Concurrent TP53 Mutations Facilitate Resistance Evolution in EGFR-Mutant Lung Adenocarcinoma.

INTRODUCTION: Patients with EGFR-mutant NSCLC experience variable duration of benefit on EGFR tyrosine kinase inhibitors. The effect of concurrent genomic alterations on outcome has been incompletely described. METHODS: In this retrospective study, targeted next-generation sequencing data were collected from patients with EGFR-mutant lung cancer treated at the Dana-Farber Cancer Institute. Clinical data were collected and correlated with somatic mutation data. Associations between TP53 mutation status, genomic features, and mutational processes were analyzed. RESULTS: A total of 269 patients were identified for inclusion in the cohort. Among 185 response-assessable patients with pretreatment specimens, TP53 alterations were the most common event associated with decreased first-line progression-free survival and decreased overall survival, along with DNMT3A, KEAP1, and ASXL1 alterations. Reduced progression-free survival on later-line osimertinib in 33 patients was associated with MET, APC, and ERBB4 alterations. Further investigation of the effect of TP53 alterations revealed an association with worse outcomes even in patients with good initial radiographic response, and faster acquisition of T790M and other resistance mechanisms. TP53-mutated tumors had higher mutational burdens and increased mutagenesis with exposure to therapy and tobacco. Cell cycle alterations were not independently predictive, but portended worse OS in conjunction with TP53 alterations. CONCLUSIONS: TP53 alterations associate with faster resistance evolution independent of mechanism in EGFR-mutant NSCLC and may cooperate with other genomic events to mediate acquisition of resistance mutations to EGFR tyrosine kinase inhibitors.

The Impact of COVID-19 on Clinical Trial Execution at the Dana-Farber Cancer Institute.

Interventions designed to limit the spread of coronavirus disease 2019 (COVID-19) are having profound effects on the delivery of health care, but data showing the impact on oncology clinical trial enrollment, treatment, and monitoring are limited. We prospectively tracked relevant data from oncology clinical trials at Dana-Farber Cancer Institute from January 1, 2018, to June 30, 2020, including the number of open trials, new patient enrollments, in-person and virtual patient visits, dispensed investigational infusions, dispensed or shipped oral investigational agents, research biopsies, and blood samples. We ascertained why patients came off trials and determined on-site clinical research staffing levels. We used 2-sided Wilcoxon rank sum tests to assess the statistical significance of the reported changes. Nearly all patients on interventional treatment trials were maintained, and new enrollments continued at just under one-half the prepandemic rate. The median number of investigational prescriptions shipped to patients increased from 0 to 74 (range = 22-107) per week from March to June 2020. The median number of telemedicine appointments increased from 0 to 107 (range = 33-267) per week from March to June 2020. Research biopsies and blood collections decreased dramatically after Dana-Farber Cancer Institute implemented COVID-19-related policies in March 2020. The number of research nurses and clinical research coordinators on site also decreased after March 2020. Substantial changes were required to safely continue clinical research during the pandemic, yet we observed no increases in serious adverse events or major violations related to drug dosing. Lessons learned from adapting research practices during COVID-19 can inform industry sponsors and governmental agencies to consider altering practices to increase operational efficiency and convenience for patients.

Tumor volume dynamics and tumor growth rate in ALK-rearranged advanced non-small-cell lung cancer treated with crizotinib.

PURPOSE: The purpose of the study is to investigate volumetric tumor burden dynamics and tumor growth rates in ALK-rearranged advanced NSCLC patients during crizotinib monotherapy. METHODS: The study included 44 ALK-rearranged advanced NSCLC patients treated with crizotinib monotherapy as their initial ALK-directed therapy, who had at least one measurable lung lesion and at least two follow-up CT scans, and experienced tumor volume increase while on crizotinib. The tumor volume (in mm3) of the dominant lung lesion was measured on serial CT scans during therapy for analysis of tumor growth rates after the volume nadir. RESULTS: A total of 231 volume measurements from the nadir to the end of crizotinib therapy or the last follow-up in 44 patients were analyzed in a linear mixed-effects model, fitting time (in months since baseline) as a random effect. When measured from the volume nadir, the tumor growth rate of the logarithm of tumor volume (logeV) was 0.04/month (SE = 0.012, P = 0.0011) in the unadjusted model. When adjusted for the baseline volume (logeV0), the growth rate was again 0.04/month (SE = 0.011, P = 0.0004). When adjusted for clinical variables and logeV0, the growth rate was 0.045/month (SE = 0.012, P = 0.0002), indicating that the tumor growth rate after nadir in this cohort remains very close to 0.04/month regardless of logeV0 or clinical factors. CONCLUSIONS: Tumor volume growth rate after nadir in ALK-rearranged NSCLC patients treated with crizotinib was obtained, providing objective reference values that can inform physicians when deciding to keep their patients on ALK directed therapy with slowly progressing lung cancer.

