bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular analysis-directed, international, phase III trial in patients with advanced non-small-cell lung cancer.
Authors: Bepler Gerold , Williams Charles C. , Schell Michael J. , Chen Wei , Zheng Zhong , Simon George R. , Gadgeel Shirish M. , Zhao Xiuhua , Schreiber Fred James , Brahmer Julie R. , Chiappori Alberto , Tanvetyanon Tawee , Pinder Mary Colleen , Gray Jhanelle Elaine , Haura Eric B. , Antonia Scott J. , Fischer Jurgen R.
Published: March 2020

8001

Background: ERCC1 (E1) and RRM1 (R1) are predictive markers for platinum agents and gemcitabine (G) respectively. In a phase II trial that utilized E1 and R1 mRNA expression levels for therapeutic decision-making, a response rate of 44%, PFS of 6.6 m, and OS of 13.3 m was achieved. Methods: Pts with advanced, chemo-naive NSCLC, PS 0-1, measurable disease, and a FFPE histological or cell block tumor specimen were eligible. E1 and R1 were analyzed by AQUA and categorized as high or low. Pts were randomized 2:1 to arm A, which received G and carboplatin (Cb) for R1/E1 low, docetaxel (D) and Cb for R1 high and E1 low, G and D for R1 low and E1 high, and D and vinorelbine (V) for R1/E1 high, or arm B, which received GC. Pts received up to 6 cycles. Efficacy was assessed every 6-8 weeks until 1 year from treatment initiation. The primary goal was to improve the 6-m PFS from 38% in arm B (median PFS 4.3 m) to 50% in arm A (median PFS 6.0 m). Secondary goals were improvements in OS (8.0 to 12.0 m) and RR (25% to 50%). Results: Of 275 eligible pts, 183 randomized to arm A. 56 were assigned to GCb, 26 to DCb, 37 to GD, and 64 to DV, which was not significantly different (p=.2) from the expected assignment (30%, 20%, 20%, 30%). In arm B, all 92 pts received GCb. Protein analysis was successful in 91% of pts. The median time from consent to completed gene analysis was 11 days. A tumor rebiopsy for the specific purpose of gene analysis was required in 17% of pts. The 6-m PFS rate and median PFS were 52.0% and 6.1 m in arm A and 56.5% and 6.9 m in arm B (p = 0.18). PFS was not significantly different among the treatment groups in arm A (p = 0.1). A significant survival advantage was found for pts with low E1 and low R1 in arm B compared to the same group in arm A (p = 0.02) although both received GCb therapy. OS and RR were not significantly different between both groups. A comparison between protein and mRNA levels for both genes revealed no significant correlation. Conclusions: This demonstrates that gene expression analysis for therapeutic decision making is feasible in newly diagnosed advanced-stage NSCLC pts. A tumor rebiopsy is safe, required in 17%, and acceptable to 89% pts. The survival results are false negative based on the internal control included in the trial. Clinical trial information: NCT00499109.
Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation–positive non-small cell lung cancer (NSCLC) patients.
Authors: Planchard David , Mazieres Julien , Riely Gregory J. , Rudin Charles M. , Barlesi Fabrice , Quoix Elisabeth A. , Souquet Pierre Jean , Socinski Mark A. , Switzky Julie , Ma Bo , Goodman Vicki L. , Carson Stanley W. , Curtis C. Martin , Streit Michael R. W. , Johnson Bruce E.
Published: March 2020

8009

Background: Activating BRAF V600E mutations in NSCLC are present in < 2% of tumors, primarily adenocarcinoma. The BRAF inhibitor dabrafenib has demonstrated clinical activity in BRAF V600 mutation–positive melanoma. Here we report interim efficacy and safety data obtained in 17 BRAF V600E–mutant NSCLC patients enrolled in dabrafenib phase II study BRF113928. Methods: Single-arm, 2-stage, phase II study in stage IV BRAF V600E mutation–positive NSCLC pts who failed at least 1 line of chemotherapy. Dabrafenib dosed at 150 mg orally twice daily. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST 1.1 criteria. Results: The median age of the 17 pts was 69 years (range, 51-77 years). Most pts (12/17) were male, all were white with adenocarcinoma, and 13 were former smokers. All pts had failed at least 1 line of prior anticancer therapy, and 5 subjects had failed ≥ 2. At the time of reporting, 11 pts remain on therapy, and 6 have stopped therapy (5 with PD and 1 due to an AE). Thirteen pts were evaluable for efficacy. The best response for these pts included 7 PRs (5 confirmed PRs), 1 SD, and 4 PD; 1 pt discontinued due to an SAE (hypersensitivity reaction) prior to response assessment (ORR, 54%). The median duration of treatment for all 17 pts is approximately 9 weeks (range, 1-69 weeks). Among the 5 pts with confirmed PRs, duration of response was 29 and 49 weeks for the 2 pts who progressed, while the remaining 3 pts were responding for 6+ to 24+ weeks. The safety of dabrafenib in NSCLC pts appears to be generally consistent with what has been previously observed. The most common AEs were decreased appetite, fatigue, asthenia, dyspnea, and nausea, mostly grade 1 or 2. Five pts (29%) had a grade 3 AE, and 1 pt (6%) had a grade 4 SAE (hemorrhage). Conclusions: Dabrafenib shows early antitumor activity in BRAF V600E mutation–positive pretreated NSCLC pts, with an ORR of 54% and with the longest duration of response of 49 weeks thus far. Dabrafenib is generally well tolerated, and the study has met the minimum response rate (≥ 3 of first 20 pts) to continue into the second stage. This study represents the first clinical evidence of BRAF as a therapeutic target in NSCLC. Clinical trial information: NCT01336634.
Detection of EGFR-activating mutations from plasma DNA as a potent predictor of survival outcomes in FASTACT 2: A randomized phase III study on intercalated combination of erlotinib (E) and chemotherapy (C).
Authors: Mok Tony , Wu Yi Long , Lee Jin Soo , Yu Chong-Jen , Sriuranpong Virote , Wen Wei , Tsai Julie , Truman Matt , Klughammer Barbara , Wu Lin
Published: March 2020

