Faculty Bibliography

Background: Anti-GITR (glucocorticoid-induced TNFR-related protein) agonist and gemcitabine (gem) combination improves anti-tumor activity pre-clinically compared to either therapy alone. We investigated the effect of this combination as part of a multi-center phase 1b multi-dose escalation and expansion trial in patients (pts) with advanced solid cancers.
Method(s): Part C of the phase 1b trial enrolled adult pts with advanced solid cancers for which gemcitabine was clinically appropriate. Pts had failed at-least one prior systemic therapy, had measurable disease and were ECOG PS 0-1 at baseline. All pts received gem (1000mg/m2) IV on D1 and D8 and TRX518 on D2 of a 21-day cycle in two escalation cohorts (2mg/kg or 4mg/kg load[L] in C1 followed by 1mg/kg maintenance[M] from C2). The highest tested safe dose identified in escalation was further evaluated in expansion. Primary endpoint was safety. Secondary and exploratory endpoints included response (RECIST v1.1), PK and PD.
Result(s): (Table Presented) From January to September 2018, 26 pts were dosed;16/26 had pancreaticobiliary cancers (PBC) of which14/16 had prior gem. There was 1 treatment-related SAE (G3 anemia G4 lymphopenia, G3 hypoalbuminemia [DLT] and G3 hypokalemia [DLT]). No treatment-related deaths occurred. Of the 14 response-evaluable pts in cohorts 1 (n=2), 2 (n=5) and expansion (n=7), 57.1% (8/14) had SD. At the 4mg/kg L/1mg/kgMTRX518 dose, 66.7% (8/12) of evaluable pts had SD. 60% of PBC had clinical benefit of which 87.5% had prior gem.
Conclusion(s): In pts with heavily pre-treated advanced cancer, for which gem is clinically appropriate, TRX518 plus gem was well tolerated with no new safety signals. Preliminary evidence of clinical benefit was observed including in pts with PBC previously treated with gem. This study is ongoing

BACKGROUND:IL-15 induces the activation and proliferation of NK and memory CD8+ T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL-15N72D:IL-15RαSu/IgG1 Fc complex) over recombinant human IL-15 (rhIL-15) in animal models, we performed this first-in-human Phase I trial of ALT-803 in patients with advanced solid tumors. METHODS:Patients with incurable advanced melanoma, renal cell, non-small cell lung, and head and neck cancer were treated with ALT-803 0.3-6 mg/kg weekly i.v. or 6-20 mg/kg weekly s.c. for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity. RESULTS:Twenty-four patients were enrolled; eleven received i.v. and 13 received s.c. ALT-803. Of these patients, 9 had melanoma, 6 renal, 3 head and neck, and 6 lung cancer. Although total lymphocyte and CD8+ T cell expansion were modest, NK cell numbers rose significantly. Neither anti-ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well-tolerated, with adverse effects including fatigue and nausea most commonly with i.v. administration, while painful injection site wheal was reported most commonly with s.c. ALT-803. CONCLUSIONS:Subcutaneous ALT-803 produced the expected NK cell expansion and was well-tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in advanced cancer patients. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anti-cancer agents.

Adenocarcinomas and active granulomas can both have a spiculated appearance on computed tomography (CT) and both are often fluorodeoxyglucose (FDG) avid on positron emission tomography (PET) scan, making them difficult to distinguish. Consequently, patients with benign granulomas are often subjected to invasive surgical biopsies or resections. In this study, quantitative vessel tortuosity (QVT), a novel CT imaging biomarker to distinguish between benign granulomas and adenocarcinomas on routine non-contrast lung CT scans is introduced. Our study comprised of CT scans of 290 patients from two different institutions, one cohort for training (N = 145) and the other (N = 145) for independent validation. In conjunction with a machine learning classifier, the top informative and stable QVT features yielded an area under receiver operating characteristic curve (ROC AUC) of 0.85 in the independent validation set. On the same cohort, the corresponding AUCs for two human experts including a radiologist and a pulmonologist were found to be 0.61 and 0.60, respectively. QVT features also outperformed well known shape and textural radiomic features which had a maximum AUC of 0.73 (p-value = 0.002), as well as features learned using a convolutional neural network AUC = 0.76 (p-value = 0.028). Our results suggest that QVT features could potentially serve as a non-invasive imaging biomarker to distinguish granulomas from adenocarcinomas on non-contrast CT scans.

