bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of neoadjuvant PD-1 blockade with sintilimab in resectable squamous non-small cell lung cancer (sqNSCLC).
Authors: Li Ning , Ying Jianming , Tao Xiuli , Zhang Fan , Zhao Ziran , Ling Yun , Gao Yushun , Zhao Jun , Xue Qi , Mao Yousheng , Lei Wendong , Wu Ning , Wang Shuhang , Duan Jianchun , Gao Yibo , Wang Zhijie , Sun Nan , Wang Jie , Gao Shugeng , He Jie
Published: March 2020

8531

Background: NSCLC patients who have potentially resectable disease often subsequently relapse after surgery. New therapy that prevents relapse after surgery is desperately needed. In this study, we tested the efficacy and safety of neoadjuvant sintilimab, an anti-PD-1 antibody, for patients with resectable sqNSCLC in China. Methods: All patients had treatment-naïve resectable sqNSCLC (stage IB-IIIA) that was confirmed by histopathology. Patients received two cycles of sintilimab (200 mg IV) on Day 1 and 22. Surgery was performed between Day 29-43. An enhanced PET/CT was obtained at baseline and seven days prior to surgery. Preliminary analysis of safety profile and efficacy was planned after at least 20 patients had received operation. Results: As of Jan. 28, 2019, 22 patients (20 males and 2 females) with sqNSCLC received two doses of sintilimab followed by radical resection. The median age was 61.5 yr (range, 48 to 70). Six (27.3%) and four (18.2%) patients experienced neoadjuvant treatment emergent adverse events (TEAEs) and neoadjuvant treatment-related AEs (TRAEs), respectively. Most of the TEAEs and TRAEs were grade 1 or 2. Three patients achieved radiological partial response: an ORR of 13.6% based on RECIST 1.1. Ten patients (45.5%) achieved a major pathologic response (MPR, ≤10% viable tumor cells), including four (18.2%) had complete pathologic response (no viable tumor cell). There was a direct correlation between pathological response and decrease in the standardized uptake values (SUV) in the primary tumor. Among nine patients with > 30% decrease of SUV, eight had MPR, compared with no MRP response in the 11 patients with ≤30% decrease of SUV. Conclusions: Neoadjuvant sintilimab for sqNSCLC patients was tolerable and the 45.5% MRP rate is encouraging. A decrease in SUV may be predictive of pathologic response after PD-1 therapy in sqNSCLC. Clinical trial information: ChiCTR-OIC-17013726.
Association of BAFFR expression in CAFs with overall survival and response to platinum-based chemotherapy in NSCLC.
Authors: Dimtrakopoulos Fotinos-Ioannis D. , Kottorou Anastasia E , Antonacopoulou Anna G , Nikolakopoulos Achilleas , Panagopoulos Nikolaos , Kalofonou Melpomeni , Dougenis Dimitrios , Koutras Angelos , Makatsoris Thomas , Tzelepi Vasiliki , Kalofonos Haralabos
Published: March 2020

8537

Background: Β-cell activating factor receptor (BAFFR) is a surface receptor, which leads to activation of the Nuclear Factor-kappaB (NF-κB) alternative pathway, a pathway with an important role in non-small cell lung cancer (NSCLC). In addition, cancer associated fibroblasts (CAFs) are major players of the tumor microenvironment promoting NSCLC. The aim of this study was to assess the possible associations of BAFFR expression in CAFs with response to first-line chemotherapy doublet and clinical outcome of NSCLC patients. Methods: Immunohistochemical analysis of BAFFR expression on CAFs was performed on tumor and tumor-adjacent formalin fixed and paraffin embedded tissue samples from 124 operated patients with NSCLC. Patients were under follow-up for at least 60 months, while response to chemotherapy was evaluated in patients who relapsed during this period. Results: BAFFR expression, which was noted exclusively in the cytoplasm of CAFs, was associated with OS only in patients with no infiltration of regional lymph nodes. Higher expression levels of BAFFR in CAFs were related to worse 2-, 3- and 5-year survival (P = 0.015, P = 0.027 and P = 0.040, respectively). This finding persisted after multivariate analysis with age, gender, histological subtype, histological differentiation and disease stage as coefficients (P = 0.009; HR, 2.734; 95% CI, 1.283-5.828). In addition, response to first line chemotherapy was associated with BAFFR expression in CAFs (P = 0.025). Patients who progressed had lower BAFFR levels. Furthermore, BAFFR expression in CAFs was associated with patients’ age. In particular, older patients had higher expression of BAFFR compared to patients younger than 55 years (P = 0.010). Additionally, carcinomas with better differentiation had lower expression of BAFFR in CAFs (P = 0.005). Finally, BAFFR expression in CAFs was related to development of metastatic disease (P = 0.033) and particularly in liver (P = 0,017) and in bones (P = 0.003). Conclusions: The present findings suggest that the expression of BAFFR in CAFs may be a useful biomarker with prognostic and predictive value, representing possibly an unknown biological relation, which merits further investigation.
Assessment of PD-L1 expression and oncogenic gene status in patients with small-cell lung cancer: Immuno-oncology biomarker study in LC-SCRUM-Japan.
Authors: Oizumi Satoshi , Yoh Kiyotaka , Matsumoto Shingo , Miyamoto Shingo , Furuya Naoki , Sasada Shinji , Okamoto Norio , Hayashi Yuichiro , Tsuta Koji , Motoi Noriko , Ishii Genichiro , Goto Koichi
Published: March 2020