8021

Background: Biomarker analysis of tumor from FASTACT 2 confirmed predictive power of EGFR mut on the benefit of intercalated combination of E and C as 1st line in advanced NSCLC (T. Mok, ESMO 2012). However, only limited tumor were available. Recent development allowed us to detect EGFR mut in cell-free DNA from plasma (pEGFRmut). In this study, we studied the concordance between pEGFRmut and EGFR mut in tumor (tEGFRmut), and the role of pEGFRmut as predictor of PFS and OS. Methods: Retrospective EGFR mut testing of FFPET and plasma from FASTACT 2 were performed with two allele-specific PCR assays, cobas EGFR_FFPET test and cobas EGFR_blood test (in development). Both tests are designed to detect EGFR activating mut (exon 19 deletions, L858R, G719X). One FFPET section was used for tissue test and 2-ml plasma was used for blood test. Results: Among 268 tumors from 451 enrolled pts, 90% (241/268) were analyzable. 40% (96/241) harbored at least one activating EGFR mut. All 427 plasmas from 451 enrolled pts were analyzable. 32% (136/427) were positive for EGFR activating mut. The concordance of two tests from 224 matched tissue and plasma samples was summarized below. Using tissue as comparator, the sensitivity of plasma test was 76% (68/89) and the specificity of plasma test was 96% (130/135) respectively. Positive and negative predictive values for EGFR activating mut were 93% (68/73) and 86% (130/151) respectively. Median PFS of patients with pEGFRmut treated with intercalated combination versus chemotherapy alone was 13.8 vs. 6.1 m (HR=0.21 p<0.0001), and for pEGFR wild-type, 6.7 vs. 6.0 m (HR=0.80, p=0.06). Median OS of patients with pEGFRmut treated with intercalated combination versus chemotherapy alone was 32.4 vs. 19.0 m (HR=0.51, p=0.0035), and for pEGFR wild-type, 16.1 vs 13.3 m (HR=0.89, p=0.39). Conclusions: cobas EGFR_blood test can be used to reliably detect EGFR mutations in plasma. pEGFRmut is a potent predictor of survival outcomes in FASTACT 2. Clinical trial information: NCT00883779/ MO22201/CTONG0902. [Table: see text]
Patterns of metastasis and survival in patients with PI3K pathway-driven stage IV squamous cell lung cancers (SQCLC).
Authors: Paik Paul K. , Moreira Andre L. , Wang Lu , Won Helen H. , Hasanovic Adnan , Rekhtman Natasha , Sima Camelia S. , Ladanyi Marc , Berger Michael F. , Kris Mark G.
Published: March 2020

8022

Background: The majority of actionable drivers in SQCLCs occur in the PI3K (30%) and FGFR1 (20%) pathways. The biologic behaviors and natural histories of these oncogenic subtypes are not well characterized. Methods: As of October 2011, all patients with SQCLCs at MSK have undergone prospective, multiplex testing of their FFPE tumors for FGFR1 amplification (FISH), PIK3CA mutations (Sequenom), PTEN loss (IHC), and PTEN mutations (exon sequencing), among others. Patient characteristics, outcomes, and metastatic sites were identified. Survival probabilities were estimated using the Kaplan-Meier method. Group comparisons were performed with log-rank tests and Cox proportional hazards methods. Results: 68 stage IV SQCLC patients were analyzed. 39 had tissue sufficient for next-gen sequencing. Genotypes were: FGFR1 amplified (16%); PTEN loss (24%), PIK3CA mutant (7%), PTEN mutant (13%). Events were non-overlapping save for 2 cases with PTENnonsense mutations and PTEN loss. The sole significant clinical difference (KPS, age, sex, lines of tx) was sex (women in PI3K group 52% vs. in others 23%, p=0.02). Metastatic patterns vs. other are shown in the Table. Median OS for PI3K vs. other: 10mo (95%CI:6.5-14.3) vs. 14mo (95%CI:9.6-36.7), p=0.02. Median OS for FGFR1 vs. others: 19mo (95%CI:9-NR) vs. 10mo (95%CI:6.5-14.3), p=0.3. Multivariate analysis for OS: PI3K vs. other, HR death=2.3 (95%CI:1.1-4.8, p=0.03); Age ≥65, HR=1.3 (95%CI:0.6-2.9, p=0.6); KPS≥70, HR=0.5 (95%CI:0.2-1.7, p=0.3); Male sex, HR=0.7 (95%CI:0.3-1.4, p=0.3). Conclusions: Patients with stage IV PI3K-aberrant SQCLCs have poorer survival compared to other patients with SQCLCs. Brain metastases occurred exclusively in patients with PI3K-aberrant tumors. These data suggest that PI3K pathway activation confers a distinct biology, and that targeting this in SQCLC patients with brain metastases may be an effective therapeutic strategy. [Table: see text]
Efficacy and safety of crizotinib in patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC).
Authors: Ou Sai-Hong Ignatius , Bang Yung-Jue , Camidge D. Ross , Riely Gregory J. , Salgia Ravi , Shapiro Geoffrey , Solomon Benjamin J. , Engelman Jeffrey A. , Kwak Eunice Lee , Clark Jeffrey W. , Tye Lesley , Wilner Keith D. , Stephenson Patricia , Varella-Garcia Marileila , Bergethon Kristin , Iafrate Anthony John , Shaw Alice Tsang
Published: March 2020

