Francisco , La Konnor , Rizvi Hira , Halpenny Darragh , Plodkowski Andrew , Long Niamh , Chatila Walid , Jonsson Philip , Arbour Kathryn Cecilia , Chaft Jamie E. , Rudin Charles M. , Kris Mark G. , Berger Michael F. , Taylor Barry S. , Zehir Ahmet , Arcila Maria E. , Ladanyi Marc , Riely Gregory J. , Schultz Nikolaus
Published: September 2018

9015

Background: Anti-PD-(L)1 therapy has revolutionized treatment for patients (pts) with NSCLC. We previously reported that non-synonymous tumor mutation burden (TMB) by whole exome sequencing associates with immunotherapy benefit. Targeted NGS is increasingly routine in clinical practice and may be a useful tool for predicting benefit to anti-PD-(L)1 blockade. Methods: Pts had advanced NSCLC treated with anti-PD-(L)1 (+/- aCTLA-4) therapy and profiling by hybrid-capture NGS of 341-468 genes (MSK-IMPACT). Efficacy assessed by RECIST v1.1; durable clinical benefit (DCB) defined as PR or SD > 6mo. TMB and copy number alteration burden (“fraction of genome altered”, FGA) were normalized by size of genome covered. Comparisons were also made to a cohort of all NSCLCs profiled by MSK-IMPACT (n = 1679). Results: Of 437 evaluable pts treated with anti-PD-(L)1, 197 (45%) had NGS profiling, of whom 30% had DCB. TMB was higher in those with DCB vs no DCB (mean 10.2 vs 7.1 SNV/MB, p = 0.02) and compared to all NSCLCs ( < 0.0001). DCB was more common and PFS was longer in pts with > vs < 85th percentile TMB of all NSCLCs (Odds ratio 2.3, 95% CI 1.1-4.9, p = 0.03; HR = 0.59, p = 0.004), but were similar when dichotomized at the 50th or 75th percentile. FGA was higher in pts with no DCB compared to all NSCLCs (p = 0.02). Molecular signatures related to deficient homologous-recombination-based DNA repair and smoking were more common in DCB vs no DCB (p = 0.042, p = 0.058) and vs all NSCLCs (p = 0.026, p = 0.01). Compared to all NSCLCs profiled by NGS, alterations in STK11and EGFRwere enriched in no DCB (p = 0.0008, p = 0.02). Alterations in JAK2and CD274(PD-L1) were uncommon (2.1%, 1.6%) but exclusively associated with no DCB. For a subset (n = 52) of these cases also profiled by whole exome sequencing, comparison with targeted NGS will be presented. Conclusions: In pts with NSCLC, targeted NGS profiling is a routinely available tool that can provide insight into predicting benefit with anti-PD-(L)1 therapy. Increased TMB associates with clinical benefit. Increased copy number alterations (FGA) and alterations in genes including STK11, JAK2, and CD274 may associate with resistance to anti-PD-(L)1 therapy.
A phase 1 study of osimertinib and bevacizumab as initial treatment for patients with EGFR-mutant lung cancers.
Authors: Yu Helena Alexandra , Hayes Sara A. , Young Robert J. , Ni Ai , Rodriguez Christopher , Makhnin Alex , Riely Gregory J. , Kris Mark G.
Published: September 2018