8558

Background: The clinical impact of PD-L1 expression and oncogenic gene status in patients with small cell lung cancer (SCLC) is not well characterized. We initiated this immuno-oncology biomarker study as part of nationwide genomic screening by LC-SCRUM-Japan (LC-SCRUM-IBIS). Methods: Tumor samples from lung cancer patients enrolled in LC-SCRUM-IBIS were primarily subjected to targeted next-generation sequencing (NGS) with Oncomine™ Comprehensive Assay. The PD-L1 expression was also analyzed by 4 immunohistochemistry (IHC) assays for 22C3, 28-8, SP263 and SP142. At this analysis, 22C3, 28-8, and SP263 were assessed in tumor cells (TC) as positive in > 1%, and SP142 in both TC and tumor-infiltrating immune cells (IC) as positive in > TC1/IC1, as previously reported. The association of PD-L1 expression, oncogenic gene status and clinical outcome was investigated in SCLC patients. Results: Between Feb 2017 and May 2018, 1017 lung cancer patients were enrolled in LC-SCRUM-IBIS. Among them, 933 patients had adequate tumor samples including 101 SCLC and 832 non-small cell lung cancer. Of 101 SCLC patients, the results of PD-L1 expression by 4 IHC assays were 18% in 22C3, 17% in 28-8, 11% in SP263 and 8% in SP142, respectively. Targeted NGS showed that 8 patients had at least one targetable oncogenic alterations, including 3 PIK3CA and 1 KRAS as mutations and 3 PTEN and 1 TSC2 as inactivating mutations. PD-L1 expression by 22C3 was associated with good performance status (P = 0.05) and the presence of oncogenic alterations (P = 0.004). PD-L1 status was not associated with response to cytotoxic chemotherapy and progression-free survival and overall survival in first-line treatment of SCLC patients. Conclusions: The frequency of PD-L1 expression in SCLC patients was relatively lower compared with that reported in other solid tumors. PD-L1 status by TC in 22C3 appears to be not correlated with clinical outcomes for cytotoxic chemotherapy of SCLC patients. Further investigation is needed to explore a predictive biomarker for immune checkpoint inhibitors. Updated results will be presented at the meeting.
BIOLUMA: A phase II trial of nivolumab in combination with ipilimumab to evaluate efficacy and safety in lung cancer and to evaluate biomarkers predictive for response—Preliminary results from the SCLC cohort.
Authors: Fischer Rieke Nila , George Julie , Scheel Andreas H. , Schloesser Hans Anton , Vehreschild Maria , Brossart Peter , Engel-Riedel Walburga , Griesinger Frank , Grohé Christian , Kambartel Karl-Otto , Kern Jens , Hermes Barbara , Nachtkamp Kathrin , Panse Jens Peter , Sebastian Martin , Lehmann Markus , Wiewrodt Rainer Gerhard , Büttner Reinhard , Thomas Roman K. , Wolf Juergen
Published: March 2020

8563

Background: Patient selection, dosing regimens and resistance mechanisms for immune checkpoint inhibitor combination therapy remain unmet medical needs in lung cancer. We present interim data from the small-cell lung cancer (SCLC) cohort of the ongoing BIOLUMA trial which evaluates efficacy and safety of nivolumab and ipilimumab in lung cancer with a broad translational program to identify potential biomarkers predictive of response and/or resistance including whole exome sequencing (WES) of serial biopsies, functional analysis of peripheral T-cells and gut microbiome analyses. Methods: BIOLUMA is an investigator initiated, multicentre non-randomised phase II trial in 2nd line patients with SCLC. The initial all-comer SCLC cohort was recently amended for inclusion of patients with high tumor mutation burden (TMB) only. Patients are pre-screened for TMB by WES at the time of first diagnosis. After progression on platinum-based therapy, 4 cycles of nivolumab 1 mg/kg q3w in combination with ipilimumab 3 mg/kg q3w and subsequent nivolumab 240 mg flat dose as monotherapy are given. Primary endpoint is overall response rate (ORR) of the upfront combination therapy. Analysis of sequential tumor biopsies, blood and gut microbiome is performed at different timepoints. Results: The SCLC cohort was amended to include TMB high patients only, after two treatment-related deaths had occurred and emerging data indicated treatment benefit depends on high TMB status for the combination therapy. Both patients with treatment-related death had a CT-scan documented partial response (not confirmed according to RECIST due to death). One each died of pneumonitis and encephalitis. From the all-comer cohort, efficacy data are available for 18 patients. ORR was 38.8% with 7 partial and no complete responses. Stable disease occurred in 16.7% (n = 3) resulting in a DCR of 55.5%. TMB pre-screening for the amended cohort is currently ongoing. Conclusions: In the SCLC cohort, upfront combination therapy of nivolumab and ipilimumab shows remarkable ORR but is accompanied by high toxicity rates. In order to ensure a reasonable balance of risks and treatment benefit, only TMB high patients are included after an amendment of the cohort to improve the risk/benefit ratio. Clinical trial information: NCT03083691.
Anti-EGFR target therapy in advanced thymic epithelial tumors.
Authors: Giuliano Mario , Ottaviano Margaret , Tortora Marianna , Gallinoro Roberta , Marino Mirella , Pizzuti Angela , Arundine Dario , Picozzi Fernanda , Di Lauro Vincenzo , Riccio Vittorio , De Placido Sabino , Palmieri Giovannella
Published: March 2020

8567

Background: Thymic epithelial tumors (TETs), show a high rate of EGFR immunohistochemistry (IHC) positivity, however, the prognostic and predictive role of EGFR has not yet been well defined, and contradictory data have emerged regarding the delivering of anti-EGFR monoclonal antibodies in TETs. The outcomes of the largest series of thymoma patients treated with cetuximab, and its hypothetic immune-modulatory role, are here described. Methods: Seven patients with diagnosis of pre-treated advanced thymoma and score positivity 2+ and 3+ at EGFR-IHC, were treated with cetuximab as off-label modality, with a dose of 400 mg/m2 in the first cycle and 250 mg/m2 in the following cycles every 7 days, until disease progression, unacceptable toxicity, withdrawal of consent. Primary endpoint was Overall Response Rate ORR, assessed radiologically. Secondary endpoints were progression Free Survival (PFS), safety, and relationship between time to cetuximab progression (TTPc) and time to previous treatment progression (TTP1). During treatment with cetuximab lymphocyte subpopulations have been carefully monitored in 4 patients affected by both thymoma and Good syndrome (GS) defined as B-cell lymphocyte counts (CD19+) <100 cells/mm3 and/or Immunoglobulin G (IgG) levels <8 g/L. Results: With a median response duration of 17 months, a partial response was achieved in five patients (ORR=71%). Statistically significant correlation was found between disease response and EGFR-IHC score 2+ vs 3+ (P, .008), which statistically correlated also with the mPFS of 14 months (95% CI, 0.0-34.5). No grade 3 or 4 adverse events were registered. TTPc was longer than TTP1 in 6/7 patients (86%), with a TTPc / TTP1 ratio equal to 2.12. During cetuximab treatment, in the longest responder patient affected also by GS, a progressive increase of IgG level and of CD4/CD8 ratio has been registered as well as an increase of both CD19+lymphocytes and CD16+ 56+ lymphocytes has been detected in all the included patients with GS. Conclusions: Despite of the small number of patients and the off-label treatment modality, the data presented are worthy of confirmation in validated prospective studies in selected population with hyper-expression of EGFR. Further studies are also needed for deeply investigate the immunomodulatory role of cetuximab which seemed to temporarily revert sever immunodeficiency in our population.
The risk of second primary malignancy in patients with localized thymoma: A U.S. population-based study.
Authors: Uprety Dipesh , Arjyal Lubina , Narayana Swapna , Polewski Peter James , Bista Amir , Vallatharasu Yazhini , Lashari Bilal Haider , Khanal Amit
Published: March 2020