8032

Background: ROS1 receptor tyrosine kinase rearrangements define a subset of NSCLC sensitive to the small-molecule tyrosine kinase inhibitor crizotinib, approved multinationally for the treatment of advanced ALK-positive NSCLC. Updated efficacy and safety data are presented for crizotinib in patients with advanced ROS1-rearranged NSCLC. Methods: ROS1 status was determined by break-apart FISH assays, and patients were enrolled into an expansion cohort of an ongoing phase 1 crizotinib study (NCT00585195). Patients received crizotinib 250 mg BID. Responses were assessed using RECIST v1.0. The disease control rate (DCR; % stable disease [SD] + partial response [PR] + complete response [CR]) was evaluated at weeks 8 and 16. Results: At the data cut-off, 33 patients with ROS1-positive NSCLC had enrolled, and 31 had received crizotinib, with 25 evaluable for response. Median age was 51 years (range 31–72), 79% of patients were never-smokers and 97% had adenocarcinoma histology. The median number of prior treatments for advanced disease was 1 (range 0–7). The objective response rate (ORR) was 56% (95% CI: 24.4–65.1), with 2 CRs, 12 PRs and 8 SDs. 8-week and 16-week DCRs were 76% and 60%, respectively. Median PFS has not been reached, with ~60% of patients still in follow-up for PFS; 6-month PFS probability was 71% (95% CI: 45.6–86.0). Median treatment duration was 24 weeks (range 2.3–112), and 24 patients were on treatment at the data cut-off; 5 patients died (all disease-related). 91% of patients had treatment-related adverse events (AEs): most commonly visual impairment (82%), nausea (36%) and diarrhea (33%). Most AEs were grade 1 in severity. Peripheral edema and elevated transaminases were also reported, similar to the previous experience of crizotinib. There were no treatment-related serious AEs or treatment-related permanent discontinuations. Accrual of patients with ROS1-positive NSCLC is ongoing. Conclusions: As observed in ALK-positive NSCLC, crizotinib had dramatic antitumor activity with a high ORR (56%) in patients with ROS1-positive NSCLC and a generally tolerable and manageable AE profile. These findings indicate that crizotinib is an effective therapy for advanced ROS1-positive NSCLC. Clinical trial information: NCT00585195.
A randomized open-label phase II study evaluating antitumor activity of the survivin antisense oligonucleotide LY2181308 (LY) in combination with docetaxel (DO) for second-line treatment of patients with non-small cell lung cancer (NSCLC) using change in tumor size (CTS).
Authors: Talbot Denis Charles , Blackhall Fiona Helen , Kowalski Dariusz , Ramlau Rodryg , Bepler Gerold , Grossi Francesco , Lerchenmuller Christian A. , Pinder Mary Colleen , Mezger Jorg , Danson Sarah , Callies Sophie , Andre Valerie , Das Mayukh , Lahn Michael M. F. , Natale Ronald B.
Published: March 2020

8051^

Background: Resistance to chemotherapy in progressive NSCLC is associated with overexpression of antiapoptotic proteins including survivin. Down-regulation of survivin can sensitize NSCLC to DO in vitro and in xenograft studies. On the basis of preclinical/phase I results we examined antitumor activity of DO+LY compared with DO alone. Methods: Key eligibility criteria: ECOG PS 0-1, stage IIIB/IV NSCLC all histologies, progression after first-line platinum regimen. Patients randomized (N=180) 2:1 to receive DO+LY (LY 750 mg IV loading ×3, Q1W maintenance) or DO alone (75 mg/m2 D1Q3W) until progression/toxicities. Antitumor activity was compared using CTS from baseline to end of cycle (C) 2 in each arm. This analysis, which uses tumor measurements as a continuous variable rather than a categorical endpoint based on RECIST, increases statistical efficiency and enables early assessment of clinical benefit. Secondary objectives included assessment of toxicity, PK, PFS and OS. Results: 114 patients received study drug and were included in the analyses. Baseline patient demographics were similar. No statistically significant difference in mean CTS ratio at C2 or in PFS was observed between the 2 arms: CTS was 1.07 with LY+DO (SD, 0.28) and 1.04 with DO (SD, 0.28); median PFS was 2.83 mo (95% CI, 1.84–3.65) with LY+DO and 3.35 mo (95% CI, 2.69–4.57) with DO (log-rank p=0.191). However, Cox regression revealed CTS to be a statistically significant factor for PFS: decreased CTS was associated with increased PFS (HR 0.45; 95% CI, 0.30–0.68, p=0.0001). Median OS was 7.9 mo (90% CI, 6.6–9.7) with LY+DO and 8.8 mo (90% CI, 5.7–13.8) with DO (log-rank p=0.481). There were no differences in toxicities or other secondary parameters. Incidence of grade III/IV toxicities was similar in both arms and was consistent with the known profile of LY+DO as was the PK profile. Conclusions: Addition of LY to DO did not improve the antitumor activity of DO. CTS appears to be a useful endpoint in phase II studies and should be considered further as an endpoint for early decision-making. Clinical trial information: NCT01107444.
Prospective observational cohort study of second-line chemotherapy administration after first-line platinum-based chemotherapy for patients with advanced NSCLC in Japan (SAPPHIRE study).
Authors: Yoh Kiyotaka , Goto Yasushi , Naito Yoichi , Kishi Kazuma , Ohashi Yasuo , Kunitoh Hideo
Published: March 2020