Tumor Volume Analysis as a Predictive Marker for Prolonged Survival in Anaplastic Lymphoma Kinase-rearranged Advanced Non-Small Cell Lung Cancer Patients Treated With Crizotinib.

PURPOSE: Targeted inhibition of anaplastic lymphoma kinase (ALK) has been widely used for the treatment of advanced non-small cell lung cancer (NSCLC) with ALK rearrangements. We performed tumor volume analysis of ALK-rearranged advanced NSCLC treated with crizotinib to identify an early predictive marker for prolonged survival. MATERIALS AND METHODS: Cases of 42 patients with ALK-rearranged advanced NSCLC (16 men, 26 women; median age: 55.7 y) treated with crizotinib as their first ALK-directed therapy were retrospectively studied. Tumor volume measurements of dominant lung lesions were performed on baseline computed tomography and follow-up computed tomography at 8 weeks of therapy. The relationships between the 8-week volume change (%) and overall survival (OS) were investigated. RESULTS: The 8-week tumor volume change ranged from -99.3% to 117.5% (median: -57.7%). Using the 25th percentile of the 8-week volume change of -74%, 11 patients with >74% volume decrease at 8 weeks had a significantly longer OS compared with 31 patients with ≤74% decrease (median OS: 92.0 vs. 22.8 mo; P=0.0048). In multivariable analyses using Cox proportional hazards models, the 8-week volume decrease of >74% was significantly associated with longer OS (hazard ratio=0.14, 95% confidence interval: 0.03-0.59; Cox P=0.008) after adjusting for tumor stage (stage IV vs. recurrent NSCLC, hazard ratio=5.6, 95% confidence interval: 1.29-24.3; P=0.02). CONCLUSIONS: The 8-week tumor volume decrease of >74% is significantly associated with longer OS in patients with ALK-rearranged NSCLC treated with crizotinib.

Interstitial lung abnormality in stage IV non-small cell lung cancer: A validation study for the association with poor clinical outcome.

PURPOSE: The presence of interstitial lung abnormality (ILA) at diagnosis of stage IV non-small cell lung cancer (NSCLC) patients has previously shown to be associated with shorter overall survival (OS). The present study aimed to validate the association between ILA and shorter OS in a larger cohort of treatment-naïve stage IV NSCLC patients. MATERIALS AND METHODS: This study includes 484 patients (205 men and 279 women) with a pathological diagnosis of stage IV NSCLC with pretreatment baseline CT available for review. ILA was visually scored on the baseline chest CT with a 3-point scale (0=no ILA, 1=indeterminate for ILA, 2 = ILA) as published previously. Clinical characteristics and overall survival (OS) were compared in patients with ILA score 2 vs. those with ILA score 0 or 1. RESULTS: ILA was present (score 2) on baseline CT in 19 of 484 patients (3.9%, 95%CI2.4-6.1%). Patients with ILA were significantly older (p = 0.0008) and more commonly male (p = 0.03) compared to those with ILA score 0 or 1. Patients with ILA score 2 showed significantly shorter OS compared to those with ILA score 0 or 1 (median OS 9.95 months vs. 16.95 months; p = 0.0002). In multivariate analyses, baseline ILA score 2 remained significant as a marker for shorter OS (HR = 2.09, p = 0.004) after adjustments for age (HR = 1.48; p = 0.001), gender (HR = 1.22, p = 0.06), and smoking (HR = 0.79; p = 0.051). CONCLUSIONS: ILA on baseline CT at diagnosis of stage IV NSCLC patients was associated with shorter OS (HR = 2.09, p = 0.004), validating ILA as an independent marker for poor clinical outcome.

