Faculty Bibliography

No predictive biomarkers can robustly identify non-small cell lung cancer (NSCLC) patients who will benefit from immune checkpoint inhibitor (ICI) therapies. Here, in a machine learning setting, we compared changes ("delta") in the radiomic texture (DelRADx) of computed tomography (CT) patterns both within and outside tumor nodules before and after 2-3 cycles of ICI therapy. We found that DelRADx patterns could predict response to ICI therapy and overall survival (OS) for patients with NSCLC. We retrospectively analyzed data acquired from 139 NSCLC patients at two institutions, who were divided into a discovery set (D1 = 50) and two independent validation sets (D2 = 62, D3 = 27). Intranodular and perinodular texture descriptors were extracted and the relative differences were computed. A linear discriminant analysis (LDA) classifier was trained with 8 DelRADx features to predict RECIST (response evaluation criteria in solid tumors)-derived response. Association of delta-radiomic risk-score (DRS) with OS was determined. The association of DelRADx features with tumor-infiltrating lymphocyte (TIL) density on the diagnostic biopsies (n = 36) was also evaluated. The LDA classifier yielded an area under the curve (AUC) of 0.88 ± 0.08 in distinguishing responders from nonresponders in D1, 0.85 and 0.81 in D2 and D3. DRS was associated with OS (hazard ratio: 1.64, 95% CI: 1.22 - 2.21, P = 0.0011, C-Index = 0.72). Peritumoral Gabor features were associated with the density of TILs on diagnostic biopsy samples. Our results show that DelRADx could be used to identify early functional responses in NSCLC patients.

Purpose/UNASSIGNED:response to chemotherapy in patients with non-small cell lung cancer (NSCLC). Materials and Methods/UNASSIGNED:Data in a total of 125 patients who had been treated with pemetrexed-based platinum doublet chemotherapy at Cleveland Clinic were retrospectively analyzed. The patients were divided randomly into two sets with the constraint that there were an equal number of responders and nonresponders in the training set. The training set comprised 53 patients with NSCLC, and the validation set comprised 72 patients. A machine learning classifier trained with radiomic texture features extracted from intra- and peritumoral regions of non-contrast-enhanced CT images was used to predict response to chemotherapy. The radiomic risk-score signature was generated by using least absolute shrinkage and selection operator with the Cox regression model; association of the radiomic signature with TTP and OS was also evaluated. Results/UNASSIGNED:= .0011). Additionally, decision curve analysis demonstrated that in terms of clinical usefulness, the radiomics signature had a higher overall net benefit in prediction of high-risk patients to receive treatment than the clinicopathologic measurements. Conclusion/UNASSIGNED:

Background: bTMB assays determine TMB using a noninvasive blood test. B-F1RST (ITT, n=152) is the first prospective trial to evaluate bTMB as a biomarker to predict benefit of 1L atezo monotherapy in advanced NSCLC. bTMB high (score of >=16; >= 14.5 mut/Mb) predicted better ORR with atezo vs bTMB low (< 16; 28.6% vs 4.4%) in the biomarker evaluable population (BEP) with >= 6 mo follow up in the primary analysis. Numerical benefit for bTMB high was seen in median (m)PFS and mOS. Here we report the B-F1RST final analysis.
Method(s): Eligibility criteria included untreated stage IIIB-IVB NSCLC and ECOG PS 0/1. Pts received atezo 1200 mg IV q3w until PD, intolerance or loss of benefit. Co-primary endpoints were investigator assessed ORR for efficacy (ITT) and PFS for biomarker analysis (BEP) at a prespecified bTMB cutoff of 16 for high (>= 16) vs low (< 16). PFS and OS, a secondary endpoint, were further evaluated at various bTMB cutoffs. Serum C-reactive protein (CRP), an inflammation marker in cancer, was evaluated as a surrogate biomarker, ratio of CRP at C3D1 to CRP at screening, to predict PFS and OS.
Result(s): With >= 18 mo follow up (data cutoff, 14 May 2019) in ITT pts, ORR was 17% (95% CI: 12, 24), mPFS was 4.1 mo (95% CI: 2.8, 4.9) and mOS was 14.8mo (95% CI: 12.7, 21.3). In bTMB >= 16 vs<16, mPFS was 5.0 vs 3.5 mo and mOS was 23.9 vs 13.4 mo (Table). For CRP ratio <0.5 vs >=0.5, mPFS was 14.1 vs 4.6 mo (HR, 0.43 [90% CI: 0.24, 0.77]), and mOS was NE vs 15.9 mo (HR, 0.30 [90% CI: 0.13, 0.72]). 14% of pts had treatment-related (TR) serious AEs, and 20% had Gr 3-4 TRAEs. 18% of pts had AEs that led to discontinuation.
Conclusion(s): B-F1RST shows the clinical utility of bTMB as a predictive biomarker for pts receiving 1L atezo monotherapy. The final analysis confirmed that pts with bTMB >= 16 had numerical benefit for PFS and OS. Decrease in serum CRP over 6 wk predicted PFS and OS benefit. No new safety signals were seen. (Table Presented)

