Citations

Purpose Identifying actionable oncogenic mutations have changed the therapeutic landscape in different types of tumors. This study investigated the utility of comprehensive genomic profiling (CGP), a hybrid capture-based next-generation sequencing (NGS) assay, in clinical practice in a developing country. Methods In this retrospective cohort study, CGP was performed on clinical samples from patients with different solid tumors recruited between December 2016 and November 2020, using hybrid capture-based genomic profiling, at the individual treating physicians’ request in the clinical care for therapy decisions. Kaplan–Meier survival curves were estimated to characterize the time-to-event variables. Results Patients median age was 61 years (range: 14–87 years), and 64.7% were female. The most common histological diagnosis was lung primary tumors, with 90 patients corresponding to 52.9% of the samples (95% CI 45.4-60.4%). Actionable mutations with FDA-approved medications for specific alterations correspondent to tumoral histology were identified in 58 cases (46.4%), whereas other alterations were detected in 47 different samples (37.6%). The median overall survival was 15.5 months (95% CI 11.7 months-NR). Patients who were subjected to genomic evaluation at diagnosis reached a median overall survival of 18.3 months (95% CI 14.9 months-NR) compared to 14.1 months (95% CI 11.1 months-NR) in patients who obtained genomic evaluation after tumor progression and during standard treatment ( P = .7). Conclusion CGP of different types of tumors identifies clinically relevant genomic alterations that have benefited from targeted therapy and improve cancer care in a developing country to guide personalized treatment to beneficial outcomes of cancer patients.

Abstract Background: Arginine deprivation with ADI-PEG20 (pegargiminase) alone or combined with chemotherapy displayed antitumor activity in early phase clinical trials of argininosuccinate synthase 1 (ASS1)-deficient cancers, including pleural mesothelioma (PM). The non-epithelioid subtype of mesothelioma is particularly aggressive and arginine-auxotrophic due to frequent ASS1 loss. ATOMIC-meso is a pivotal phase 2-3 trial comparing standard of care (SOC) chemotherapy plus pegargiminase or placebo for patients (pts) with non-epithelioid PM. Methods: In this double-blind, placebo-controlled, phase 2-3 trial, we randomly assigned ECOG PS 0-1 pts with chemonaïve non-epithelioid PM in an intention-to-treat 1:1 ratio to receive q3 week SOC chemotherapy with pemetrexed (500mg/m2 i.v.) and cisplatin (75mg/m2 i.v.) with q1 week pegargiminase (36 mg/m2 i.m.) or placebo i.m. up to 6 cycles. Carboplatin (AUC5) was permitted in the phase 3 portion instead of cisplatin. Maintenance therapy with pegargiminase or placebo was continued until progression, toxicity or 24 months. The primary end point was median OS (mOS) and secondary end points included median PFS (mPFS), safety, pharmacodynamics and immunogenicity. ORR was assessed by blinded independent central review (BICR) for the phase 2 portion only using modified RECIST or RECIST v1.1. Results: 249 pts with non-epithelioid PM (median age 71, range 28-86; male 82.7%; 48.2% biphasic and 51.8% sarcomatoid) from 5 countries were randomized between Aug 2017 and Aug 2021: 125 pts were assigned to the pegargiminase-chemotherapy group and 124 pts to the placebo-chemotherapy group. The experimental arm showed a superior mOS respect to SOC: 9.3 months (95% confidence interval [CI], 7.9-11.8) vs. 7.7 months (95% CI, 6.1-9.5) (hazard ratio [HR], 0.71; 95% CI, 0.55-0.93; p=0.023). Also, the mPFS was higher in the experimental vs. control arm: 6.2 months (95% CI, 5.8-7.4) vs. 5.6 months (95% CI, 4.14-5.91) ([HR], 0.65; 95% CI, 0.46-0.90; p=0.019). The ORR by BICR was 13.8% in the pegargiminase-chemotherapy group vs. 13.5% in the placebo-chemotherapy group (p=0.95) with more stable disease in the former (71.3% vs. 62.9%). Plasma arginine declined with a reciprocal increase in citrulline. Anti-ADI-PEG20 antibodies were detected in 97.4% of patients by week 25 on pegargiminase. Grade ≥ 3 treatment-related adverse events to pegargiminase occurred in 28.8% and to placebo in 16.9%; grade ≥ 3 drug hypersensitivity and skin reactions occurred in 3.2% and 1.6% in the experimental arm, respectively, and none on placebo. Post-study drug treatment was comparable in both arms (45.6% post-pegargiminase vs. 46.8% post-placebo). Conclusions: In this first randomized trial of an arginine-depleting chemotherapy in cancer, the pegargiminase-pemetrexed-platinum triplet prolonged survival and had a favorable safety profile in pts with non-epithelioid PM (ClinicalTrials.gov Identifier NCT02709512) Citation Format: Peter W. Szlosarek, Ben Creelan, Thomas Sarkodie, Luke Nolan, Paul Taylor, Olga Olevsky, Federica Grosso, Diego Cortinovis, Meenali Chitnis, Amy Roy, David Gilligan, Hedy Kindler, Dionysis Papadatos-Pastos, Giovanni L. Ceresoli, Aaron Mansfield, Anne Tsao, Ken O’Byrne, Anna K. Nowak, Jeremy Steele, Michael Sheaff, Amanda Johnston, John Bomalaski, Marjorie Zauderer, Dean A. Fennell. Phase 2-3 trial of pegargiminase plus chemotherapy versus placebo plus chemotherapy in patients with non-epithelioid pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT007.