8058

Background: Maintenance therapy after first-line platinum-based chemotherapy (first-CT) is reported to be beneficial to patients with advanced non-small cell lung cancer (NSCLC). However, its impact on overall survival appears to be marginal or negligible, if those without maintenance receive active second-line chemotherapy (second-CT), which is initiated at disease progression. The purpose of this study is to investigate the proportion of second-CT administration after first-CT for patients with advanced NSCLC. Methods: From April 2010 to September 2011, 865 patients with advanced NSCLC who were initiated on first-CT at 30 institutions in Japan were enrolled in this prospective observational study. Baseline characteristics, regimens and responses to first-CT, whether or not they received second-CT, and if not, reasons for non-administration were recorded. This report describes from patients with at least 6 months of follow up. This study was supported by the Public Health Research Center Foundation CSPOR. Results: A total of 865 eligible patients with advanced NSCLC provided patient characteristics and details of first-CT. Of all patients, 70% had adenocarcinoma, 20% had squamous cell carcinoma, and 10% were positive for the EGFR mutation. At this data cut off, 225 patients were excluded from the analysis due to disease progression and loss of follow-up during first-CT, and 194 (22%) patients received maintenance therapy after first-CT. Among the 508 patients who were followed up for at least 6 months, 131 patients (26%) could not receive second-CT; the reasons were as follows: declined PS, 79 (60%); patient refusal, 28 (21%); death of any cause, 6 (5%); others, 18 (14%). Conclusions: Preliminary results of this large observational study in Japan suggested that around 20% of patients missed an opportunity to receive appropriate second-CT despite the follow-up of advanced NSCLC patients after first-CT. Further investigation is needed to elucidate the selection criteria of patients that may benefit the most from maintenance therapy, not second-CT at disease progression.
A phase I study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus platinum-based doublet chemotherapy (PT-doublet) in chemotherapy-naive non-small cell lung cancer (NSCLC) patients (pts).
Authors: Rizvi Naiyer A. , Antonia Scott J. , Chow Laura Quan Man , Brahmer Julie R. , Juergens Rosalyn A. , Borghaei Hossein , Shepherd Frances A. , Laurie Scott Andrew , Gerber David E. , Goldman Jonathan Wade , Shen Yun , Harbison Christopher , Alaparthy Suresh , Chen Allen C. , Gettinger Scott N.
Published: March 2020

8072

Background: A phase I study ofnivolumab (a PD-1 receptor blocking Ab) demonstrated durable responses and a tolerable safety profile in NSCLC pts who failed ≥1 chemotherapy regimen. We report an interim analysis of a phase I study with nivolumab + PT-doublets in chemotherapy-naive advanced NSCLC pts. Methods: Stage IIIB/IV NSCLC pts were randomized by histology ≥9 wk prior to data lock (Dec 2012) to: A) nivolumab/gemcitabine/cisplatin; B) nivolumab/pemetrexed/cisplatin; or C) nivolumab/carboplatin/paclitaxel according to a phase I dose de-escalation design to assess the toxicities and incidence of DLTs in the first 6 wk of dosing. Nivolumab doses were started at 10 mg/kg IV Q3W and given until progression. PT-doublet was given for 4 cycles at standard dosing. At a tolerable dose, cohorts were expanded up to 20 pts. Results: 43 pts were treated with nivolumab + PT-doublet: Arm A, n=12 squamous (sq); Arm B, n=15 (non-sq); and Arm C, n=16 (3 sq + 13 non-sq). No DLTs were seen across arms. Gr 3-4 regimen-related AEs were 49% across arms, and 25%, 47%, and 69% for Arms A, B, and C, respectively. Select Gr 3-4 toxicities reported included: pneumonitis, rash, nephritis, and colitis (Table). 3 pts had Gr 3 pneumonitis and were addressed with management algorithms (dose discontinuation and immune-modulating therapies). 2 pts fully resolved, however 1 resolved pt subsequently died from Aspergillus pneumonia. 1 pt died of disease progression with unresolved pneumonitis (autopsy confirmed). Total/Confirmed ORRs (RECIST 1.1) were 43/33%, 40/33%, and 31/31% in Arms A, B, and C, respectively. Conclusions: No DLTs were seen with 10 mg/kg nivolumab combined with PT-doublets; maintenance treatment is ongoing. Similar to monotherapy, select nivolumab related toxicities can be addressed with management algorithms. Safety, durability, and confirmation of responses will be updated based on a 2013 data analysis, including a 5 mg/kg nivolumab dose cohort. Clinical trial information: NCT01454102. [Table: see text]
Phase I study of ridaforolimus with cetuximab for patients with advanced non-small cell lung cancer (NSCLC), colorectal cancer, and head and neck cancer.
Authors: Taber Angela Marie , Khurshid Humera , Perez Kimberly , Birnbaum Ariel E. , Olszewski Adam J. , Luppe Denise , Jean Maureen , Rosati Kayla , Safran Howard
Published: March 2020

8075

Background: mTOR inhibition may overcome PI3K/AKT pathway mediated resistance to anti-EGFR therapy. We performed a phase I study to determine the dose-limiting toxicity (DLT) of ridaforolimus, an investigational oral mTOR inhibitor, in combination with the anti-EGFR antibody cetuximab. Methods: Patients with advanced NSCLC, colorectal cancer, and head and neck cancer that progressed after at least 1 prior regimen for metastatic disease were eligible. ECOG performance status 0-1. Patients with previously treated brain metastases that were stable for >3 months were eligible. Wild-type K-RAS was required in colon cancer. All patients received cetuximab 400 mg/m2 week 1 followed by 250 mg/m2 weekly. Three dose levels of ridaforolimus were planned: 20mg, 30mg, and 40mg daily, 5 days each week, on a 28-day cycle. Results: 12 patients were entered with NSCLC (n=7), colon cancer (n=4), and head and neck cancer (n=1). The median age was 58 (42-69). The median number of prior regimens for metastatic disease, by disease type, was NSCLC (n=3), colorectal (n=4), head & neck (n=4). Three patients completed the first dose level without DLT. Two of 3 patients at dose level 2 had dose-limiting mucositis. The first dose level was then expanded with six additional patients with NSCLC without any further dose-limiting toxicities. The recommended phase II dose of ridaforolimus is 20 mg daily, 5 days a week, in combination with cetuximab. Response and prolonged stable disease was demonstrated in NSCLC. Conclusions: The DLT of the combination of ridaforolimus and cetuximab is mucositis. The activity observed in heavily pretreated patients with NSCLC suggests that the combination of an mTOR inhibitor with an EGFR antibody merits further investigation in NSCLC. Clinical trial information: NCT01212627.
Progression patterns at RECIST PD during EGFR-TKIs in advanced NSCLC patients harboring EGFR mutation.
Authors: Yoshida Tatsuya , Yoh Kiyotaka , Goto Koichi , Matsumoto Shingo , Umemura Shigeki , Niho Seiji , Ohmatsu Hironobu , Ohe Yuichiro
Published: March 2020