9033

Background: EGFR tyrosine kinase inhibitors (TKI) are the recommended first line treatment for EGFR-mutant lung cancers. Osimertinib, an EGFR TKI that inhibits both sensitizing EGFR mutations and EGFR T790M, is approved for use after progression on an EGFR TKI with evidence of EGFR T790M, and is currently being assessed as initial treatment for EGFR-mutant lung cancers. The addition of bevacizumab to erlotinib resulted in improved progression free survival (PFS) compared to erlotinib alone as initial treatment (16 vs 10 months, HR 0.41). This phase 1/2 study is assessing osimertinib and bevacizumab as initial treatment for patients with EGFR-mutant lung cancers. Methods: We evaluated toxicity and efficacy of osimertinib and bevacizumab as initial treatment for patients with advanced EGFR-mutant lung cancers. Using a 3+3 design, full doses of osimertinib (80mg PO daily) and bevacizumab (15mg/kg IV q3 weeks) were given, with a planned dose de-escalation (osimertinib 40mg PO daily) should grade 3 or greater toxicity be seen. Six patients must be treated without a dose-limiting toxicity (DLT) to determine the MTD. 43 additional patients will be treated at the MTD in the phase 2 study, with a primary endpoint of PFS at 12 months. Response was evaluated by RECIST 1.1. Results: From Sept 2016 to Jan 2017, 15 patients were enrolled. Median age: 63; Women 11; EGFR L858R = 8, Ex19del = 6, G709A/G719S = 1. After median duration of treatment of 2.7 months, no DLTs were seen in any patient. The MTD was determined to be osimertinib 80mg, bevacizumab 15mg/kg q3 weeks. In total, 15 patients are being treated at the MTD to date. Treatment-related adverse events (AE) were all grade 1-2, except for grade 3 hypertension. The most frequent treatment-related AEs (any grade) were rash (53%), diarrhea (40%), hypertension (33%), fatigue (20%), and itching (20%). All 15 patients continue on study. Conclusions: Combination osimertinib and bevacizumab is a tolerable first-line treatment for patients with EGFR-mutant lung cancers and the MTD is osimertinib 80mg and bevacizumab 15mg/kg q3 weeks. Assessment of efficacy with an endpoint of PFS at 12 months is ongoing. Supported by AstraZeneca (NCT02803203). Clinical trial information: NCT02803203.
Afatinib (Afa) plus bevacizumab (Bev) combination after acquired resistance (AR) to EGFR-tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC): Multicenter single arm phase II trial (ABC-study).
Authors: Hata Akito , Katakami Nobuyuki , Kaji Reiko , Yokoyama Toshihide , Kaneda Toshihiko , Tamiya Motohiro , Inoue Takako , Kimura Hiromi , Yano Yukihiro , Tamura Daisuke , Morita Satoshi , Negoro Shunichi
Published: September 2018

9034

Background: Irreversible EGFR-TKI monotherapies showed only moderate efficacy after AR to reversible EGFR-TKIs. Preclinical studies suggested that addition of Bev to EGFR-TKIs could overcome AR, and Bev demonstrated synergistic effects with Afa in TKI-resistant xenograft models. Methods: ECOG PS 0-2 patients (pts) with EGFR-mutant NSCLC after AR to EGFR-TKIs were enrolled at any lines. Rebiopsy was essential to confirm T790M status after AR. Afa was prescribed at 30 mg, and Bev administered at 15 mg/kg tri-weekly until progression. Results: Between October 2014 and September 2016, 33 eligible pts were enrolled. Median age was 66 (range, 48-86). Twenty-one (64%) pts were female, and 22 (67%) were never smoker. Mutation subtypes were 20 (61%) Del-19, 12 (36%) L858R, and 1 (3%) L861Q. T790M was detected in 14 (42%) pts. Median number of prior regimens was 4 (range, 1-10). First prior TKIs were 20 (61%) gefitinib, 10 (30%) erlotinib or 3 (9%) Afa. Six pts obtained partial response and 23 stable disease, resulting in response rate (RR) of 18.2% (95% confidence interval [CI], 7.0-35.5%) and disease control rated of 87.9% (95% CI, 71.8-96.6%). Median progression-free survival (PFS) and overall survival were 5.9 (95% CI, 3.5-8.8) months and not reached, respectively. Median RR and PFS of T790M+ vs. T790M- were 14.3% vs. 21.2% (p = 0.6189) and 6.2 vs. 5.2 months (p = 0.8619), respectively. Median RR and PFS of Del-19 vs. L858R were 20.0% vs. 8.3% (p = 0.3789) and 5.9 vs. 5.1 months (p = 0.8996), respectively. Afa dosage was reduced to 20 mg in 15 (45%) pts and increased to 40 mg in 2 (6%) pts. Median number of Bev administrations was 6 (range, 1-14). Bev was interrupted in 5 (15%) pts. Adverse events ≥grade 3: rash (3%); paronychia (24%); mucositis (6%); diarrhea (3%); liver dysfunction (3%); hypertension (39%); and proteinuria (15%) were observed. There were no treatment-related deaths, interstitial lung disease, nor Bev-associated severe bleedings. Conclusions: Afa + Bev demonstrated the efficacy and safety after AR to EGFR-TKIs. It could be a therapeutic salvage option for T790M- populations. Clinical trial information: UMIN000014710.
Gefitinib as third-line re-challenge treatment in advanced NSCLC patients with EGFR activating mutation who benefited from first-line gefitinib treatment followed by second-line chemotherapy.
Authors: Song Yong , Wu Yi-Long , Cao Lejie , Chen Jianhua , Ma Zhiyong , Cui Jiuwei , Ye Xin , Ding Jingyan
Published: September 2018