Abstract Background DICER1 alterations are associated with intracranial tumors in the pediatric population, including pineoblastoma, pituitary blastoma, and the recently described “primary DICER1-associated CNS sarcoma” (DCS). DCS is an extremely aggressive tumor with a distinct methylation signature and a high frequency of co-occurring mutations. However, little is known about its treatment approach and the genomic changes occurring after exposure to chemoradiotherapy. Methods We collected clinical, histological, and molecular data from eight young adults with DCS. Genomic analysis was performed by Next-generation Sequencing (NGS). Subsequently, an additional germline variants analysis was completed. In addition, an NGS analysis on post-progression tumor tissue or liquid biopsy was performed when available. Multiple clinicopathological characteristics, treatment variables, and survival outcomes were assessed. Results Median age was 20 years. Most lesions were supratentorial. Histology was classified as fusiform cell sarcomas (50%), undifferentiated (unclassified) sarcoma (37.5%), and chondrosarcoma (12.5%). Germline pathogenic DICER1 variants were present in two patients, 75% of cases had more than one somatic alteration in DICER1, and the most frequent commutation was TP53. Seven patients were treated with surgery, Ifosfamide, Cisplatin, and Etoposide (ICE) chemotherapy and radiotherapy. The objective response was 75%, and the median time to progression (TTP) was 14.5 months. At progression, the most common mutations were in KRAS and NF1. Overall survival was 30.8 months. Conclusions DCS is an aggressive tumor with limited therapeutic options that requires a comprehensive diagnostic approach, including molecular characterization. Most cases had mutations in TP53, NF1, and PTEN, and most alterations at progression were related to MAPK, RAS and PI3K signaling pathways.

Abstract Seven different anti–PD-1 and PD-L1 mAbs are now widely used in the United States to treat a variety of cancer types, but no clinical trials have compared them directly. Furthermore, because many of these Abs do not cross-react between mouse and human proteins, no preclinical models exist in which to consider these types of questions. Thus, we produced humanized PD-1 and PD-L1 mice in which the extracellular domains of both mouse PD-1 and PD-L1 were replaced with the corresponding human sequences. Using this new model, we sought to compare the strength of the immune response generated by Food and Drug Administration–approved Abs. To do this, we performed an in vivo T cell priming assay in which anti–PD-1/L1 therapies were given at the time of T cell priming against surrogate tumor Ag (OVA), followed by subsequent B16-OVA tumor challenge. Surprisingly, both control and Ab-treated mice formed an equally robust OVA-specific T cell response at the time of priming. Despite this, anti–PD-1/L1-treated mice exhibited significantly better tumor rejection versus controls, with avelumab generating the best protection. To determine what could be mediating this, we identified the increased production of CX3CR1+PD-1+CD8+ cytotoxic T cells in the avelumab-treated mice, the same phenotype of effector T cells known to increase in clinical responders to PD-1/L1 therapy. Thus, our model permits the direct comparison of Food and Drug Administration–approved anti–PD-1/L1 mAbs and further correlates successful tumor rejection with the level of CX3CR1+PD-1+CD8 + T cells, making this model a critical tool for optimizing and better utilizing anti–PD-1/L1 therapeutics.

Abstract We have observed Th2 polarization in patients with metastatic malignant melanoma. We hypothesized that changes in the immune system with age may parallel changes we have seen in patients with cancer. We analyzed the peripheral blood of 389 healthy blood donors. We profiled T cell subsets in 389 of the subjects, and antigen-specific tetramers for CMV, influenza and MART-1 in 58 of the subjects. We used a cytokine multiplex to analyze 42 cytokines in 95 of the subjects. We observed significant increases in CD4+ Th2 cells, and decreases in CD3+ T cells, cytotoxic T cells and helper T cells with age. There were fewer CMV-, influenza- and MART-1- specific naïve and CD8+ T cells with age. There were also significant increases in MCP-1 and RANTES with age. We observed differences between males in females in their cytokine profiles in their 20-40’s but not in their 50-60’s. In summary, we have found that aging is associated with an increase in CD4+ Th2 cells and concomitant decreases in total T cell count, cytotoxic T cells and helper T cells. Furthermore, aging is associated with increases in MCP-1 and RANTES. Females had different cytokine profiles than males before menopause, but not after.