8078

Background: The progression patterns at RECIST PD during EGFR-TKIs in advanced NSCLC patients harboring EGFR mutation are clinically heterogeneous. The aim of this study is to evaluate progression patterns at RECIST PD during EGFR-TKIs in advanced NSCLC patients harboring EGFR mutation. Methods: From 2008 to 2012, 160 consecutive patients with advanced NSCLC harboring EGFR mutation were treated with EGFR-TKIs (erlotinib or gefitinib) at our institution. Among these patients, 104 patients who experienced RECIST PD assessed by radiologic findings were retrospectively evaluated for initial response on EGFR-TKIs, progression sites, focus of progression (solitary lesion or multiple lesions), patients status at RECIST PD, and post progression survival (PPS) from RECIST PD. Results: In 104 patients, 96 (92%) patients had EGFR major mutation (Exon 19 deletion and L858R), and 49 (47%) received EGFR-TKIs as first-line. The overall response rate and median progression free survival on EGFR-TKIs was 69 % and 8.2 months. At the time of RECIST PD, 44 (42%) patients had symptomatic, and 60 (58%) had asymptomatic. The progression sites were isolated CNS in 17 (16%) patients, isolated bone in 7 (7%), isolated pulmonary in 13 (12%), systemic in 67 (65%) patients. In the focus of progression, 24 (23%) patients have solitary lesion, and 80 (77%) have multiple lesions. After RECIST PD, 40 (38%) patients continued EGFR-TKIs, 25 (24%) were switched to cytotoxic agents, and 39 (38%) had best supportive care. 10 (10%) patients received local radiotherapy for isolated progression site (brain 6; bone 3; lung 1) and 8 of these patients continued EGFR-TKIs. The median PPS from RECIST PD was 10.6 months. Multivariate analysis identified that asymptomatic or solitary progression lesion at RECIST PD were associated with significantly longer PPS (asymptomatic: HR 0.34, 95% CI 0.19-0.58, P<0.001; solitary progression lesion: HR 0.39, 95% CI 0.16-83, P=0.013). Conclusions: The progression patterns at RECIST PD during EGFR-TKIs in advanced NSCLC patients harboring EGFR mutation have widely diversity. Further investigation for association between progression patterns at RECIST PD and clinical outcome after RECIST PD is warranted.
Phase I study of peptide vaccine targeting indeolamine 2,3 dioxygenase in metastatic lung cancer patients.
Authors: Iversen Trine Zeeberg , Engell-Noerregaard Lotte , Ellebaek Eva , Andersen Rikke , Larsen Stine Kiaer , Bjoern Jon , Jonassen Merete , Kalbacher Hubert , Zeyher Claus , Gouttefangeas Cecile , Thomsen Inger Birthe Moerk , Holm Bente , Mellemgaard Anders , Straten Per thor , Andersen Mads Hald , Svane Inge Marie
Published: March 2020

8084

Background: To investigate the targeting of indeolamine 2,3 dioxygenase (IDO) enzyme by a synthetic peptide vaccine for patients with metastatic non small-cell lung cancer (NSCLC). Methods: We treated15 HLA-A2 positive patients with stage III-IV NSCLC and disease stabilization (SD) after standard chemotherapy. Patients were treated every second week (induction) for three months, and thereafter monthly until progression (maintenance) with imiquimod ointment and vaccine (100 µg IDO5 peptide sequence ALLEIASCL mixed with 900 µL montanide) administered subcutaneously. Primary end point was toxicity. Clinical benefit and immune monitoring were assessed. Results: Patient characteristics: mean age (63, range 51-71), sex (F=8,M=7), PS(0=9,1=6), histology (adenocarcinoma=93%), previously anti-neoplastic treatments (1st line=100%, 2nd =40% and 3rd=27% of patients). No grade 3-4 CTCAE toxicity was observed. Median PFS was 5.2 months and median OS 2.1 years. Long-lasting disease stabilization (SD≥8.5 months) was demonstrated in 7 patients (47%). Patients demonstrated significant improved OS (P=0.02) when compared to the untreated group of excluded HLA-A2 negative NSCLC patients. IDO expression was frequently detected in tumour biopsies by immune-histochemistry staining. Immune induction of IDO specific CD8 T-cells were demonstrated by IFN-y Elispot and Tetramer staining. Immune correlates of T-lymphocyte subsets were performed by flow cytometry. HPLC analyses of Trp/Kyn ratio suggested stabilization or decrease of IDO activity in 11/15 (73%) of the patients. Conclusions: The vaccine was safe and well-tolerated with no grade 3/4 toxicity occurring. Long-lasting SD was seen in 47% of the patients demonstrating a median OS of 2.1 year. IHC demonstrated frequent IDO activity in NSCLC tumour biopsies, and blocking of IDO activity was indicated by Kyn/Trp ratio measurements. Clinical trial information: NCT01219348.
Overcoming barriers in incorporating evaluation of quality of life (QL) and symptoms by using the ePRO version of the LCSS (eLCSS-QL) in a large-scale multinational NSCLC trial (AP-QL Trial).
Authors: Thongprasert Sumitra , Gralla Richard J. , Hollen Patricia J , Kim Hoon-Kyo , Hsia Te-Chun , Yuankai Shi , Alexis Karenza M. , Kohn Nina , Lesser Martin
Published: March 2020