8568

Background: Thymoma is a rare neoplasm of anterior mediastinum. Patients often have an indolent disease. The prognosis of limited stage disease is excellent with a 10-year survival rate of 70 to 80%. Data regarding the risk of second primary malignancy in thymoma survivors are limited in recent years. In this study, we aimed to determine the risk of second primary malignancies (SPMs) among patients with limited stage thymoma. Methods: We utilized the Surveillance, Epidemiology and End Results (SEER)-13 registry to identify adult patients (≥ 18 years) with limited stage thymoma. We calculated the risk of SPM, developing ≥ 6 months after an index thymoma diagnosis, using Multiple Primary Standardized Incidence Ratio and an Absolute Excess Risk (AER) between 2004 and 2010. Statistical significance was defined as p < 0.05. Results: The database identified a cohort of 1,544 patients with limited stage thymoma with a median follow-up duration of 107 months (11-281 months). A total of 176 (11.39%) patients developed SPMs with a median latency of 62.5 months (range 6-272 months). Median age at diagnosis of SPM was 69 years (range 25- 96 years). Overall, SPM occurred at an observed to expected (O/E) ratio of 1.53 (95% CI 1.32-1.76), p < 0.001 with an AER of 60.52 per 10,000 patient-years at risk. A significantly increased risk was noted for cancer of lung and bronchus (O/E 1.77, 95% CI 1.21-2.52, p = 0.004; AER 12.17/10,000), skin excluding basal and squamous (O/E 2.09, 95% CI 1.04-3.75, p = 0.03; AER 5.17/10,000), urinary bladder (O/E 2.14, 95% CI 1.17-3.6, p = 0.014; AER 6.72/10,000), thyroid (O/E 3.48, 95% CI 1.4-7.17,p = 0.009; AER 4.49/10,000), and leukemia (O/E 3.26, 95% CI 1.63-5.83, p = 0.001; AER 6.86/10,000), including acute lymphocytic leukemia (O/E 16.09, CI: 1.95-58.11; AER 1.69/10,000), acute myeloid leukemia (O/E 3.83, CI: 1.04-9.8; AER 2.66/10,000) and other acute leukemia (O/E 29.45, CI: 3.57-106.39; AER 1.74/10,000). The risk was not significant for lymphoma (Hodgkin and non-Hodgkin), chronic leukemia, oropharyngeal, digestive tract and hepatobiliary cancer as SPM. Conclusions: The risk for SPMs is significantly increased in patient with thymoma compared to general population. Given the long-term risk of SPM, patient should be followed closely with judicious use of age-appropriate cancer screening.
ECOG-ACRIN 5508: Pemetrexed, bevacizumab or the combination as maintenance therapy for advanced non-squamous NSCLC.
Authors: Ramalingam Suresh S. , Dahlberg Suzanne Eleanor , Belani Chandra Prakash , Saltzman Joel N. , Nambudiri Gopakumar S. , McCann John , Winegarden Jerome D. , Kassem Mohammed Azher , Mohamed Mohamed K. , Rothman Jan M. , Lyss Alan P. , Horn Leora , Stinchcombe Tom , Schiller Joan H. ,   ECOG-ACRIN Cancer Research Group
Published: March 2020

9002

Background: Maintenance therapy is a standard approach for advanced non-squamous NSCLC. Pemetrexed or bevacizumab are considered evidence-based options. The combination of bevacizumab and pemetrexed has been documented to improve progression-free survival (PFS). We conducted a phase 3 study to determine the optimal maintenance therapy for advanced NSCLC. Methods: Patients (pts) with advanced non-squamous NSCLC, no prior systemic therapy, and ECOG performance status 0/1 were treated with carboplatin (AUC = 6), paclitaxel (200 mg/m2) and bevacizumab (15 mg/Kg) every 3 weeks for up to 4 cycles (step 1). Patients with CR/PR/SD after 4 cycles were then randomized 1:1:1 to maintenance therapy with bevacizumab (15 mg/Kg), pemetrexed (500 mg/m2) or the combination of the two agents every 3 weeks until disease progression (step 2). The primary endpoint was overall survival (OS), defined as the time from randomization to death from any cause and censoring defined at the last date of followup. 1495 pts provided 81% power to detect a hazard ratio of 0.75 while controlling the 2-sided type I error at 0.025 for each comparison, assuming approximately 60% of those patients would be randomized. Results: We enrolled 1516 pts to step 1 (male 52%; ECOG PS 1 62%; adenocarcinoma 90%); After induction therapy, 874 (57%) pts were randomized to step 2 (median age 64 yrs; male 49%; ECOG PS 1 55%). Baseline characteristics were balanced across all three groups. The median follow-up in maintenance is 50.6 months. Conclusions: Single agent bevacizumab or pemetrexed is the optimal maintenance therapy for advanced non-squamous NSCLC. The combination of bevacizumab and pemetrexed cannot be recommended due to the lack of survival benefit in this definitive study. (Drs. Ramalingam, Dahlberg and Belani contributed equally to this work). Supported by the NCI: CA180820, CA180794,CA180799, CA180821, CA180838, CA180844, CA180847, CA180853, CA180857, CA180864, CA180867, CA180868, CA180870, CA180882, CA189830, CA189859, CA189863, CA189971. Clinical trial information: NCT01107626. [Table: see text]
A randomized phase III study of continuous maintenance bevacizumab with or without pemetrexed after induction therapy with carboplatin (Car), pemetrexed (Pem), and bevacizumab (Bev) for advanced non-squamous non-small cell lung cancer (nSQ-NSCLC) without sensitizing EGFR mutations: The COMPASS study (WJOG5610L).
Authors: Seto Takashi , Azuma Koichi , Yamanaka Takeharu , Sugawara Shunichi , Yoshioka Hiroshige , Ono Akira , Atagi Shinji , Iwamoto Yasuo , Hayashi Hidetoshi , Okamoto Isamu , Saka Hideo , Shigeki Mitsuoka , Fujimoto Daichi , Nishino Kazumi , Horiike Atsushi , Daga Haruko , Sone Takashi , Yamamoto Nobuyuki , Nakagawa Kazuhiko , Nakanishi Yoichi
Published: March 2020

