Clinical trials are the backbone for advancing therapeutic options for patients diagnosed with cancer. Yet only 7.1% of patients with cancer participate in clinical trials in the United States. In this article, we review some of the reasons for poor accrual and discuss potential solutions. See related article by van Berge Henegouwen et al., p. 3937.
<p>The key pharmacokinetic (PK) parameters (Supplemental Table 3) at the recommended phase 2 dose of 225 mg show that food has minimal impact on absorption of ensartinib.</p>
9137 Background: Amivantamab (ami), an EGFR and cMET bispecific antibody with immune cell-directing activity, and lazertinib (laz), a CNS-penetrant 3 rd -generation EGFR tyrosine kinase inhibitor have shown clinical activity in biomarker-selected patients (pts) with advanced NSCLC. Antitumor activity has been suggested to be improved when the agents are given in combination (Leighl Ann Oncol 2021;32:suppl_5, 1192MO). We examined the incidence of VTE, a common adverse event (AE) among pts with lung cancer, for those receiving ami monotherapy, laz monotherapy, and ami+laz to investigate if there is elevated risk and understand potential predisposing risk factors. Methods: CHRYSALIS (NCT02609776; ami monotherapy and ami+laz), CHRYSALIS-2 (NCT04077463; ami+laz), and LASER201 (NCT04075396; laz monotherapy) are ongoing open-label studies of locally advanced/metastatic NSCLC. Two descriptive, univariate risk analyses were performed, with the primary analysis including all treatment-emergent VTE events (grouped term) and a secondary analysis that excluded VTE events occurring after progression of disease (PD) or within 30 days prior to PD. Results: This analysis included 560 pts who received ami monotherapy, 536 ami+laz, and 252 laz monotherapy, predominantly in the TKI-relapsed setting. The incidence of VTE events of any grade was numerically higher in pts who received ami+laz (21%) than those who received ami (11%) or laz (11%) monotherapy. The median time to onset of the first VTE event was 84.5 days for ami, 79 days for ami+laz, and 170 days for laz. The majority (64%) of ami+laz pts had VTE events in the first 4 months. The most common VTE events by preferred term were pulmonary embolism and deep vein thrombosis. The incidence of grade ≥3 VTE events was comparable among pts receiving ami (5%), ami+laz (6%), and laz (6%), and there were no grade 5 VTE events for ami+laz. The overall incidence of serious VTE AEs was low (ami, 3%; ami+laz, 5%; laz, 4%). There were 6 discontinuations due to VTE, 1 (0.2%) ami, 2 (0.4%) for ami+laz, and 3 (1.2%) laz. In the primary analysis, age ≥60 years was a significant risk factor ( P< 0.05). In the secondary analysis, age ≥60 years, ECOG performance status of 1 (vs 0), and response to therapy (partial response or better) were significant risk factors ( P< 0.05). Conclusions: Lung cancer diagnosis is a known risk factor for VTE. In a review across clinical trials, single-arm cohort data suggest there is a numerically higher incidence of VTE for ami+laz compared with each monotherapy. Age ≥60 years, ECOG performance status, and response to treatment are potential risk factors. The relationship between response and VTE is emerging and may reflect possible immune or inflammatory-mediated mechanisms. Further efforts to understand VTE-associated risk factors in randomized clinical trials are ongoing. Clinical trial information: NCT02609776 , NCT04077463 , NCT04075396 .
9546 Background: Viagenpumatucel-L (HS-110) is an allogeneic cellular vaccine derived from a human lung adenocarcinoma cell line transfected with gp96-Ig fusion protein. Gp96-Ig functions as an antigen chaperone for dendritic cell activation and direct CD8+T cell expansion via cross presentation. DURGA is a multi-cohort study evaluating HS-110 plus anti-PD-1 mAbs in patients (pts) with advanced NSCLC. We report on Cohort A, which enrolled previously-treated pts who had not received an anti-PD(L)1 prior to study entry. Methods: Primary objectives were safety and objective response rate (ORR). Overall Survival (OS) was a secondary endpoint. Pts received 1 X 10 7 HS-110 cells intradermally every week for 18 wks and nivolumab until tumor progression. To determine cancer testis antigen (CTA) overexpression from baseline pt tumor samples, hybrid-capture RNA-seq libraries were prepared from macrodissected formalin fixed paraffin embedded tumor tissue and sequenced on an Illumina NovaSeq 6000. Gene-level transcripts were quantified using the Salmon software package. Results: 47 pts were enrolled into Cohort A. ORR and clinical benefit rate (CR + PR + SD) were 21% and 43%, respectively, with a 17.2 month median duration of response. Median OS was 28.7 months (mos), with a median follow up of 15.7 mos. One and 2-year survival were 57% and 36%, respectively. A prespecified exploratory analysis of CTA expression level in baseline pt tumor tissue was performed. 50% of pts shared at least 8 of the 39 total antigens overexpressed by HS110. Although there was no difference in ORR between these groups, mOS was higher in pts with tumors that shared ≥ 8 antigens with HS-110 (not reached (NR) [95%CI: 10.3 mos, NR] vs 6.7 mos [95%CI: 1.4 mos, NR]), p = 0.028. Pts whose tumors expressed the ZNF492 antigen also had improved OS (NR [95%CI: 11.6 mos, NR] vs 7.2 mos [95%CI: 1.6 mos, NR]), p = 0.03. All pts experienced at least one adverse event (AE), and the most common AEs were fatigue (28%), arthralgia (19%) and cough (17%). There were 2 grade 5 AEs not related to treatment. Conclusions: The combination of HS-110 and nivolumab appears safe and well tolerated. OS was improved in pts whose tumors express ≥ 8 shared antigens with HS110, as well as in those who specifically expressed ZNF492. Further exploration of antigen expression as a predictor for treatment outcome with HS110 plus nivolumab is ongoing. Clinical trial information: NCT02439450 .