9035

Background: Several studies show that EGFR-mutant NSCLC patients (pts) gained response to EGFR-TKI treatment again after a TKI free interval. To date, no prospective evaluation of the clinical effects of EGFR-TKI re-challenge in EGFR-mutant NSCLC pts has been performed. Methods: This was a multicenter, open-label, single-arm, phase II study (CTONG1304, NCT01933347). Stage IIIB/IV NSCLC pts with EGFR exon 19del/L858R mutation, who previously benefited from first-line gefitinib treatment followed by second-line chemotherapy, took gefitinib 250mg/d until disease progression or death or intolerable toxicity occurred. Blood samples were dynamically collected for EGFRmutation testing using droplet digital PCR at every visit (from baseline to the end of gefitinib treatment). The primary objective was disease control rate (DCR) at week 8. Secondary objectives were objective response rate (ORR), progression free survival (PFS), and overall survival (OS). Results: From March 2014 to May 2016, 45 eligible pts were enrolled and 43 pts were included in the full analysis set (FAS) for efficacy analysis. Gefitinib re-challenge achieved DCR of 69.8%. ORR was 4.7%. Median PFS and OS were 4.4 and 8.0 months (m) respectively. T790M- subgroup at baseline had higher DCR, longer mPFS and mOS, compared with T790M+ subgroup. EGFRstatus changed significantly after gefitinib re-challenge. Conclusions: Gefitinib re-challenge was an effective option in EGFR-mutant NSCLC pts. T790M negativity is a potentially predictive efficacy biomarker for gefitinib re-challenge. Clinical trial information: NCT01933347. [Table: see text]
Tolerability and antitumor activity of ASP8273 in TKI-naive Japanese subjects with EGFR mutation–positive non-small cell lung cancer.
Authors: Sugawara Shunichi , Azuma Koichi , Nishio Makoto , Hayashi Hidetoshi , Kiura Katsuyuki , Satouchi Miyako , Hida Toyoaki , Nakamura Atsushi , Iwamoto Yasuo , Inoue Akira , Takeda Koji , Ikeda Satoshi , Nakagawa Tomoki , Asahina Seitaro , Komatsu Kanji , Morita Satoshi , Fukuoka Masahiro , Nakagawa Kazuhiko
Published: September 2018