9003

Background: Two continuous maintenance therapies, “Pem after Pem+Platinum” and “Bev after Bev+Plt-doublet”, demonstrated the prolongation of survival for advanced nSQ-NSCLC. We conducted a randomized trial of Bev versus Bev+Pem as continuation maintenance therapy after Car+Pem+Bev induction therapy. Methods: Patients were eligible if they had previously untreated advanced nSQ-NSCLC whose EGFR status was either wild-type, unknown, or other than Del19 or L858R. They received the induction treatment with Car (AUC6), Pem (500 mg/m2), and Bev (15mg/kg) every 3 weeks for 4 cycles. Those who showed no progression during the induction therapy were randomized to receive maintenance therapy using Bev or Bev+Pem in a 1:1 ratio. The primary endpoint was overall survival (OS) from randomization. The planned sample size was 620 to provide a power of 85% at one-sided significance level of 5%. Violations found at a study site led us to conduct source document verification for 95.4% of patients to assure data quality. (Trial Identifier, UMIN000004194). Results: Between September 2010 and September 2015, 907 patients had the induction therapy. Of those, 621 patients were randomized; five did not receive study treatment and 22 did not meet the eligibility criteria. Among 594 patients for evaluable (299 in the Bev+Pem arm and 295 in the Bev arm), median age was 65 years; Male, 72%; PS 0/1, 60/40%; Stage IV, 83%; EGFR status, wild-type/others, 91/7%. Median OS was 23.3 vs 19.6 months (mo) with a hazard ratio (HR) of 0.87 (95%CI, 0.72-1.04) and one-sided logrank P= 0.069; in patients with wild-type EGFR tumor, HR for OS was 0.82 (0.68-0.99). Median progression-free survival was 5.7 vs 4.0 mo with a HR of 0.67 (0.57-0.79). 87.4% of patients received subsequent therapy. No new safety signals were observed. Conclusions: The primary analysis was not met. However, the incorporation of Pem significantly prolonged OS in patients with wild-type EGFR. Clinical trial information: UMIN000004194.
KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC.
Authors: Gadgeel Shirish M. , Garassino Marina Chiara , Esteban Emilio , Speranza Giovanna , Felip Enriqueta , Hochmair Maximilian J. , Powell Steven Francis , Cheng Susanna Y. , Bischoff Helge , Peled Nir , Hui Rina , Reck Martin , Kurata Takayasu , Garon Edward B. , Boyer Michael J. , Yang Jing , Pietanza Maria Catherine , Rodriguez-Abreu Delvys
Published: March 2020

9013

Background: Pembro + chemo significantly improved OS and PFS over chemo alone and had manageable safety as 1L therapy for metastatic nonsquamous NSCLC in the KEYNOTE-189 study (NCT02578680). The benefit was observed irrespective of PD-L1 TPS. We present updated OS based on longer follow-up and, for the first time, PFS2. Methods: Eligible pts were randomized 2:1 to pembro (n = 410) or placebo (n = 206) + pemetrexed and carboplatin or cisplatin for 4 cycles followed by pembro or placebo for up to 35 cycles + maintenance pemetrexed. Pts in the chemo arm could crossover to pembro alone upon PD. Poststudy anticancer therapy and outcomes were collected. PFS2 was defined as time from randomization to PD per investigator after start of 2L therapy or death, whichever occurred first. There was no multiplicity adjustment, and all P values are nominal. Data cutoff was 21 Sep 2018. Results: With 18.7-mo median follow-up, pembro + chemo continued to provide longer OS (HR 0.56 [95% CI 0.45-0.70], P < .00001; median 22.0 mo vs 10.7 mo) and PFS (HR 0.48 [95% CI 0.40-0.58], P < .00001). Benefit was seen in all PD-L1 TPS groups (Table). 2L+ therapy was received by 45% in the pembro + chemo arm and 59% (54% 2L+ immunotherapy) in the placebo + chemo arm. PFS2 was longer for 1L pembro + chemo (HR 0.49 [95% CI 0.40-0.59], P < .00001; median 17.0 mo vs 9.0 mo), with no difference by TPS (Table). Conclusions: 1L pembro + pemetrexed/platinum continued to show substantial OS benefit in metastatic nonsquamous NSCLC, regardless of PD-L1 TPS and despite 54% of pts in the placebo + chemo arm receiving subsequent immunotherapy. Median OS, PFS and PFS2 were approximately doubled with pembro + chemo. These data confirm that pembro should be given as part of 1L therapy to maximize outcomes in both PD-L1expressing and PD-L1non-expressing NSCLC. Clinical trial information: NCT02578680. [Table: see text]
c-Met expression and response to telisotuzumab vedotin (teliso-v) in patients with non-small cell lung cancer.
Authors: Heist Rebecca Suk , Motwani Monica , Barlesi Fabrice , Goldman Jonathan Wade , Kelly Karen , Sun Yan , Wu Jun , Bach Bruce Allen , Camidge D. Ross
Published: March 2020