M1b Disease in the 8th Edition of TNM Staging of Lung Cancer: Pattern of Single Extrathoracic Metastasis and Clinical Outcome.

BACKGROUND: The 8th edition of TNM staging of non-small cell lung cancer (NSCLC) has revised M classification and defined M1b disease with single extrathoracic metastasis, which is distinguished from M1c with multiple extrathoracic metastases. We investigated the prevalence, characteristics, and overall survival (OS) of M1b disease in patients with stage IV NSCLC. METHODS: The study reviewed the medical records and imaging studies of 567 patients with stage IV NSCLC to determine M stage using the 8th edition of TNM staging. Clinical characteristics and OS were compared according to M stages. RESULTS: Among 567 patients, 57 patients (10%) had M1b disease, whereas 119 patients (21%) had M1a disease and 391 patients (69%) had M1c disease. Squamous histology was more common in M1b (16%) than in M1a (6%) and M1c (6%; p = .03). The median OS of patients with M1b disease was 14.8 months, compared with 22.6 months for patients with M1a and 13.4 months for those with M1c disease (p < .0001). Significant OS differences of M1b compared with single-organ M1c and multiorgan M1c groups were noted (single-organ M1c vs. M1b: hazard ratio [HR], 1.49; p = .02; multiorgan M1c vs. M1b: HR, 1.57; p = .01) in multivariable analyses adjusting for smoking and systemic therapy types. Among patients with M1b disease, the brain was the most common site of single metastasis (28/57; 49%), followed by bone (16/57; 28%). Single brain metastasis was more frequently treated with local treatment (p < .0001). CONCLUSION: M1b disease was noted in 10% of patients with stage IV NSCLC. Squamous histology was more common in M1b group than others. The brain was the most common site of single metastasis and was often treated locally. IMPLICATIONS FOR PRACTICE: The newly defined group of M stage consists of a unique subset among patients with stage IV non-small cell lung cancer that can be studied further to optimize treatment approaches.

Safety and Efficacy of PD-1 Inhibitors Among HIV-Positive Patients With Non-Small Cell Lung Cancer.

INTRODUCTION: Despite widespread administration of programmed death receptor 1 (PD-1) pathway inhibitors among individuals with NSCLC, little is known about the safety and activity of these agents among human immunodeficiency virus (HIV) - infected patients since this population has largely been excluded from immunotherapy clinical trials. METHODS: Here, we describe seven patients with metastatic NSCLC and HIV infection who were treated with PD-1 inhibitors nivolumab (two cases) or pembrolizumab (five cases with three in the first-line setting). RESULTS: Partial responses to immune checkpoint inhibitors were observed in three of seven cases. Among four patients with a programmed death ligand-1 tumor proportion score ≥50%, three partial responses were observed. All patients received antiretroviral therapy while on anti-PD-1 treatment. None of the patients experienced grade 3 or 4 immune-related adverse events or immune reconstitution inflammatory syndrome, and none required PD-1 inhibitor dose interruption or discontinuation due to toxicity. CONCLUSIONS: Nivolumab and pembrolizumab can be safe and effective among patients with NSCLC and HIV. Larger studies will be needed to determine the overall safety and efficacy of immune checkpoint inhibitors among cancer patients with HIV.

Epitope mapping of spontaneous autoantibodies to anaplastic lymphoma kinase (ALK) in non-small cell lung cancer.