Nearly all patients with small cell lung cancer (SCLC) eventually relapse with chemoresistant disease. The molecular mechanisms driving chemoresistance in SCLC remain un-characterized. Here, we describe whole-exome sequencing of paired SCLC tumor samples procured at diagnosis and relapse from 12 patients, and unpaired relapse samples from 18 additional patients. Multiple somatic copy number alterations, including gains in ABCC1 and deletions in MYCL, MSH2, and MSH6, are identifiable in relapsed samples. Relapse samples also exhibit recurrent mutations and loss of heterozygosity in regulators of WNT signaling, including CHD8 and APC. Analysis of RNA-sequencing data shows enrichment for an ASCL1-low expression subtype and WNT activation in relapse samples. Activation of WNT signaling in chemosensitive human SCLC cell lines through APC knockdown induces chemoresistance. Additionally, in vitro-derived chemoresistant cell lines demonstrate increased WNT activity. Overall, our results suggest WNT signaling activation as a mechanism of chemoresistance in relapsed SCLC.
// Lauren Averett Byers 1 , Leora Horn 2 , Jitendra Ghandi 3 , Goetz Kloecker 4 , Taofeek Owonikoko 5 , Saiama Naheed Waqar 6 , Maciej Krzakowski 7 , Robert J. Cardnell 1 , Junya Fujimoto 1 , Pietro Taverna 8 , Mohammad Azab 8 and David Ross Camidge 9 1 University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA 2 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA 3 Associates in Oncology and Hematology, Chattanooga, TN, USA 4 James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA 5 Winship Cancer Institute, Emory University, Atlanta, GA, USA 6 Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA 7 Centrum Onkologii-Instytut Im. M. Skłodowskiej-Curie w Warszawie, Warszawa, Poland 8 Astex Pharmaceuticals, Inc. Pleasanton, CA, USA 9 Anschutz Cancer Pavilion, University of Colorado Cancer Center, Aurora, CO, USA Correspondence to: Lauren Averett Byers, email: lbyers@mdanderson.org Keywords: amuvatinib, MP-470, platinum-refractory, etoposide, SCLC (small cell lung cancer) Received: June 08, 2017 Accepted: July 09, 2017 Published: August 03, 2017 ABSTRACT Background: Amuvatinib (MP-470) is a multi-targeted kinase inhibitor with potent activity against c-Kit, synergistic with DNA-damaging agents. We evaluated amuvatinib in combination with platinum-etoposide (EP) chemotherapy by objective response rate, survival, and tolerability in platinum-refractory small cell lung cancer (SCLC) patients. Methods: This study used a Simon 2-stage design requiring ≥3 centrally confirmed responses in the first 21 subjects. Subjects received EP with 300 mg amuvatinib orally three times daily in cycles of 21 days. A three-day amuvatinib run-in period before EP occurred in Cycle 1. Subjects received the same EP chemotherapy regimen given prior to progression/relapse. Results: Among 23 subjects treated, we observed four PRs (17.4%) per RECIST 1.1, only two of which were centrally confirmed (8.7%, response duration 119, 151 days). Three subjects (13%) had confirmed stable disease. c-Kit H-score was ≥100 in two subjects whose respective durations of disease control were 151 and 256 days. Conclusions: The addition of amuvatinib to EP chemotherapy in unselected, platinum-refractory SCLC did not meet the primary endpoint of ≥3 confirmed responses in stage 1. However, high c-Kit expression in two subjects with durable disease control suggests the potential for further study of amuvatinib in SCLC patients with high c-Kit expression.