9023

Background: c-Met overexpression (OE) and MET amplification (amp) are prognostic of poor outcome for non-small cell lung cancer (NSCLC). Telisotuzumab vedotin (ABBV-399; teliso-v [T]), an anti–c-Met Ab and monomethyl auristatin E drug conjugate, showed efficacy as monotherapy (mono) and combined with erlotinib (T+Er) in a phase 1/1b trial (NCT02099058) in NSCLC patients (pts) with c-Met OE. Here, c-Met OE (by immunohistochemistry [IHC]) and its association with T efficacy were explored. IHC, mRNA, and amp platforms for MET were also compared. Methods: Archival tissue from pts with NSCLC in the phase 1/1b trial was examined. c-Met was assessed centrally by IHC with SP44 Ab (Ventana Medical Systems) and pts with c-Met OE (membrane H-score [H-S] of ≥150) were enrolled. MET mRNA expression was analyzed from total RNA and sequenced on HiSeq 3000 (Illumina). MET amp was analyzed by FISH ( MET/ CEP7 ratio of ≥2) or whole-exome sequencing (copy number ≥2). Efficacy in the T mono every 2 (TQ2W) or 3 (TQ3W) weeks and the T+Er EGFR mutant cohorts was assessed for IHC H-S ≥150 and ≥225. Results: As of Dec 2018, 238 pts with NSCLC were screened centrally for c-Met OE. Of these, 118 pts were enrolled. For screened pts, 76%/37% of nonsquamous (NSQ, n = 201) and 58%/16% of squamous (SQ, n = 32) pts had H-S ≥150/≥225; 75%/41% of NSQ and 55%/16% of SQ NSCLC pts had ≥50% cells with 2+/3+ staining intensity. MET amp was reported for 5 pts, all with high H-S (≥270); there was an association between MET amp and MET RNA levels (n = 4) (t-test p value: 0.0002). See Table for ORR and median PFS by H-S and T treatment. Conclusions: c-Met expression prevalence in NSCLC showed a similar trend as in previous reports. In T+Er-treated pts, ORR was higher for those with c-Met H-S ≥225 than ≥150– < 225, suggesting that biomarker expression may act as an effect size multiplier. Optimization of the c-Met IHC cutoff warrants further investigation. Clinical trial information: NCT02099058. [Table: see text]
A comparative analysis of survival in patients with non-small cell lung cancer with brain metastases receiving intracranial radiation with and without immunotherapy.
Authors: Patruni Sunita , Khattab Ahmed , Abel Stephen , Hasan Shaakir , Rizwan Saleha , Finley Gene Grant , Monga Dulabh K. , Verma Vivek , Wegner Rodney E
Published: March 2020

9025

Background: Many patients diagnosed with advanced non-small cell lung cancer (NSCLC) will develop intracranial metastasis, contributing significantly to morbidity and mortality. Immunotherapy (IMT) has emerged as the standard of care in select cases of metastatic NSCLC, though data investigating the survival impact of IMT and radiation (XRT) in these patients is limited. To characterize the survival impact of intracranial XRT and IMT in NSCLC patients with brain metastasis, we analyzed the National Cancer Database (NCDB). Methods: We queried the NCDB for patients with metastatic NSCLC having brain metastasis receiving intracranial XRT ± IMT. Univariable and multivariable analyses identified characteristics predictive of overall survival. Cox proportional hazard ratios with propensity matching mitigated indication bias between the two arms. Results: 13,998 NSCLC patients who received IMT (n = 545) or did not receive IMT (n = 13,545) were eligible for analysis. Univariable analysis demonstrated a median overall survival of 13.1 months (95% CI: 11.8-15.0) vs. 9.7 months (95% CI: 9.5-9.9) (p < 0.0001) and 3-year overall survival of 17% vs. 12% [p < 0.0001; HR: 0.77 (0.71-0.84)] in patients receiving and not receiving IMT respectively. Patients with N3 disease and those diagnosed between 2012 and 2014 were more likely to have received IMT. Receipt of IMT remained an independent predictor of increased survival on propensity score matched multivariable comparison (p = 0.0002). Conclusions: Receipt of IMT was an independent predictor of increased overall survival in patients with NSCLC having intracranial metastasis. Randomized, prospective studies are needed to further validate these findings. [Table: see text]
Lazertinib, a 3rd generation EGFR-TKI, in patients with EGFR-TKI resistant NSCLC: Updated results of phase I/II Study.
Authors: Ahn Myung-Ju , Han Ji-Youn , Kim Sang-We , Lee Ki Hyeong , Kim Dong-Wan , Lee Yun-Gyoo , Cho Eun Kyung , Lee Gyeong-won , Lee Jong-Seok , Kim Joo-Hang , Kim Jin-Soo , Min Young Joo , Lee Sung Sook , Shin Sang Won , Kim HyeRyun , Hong Min Hee , Ahn Jin Seok , Lee Seoung Oh , Kim Sohee , Cho Byoung Chul
Published: March 2020

9037

Background: Lazertinib (YH25448) is a highly mutant-selective, irreversible 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets the activating EGFR mutations (Del19 and L858R), as well as the T790M mutation, while sparing wild type. We report the updated results from a Phase I/II study of lazertinib (NCT03046992). Methods: Patients with advanced and metastatic NSCLC who had progressed after treatment with standard EGFR-TKIs with/without asymptomatic brain metastases (BM) were enrolled in an open-label, multicenter, phase I/II study with dose-escalation and expansion cohorts. Lazertinib was administered once daily at doses between 20 to 320 mg in a 21-day cycle. Patients were assessed for safety, tolerability and efficacy. T790M mutation was required in the dose-expansion cohorts. Results: As of 26 Nov 2018, a total of 127 patients were enrolled. The dose-escalation cohort included 38 patients administered with 20 to 320 mg across 7 dose levels, and 89 patients in the dose-expansion cohort were administered with 40 to 240 mg across 5 dose levels. No dose-limiting toxicities were observed. The median duration of treatment was 9.7 months and 58 patients are still ongoing. The objective response rate (ORR) was 60% in all patients, 64% in T790M+ patients, and 37% in T790M- patients by investigators assessment. In BM patients with measurable lesion (n = 14), the intracranial ORR was 50%. The median progression-free survival (PFS) was 8.1 months in all patients, 9.5 months in T790M+ patients, and 5.4 months in T790M- patients. Subgroup analysis showed that ORR was 65% and PFS was 12.2 months in T790M+ patients with ≥ 120 mg (n = 62). The most common treatment-emergent adverse events (TEAEs) were pruritus (27%), rash (24%), constipation (20%), decreased appetite (19%) and diarrhea (14%). TEAEs leading to dose discontinuation were observed in 3% of patients. Drug related TEAEs of grade ≥ 3 was observed in 3% of the patients. Conclusions: Lazertinib was safe, well-tolerated and exhibits promising systemic and intracranial antitumor activity in EGFR T790M+ NSCLC patients. Dose extension cohorts in the 1st and 2nd line settings are underway at 240 mg dose. Clinical trial information: NCT03046992.
Dendritic-cell vaccine (DCVAC) with first-line chemotherapy in patients with stage IV NSCLC: Final analysis of phase II, open label, randomized, multicenter trial.
Authors: Havel Libor , Kolek Vitezslav , Pesek Milos , Cernovská Markéta , Bartunkova Jirina , Spisek Radek , Pecen Ladislav , Krasnopolskaya Inna , Zemanova Milada ,   SLU01 Investigators
Published: March 2020