The anaplastic lymphoma kinase (ALK) is recognized by the immune system as a tumor antigen, and preclinical evidence suggests that ALK-rearranged NSCLCs can also be successfully targeted immunologically using vaccine-based approaches. In contrast to ALK-rearranged lymphomas, the frequency and clinical significance of spontaneous ALK immune responses in patients with ALK-rearranged NSCLCs are largely unknown. We developed an enzyme-linked immunosorbent assay (ELISA) to measure anti-ALK antibody levels and mapped specific peptide epitope sequences within the ALK cytoplasmic domain in patients with non-small cell lung cancer. The ELISA method showed good correlation with ALK antibody titers measured with a standard immunocytochemical approach. Strong anti-ALK antibody responses were detected in 9 of 53 (17.0%) ALK-positive NSCLC patients and in 0 of 38 (0%) ALK-negative NSCLC patients (P<0.01), and the mean antibody levels were significantly higher in ALK-positive than in ALK-negative NSCLC patients (P=0.02). Across individual patients, autoantibodies recognized different epitopes in the ALK cytoplasmic domain, most of which clustered outside the tyrosine kinase domain. Whether the presence of high ALK autoantibody levels confers a more favorable prognosis in this patient population warrants further investigation.

Tumor Response Dynamics of Advanced Non-small Cell Lung Cancer Patients Treated with PD-1 Inhibitors: Imaging Markers for Treatment Outcome.

Purpose: We evaluated tumor burden dynamics in patients with advanced non-small cell lung cancer (NSCLC) treated with commercial PD-1 inhibitors to identify imaging markers associated with improved overall survival (OS).Experimental Design: The study included 160 patients with advanced NSCLC treated with commercial nivolumab or pembrolizumab monotherapy as a part of clinical care. Tumor burden dynamics were studied for the association with OS.Results: Tumor burden change at best overall response (BOR) ranged from -100% to +278% (median, +3.5%). Response rate (RR) was 18% (29/160). Current and former smokers had a higher RR than never smokers (P = 0.04). Durable disease control for at least 6 months was noted in 26 patients (16%), which included 10 patients with stable disease as BOR. Using a landmark analysis, patients with <20% tumor burden increase from baseline within 8 weeks of therapy had longer OS than patients with ≥20% increase (median OS, 12.4 vs. 4.6 months, P < 0.001). Patients with <20% tumor burden increase throughout therapy had significantly reduced hazards of death (HR, 0.24; Cox P < 0.0001) after adjusting for smoking (HR, 0.86; P = 0.61) and baseline tumor burden (HR, 1.55; P = 0.062), even though some patients met criteria for RECIST progression while on therapy. One patient (0.6%) had atypical response pattern consistent with pseudoprogression.Conclusions: Objective response or durable disease control was noted in 24% of patients with advanced NSCLC treated with commercial PD-1 inhibitors. A tumor burden increase of <20% from baseline during therapy was associated with longer OS, proposing a practical marker of treatment benefit. Pseudoprogression is rare in NSCLCs treated with PD-1 inhibitors. Clin Cancer Res; 23(19); 5737-44. ©2017 AACR.

Cost and Survival Analysis Before and After Implementation of Dana-Farber Clinical Pathways for Patients With Stage IV Non-Small-Cell Lung Cancer.

PURPOSE: Increasing costs and medical complexity are significant challenges in modern oncology. We explored the use of clinical pathways to support clinical decision making and manage resources prospectively across our network. MATERIALS AND METHODS: We created customized lung cancer pathways and partnered with a commercial vendor to provide a Web-based platform for real-time decision support and post-treatment data aggregation. Dana-Farber Cancer Institute (DFCI) Pathways for non-small cell lung cancer (NSCLC) were introduced in January 2014. We identified all DFCI patients who were diagnosed and treated for stage IV NSCLC in 2012 (before pathways) and 2014 (after pathways). Costs of care were determined for 1 year from the time of diagnosis. RESULTS: Pre- and postpathway cohorts included 160 and 210 patients with stage IV NSCLC, respectively. The prepathway group had more women but was otherwise similarly matched for demographic and tumor characteristics. The total 12-month cost of care (adjusted for age, sex, race, distance to DFCI, clinical trial enrollment, and EGFR and ALK status) demonstrated a $15,013 savings after the implementation of pathways ($67,050 before pathways v $52,037 after pathways). Antineoplastics were the largest source of cost savings. Clinical outcomes were not compromised, with similar median overall survival times (10.7 months before v 11.2 months after pathways; P = .08). CONCLUSION: After introduction of a clinical pathway in metastatic NSCLC, cost of care decreased significantly, with no compromise in survival. In an era where comparative outcomes analysis and value assessment are increasingly important, the implementation of clinical pathways may provide a means to coalesce and disseminate institutional expertise and track and learn from care decisions.

Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study.

PURPOSE: Implementing cancer precision medicine in the clinic requires assessing the therapeutic relevance of genomic alterations. A main challenge is the systematic interpretation of whole-exome sequencing (WES) data for clinical care. METHODS: One hundred sixty-five adults with metastatic colorectal and lung adenocarcinomas were prospectively enrolled in the CanSeq study. WES was performed on DNA extracted from formalin-fixed paraffin-embedded tumor biopsy samples and matched blood samples. Somatic and germ-line alterations were ranked according to therapeutic or clinical relevance. Results were interpreted using an integrated somatic and germ-line framework and returned in accordance with patient preferences. RESULTS: At the time of this analysis, WES had been performed and results returned to the clinical team for 165 participants. Of 768 curated somatic alterations, only 31% were associated with clinical evidence and 69% with preclinical or inferential evidence. Of 806 curated germ-line variants, 5% were clinically relevant and 56% were classified as variants of unknown significance. The variant review and decision-making processes were effective when the process was changed from that of a Molecular Tumor Board to a protocol-based approach. CONCLUSION: The development of novel interpretive and decision-support tools that draw from scientific and clinical evidence will be crucial for the success of cancer precision medicine in WES studies.Genet Med advance online publication 26 January 2017.

Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer.

Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped, and understanding of mechanisms of resistance to MET TKIs is limited. Here, we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib. When resistance developed to this combination, a new MET kinase domain mutation, D1228V, was detected. Our in vitro findings demonstrate that METD1228V induces resistance to type I MET TKIs through impaired drug binding, while sensitivity to type II MET TKIs is maintained. Based on these findings, the patient was treated with erlotinib combined with cabozantinib, a type II MET inhibitor, and exhibited a response. SIGNIFICANCE: With several structurally distinct MET inhibitors undergoing development for treatment of NSCLC, it is critical to identify mechanism-based therapies for drug resistance. We demonstrate that an acquired METD1228V mutation mediates resistance to type I, but not type II, MET inhibitors, having therapeutic implications for the clinical use of sequential MET inhibitors. Cancer Discov; 6(12); 1334-41. ©2016 AACR.See related commentary by Trusolino, p. 1306This article is highlighted in the In This Issue feature, p. 1293.

Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs.

INTRODUCTION: Activating mutations in the epidermal growth factor receptor gene (EGFR) predict for prolonged progression-free survival in patients with advanced non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs) versus chemotherapy. Long-term survival outcomes, however, remain undefined. The objective of this study was to determine the 5-year survival in these patients and identify clinical factors associated with overall survival (OS). METHODS: Patients with EGFR-mutant metastatic lung adenocarcinoma who had been treated with erlotinib or gefitinib at Dana-Farber Cancer Institute between 2002 and 2009 were included. OS was analyzed. RESULTS: Among 137 patients, median progression-free survival and OS were 12.1 months (95% CI: 10.2-13.5) and 30.9 months (95% CI: 28.2-35.7), respectively. Twenty patients (14.6%) were 5-year survivors. In multivariate analysis, exon 19 deletions (hazard ratio [HR] = 0.63, 95% CI: 0.44-0.91, p = 0.01), absence of extrathoracic (HR = 0.62, 95% CI: 0.41-0.93, p = 0.02) or brain metastasis (HR = 0.48, 95% CI: 0.30-0.77, p = 0.002), and not a current smoker (HR = 0.23, 95% CI: 0.09-0.59, p = 0.002) were associated with prolonged OS. Age; sex; stage at diagnosis; liver, bone, or adrenal metastasis; specific TKI; and line of TKI therapy were not associated with OS. CONCLUSIONS: Our data suggest that the rate of 5-year survival among patients with EGFR-mutant metastatic lung adenocarcinoma treated with erlotinib or gefitinib is 14.6%. Exon 19 deletions and absence of extrathoracic or brain metastasis are associated with prolonged survival. On the basis of our findings, clinicians can gain an enhanced estimation of long-term outcomes in this population.