9037

Background: EGFR-activating mutations (eg, exon 19 deletions [ex19del], L858R) occur in ~50% of East Asian patients with non-small cell lung cancer (NSCLC) and confer sensitivity to tyrosine kinase inhibitor (TKI) treatment. ASP8273, an orally administered EGFR TKI that inhibits EGFR-activating mutations, has demonstrated clinical activity in subjects with EGFR mutation-positive (EGFRmut+) NSCLC. Methods: EGFR TKI-naïve adult subjects (≥20 yr) with EGFRmut+ NSCLC were enrolled in this single arm Phase 2 study conducted in Japan (NCT02500927). Subjects received open-label ASP8273 300 mg once daily until discontinuation criteria were met. Primary endpoint was tolerability; secondary endpoint was antitumor activity defined by RECIST v1.1. Results: A total of 31 Japanese subjects (12 M/19 F; median age 64 years [range: 31–82]) were enrolled. Based on local testing, 27 subjects had an ex19del (n = 13, 42%) or a L858R (n = 14, 45%) EGFR activating mutation; 4 subjects (13%) had other EGFR activating mutations (L861Q [n = 2], G719X [n = 2]). ASP8273 300 mg had tolerable adverse events with diarrhea and peripheral neuropathy being most common; no interstitial lung disease events were reported (Table). Across all 31 subjects, based on investigator assessment, treatment with 300 mg ASP8273 was associated with an overall response rate (ORR) of 52%, disease control rate (DCR) of 94%, and a median duration of progression-free survival (PFS) of 11.3 months (95% CI: 7.2, 15.5). In subjects with ex19del, ASP8273 300 mg was associated with an ORR of 46% and DCR of 85%; median PFS was 8.3 months (95% CI: 2.9, -). In subjects with the L858R, ASP8273 300 mg was associated with an ORR of 57% and DCR of 100%; median PFS was 15.5 months (95% CI: 7.2, 15.5). Conclusions: Once-daily ASP8273 300 mg was tolerable in TKI-naïve Japanese subjects with EGFRmut+ NSCLC and demonstrated antitumor activity. Clinical trial information: NCT02500927. [Table: see text]
YES1 amplification as a mechanism of acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs) identified by a transposon mutagenesis screen and clinical genomic testing.
Authors: Fan Pang-Dian , Narzisi Giuseppe , Jayaprakash Anitha , Venturini Elisa , Robine Nicolas , Smibert Peter , Germer Soren , Jordan Emmet , Wang Lu , Jungbluth Achim A , Spraggon Lee , Lovly Christine Marie , Kris Mark G. , Yu Helena Alexandra , Riely Gregory J. , Varmus Harold , Politi Katerina A. , Ladanyi Marc
Published: September 2018

9043

Background: Overcoming AR to EGFR TKIs remains challenging, and in many cases the mechanisms are still unclear. To identify novel mechanisms of resistance to EGFR TKIs, we performed a forward genetic screen using transposon mutagenesis in EGFR-mutant lung adenocarcinoma cells. Methods: EGFR TKI-sensitive PC9 cells were co-transfected with plasmids encoding a mutagenic piggyBactransposon and hyperactive piggyBac transposase. Transposon-tagged, afatinib-resistant clones were generated by sequential selection of transfected cells with puromycin and 1µM afatinib. Transposon insertion sites were mapped using a modified TraDIS-type method and next-generation sequencing (NGS). Selected clones were characterized using Western blots, receptor tyrosine kinase (RTK) arrays, and viability assays following treatment with TKIs or siRNA-mediated gene knockdowns. We reviewed MSK-IMPACT™ NGS data on 100 patient tumors with EGFR TKI AR. Available tumor samples were analyzed by fluorescence in situ hybridization (FISH). Results: In 187/188 afatinib-resistant clones, transposon insertion sites consistent predominantly with gene upregulation were found in MET, the Src family kinase (SFK) member YES1, or both. Clones with activating YES1 insertions exhibited resistance to all three generations of EGFR TKIs; high levels of expression of tyrosine-phosphorylated YES1; sensitivity to the SFK TKI dasatinib and to siRNA-mediated knockdown of YES1; and tyrosine phosphorylation of YAP1 and ERBB3. A query of the MSK-IMPACT™ data on EGFR TKI AR patients revealed amplification of YES1 and no alteration of MET, ERBB2 or BRAF in 3/54 T790M-negative (95% CI 1 to 16%) and 1/46 (95% CI 1 to 12%) T790M-positive cases. Amplification of YES1was confirmed by FISH in 2/2 cases, and was absent in matched pre-TKI samples in 2/2 cases. Conclusions: YES1 amplification is found in 4% of patients with acquired resistance to EGFR TKIs and is potentially targetable by Src family kinase inhibitors. Forward genetic screens using transposon mutagenesis and routine clinical NGS of patient samples can identify novel mechanisms of resistance to targeted therapies.
Association between hospital volume and overall survival of patients with metastatic non-small cell lung cancer.
Authors: Goyal Gaurav , Bartley Adam C. , Go Ronald S.
Published: September 2018

