Serial Monitoring of Circulating Tumor DNA by Next-Generation Gene Sequencing as a Biomarker of Response and Survival in Patients With Advanced NSCLC Receiving Pembrolizumab-Based Therapy.

Although the majority of patients with metastatic non-small-cell lung cancer (mNSCLC) lacking a detectable targetable mutation will receive pembrolizumab-based therapy in the frontline setting, predicting which patients will experience a durable clinical benefit (DCB) remains challenging. MATERIALS AND METHODS: Patients with mNSCLC receiving pembrolizumab monotherapy or in combination with chemotherapy underwent a 74-gene next-generation sequencing panel on blood samples obtained at baseline and at 9 weeks. The change in circulating tumor DNA levels on-therapy (molecular response) was quantified using a ratio calculation with response defined by a > 50% decrease in mean variant allele fraction. Patient response was assessed using RECIST 1.1; DCB was defined as complete or partial response or stable disease that lasted > 6 months. Progression-free survival and overall survival were recorded. RESULTS: Among 67 patients, 51 (76.1%) had > 1 variant detected at a variant allele fraction > 0.3% and thus were eligible for calculation of molecular response from paired baseline and 9-week samples. Molecular response values were significantly lower in patients with an objective radiologic response (log mean 1.25% v 27.7%, P < .001). Patients achieving a DCB had significantly lower molecular response values compared to patients with no durable benefit (log mean 3.5% v 49.4%, P < .001). Molecular responders had significantly longer progression-free survival (hazard ratio, 0.25; 95% CI, 0.13 to 0.50) and overall survival (hazard ratio, 0.27; 95% CI, 0.12 to 0.64) compared with molecular nonresponders. CONCLUSION: Molecular response assessment using circulating tumor DNA may serve as a noninvasive, on-therapy predictor of response to pembrolizumab-based therapy in addition to standard of care imaging in mNSCLC. This strategy requires validation in independent prospective studies.

Delayed-Phase Enhancement for Evaluation of Malignant Pleural Mesothelioma on Computed Tomography: A Prospective Cohort Study.

BACKGROUND: Radiologic assessment of malignant pleural mesothelioma (MPM) on computed tomography (CT) imaging can be limited by similar attenuations of MPM and adjacent tissues. This can result in inaccuracies in defining the presence and extent of pleural tumor burden. We hypothesized that increasing the time delay for pleural enhancement will optimize discrimination between MPM and noncancerous tissues on CT. Here we conduct a prospective observational study to determine the optimal time delay for imaging MPM on CT. PATIENTS AND METHODS: Adult MPM patients (n = 15) were enrolled in this prospective exploratory imaging trial. Patients with < 1 cm MPM thickness, prior pleurectomy, pleurodesis, pleural radiotherapy, or antiangiogenic therapy were excluded. All patients underwent a dynamically-enhanced CT with multiple time delays (0 - 10 minutes) after intravenous contrast administration. Tumor tissue attenuation was measured at each phase of enhancement. A qualitative assessment of tumor enhancement kinetics was also performed. The optimal phase of enhancement based on qualitative lesion conspicuity and quantitative tumor enhancement was then compared. RESULTS: MPM tumor enhancement was quantitatively and qualitatively increased at time delays beyond the conventional time delay for thoracic CT imaging (40-60 seconds). Patient tumor enhancement kinetics, displayed as the fraction of maximal tumor tissue attenuation as a function of time, revealed an optimal time delay of 230 to 300 seconds after intravenous contrast administration. There was an association between degree of tumor enhancement and subjective lesion conspicuity. CONCLUSION: Optimal MPM contrast enhancement occurs at a later phase than typically acquired with conventional thoracic CT imaging.

Thoracic Imaging of Non-Small Cell Lung Cancer Treated With Anti-programmed Death Receptor-1 Therapy.