BACKGROUND:In RET-rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. METHODS:A global, multi-institutional registry (cohort A, n=114) and a bi-institutional data set (cohort B, n=71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. RESULTS:The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95%CI 18%-32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95%CI 34%-58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p=0.0039) between RET-, ROS1-, and ALK-rearranged lung cancers, with RET intermediate between the other two groups. While intracranial response data was not available in cohort A, the median progression-free survival (PFS) of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95%CI 1.3-2.9 months, n=10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (±everolimus), ponatinib, or alectinib; the median overall PFS (intracranial and extracranial) was 3.9 months (95%CI 2.0-4.9 months). CONCLUSIONS:Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.

The current standard of Response Evaluation Criteria in Solid Tumors (RECIST)-based tumor response evaluation is limited in its ability to accurately monitor treatment response. Radiomics, an approach involving computerized extraction of several quantitative imaging features, has shown promise in predicting as well as monitoring response to therapy. In this article, we provide a brief overview of radiomic approaches and the various analytical methods and techniques, specifically in the context of predicting and monitoring treatment response for non-small cell lung cancer (NSCLC). We briefly summarize some of the various types of radiomic features, including tumor shape and textural patterns, both within the tumor and within the adjacent tumor microenvironment. Additionally, we also discuss work in delta-radiomics or change in radiomic features (e.g., texture within the nodule) across longitudinally interspersed images in time for monitoring changes in therapy. We discuss the utility of these approaches for NSCLC, specifically the role of radiomics as a prognostic marker for treatment effectiveness and early therapy response, including chemoradiation, immunotherapy, and trimodality therapy.

Self-replication is the engine that drives all biologic evolution, including neoplastic evolution. A key oncotherapy challenge is to target this, the heart of malignancy, while sparing the normal self-replication mandatory for health and life. Self-replication can be demystified: it is activation of replication, the most ancient of cell programs, uncoupled from activation of lineage-differentiation, metazoan programs more recent in origin. The uncoupling can be physiologic, as in normal tissue stem cells, or pathologic, as in cancer. Neoplastic evolution selects to disengage replication from forward-differentiation where intrinsic replication rates are the highest, in committed progenitors that have division times measured in hours versus weeks for tissue stem cells, via partial loss of function in master transcription factors that activate terminal-differentiation programs (e.g., GATA4) or in the coactivators they use for this purpose (e.g., ARID1A). These loss-of-function mutations bias master transcription factor circuits, which normally regulate corepressor versus coactivator recruitment, toward corepressors (e.g., DNMT1) that repress rather than activate terminal-differentiation genes. Pharmacologic inhibition of the corepressors rebalances to coactivator function, activating lineage-differentiation genes that dominantly antagonize MYC (the master transcription factor coordinator of replication) to terminate malignant self-replication. Physiologic self-replication continues, because the master transcription factors in tissue stem cells activate stem cell, not terminal-differentiation, programs. Druggable corepressor proteins are thus the barriers between self-replicating cancer cells and the terminal-differentiation fates intended by their master transcription factor content. This final common pathway to oncogenic self-replication, being separate and distinct from the normal, offers the favorable therapeutic indices needed for clinical progress.

BACKGROUND:Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rβγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC. METHODS:In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 μg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing. FINDINGS/RESULTS:Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 μg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks. INTERPRETATION/CONCLUSIONS:ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC. FUNDING/BACKGROUND:Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center.