Background Regulatory T cells (Tregs) mediate potent tolerogenic signals, are involved in adaptive anti-tumor immune responses and T-cell reinvigoration using immune checkpoint blockers. Despite their prominent immune suppressive role, the tissue distribution and contribution of Tregs to clinical outcomes in human lung cancer is not well understood. Methods The levels and tissue distribution of Tregs and major tumor infiltrating lymphocyte (TIL) subsets were measured using simultaneous detection of FOXP3, CD4, CD8, pancytokeratin and DAPI by multiplexed quantitative immunofluorescence in 619 formalin-fixed paraffin embedded (FFPE) NSCLCs from 4 independent cohorts represented in tissue microarrays (cohort#1 [Yale, n=210], cohort#2 [Greece, n=192]; cohort#3] [80 immunotherapy-treated NSCLCs]; cohort#4 [Yale, n=137, adenocarcinomas with mutation testing). Markers were measured in different tissue compartments and cell phenotypes were used for individual cell counts and machine-learning-based spatial analysis. We studied the association between T-cell populations, tissue distribution, clinicopathologic/ molecular characteristics and outcomes. Results Tregs (DAPI+/CD4+/FOXP3+ cells) were predominantly located in the stromal compartment and represented 3-10% of the total T-cell population. The level of Tregs was positively associated with higher CD8+ Tcell infiltration across the cohorts. There was no consistent association between Treg levels and patient age, gender, smoking status, clinical stage or tumor histology. However, Tregs were significantly higher in KRAS mutated lung adenocarcinomas than in EGFR mutant or KRAS/ EGFR wild-type cases. As a single marker, the level of Tregs was not significantly associated with survival. However, the Treg to CD8 signal ratio was associated with shorter 5-year overall survival across the cohorts. Reduced survival was also seen in cases with a higher 5-nearest neighbor (5NN) mean distance between CD4+/Tregs and CD8+/CD4+ cells. Notably, the survival effect of the Treg-associated metrics was numerically higher in patients treated with immune checkpoint blockers. Conclusions Tregs are prominently less abundant than other TIL subsets in NSCLC microenvironments and they are increased in T-cell inflamed tumors. Their positive association with CD8+ cytotoxic TILs suggests their upregulation upon adaptive anti-tumor immune pressure and could explain the inconsistent reported relationship between Tregs and prognosis. Elevated Treg to CD8 signal ratio and reduced spatial clustering between CD4-Tregs and CD8-CD4 are indicative of poor outcome preferentially in NSCLC patients treated with checkpoint blockade suggesting a biomarker role