9039

Background: Immunotherapy aiming the induction of tumor cell specific immune responses controlling the tumor growth, has emerged as a promising treatment modality in lung cancer(LuCa). Autologous DCVAC can present tumor antigens to elicit a durable immune response. We hypothesized that adding DCVAC to the standard of care chemotherapy (ct) could prolong overall survival (OS) and progression-free survival (PFS). Methods: This study evaluated the efficacy and safety of DCVAC/LuCa (active cellular immunotherapy based on dendritic cells) concomitantly added to ct (carboplatin/paclitaxel) - Arm A (A) vs DCVAC/LuCa + immune modulators (IFN-α and hydroxychloroquine) - Arm B (B)+ct vs ct - Arm C (C) in NSCLC patients (pts). Randomization 1:1:1; pts in A and B received up to 15 doses of DCVAC, ct was given 4-6 cycles in A and C. Stage IV NSCLC was confirmed histologically or cytologically, ECOG 0-1 pts were eligible. Stratification was done by histology subtype and smoking history. Primary efficacy analysis compared A vs C only as enrollment to B was closed early based on Sponsor’s assessment of further clinical development potential, there were no safety concerns or signals. Results: 112 pts at 12 sites were randomized (A/45 B/29 C/38). Patients characteristics were comparable across the study groups with the exception of gender (m/f, %: 65/35 (A) and 74/26 (C) and smoking history (75 % of smokers in A, 97 % in C). Median follow up time was 25.8 months, range 0.1-41.8. Median OS was 15.5 months in A compared to 11.8 months in C, hazard ratio (HR) 0.55, p-value 0.0232, 95% CI [0.33, 0,93], data maturity 77%. Median PFS was 6.74 in A and 5.63 months in C, HR 0.59, p-value 0.0415, 95% CI [0.36, 0.99], data maturity 86%. Overall response rate was 45% in A vs 34% in C. Most TEAEs were related to ct (anemia [35%-A, 32%-C], neutropenia [48% in A, 21%-C], thrombocytopenia [25% in A, 27% in C]). There were no grade ≥ 3 TEAEs solely related to DCVAC. Most common leukapheresis (lp)-related AE was vomiting in 2 pts out of 67 pts undergone lp. Conclusions: Addition of DCVAC-based immunotherapy to the standard of care chemotherapy significantly improved OS in stage IV NSCLC. Clinical trial information: NCT02470468.
Clonal evolution and osimertinib resistance mechanisms identified by whole exome and transcriptome sequencing in EGFR mutant NSCLC.
Authors: Roper Nitin , Brown Anna-Leigh , Sindiri Sivasish , Cultraro Constance M. , Gao Shaojian , Kim Chul , Hoang Chuong D. , Maity Tapan K , Akoth Elizabeth , Rajan Arun , Venugopalan Abhilash Karavattu , Trindade Christopher , Wei Jun S. , Panchenko Anna , Hewitt Stephen M. , Khan Javed , Guha Udayan
Published: March 2020

9049

Background: Osimertinib, a 3rd generation EGFR TKI, has been approved for treatment naïve patients (pts) with metastatic EGFR mutant NSCLC. Mechanisms of resistance to osimertinib are emerging from limited studies using targeted sequencing platforms. Methods: We performed whole exome (WES) and RNA-sequencing of osimertinib resistant tumors of EGFR-mutant NSCLC pts treated in a prospective clinical trial (NCT02759835). Treatment naïve EGFR mutant pts or pts with T790M-positive NSCLC after EGFR-TKI treatment receive osimertinib. Upon progression, pts with ≤5 progressing sites undergo local ablative therapy (LAT; surgery, radiation, RFA) and resume osimertinib. We analyzed paired pre-treatment and post-progression tumors in 10 patients and post-progression tumors in 3 additional patients and investigated intra- and inter-metastatic tumor heterogeneity using tumors procured from LAT surgeries and autopsies. Results: Acquired, focal copy number amplifications (CNA) of oncogenes occurred in the majority of patients (54%, n = 7/13) whereas acquired osimertinib resistance mutation EGFR C797S was less common (15%, n = 2/13). Early progression on osimertinib ( < 12 months PFS) in treatment naïve pts was associated with acquired, focal CNA. Despite pre-existing EGFR amplification, further amplification of the mutant allele of EGFR was the most common focal CNA (33%, n = 3/9). Other oncogenes amplified in resistant tumors include MET, KRAS, ERBB2 and YES1. CD274 (PD-L1) amplification occurred as the only putative mechanism of resistance in a pt without prior EGFR-TKI treatment. Using RNA-seq, we identified a pt who retained NSCLC histology, but upregulated genes associated with neuroendocrine differentiation upon osimertinib resistance. Clonal evolutionary analysis using WES of prospectively collected sensitive and resistant tumor tissue, including at autopsy is underway. Conclusions: Unbiased WES and transcriptome sequencing revealed heterogeneity, clonal evolution and novel osimertinib resistance mechanisms. Majority of pts had two or more resistance mechanisms suggesting the requirement of combination therapies to overcome resistance. Clinical trial information: NCT02759835.
Impact of HER2 aberrations on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS STUDY subset analysis.
Authors: Kayatani Hiroe , Aoe Keisuke , Ohashi Kadoaki , Yoshioka Hiroshige , Bessho Akihiro , Ishikawa Nobuhisa , Yamasaki Masahiro , Kozuki Toshiyuki , Fujimoto Nobukazu , Ueda Yutaka , Bandoh Syuuji , Murakami Isao , Ichikawa Hirohisa , Kubota Tetsuya , Sugimoto Keisuke , Takigawa Nagio , Sumikawa Takashi , Kiura Katsuyuki
Published: March 2020