9044

Background: Prior studies have shown superior surgical outcomes of stage I-III non-small cell lung cancer (NSCLC) in centers with higher patient volumes. However, there is a lack of such information in stage IV NSCLC. In this study, we aim to determine the association between the number of patients with stage IV NSCLC treated annually at a treatment facility (volume) and all-cause mortality (outcome). Methods: Using the National Cancer Database, we identified patients diagnosed with stage IV NSCLC between 2004 and 2013. We classified the facilities by quartiles (Q; mean patients with NSCLC treated per year): Q1: < 13.8; Q2: 13.8 to 23.6, Q3: 23.6 to 30.3, and Q4: > 30.3. We used sandwich variance estimators to account for clustering of patients within facilities and Cox regression to determine the volume-outcome relationship, adjusting for demographic (sex, age, race), socioeconomic (insurance type), receipt of chemotherapy, and comorbid (Charlson-Deyo score) factors and year of diagnosis. Results: There were 281,654 patients with stage IV NSCLC treated at 1,275 facilities. The median age at diagnosis was 66 years, and 55.7% were men. The median annual facility volume was 23.6 patients per year (range, 1.0 to 301.4). The distribution of patients according to facility volume was: Q1: 6.6%, Q2: 14.9%, Q3: 25.4%, and Q4: 53.1%. The unadjusted median overall survival by facility volume was: Q1: 4.4 months, Q2: 4.5 months, Q3: 4.7 months, and Q4: 5.3 months ( P< .001). Multivariable analysis showed that facility volume was independently associated with all-cause mortality. Compared with patients treated at Q4 facilities, patients treated at lower-quartile facilities had a small but significantly higher risk of death (Q3 hazard ratio [HR], 1.05 [95% CI, 1.03 to 1.07]; Q2 HR, 1.06 [95% CI, 1.03 to 1.09]; Q1 HR, 1.09 [95% CI, 1.06 to 1.13]). Conclusions: Patients who were treated for stage IV NSCLC at lower-volume facilities had a significantly higher risk of all-cause mortality compared with those who were treated at lower-volume facilities. [Table: see text]
Impact of prior radiation on survival in metastatic lung cancer ECOG-ACRIN trials.
Authors: Khan Saad A. , Puligandla Maneka , Dahlberg Suzanne Eleanor , Masters Gregory A. , Langer Corey J. , Brahmer Julie R. , Hanna Nasser H. , Bonomi Philip , Gerber David E. , Johnson David H. , Schiller Joan H. , Ramalingam Suresh S.
Published: September 2018

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.
Phase II study of the FGFR inhibitor AZD4547 in previously treated patients with FGF pathway-activated stage IV squamous cell lung cancer (SqNSCLC): LUNG-MAP sub-study SWOG S1400D.
Authors: Aggarwal Charu , Redman Mary Weber , Lara Primo , Borghaei Hossein , Hoffman Philip C. , Bradley Jeffrey D. , Griffin Katie , Miao Jieling , Mack Philip C. , Papadimitrakopoulou Vassiliki , Herbst Roy S. , Kelly Karen , Gandara David R.
Published: September 2018