8092

Background: Survival and QL improvements are primary treatment goals in advanced NSCLC. Few trials evaluate both of these major endpoints well: typically only a minority of patients (pts) have QL followed over time, preventing such data from assisting in key decisions concerning the effectiveness and value of treatment. To overcome barriers, we used a computer-assisted version of the validated LCSS measure and tested this prospectively in a large study. Prior trials indicated that the eLCSS-QL requires only 2 minutes to complete the pt version and is highly acceptable. Methods: 622 pts received initial docetaxel (D)-based chemo, at 65 sites in 9 Asian countries. 70% male; 65% adenocarcinoma; median: KPS = 90; ECOG = 1 (27% ECOG 0). Stages: IV (72%), IIIB (28%). 84% had > two major symptoms. 80% had combination chemo with cisplatin (52%) or carboplatin (28%). Computer skills were low in 73%. eLCSS-QL was completed every 3 weeks at the clinic. We also surveyed 98 physicians (MD) and nurses (RN) treating these pts regarding communication, usefulness and acceptability of the eLCSS-QL. Results: 97% of pts completed the eLCSS-QL at baseline; 90% completed follow-up evaluations. Over 90% found the eLCSS-QL easy to use, acceptable to complete at each visit; >80% reported increased awareness of symptoms; making it easier to speak with MDs / RNs. 1% refused eLCSS-QL completion. Of MDs/RNs: >90% found the eLCSS-QL easy to use and increased symptom awareness; >80% reported improved communication, enhanced satisfaction with the pt visit, and recommend its use. Nearly 90% of MDs reported they could identify benefit from chemo earlier; 76% would order fewer imaging tests and 80% said the eLCSS-QL could save time. Major response rate 37%; median survivals: 13.9 months (D + cisplatin), 12.7 months (D + carboplatin). Conclusions: Patients, MDs, RNs all found the eLCSS-QL to be highly acceptable and easy to use with 90% of pts doing repeated QL measures. This large prospective trial demonstrates the potential for QL / symptom evaluation to aid in decision making and to guide appropriate use of chemotherapy and imaging while enhancing staff and pt satisfaction.
Differential activity of afatinib (AFAT), cetuximab (CET), and erlotinib (E) in a patient-derived xenograft (PDX) model of acquired E resistance.
Authors: Mack Philip C. , Goodwin Neal , Holland William S. , Kelly Karen , Lara Primo , Gandara David R.
Published: March 2020

8110

Background: The UC Davis - Jackson Labs Consortium has established a PDX resource of over 50 NSCLC models (12 EGFR mutant) for experimental therapeutics and personalized medicine, using the NSG mouse. Here we report on a unique PDX model, LG703, derived from a patient at time of acquired E resistance. This tumor harbors EGFR L858R with no T790M mutation, high MET and very high EGFR protein expression. The patient is in remission following treatment with AFAT-CET. In this model, we investigated the respective contribution of CET and AFAT relative to E on tumor growth and signal transduction. Methods: Individual mice implanted with LG703 tumor fragments were randomized to E (50 mg/kg qd po), AFAT (20 mg/kg qd po), CET (10 mg/kg twice weekly iv), AFAT-CET, or vehicle control (n per arm = 12) for 3 weeks followed by a 75-day monitoring period. Changes in signal transduction mediators and RTKs were assessed after 6 and 24h treatment exposures using kinase arrays (R&D systems) and immunoblotting. Results: AFAT, CET and AFAT-CET resulted in complete tumor response (CR) during the 21-day treatment period; whereas E resulted in temporary growth delay. After cessation of treatment, E-treated mice progressed rapidly and AFAT-treated mice progressed within 2 weeks. Mice treated with CET or AFAT-CET remained in complete remission. At 6h, E and AFAT significantly (>70%) reduced EGFR phosphorylation as well as that of AKT1, AKT2, ERK1, p38a, RSK1 and p70S6K. At 24h, E-treated tumors had returned to baseline-like states for all factors, AFAT showed an intermediate response, and CET, alone or with AFAT, achieved the greatest inhibition of pEGFR with sustained inhibition of all downstream effectors. Conclusions: In the LG703 PDX model, CET and AFAT+CET resulted in CRs, mirroring the patient's response to similar therapy, associated with sustained inhibition of pEGFR and multiple downstream signaling factors. In contrast, E exhibited only temporary growth delay associated with transient inhibition of EGFR pathway factors. These experiments demonstrate the potential of this PDX resource to assess new therapeutic strategies in models representing individual patients. Supported by BJALCF.
Biomarker prediction of chemotherapy-related amenorrhea.
Authors: Ruddy Kathryn Jean , O'Neill Anne M. , Miller Kathy , Schneider Bryan P. , Baker Emily , Sparano Joseph A. , Dang Chau T. , Northfelt Donald W. , Sledge George W.
Published: March 2020

9508

Background: Chemotherapy-related amenorrhea (CRA) is associated with infertility and may impact treatment decision-making. We investigated whether anti-mullerian hormone (AMH) levels before chemotherapy predict likelihood of CRA. Methods: 591 patients enrolled on the quality of life substudy of ECOG5103, which randomized breast cancer patients to doxorubicin-cyclophosphamide followed by paclitaxel: 1) alone; 2) with concurrent bevacizumab; or 3) with prolonged bevacizumab. 144 of the 195 women who reported a period <12 months before enrollment consented to serum collection prior to chemotherapy. AMH was measured in 143 with available serum. Participants self-reported menstrual frequency at 12 and 18 months after enrollment. 12-month CRA was defined as no menses for 6 months before the 12-month survey, and 18-month CRA as no menses for 6 months before the 18-month survey. Fisher’s exact test was used to identify associations with CRA. Results: Of the 143, 16 were excluded due to bilateral oophorectomy or initiation of ovarian function suppression within 12 months, and 2 due to missing data at 12 months. In the remaining 125, median age at enrollment was 45 (range 25-55). 103 (82%) had CRA at 12 months, including 68% of patients </= 45 (43/63) and 97% of patients >45 (60/62). Median pre-chemotherapy AMH was 0.11 (range 0.01-8.63). 12-month CRA was more likely in women who received bevacizumab (p<0.01), were >45 (p<0.01), and had AMH </=0.11 (p<0.01) pre-treatment. Hormonal tx was not associated with 12-month CRA (p=0.63). 100 patients were eligible for 18-month CRA analysis: 81 (81%) had CRA, including 63% of patients </= 45 (33/52) and 100% (48/48) of patients >45. 18-month CRA was more likely in women >45 (p<0.01) and with AMH </=0.11 (p<0.01) pre-treatment. Bevacizumab (p=0.15) and hormonal tx (p=0.07) were not statistically significant predictors of 18-month CRA. Conclusions: Pre-chemotherapy AMH predicts risk of CRA at 12 and 18 months, and is a promising biomarker of ovarian reserve in young breast cancer survivors. Longer studies will be needed to ascertain whether lower pre-treatment AMH is associated with increased risk of later infertility. Clinical trial information: NCT00433511.
Does gabapentin prevent delayed chemotherapy-induced nausea and vomiting (N/V)? Results of a randomized placebo controlled trial, NCCTG N08C3 (Alliance).
Authors: Barton Debra L. , Sloan Jeff A. , Novotny Paul J , Fuloria Jyotsna , Kottschade Lisa A. , Lyss Alan P. , Jaslowski Anthony John , Mazurczak Miroslaw , Blair Scott Cameron , Terstriep Shelby A. , Loprinzi Charles L.
Published: March 2020