9056

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a key treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC). To date, a biomarker to predict whether NSCLC will exhibit a short- or long-term response to first- or second-generation EGFR-TKIs has not been established for clinical use. Human epidermal growth factor receptor-2 (HER2) aberrations are mechanisms for acquired resistance to EGFR-TKIs; however, their impact on EGFR-TKI therapy outcomes in EGFR-mutant NSCLC has not yet been systematically evaluated. Methods: Patients with advanced NSCLC were prospectively registered from more than 35 institutes (HER2-CS STUDY UMIN 000017003). EGFR mutations or anaplastic lymphoma kinase gene translocations were assessed at each institution using a commercially approved test. HER2 protein expression levels were determined by immunohistochemistry (IHC) using the Ventana I-VIEW PATHWAY anti-HER-2/neu (4B5). The IHC status scoring system applied to gastric cancer was used. Results: Of 1,126 screened patients with NSCLC, 354 (31.8%) had EGFR-mutated tumors, and the HER2 protein statuses were as follows: IHC0 (n = 71, 26%), IHC1+ (n = 148, 53%), IHC2+ (n = 51, 18%), and IHC3+ (n = 7, 3%). The patients’ demographics were almost identical in those with lung tumors harboring EGFR mutations and HER2-IHC2+/3+ (group P) or EGFR mutations and HER2-IHC0/1 (group N). The EGFR-TKI response rates were not different between these groups (Table). However, group P showed significantly shorter time to EGFR-TKI treatment failure than group N (median 19.1 vs. 13.3 months; log rank p = 0.038). Conclusions: These data from a large prospective cohort show that HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs. A clinical trial of EGFR/HER2-TKIs (e.g., afatinib) is warranted for this population. [Table: see text]
Osimertinib (Osi) plus necitumumab (Neci) in EGFR-mutant NSCLC: An ETCTN California cancer consortium phase I study.
Authors: Riess Jonathan W. , Groshen Susan G. , Reckamp Karen L. , Wakelee Heather A. , Oxnard Geoffrey R. , Padda Sukhmani Kaur , Koczywas Marianna , Piotrowska Zofia , Sholl Lynette M. , Paweletz Cloud P. , Lau Christie J. , Kolesar Jill , Mack Philip C. , Moscow Jeffrey , Janne Pasi A. , Lara Primo , Newman Edward M. , Gandara David R.
Published: March 2020

9057

Background: Osi (3rd gen EGFR TKI) has robust activity in 1st line EGFR mutant NSCLC and TKI resistant T790Mpos NSCLC but progressive disease (PD) occurs and outcomes with Osi alone are poor in T790Mneg, C797Xpos and EGFR exon 20 insertion (ins20) disease. This study examined the EGFR monoclonal antibody Neci with Osi in select settings of EGFR TKI resistance. Methods: Using a 3+3 design, Neci was examined in advanced EGFR mutant NSCLC at dose levels (DL) of 600 mg (DL1) & 800 mg (DL2) D1, D8 IV q21 days + Osi 80 mg qd. Four expansion cohorts (ExC; 18 each) included: A) T790Mneg PD on 1st/2nd gen TKI as last therapy, B) T790Mneg PD on 3rd gen TKI, C) T790Mpos PD on 3rd gen TKI, D) EGFR ex20ins PD on chemotherapy. Central T790M testing by ddPCR in ExC A-C. Additional studies performed include: NGS panel of > 400 genes, EGFR FISH, plasma for PK and serial EGFR ctDNA by ddPCR as exploratory analyses. Adverse events (AEs) graded (Gr) by CTCAEv5 with ORR and PFS by RECIST 1.1. Results: Dose escalation and ExC B completed accrual. In total 55 pts were evaluable (Table). 1 pt had DLT at DL2, Gr 3 sinus bradycardia. Drug related Gr 3 AEs were seen in 27% (15) of pts, mainly rash (7;13%). ctDNA showed decreased mutant allele frequency with therapy in all pts studied with detected EGFR at baseline, with complete plasma clearance in a pt with detectable C797S. Conclusions: The RP2D (Osi 80 mg qd and Neci 800 mg D1, D8 IV on q21d cycle) is feasible and tolerable. In ExC A,T790Mneg pts with 1st/2nd gen EGFR TKI as last treatment, using curtailed sampling, the pre-specified efficacy signal was reached for Osi + Neci comparing favorably to Osi alone in analogous pts from the AURA trial. Clinical activity was also seen in EGFR-dependent resistance (T790Mpos C797Spos) after PD on 3rd gen TKI and in EGFR ins 20. Clinical trial information: NCT02496663. [Table: see text]
Prognostic significance of radiologic features of pneumonitis induced by anti-PD-1 therapy.
Authors: Watanabe Satoshi , Ota Takeshi , Hayashi Masachika , Ishikawa Hiroyuki , Miyabayashi Takao , Terada Masaki , Sato Kazuhiro , Ishida Takashi , Tanaka Hiroshi , Iwashima Akira , Shoji Satoshi , Nozaki Koichiro , Ichikawa Kosuke , Kondo Rie , Yoshizawa Hirohisa , Kikuchi Toshiaki
Published: March 2020

9065

Background: Anti-PD-1 therapy is now a standard treatment for patients with NSCLCs. Pneumonitis induced by immune-check point inhibitors is potentially fatal; however, some studies have shown that antitumor effects were enhanced in patients with pneumonitis. Although several radiologic patterns of pneumonitis induced by anti-PD-1 therapy have been reported, the association between radiologic features and clinical outcomes, especially enhancement of antitumor effects remains unclear. Methods: We retrospectively evaluated data of NSCLC patients treated in 1st to 3rd line with anti-PD-1 antibodies (nivolumab or pembrolizumab) at Niigata Lung Cancer Treatment Group. Pneumonitis was diagnosed by the treating investigators. The chest CT scans of patients with pneumonitis were independently reviewed by one radiologist and two pulmonologists to classify pneumonitis into 5 subtypes: cryptogenic organizing pneumonia-like (COP), ground glass opacities (GGO), interstitial, hypersensitivity and pneumonitis not otherwise specified (NOS). Results: Of 231 patients who received anti-PD-1 antibodies, pneumonitis developed in 33 patients (14.3%) at 7 institutions between January 2016 to October 2017. Of 33 patients with pneumonitis, the median age was 66 (range 45 to 82 years), 7 were female, 25 received nivolumab, and 8 received pembrolizumab. Sixteen patients were classified as GGO, 16 patients had COP-like appearance and one patient had NOS. The median survival time was significantly longer among patients with COP than among those with GGO (not reached vs. 7.8 months; HR 0.29, 95% CI 0.09-0.81; p = 0.0071). Pneumonitis improved in 94% (31 of 33) of cases, and one patient died from pneumonitis. The overall response ratio (CR+PR) was 44% in patients with COP and 31% in patients with GGO (p = 0.47). There was no statistical difference in OS between patients with systemic corticosteroid therapy for pneumonitis and those without (not reached vs. 14.8 months; HR 1.4, 95% CI 0.52-4.1; p = 0.51). Conclusions: Patients with pneumonitis classified as COP had significantly longer survival time than those with pneumonitis classified as GGO. Radiologic features of pneumonitis may reflect clinical outcomes after anti-PD-1 therapy.
Longitudinal analysis of plasma ALK mutations during treatment with next-generation ALK inhibitors.
Authors: Dagogo-Jack Ibiayi , Rooney Marguerite , Nagy Rebecca , Digumarthy Subba , Chin Emily , Ackil Jennifer , Gainor Justin F. , Lin Jessica Jiyeong , Lanman Richard B. , Shaw Alice Tsang
Published: March 2020