Importance Although cancer-related mortality continues to decline, lung cancer remains the No. 1 cause of cancer deaths in the US. Almost half of the patients with non–small cell lung cancer (NSCLC) are diagnosed with early-stage, local or regional disease and are at high risk of recurrence within 5 years of diagnosis. Observations Immune checkpoint inhibitors (ICIs) have improved outcomes for patients with metastatic NSCLC and have recently been tested in multiple clinical trials to determine their efficacy in the neoadjuvant or adjuvant setting for patients with local or regional disease. The landscape for perioperative ICIs in lung cancer is evolving rapidly, with recently reported and soon to mature clinical trials; however, the recent data highlight the potential of ICIs to increase response rates and decrease rates of relapse in early stages of lung cancer. Concurrently, novel applications of cell-free DNA may guide perioperative management strategies. Conclusions and Relevance This article reviews the various approaches of incorporating perioperative use of immunotherapeutic agents for the treatment of early stages of NSCLC.

Abstract Diffuse gliomas are aggressive brain tumors that lack effective therapies. Despite advances in the molecular characterization of gliomas, targeted treatments have failed to improve patient outcomes to date. Here, we employed a functional genomics approach to rapidly identify therapeutic vulnerabilities and provide a strategy to individualize patient treatment. Our process combined comprehensive genomic and transcriptomic tumor profiling, custom algorithms and visualization software for data integration, and preclinical 3-dimensional ex vivo models (mcancers) for drug screening to assess response to therapeutic agents targeting specific molecular alterations. A total of 32 cases, including 5 oligodendrogliomas (1 primary and 4 recurrent), 5 astrocytomas (1 primary and 4 recurrent), and 22 glioblastomas (5 primary and 17 recurrent), were included in the study. Immunohistochemistry and integrated genomics confirmed that mcancers maintain key molecular alterations, including mutations, chromosomal rearrangements and focal amplifications, cellularity, and heterogeneity, faithfully recapitulating the original tumor. A total of 119 single drugs and 183 combinations were tested, including a panel of 26-brain penetrant targeted agents (18 single drugs and 8 combinations) that was curated to target common glioma oncogenic pathways and was tested across all cases. A strong correlation was observed between therapeutic vulnerabilities of glioma mcancers to targeted agents (EGFR, MET, PDGFR, HDAC inhibitors, etc.) and clinical experience. Single agent activity of panel compounds in the ex vivo setting was generally poor, with only 35% mCancers exhibiting > 70% growth inhibition at Cmax. In contrast, combination strategies, especially ones including epigenetic drugs, were significantly more effective (affecting 22 out of 32 mCancers), underscoring the molecular complexity of gliomas and the need for clinical trials testing combination treatments. Our data identified a number of novel combination treatments with significant efficacy across glioma subtypes and molecular profiles, suggesting that our functional genomics pipeline can guide treatment selection and inform clinical trial enrollment for gliomas.

125 Background: The advent of immunotherapy (IO) has led to significant improvement in outcomes for patients (pts) with advanced non-small cell lung cancer (adv NSCLC). The rate of crossovers and receipt of post-protocol IO in pivotal trials leading to FDA approvals of IO in NSCLC has not been systematically evaluated. Here, we evaluate crossover rates and post protocol therapies for pts with adv NSCLC across multiple first-line (1L) IO monotherapy and chemotherapy/IO (chemo/IO) combination trials. Methods: We utilized the publicly available data from pivotal clinical trials leading to approvals of IO or chemo/IO regimens in 1L treatment of adv NSCLC. We extracted data on outcomes, rate of crossover from control arm to IO, proportion of pts in control arm receiving IO and the start dates of these clinical trials. The primary outcomes were the rates of crossover and the proportion of patients in control arms who received post-control IO. Results: The study included 4 trials with IO monotherapy and 12 trials with chemo/IO combinations in 1L adv NSCLC. The primary endpoints for these trials were PFS (25%), OS (19%), and both PFS and OS (56%). The crossover rate from control arm to experimental arm (with IO) ranged from 0-74% in IO monotherapy trials and 0-49% in chemo/IO trials. Two IO monotherapy trials and five chemo/IO trials did not allow crossover; among them, 3 trials had a PFS/OS co-primary endpoint, while others had OS as primary endpoint. Ten of 16 trials provided explicit information on use of subsequent post-protocol therapies in their publications. Among the two IO monotherapy trials which did not allow crossover, post-protocol IO was administered in only 20-30% of patients. Among the six chemo/IO trials with information on post-protocol therapies, 30%-59% patients on the control arm subsequently received some form of IO on progression. Nine of 12 trials started accrual after 10/2015, when nivolumab was approved in the United States as second-line (2L) therapy for adv NSCLC regardless of tumor PD-L1 expression. Conclusions: Despite the highly significant OS benefit from 2L IO, which was the standard of care (SOC) in the United States, the rates of crossover and post-protocol IO administration was distressingly low in 1L IO monotherapy and chemo/IO trials for 1L adv NSCLC. This low rate of 2L treatment with IO may have been due to limited global availability prior to widespread regulatory approval during the conduct of these trials. There is an increased need for consistency in reporting of crossover treatment and post-protocol treatments to allow adequate assessment of the true 1L benefit with IO. Control arms in pivotal trials require scrutiny to ensure confirmation with SOC to provide access to optimal treatments for patients and prevent magnification of observed benefits in experimental arms. The difficulty lies in the global conduct of large randomized clinical trials with differing regulatory approvals.