9513

Background: The need for more research in N/V control is exemplified by agents that are costly, interfere with cytochrome P450 metabolism, and inadequately address delayed N/V. Based on pilot data, there was justification for evaluating whether gabapentin could improve the prevention of delayed N/V from highly emetogenic chemotherapy (HEC). Methods: Patients (pts) about to receive HEC were randomized to prophylactic treatment with 20 mg of dexamethasone (dex) and a 5HT3 receptor antagonist (RA) on the day of chemotherapy, followed by either gabapentin (gaba) 300 mg BID and dex or placebo (plac) and dex. Gaba/plac was started the evening of the day of chemotherapy and continued through day 5 of the first chemotherapy cycle. Dex was given at 8 mg BID days 2-3, then 4 mg BID for day 4, in both arms. The primary endpoint was complete response (CR), defined as no emesis and no rescue medications day 2-6, using a nausea and vomiting diary. The percent of CR were compared in each group by Fisher’s exact test. Secondary outcomes included the Functional Living Index-Emesis (FLIE), satisfaction, and a side effect questionnaire. Results: 430 pts were enrolled in this study between 5/2009 and 2/2011. 47% of pts in the gaba arm and 41% in the plac arm had a CR (p=.23). At some time during days 2-6, 30% in the gaba and plac arms experienced emesis, and 45% and 53% in the gaba and plac arms, respectively, took rescue medication. Mean diary nausea scores over days 2-6 ranged from 0.9 – 1.2 (gaba arm) and 1.0-1.3 (plac arm)(7 = the worst); mean number of diary emetic episodes ranged from 0.1 -0.3 (gaba arm) and 0.1-0.2 (plac arm). The FLIE was not significantly different between arms. Mean vomiting satisfaction was 9.1 in both arms and for nausea was 8.3 for gaba, 8.1 for plac (10= totally satisfied). There were no significant differences in toxicities by CTCAE provider grading or by self-report. Conclusions: In this study, gaba did not improve delayed N/V. Overall, there was little emesis and nausea severity was low. Patients were satisfied with the control of their N/V, irrespective of arm. The use of standard prophylactic guidelines that include a 5HT3RA and dex provided good control of N/V for most patients. Clinical trial information: NCT00880191.
Screening for depression in community-based radiation oncology settings: Results from RTOG 0841.
Authors: Wagner Lynne I. , Pugh Stephanie L. , Small William , Kirshner Jeffrey J. , Sidhu Kulbir , Bury Martin Joseph , DeNittis Albert S. , Alpert Tracy E. , Tran Binh N. , Bloom Beatrice , Mai Julie , Bruner Deborah
Published: March 2020

9527

Background: Depression screening is recommended in routine cancer care. Brief tools are needed to identify depressed patients in radiation oncology treatment settings. Methods: Patients starting radiotherapy for first diagnosis of any tumor were eligible. Screening measures administered prior to or within the first 2 weeks of radiation therapy included: Hopkins Symptom Checklist (HSCL-25), Patient Health Questionnaire (PHQ-9; PHQ-2), and the National Comprehensive Cancer Network-Distress Thermometer (NCCN-DT). Patients exceeding validated cutoff scores on the HSCL-25, PHQ-9 or PHQ-2, and a systematic sample of patients who screened negative, completed telephone-based administration of the Structured Clinical Interview for DSM-IV (SCID) Mood Disorder modules. Results: 463 patients from 35 community-based and 2 academic radiation oncology sites were accrued. The majority were women (n=298, 66%). Participants had breast (45%), GI (11%), lung (10%), gynecologic (6%), or other (27%) cancers. All 454 eligible patients completed the screening questionnaires and 100% of questionnaire items were completed. 75 (16%) screened positive for depressive symptoms. A total of 70 SCID interviews were administered to 37 patients who screened positive and 33 who screened negative. Among those who screened positive, 14 (20%) met SCID criteria for major depression. One participant who screened negative met depression criteria (1.4%). Results indicate the prevalence of depression is 3%. The PHQ-2 demonstrated good psychometric properties for identifying current major depressive episode, using a cut-off score > 3 (ROC area under the curve=0.839). The PHQ-9 > 9 was comparable (AUC=0.837). The NCCN-DT > 4 did not adequately detect depression (AUC=0.64). Conclusions: The prevalence of depression was low (3%) among this community-based sample of adults receiving radiotherapy. The PHQ-2 demonstrated excellent psychometric properties to detect depression, which were equivalent to the PHQ-9 and superior to the NCCN-DT. Our findings support using the PHQ-2 to identify patients in need of further assessment and treatment for depression, a low prevalence but clinically significant comorbidity.
The impact of positive spousal support on trauma symptoms and sleep disturbance among prostate cancer survivors.
Authors: Kamen Charles Stewart , Peoples Anita Roselyn , Tejani Mohamedtaki Abdulaziz , Palesh Oxana , Mustian Karen Michelle , Peppone Luke Joseph , Janelsins Michelle Christine , Kamen Francis , Lord Raymond S. , Flynn Patrick J. , Weiss Matthias , Spiegel David , Morrow Gary R.
Published: March 2020