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.
Retinoblastoma mutation to predict poor outcomes in non-small cell lung cancer (NSCLC).
Authors: Bhateja Priyanka , Wildey Gary , Fu Pingfu , Lipka Mary Beth , Ardeshir-Larijani Fatemeh , Sharma Neelesh , Dowlati Afshin
Published: September 2018

9060

Background: Genomic profiling of tumor DNA has revealed the diversity in NSCLC. The retinoblastoma gene ( RB1) encodes for RB pocket protein that plays an important role in cell cycle progression by interacting with various transcriptional factors. Here we determine the frequency and prognostic significance of RB1mutation in NSCLC and compare it to that in small cell lung cancer (SCLC). Methods: This IRB-approved retrospective review on NSCLC patients included Stage III and IV patients with genomic and clinical data. Primary outcome was median overall survival (OS) and secondary outcome was progression-free survival (PFS). OS and PFS were calculated by the Kaplan-Meier method and compared between mutant and wild-type (wt) RB1using the Log-Rank test. The effect of RB1mutation status on OS and PFS was further evaluated using the multivariable Cox model, controlling the effects of age, sex, stage, smoking history and chemotherapy. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Results: We identified RB1 mutation in 8.2% of NSCLC patients (16 of 195 patients). With a median follow-up of 15.1 months, the median OS for wt RB1was 28.3 months and for mutant RB1 was 8.3 months (HR = 2.59, p-value = 0.002). The median PFS for wt RB1 was 21.8 months vs 6.4 months for mutant RB1 (HR = 2.85, p-value = 0.0002). RB1 mutation was associated with worse OS ( p= 0.017, HR = 2.17) and PFS ( p= 0.005, HR = 2.37) in multivariate analyses after adjusting for traditional risk factors like, age, sex, stage, smoking history and chemotherapy. Interestingly, a previously described benign deletion (A16-A18) in RB1 protein was identified in 5 of the 16 RB1 mutant patients and was associated with far worse outcomes compared to other RB1 mutations. In contrast to NSCLC, RB1 mutation was identified in 75% of 64 SCLC patients. Furthermore, wt RB1 was associated with significantly shorter OS ( p= 0.002), PFS ( p= 0.004) and chemotherapy refractoriness ( p= 0.033) in SCLC. Conclusions: RB1 mutation is present in a minority of patients with advanced NSCLC and is associated with poor prognosis. In contrast, RB1 mutation is present in the majority of SCLC patients and is associated with a favorable prognosis.
Targeted therapy for non-small cell lung cancer (NSCLC) with HER2, BRAF, or hedgehog alterations: Interim data from MyPathway.
Authors: Hainsworth John D. , Bose Ron , Sweeney Christopher , Meric-Bernstam Funda , Hurwitz Herbert , Swanton Charles , Burris Howard A. , Kurzrock Razelle , Yoo Bongin , Beattie Mary Stanley , Gupta Ravindra , Patel Rajesh D. , Schulze Katja , Spigel David R.
Published: September 2018