e20555 Background: The indications for post-operative radiation therapy (PORT) in locally advanced non-small cell lung cancer (NSCLC) remain undefined and a major concern is the perceived risk of increased mortality from cardiopulmonary causes. The purpose of this study was to quantify the rate of cardiopulmonary death in patients with resected NSCLC receiving PORT using a large national database. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database for lung cancer, patients with Stage IIIA or Stage IIIB NSCLC according to the 6 th AJCC edition treated with surgery followed by PORT, who also received chemotherapy were identified. Cause of death was categorized as due to lung cancer, other cancer, cardiac, pulmonary, or other and reported as a percentage of total deaths at one and 2 years. Kaplan-Meier survival analysis was done to compare overall survival between Stage IIIA and IIIB patients. Results: From 2004 to 2015, 4387 patients with stage IIIA and IIIB meeting the eligibility criteria were identified. The median age at diagnosis was 65 years old, most patients were male (53%), Caucasian (83%), had adenocarcinoma (54.8%), stage IIIA disease (69%), and N2 disease (78%). The median overall survival for Stage IIIA and IIIB patients was 39 months and 27 months respectively (p < 0.001). Among the 2586 patients that died during the study period, the most common COD was lung cancer (81.3%). Cardiac and pulmonary COD occurred in 86 patients (3.3% of deaths) and 84 patients (3.2% of deaths) respectively, whereas 158 patients (6.1%) died from other cancers and 154 (5.9%) from other causes. There were 77 deaths from cardiopulmonary cause at 2 years (1.7% of patients and 2.9% of deaths). Cardiopulmonary COD was more common in patients with stage IIIB compared to IIIA disease (4.9% vs 3.3% of deaths, p < 0.001). Lung cancer was the most common COD both at 1 and 2 years (85%) whereas cardiopulmonary was the COD in 5.2% of patients at 1 year and 5.1% at 2 years. Conclusions: This analysis showed a low cardiopulmonary mortality from PORT in the first 2 years. The role for adjuvant radiotherapy remains undefined and treatment decisions for patients with resected stage III NSCLC should be guided by co-morbidities and the competing risk for death from lung cancer.
Progress in the overall treatment of small-cell lung cancer (SCLC) has moved at a slower pace than non-small-cell lung cancer. In fact, the standard treatment regimen for limited stage SCLC has not appreciably shifted in more than 20 years, consisting of four to six cycles of cisplatin and etoposide chemotherapy concurrent with thoracic radiotherapy (TRT) followed by prophylactic cranial irradiation (PCI) for responsive disease. Nevertheless, long-term outcomes have improved with median survival approaching 25-30 months, and approximately one third of patients now survive 5 years. This is likely attributable in part to improvements in staging, including use of brain magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography imaging, advances in radiation treatment planning, and supportive care. The CONVERT and CALGB 30610 phase III trials failed to demonstrate a survival advantage for high-dose, once-daily TRT compared with standard 45 Gy twice-daily TRT, although high-dose, once-daily TRT remains common in practice. A phase III comparison of high-dose 60 Gy twice-daily TRT versus 45 Gy twice-daily TRT aims to confirm the provocative outcomes reported with 60 Gy twice daily in the phase II setting. Efforts over time have shifted from intensifying PCI, to attempting to reduce treatment-related neurotoxicity, to more recently questioning whether careful magnetic resonance imaging surveillance may obviate the routine need for PCI. The addition of immunotherapy has resulted in mixed success in extensive-stage SCLC with modest benefit observed with programmed death-ligand 1 inhibitors, and several ongoing trials assess programmed death-ligand 1 inhibition concurrent or adjuvant to chemoradiotherapy in limited-stage SCLC. Major advances in future treatment will likely depend on a better understanding and exploiting of molecular characteristics of SCLC with increasing personalization of therapy.
PURPOSE Approximately 10%-40% of patients with lung cancer report no history of tobacco smoking (never-smokers). We analyzed whole-exome and RNA-sequencing data of 160 tumor and normal lung adenocarcinoma (LUAD) samples from never-smokers to identify clinically actionable alterations and gain insight into the environmental and hereditary risk factors for LUAD among never-smokers. METHODS We performed whole-exome and RNA-sequencing of 88 and 69 never-smoker LUADs. We analyzed these data in conjunction with data from 76 never-smoker and 299 smoker LUAD samples sequenced by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium. RESULTS We observed a high prevalence of clinically actionable driver alterations in never-smoker LUADs compared with smoker LUADs (78%-92% v 49.5%; P < .0001). Although a subset of never-smoker samples demonstrated germline alterations in DNA repair genes, the frequency of samples showing germline variants in cancer predisposing genes was comparable between smokers and never-smokers (6.4% v 6.9%; P = .82). A subset of never-smoker samples (5.9%) showed mutation signatures that were suggestive of passive exposure to cigarette smoke. Finally, analysis of RNA-sequencing data showed distinct immune transcriptional subtypes of never-smoker LUADs that varied in their expression of clinically relevant immune checkpoint molecules and immune cell composition. CONCLUSION In this comprehensive genomic and transcriptome analysis of never-smoker LUADs, we observed a potential role for germline variants in DNA repair genes and passive exposure to cigarette smoke in the pathogenesis of a subset of never-smoker LUADs. Our findings also show that clinically actionable driver alterations are highly prevalent in never-smoker LUADs, highlighting the need for obtaining biopsies with adequate cellularity for clinical genomic testing in these patients.