PURPOSE: Treatment with anti-programmed death receptor-1 (PD-1) therapeutics can lead to unconventional responses and side effect profiles due to their potentiating effects on the immune system. Here we evaluate the radiologic manifestations of anti-PD-1 therapy in the chest in patients with non-small cell lung cancer (NSCLC) receiving anti-PD-1 therapy. MATERIALS AND METHODS: A retrospective review of real-world clinical practice was conducted of all the patients with NSCLC receiving anti-PD-1 therapy at our institution between 2013 and 2016. All patients without adequate clinical or radiologic follow-up data in the electronic medical records were excluded. Imaging examinations for all patients deemed by their thoracic oncologists to have radiologic pseudoprogression or therapy-associated pneumonitis were reviewed by experienced thoracic radiologists. RESULTS: A total of 166 patients with NSCLC had available clinical and imaging data for retrospective review. Of these patients, 4 (2%) were considered to have radiologic pseudoprogression, 3 of which manifested as increased tumor size and 1 of which manifested with new lesions. A total of 5 patients (3%) were clinically deemed to have pneumonitis attributable to anti-PD-1 therapy, 4 of which had radiologic manifestations on computed tomography. CONCLUSION: Radiologic pseudoprogression and drug-induced pneumonitis are uncommon but important manifestations of anti-PD-1 therapy on thoracic imaging.

Modeling Epidermal Growth Factor Inhibitor-mediated Enhancement of Photodynamic Therapy Efficacy Using 3D Mesothelioma Cell Culture.

We have demonstrated that lung-sparing surgery with intraoperative photodynamic therapy (PDT) achieves remarkably extended survival for patients with malignant pleural mesothelioma (MPM). Nevertheless, most patients treated using this approach experience local recurrence, so it is essential to identify ways to enhance tumor response. We previously reported that PDT transiently activates EGFR/STAT3 in lung and ovarian cancer cells and inhibiting EGFR via erlotinib can increase PDT sensitivity. Additionally, we have seen higher EGFR expression associating with worse outcomes after Photofrin-mediated PDT for MPM, and the extensive desmoplastic reaction associated with MPM influences tumor phenotype and therapeutic response. Since extracellular matrix (ECM) proteins accrued during stroma development can alter EGF signaling within tumors, we have characterized novel 3D models of MPM to determine their response to erlotinib combined with Photofrin-PDT. Our MPM cell lines formed a range of acinar phenotypes when grown on ECM gels, recapitulating the locally invasive phenotype of MPM in pleura and endothoracic fascia. Using these models, we confirmed that EGFR inhibition increases PDT cytotoxicity. Together with emerging evidence that EGFR inhibition may improve survival of lung cancer patients through immunologic and direct cell killing mechanisms, these results suggest erlotinib-enhanced PDT may significantly improve outcomes for MPM patients.

Impact of Enlarged Nonhypermetabolic Lymph Nodes on Outcomes After Stereotactic Body Radiotherapy for Early-Stage Non-Small-Cell Lung Cancer.

BACKGROUND: Up to 15% of patients undergoing positron emission tomography (PET)/computed tomography (CT) before stereotactic body radiotherapy (SBRT) harbor occult nodal disease. In the absence of invasive mediastinal staging, the clinical significance of enlarged nonhypermetabolic lymph nodes (LNs) remains unclear. We performed what is to our knowledge the first study to address whether enlarged nonhypermetabolic LNs were associated with higher post-SBRT failure rates. PATIENTS AND METHODS: Two academic centers assessed 157 consecutive patients treated with SBRT for cT1-2aN0M0 non-small-cell lung cancer who underwent PET/CT without pathologic nodal staging. The cutoff of an enlarged node was ≥ 1.0 cm, although a 7 mm threshold was also evaluated. Local recurrence-free survival (RFS), regional RFS, distant metastasis-free survival, RFS, and overall survival (OS) were calculated by Kaplan-Meier methodology. Multivariate Cox modeling addressed factors associated with RFS and OS. RESULTS: There were 120 patients (76%) with LNs < 1 cm and 37 (24%) with nodes ≥ 1 cm. Most patients had peripheral and/or T1 tumors. Median follow-up was 25.5 months. There were no differences between cohorts in actuarial local RFS, regional RFS, distant metastasis-free survival, RFS, or OS (P > .05 for all). Thirteen percent of patients experienced any nodal relapse, 15% of which occurred in the same station as that of the largest pre-SBRT LN. Stratification by largest LN location in an N1 versus N2 station showed no differences in RFS or OS (P > .05 for both). A 7 mm cutoff also showed no differences in outcomes (P > .05 for all). LN size was not correlated with RFS/OS on multivariable analysis (P > .05 for both). CONCLUSION: The presence of enlarged nonhypermetabolic LNs on PET/CT is not associated with increased post-SBRT failure rates.