9073

Background: Treatments targeting critical molecular alterations (EGFR, ALK, and ROS1) in NSCLC are highly effective. MyPathway (NCT02091141) is an ongoing, phase 2, multi-basket study evaluating the efficacy of targeted treatment in non-indicated tumor types harboring alterations in the HER2, BRAF, Hedgehog (Hh), or EGFR pathways. Interim results in NSCLC are presented. Methods: Patients with previously treated advanced NSCLC and alterations in the HER2 (amplification and/or mutation), BRAF (V600E or other mutations), Hh (SMO or PTCH-1 mutations), or EGFR (mutations other than known activating mutations) pathways received standard doses of pertuzumab + trastuzumab, vemurafenib, vismodegib, or erlotinib, respectively, until disease progression or unacceptable toxicity. The HER2, BRAF, and Hh cohorts are included in this analysis. The primary endpoint is investigator-assessed objective response rate (ORR, defined as complete response [CR] + partial response [PR]) by RECIST v1.1. Results: As of November 30, 2016, 61 patients with NSCLC and HER2 (n = 36), BRAF (n = 22), or Hh (n = 3) alterations have been treated (median age of 64 years, 49% male, 85% adenocarcinoma, and a median of 2 previous regimens). Median treatment duration was 1.8 (range, 0–21.4) months. Efficacy in the 55 patients with the minimum required follow-up for efficacy analysis is summarized in the table. Conclusions: Targeted therapy is active in patients with previously treated NSCLC harboring BRAF V600E mutations or HER2 alterations (amplifications and/or mutations). These cohorts have been expanded as MyPathway accrual continues. Additional efficacy data and details regarding molecular alterations will be presented. Clinical trial information: NCT02091141. [Table: see text]
Clinical outcomes of patients with non-small cell lung cancer (NSCLC) receiving chemotherapy after immune checkpoint blockade.
Authors: Grigg Claud , Reuland Brian D. , Sacher Adrian G. , Yeh Randy , Rizvi Naiyer A. , Shu Catherine A.
Published: September 2018

9082

Background: Objective response rates (ORR) to chemotherapy beyond the first-line for advanced NSCLC are low (5-10%). Pre-clinical studies suggest that some chemotherapies may act, in part, through immune mediated mechanisms. Additionally, results from phase I/II studies of chemotherapy combined with immune checkpoint inhibitors (ICIs) suggest high response rates ( > 50%) and potential synergy. It is unknown whether chemotherapy is more efficacious when given after ICIs. Methods: We reviewed demographics, imaging, treatment history, and clinical course for all patients at our institution with a diagnosis of metastatic NSCLC who received at least one dose of nivolumab, pembrolizumab, atezolizumab, or durvalumab prior to December 8, 2016. Patients who received any subsequent chemotherapy were included for analysis. Objective response was determined by RECIST v1.1, and date of progression was determined radiographically or clinically (treatment discontinuation with documented clinical deterioration). Results: 145 patients received at least one dose of any ICI, and 38 patients received subsequent chemotherapy. The median age was 68 years (range 44-88). Six chemotherapy-naïve patients received carboplatin + pemetrexed +/- bevacizumab. There were 3 partial responses (PR) including one exceptional response that is ongoing after 2 years. Among 32 chemotherapy non-naïve patients, the median number of prior chemotherapy regimens was 2 (range 1-6). Post-ICI chemotherapy included docetaxel + ramucirumab (n = 12), vinorelbine (n = 7), gemcitabine-based chemotherapy (n = 6), carboplatin doublets (n = 4), pemetrexed + bevacizumab (n = 2), and paclitaxel (n = 1). Six patients had documented poor performance status and died within 1 month of starting treatment. The ORR was 25% (1CR, 7PR), median time to progression was 116 days, and 9 patients (28%) experienced stable disease (SD) or better lasting > 150 days. Exceptional responses occurred across regimens. Nine patients received a further line of chemotherapy, with 3 ongoing PR or SD lasting > 100 days. Conclusions: For NSCLC, chemotherapy response rates may be higher when administered after an ICI.
Response to single-agent (SA) chemotherapy (CTx) after immunotherapy exposure in non-small cell lung cancer (NSCLC).
Authors: Schvartsman Gustavo , Peng S. Andrew , Bis Giorgios , Lee J. Jack , Benveniste Marcelo Felipe Kuperman , Zhang Jianjun , Rinsurongkawong Waree , Lewis Jeff , Roarty Emily , Lacerda Lara , Roth Jack A. , Swisher Stephen , Heymach John , Fossella Frank V. , William William Nassib
Published: September 2018