9533

Background: Receiving a diagnosis of cancer can lead to psychological effects including symptoms of traumatic stress. Trauma symptoms can dysregulate sleep and sleep disturbance has been linked with negative health outcomes. Cancer-related trauma symptoms and sleep disturbance can affect the spouse of the cancer patient and the couple’s relationship; conversely, a supportive relationship can improve cancer survivors’ mental health. The impact of spousal support on trauma and sleep disturbance among prostate cancer survivors has not yet been examined. Methods: 315 prostate cancer survivors (mean age 66, 89% Caucasian), of whom 265 were married and 50 were unmarried (single, widowed, separated or divorced) completed the Impact of Events Scale (IES), Stanford Sleep Questionnaire, and a measure of positive spousal support. Data are self-report. Rates of trauma symptoms and sleep disturbance by marital status were compared using t-tests, and the contribution of marital status and spousal support to variance in these outcomes was evaluated using linear regression. Results: 13.4% of survivors reported significant (i.e., >27 point IES cutoff) symptoms of traumatic stress and 23.2% reported moderate or higher rates of sleep disturbance. Trauma symptoms (t= -2.16, p<.01) and sleep disturbance (t= -3.14, p<.01) were significantly lower in married than unmarried survivors. Spousal support was negatively associated with trauma symptoms (r= -.18, p<.01) and sleep disturbance (r= -.20, p<.05), and inclusion of spousal support as a covariate rendered the linear relationship between marital status and both trauma symptoms and sleep disturbance non-significant (p>.05). Conclusions: Spousal support is associated with reductions in trauma and sleep disturbance, over and above dichotomous marital status. This area needs further study, given high rates of trauma symptoms and difficulty disclosing health-related concerns among men with prostate cancer. Future research needs to explore mechanisms by which spousal support leads to improvement in trauma symptoms and sleep outcomes. Interventions bolstering spousal support could improve mental health in prostate cancer survivors.
Palliative sedation (PS) given to patients treated at the Fundación Santa Fe de Bogotá.
Authors: Lombana Quinonez Milton Alberto , Santacruz Juan G. , Pino Luis , Camacho Maria I. , Acevedo Andres , Buendia Maria J. , Zamora Ivonne , Torres Ana , Mendez Catalina , Cardona Zorrilla Andres Felipe
Published: March 2020

9541

Background: Around 50% of advanced-stage cancer patients have inadequate control of symptoms during the final period of life; palliative sedation (PS) would seem to be appropriate in such scenario. Methods: A retrospective cohort analytical study was carried out for determining the effectiveness of PS, evaluating the non-reduction of the number of final days of life in patients suffering advanced-stage cancer. PS therapy consisted of using a continuous infusion of benzodiazepines, opioids, antipsychotics and/or anaesthetics. Results: The study included 145 patients recorded between July 2008 and October 2012. Median age was 68 years (24% of the patients being aged over 80). The main motives for considering PS were dyspnoea (30%), uncontrolled pain (25%), delirium (26%) and presenting more than one of these symptoms (19%). The drugs used were opioids (in 87% of the patients), benzodiazepines (54%) and anaesthetics (2%). Using PS led to symptoms becoming controlled in 79% of the cases compared to 53% without it; symptoms became controlled in 85% of the cases in less than 24 hours when PS was used compared to 15% when it was not used (p<0.001). Mean overall survival (OS) was 6.8 days for those who received PS and 7.2 for those who did not (RR 0.94, 0.97-1.33 95%CI; p=0.72) and final days of life after starting PS was 2.2 days (<1-16 days). Multivariate analysis showed that using PS (HR 1.49, 1.08-2.07 95%CI; p=2.04) and the presence of oedema (RR 0.79, 0.61-1.0 95%CI; p=0.01) modified the course of controlling symptoms. Conclusions: PS improved the time to controlled cancer symptoms in patients suffering terminal illness, and their presentation profile without modifying the OS.
Differences in patterns of care and outcomes of elderly versus younger metastatic pancreatic cancer (mPC) patients.
Authors: Vijayvergia Namrata , Dotan Efrat , Devarajan Karthik , Hatahet Kamel , Rahman Farah , Cohen Steven J.
Published: March 2020

9546

Background: Despite a median age at diagnosis of 72, elderly pancreatic cancer patients (pts) are poorly represented in clinical trials. We thus compared patterns of care and outcomes of mPC pts ≤ and > 65 yrs of age. Methods: We retrospectively analyzed medical charts of 277 mPC pts treated at an academic center between 2000 and 2009. Age groups ≤ 65 yrs and >65 yrs were compared with respect to gender, comorbidities, performance status (PS), tobacco/alcohol use, primary site, stage, histological grade, metastatic sites, treatment modalities, type and number of chemotherapeutic agents received, and survival after diagnosis of mPC (OS). Log-rank tests and Cox proportional hazards models were used to analyze survival endpoints and Fisher’s exact test to compare categorical variables. Results: 155 pts ≤65 yrs with median age of 58 and 122 pts >65 yrs with median age of 73.5 were evaluated. The groups were well balanced with respect to sex (majority male), PS (majority ≤1), stage (majority 3, 4), and primary site (majority head). Cardiovascular (CV) disease was more prevalent among older pts (OR 1.7, p=0.04). Older pts were less likely to receive any chemotherapy for mPC (79% vs 92%; OR 0.33, p< 0.001) and if treated were less likely to receive more than one agent (34% vs 52%; OR 0.48, p=0.003). Median OS was shorter in older pts (5m vs 6m, p=0.01). OS was longer with higher number of agents received (RR: 0.57 for young, 0.51 for old; p< 0.001). CV and renal disease negatively impacted OS only in younger pts. The presence of lung metastases was associated with longer survival (10m vs 6m (p=0.01)) and liver metastases with decreased survival (5m vs 8m (p<0.01)) only among younger pts. Conclusions: Elderly mPC pts have shorter OS, are less likely to receive chemotherapy, and if treated receive fewer agents compared to younger pts. These differences cannot be explained solely by PS or disease characteristics and warrant further study.