9068

Background: Next-generation ALK tyrosine kinase inhibitors (TKIs) are the cornerstone of management of ALK-positive (ALK+) lung cancer. Each ALK TKI has a unique spectrum of activity against distinct ALK kinase domain mutations (muts). Plasma genotyping is a promising strategy for identifying ALK muts at relapse on ALK TKIs. Methods: To detect ALK muts, we performed next-generation sequencing (Guardant360) of circulating tumor DNA from patients (pts) with ALK+ lung cancer relapsing on a second-generation (2nd-gen) ALK TKI (n = 65) or the third-generation (3rd-gen) TKI lorlatinib (n = 26). Results: Among 65 pts progressing on a 2nd-gen TKI, 49 (75%) had only received one 2nd-gen ALK TKI prior to analysis: n = 42 alectinib, n = 3 each brigatinib/ceritinib, and n = 1 ensartinib. We detected an ALK mut in 42/65 (65%) specimens at relapse, among which ALK G1202R (32%) and I1171X (23%) were the most common. Sixteen (25%) pts had ≥2 ALK muts at progression on a 2nd-gen TKI. Among 26 pts progressing on lorlatinib (all of whom had previously relapsed on a 2nd-gen ALK TKI), we identified ALK muts in 20 (76%), including 14 (54%) with ≥2 ALK muts. Detection of ≥2 ALK muts was more common at relapse on lorlatinib compared to a 2nd-gen TKI (p = 0.013). To assess the evolution of ALK muts during treatment with different TKIs, we analyzed serial plasma specimens from 20 pts treated with sequential 2nd-gen/2nd-gen or 2nd-gen/3rd-gen TKIs. Among six pts who received alectinib followed by brigatinib, repeat plasma analysis at brigatinib progression revealed persistence of pre-brigatinib ALK muts in two pts (one L1196M and one G1202R), expansion of G1202R in one pt, and acquisition of new ALK muts in three pts. Among 14 pts who received a 2nd-gen TKI followed by lorlatinib, 11 had persistence of pre-lorlatinib ALK muts and 8 acquired ≥1 additional ALK muts at lorlatinib progression. The most frequently acquired ALK mut was D1203N in four of eight cases. Conclusions: ALK resistance muts are prevalent at relapse on next-generation ALK TKIs and increase with each successive generation of ALK TKIs. These findings suggest that sequential therapy with increasingly potent ALK TKIs may select for compound ALK muts and/or fuel tumor heterogeneity.
Time-to-treatment discontinuation (TTD) and real-world progression-free survival (rwPFS) as endpoints for comparative efficacy analysis between entrectinib trial and crizotinib real-world ROS1 fusion-positive (ROS1+) NSCLC patients.
Authors: Doebele Robert Charles , Perez Laura , Trinh Huong , Martinec Michael , Martina Reynaldo , Riehl Todd , Krebs Matthew , Meropol Neal J. , Wong William Bruce , Crane Gracy
Published: March 2020

9070

Background: Entrectinib is an oral tyrosine kinase inhibitor for ROS1+ NSCLC. Three phase 1/2 single-arm studies showed entrectinib efficacy in this population (Doebele WCLC 2018). Due to the rarity of ROS1+ pts generating direct comparative evidence in prospective randomized trials is difficult. We identified a retrospective real-world cohort of ROS1+ NSCLC pts from electronic health records (EHR), to compare crizotinib, the current standard of care, to entrectinib as reported in clinical trials. Methods: Crizotinib-treated pts with advanced ROS1+ NSCLC diagnosed 1 Jan 2011 to 30 Jun 2018, were identified with technology-enabled abstraction in the Flatiron Health EHR-derived database ( > 2.1 million cancer pts from US oncology practice). Entrectinib trial inclusion/exclusion criteria were applied to match the crizotinib cohort as closely as possible. Primary endpoint: TTD, adapted from Gong (ASCO 2018); rwPFS (physician/scan report) and OS were secondary outcomes. Time-to-event analyses used Kaplan-Meier survival curves and Cox proportional hazard models on propensity score weighted populations; age, gender, race/ethnicity, smoking status, brain metastasis and previous lines of therapy were prognostic factors. Results: We analyzed 53 entrectinib and 69 crizotinib ROS1+ NSCLC pts. Median weighted TTD: entrectinib, 14.6 mo (95% CI: 8.3–23.8); crizotinib, 8.8 mo (95% CI: 8.2–9.9). When rwPFS from crizotinib was compared to trial PFS, entrectinib had longer PFS vs crizotinib (weighted HR: 0.44; 95% CI: 0.27–0.74). Median OS with entrectinib was not reached (median follow-up: 15.5 mo); weighted median OS with crizotinib was 18.5 mo (95% CI: 15.1–19.9). Findings were consistent across multiple sensitivity analyses. Conclusions: Entrectinib was associated with longer TTD and PFS in ROS1+ NSCLC pts vs a matched real-world crizotinib population. Control populations derived from real-world cohorts can supplement evidence from clinical trials in settings where new standards of care are needed, but where only limited data are available and randomization is not feasible.