9083

Background: Overall response rates (ORR) to 2nd-line SACTx in NSCLC have consistently not exceeded 15%. Exploratory analysis of clinical trials in various tumor types have demonstrated potential improvements in ORR to CTx after exposure to vaccine-based immunotherapy. The objective of this retrospective study was to determine if SACTx (3rd-line or beyond) would yield improved ORR when given after exposure to programmed-death-(ligand)1 inhibitors (PD1i) in metastatic NSCLC. Methods: Eligibility criteria - patients registered in the Thoracic GEMINI database of MD Anderson treated between 06/12 and 11/16 who received at least one SACTx as 3rd-line or beyond, following progression after platinum-based CTx and PD1i. We computed efficacy outcomes to each therapy, including ORR by RECIST v1.1, progression-free survival (PFS) and overall survival (OS). Results: Of 306 PD1i-treated patients registered in the database, 28 met eligibility criteria - 54% were male, median age 66 years, 82% adenocarcinoma, 29% never smokers. The PD1i and SACTx most commonly used were nivolumab (82%) and docetaxel (54%). ORR to SACTx after exposure to PD1i was 39% (11/28 patients, 8 confirmed). In contrast, ORR to 1st-line CTx in this cohort was 30% (Table). Liver metastasis and pembrolizumab as the PD1i of choice were the only factors associated with response to SACTx on univariate analysis (p < 0.05). Conclusions: In NSCLC patients, ORR to SACTx after immunotherapy exposure was higher compared to historical data from the pre-PD1i era, and approached ORR to 1st-line platinum-based CTx. Further investigation of a possible chemosensitization effect by immunotherapy is warranted. [Table: see text]
Tumor response dynamics of advanced non-small-cell lung cancer (NSCLC) patients (pts) treated with commercial PD-1 inhibitors in the clinical setting.
Authors: Nishino Mizuki , Dahlberg Suzanne Eleanor , Adeni Anika E , Lydon Christine A. , Hatabu Hiroto , Janne Pasi A. , Hodi F. Stephen , Awad Mark M.
Published: September 2018

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.
A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC).
Authors: Long Georgina V. , Atkinson Victoria , Menzies Alexander M. , Lo Serigne , Guminski Alexander David , Brown Michael Paul , Gonzalez Maria Magdalena , Diamante Katrina , Sandhu Shahneen Kaur , Scolyer Richard A. , Emmett Louise , McArthur Grant A.
Published: September 2018

9508

Background: Nivolumab (nivo) and the combination of nivo + ipilimumab (ipi) improve response rates (RR) and progression-free survival (PFS) compared with ipi alone in clinical trials of metastatic melanoma pts, but pts with untreated brain mets were excluded. Brain mets are a major cause of morbidity and mortality in melanoma and their management is critical. We sought to determine the antitumour activity and safety of nivo and nivo+ipi in pts with active melanoma brain mets (NCT02374242). Methods: This open-label, ph II trial enrolled 3 cohorts of pts naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014 - Feb 2017. Pts with asymptomatic melanoma brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3W x4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets 1) that failed local therapy (new +/- progressed in previously treated met), 2) were neurologically symptomatic and/or 3) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥ wk12. Secondary endpoints were best extracranial response (ECR), best overall response (OR), IC PFS, EC PFS, overall PFS, OS, and safety. Results: A total of 66 pts (med f/u 14 mo) were included in this analysis of total 76 planned; median age 60y, 77% male. For cohorts A, B and C: elevated LDH 48%, 58% and 19%; V600BRAF 44%, 56% and 81%; prior BRAFi 24%, 24%, 75%. Table shows RR, PFS and OS. ICR in cohort A treatment naïve vs prior BRAFi was 53% vs 16%. Treatment-related gd 3/4 toxicity in cohorts A, B and C were 68%, 40% and 56%, respectively. There were no treatment-related deaths. Conclusions:Nivo monotherapy and ipi+nivo and are active in melanoma brain mets. Ipi+nivo had reduced activity in pts who progressed on BRAFi. Pts with symptomatic brain mets, leptomeningeal mets or previous local therapy responded poorly to nivo alone. Clinical trial information: NCT02374242. [Table: see text]