Background ALKS 4230 is an engineered fusion of IL-2 and IL-2Ralpha designed to selectively expand NK and CD8+ T cells (Figures 1 and 2). In preclinical studies, ALKS 4230 exhibited enhanced pharmacokinetic and selective pharmacodynamic properties with improved antitumor efficacy relative to IL-2 [1]. Methods ARTISTRY-1 (NCT02799095) is a phase 1/2 study investigating ALKS 4230 as monotherapy and in combination with pembrolizumab in adults with advanced solid tumors [2]. For monotherapy dose escalation, ALKS 4230 is administered intravenously over 30 minutes once daily for 5 days every 14 or 21 days. For combination therapy, the same regimen of ALKS 4230 is administered with pembrolizumab every 21 days in cohorts based on tumor type, prior anti-PD-1 therapy, and rollover from monotherapy. Outcomes include the monotherapy recommended phase 2 dose (RP2D), safety, pharmacodynamics, and antitumor activity (RECIST 1.1). Results of the completely enrolled cohorts of dose-escalation phase and of combination therapy in anti-PD-1-unapproved tumors as of June 21, 2019, are presented. Results For dose escalation, 36 patients received ALKS 4230 monotherapy <=6 mug/kg/d. Maximum tolerated dose has not been reached. Most frequent adverse events (AEs), regardless of relationship, were pyrexia (75%) and chills (72%); the majority were grades 1 or 2. Grade >=3 AEs related to ALKS 4230 occurred in 11 patients (31%) and were mainly transient leukopenia. One death from aspiration pneumonia was considered unrelated to ALKS 4230 by the investigator. ALKS 4230 induced dose-dependent increases in circulating NK and CD8+ T cells with minimal, non-dose-dependent effects on regulatory T cells (Tregs). At 3 and 6 mug/kg/d, 8 of 14 patients with evaluable scans had stable disease. One patient with heavily pretreated pancreatic adenocarcinoma had prolonged stable disease with 6+ months of monotherapy; CA19-9 decreased from 2571 U/mL (pretherapy) to 673 U/mL (nadir). Data from 20 patients enrolled in the combination therapy cohort of PD-1-unapproved tumors indicate no new toxicities; 7 of 11 patients with evaluable scans had stable disease or better. One patient (ovarian cancer) had confirmed partial response; CA-125 normalized from a peak of 282 to 24.5 U/mL after 2 months of therapy. Conclusions ALKS 4230 is a promising agent with acceptable tolerability and preliminary clinical benefit. It selectively expanded CD8+ T cells and NK cells with minimal Treg expansion. The intravenous monotherapy RP2D was established as 6 mug/kg/d. Safety and pharmacodynamic data enabled selection of the 3 mug/kg dose for initial evaluation in combination with pembrolizumab

Aim: To determine real-world outcomes with first-line pembrolizumab monotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor expression ≥50%. Methods: This retrospective study included adults with ECOG 0-1 initiating first-line pembrolizumab monotherapy on/after 24 October 2016 (EHR cohort) or from 1 December 2016 through 30 November 2017 (spotlight cohort) with ≥6-month follow-up. We estimated Kaplan-Meier overall survival (OS, both cohorts), and, for spotlight, real-world progression-free survival (rwPFS) by Kaplan-Meier and real-world tumor response (rwTR). Results: For 423 patients in the EHR cohort and 188 in spotlight, median OS was 18.9 months (95% CI: 14.9-25.5) and 19.1 months (12.6-not reached), respectively. For spotlight, median rwPFS was 6.8 months (5.3-8.1); rwTR of complete/partial response was 48% (41-56%). Conclusion: Observed OS, rwPFS and rwTR were consistent with clinical trial findings.

OBJECTIVES/OBJECTIVE:Despite improved outcomes associated with immunotherapies for non-small cell lung cancer (NSCLC), many patients do not respond to treatment. Therefore, there is still an unmet need for molecularly targeted therapies in this patient population. Fusions of the RET oncogene have been identified as driver alterations in patients with NSCLC. Lenvatinib is a multityrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, RET, and other targets. This study evaluated the safety and efficacy of lenvatinib in patients with RET fusion-positive lung adenocarcinoma. MATERIALS AND METHODS/METHODS:In this phase 2, multicenter, open-label study (NCT01877083), patients with RET-positive lung adenocarcinoma received oral lenvatinib 24 mg/day. The primary end point was objective response rate (ORR) by investigator review per Response Evaluation Criteria In Solid Tumors v1.1 criteria. The secondary end points included safety and tolerability, progression-free survival (PFS), and overall survival (OS). RESULTS:Of 536 patients who screened for study inclusion and exclusion, 25 patients with RET translocations (KIF5B-RET [n = 13] and CCDC6-RET [n = 12]) were identified and received lenvatinib. The overall ORR was 16% (95% CI: 4.5%-36.1%). At data cutoff (February 3, 2016), the median PFS was 7.3 months (95% CI: 3.6-10.2) and the median OS was not reached. Duration of response was not estimable at the time of data cutoff. All patients experienced a treatment-emergent adverse event (TEAE); 23 (92%) patients experienced a TEAE of ≥ grade 3, and 6 (24%) patients discontinued lenvatinib due to a TEAE. The most common TEAEs were hypertension (68%), nausea (60%), decreased appetite (52%), diarrhea (52%), and proteinuria (48%). CONCLUSIONS:Lenvatinib demonstrated activity in patients with RET fusion-positive lung adenocarcinomas; although the response rate was relatively low, the median PFS supports the activity of lenvatinib in these patients.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.