Mansfield, Aaron S.

TPS8603 Background: Peritoneal mesothelioma is a rare and poorly studied disease with few treatment options. For patients (pts) who are not surgical candidates, treatment recommendations for systemic therapy have been extrapolated from clinical trials for pleural mesothelioma that commonly exclude pts with peritoneal mesothelioma. Recently, the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab received FDA-approval for the frontline treatment of non-resectable pleural mesothelioma. Additionally, a prospective, non-randomized phase 2 trial demonstrated activity with combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade in peritoneal mesothelioma. In parallel, encouraging activity with combined chemo-immunotherapy has been reported in pleural mesothelioma. Given the benefits observed with immunotherapy, and the potential to improve upon those with chemotherapy and VEGF inhibition, we seek to determine whether the addition of the PD-L1 inhibitor atezolizumab improves outcomes with chemotherapy and bevacizumab in pts with newly diagnosed peritoneal mesothelioma. Methods: Alliance for Clinical Trials in Oncology A092001 is a prospective, randomized phase 2 clinical trial. All pts with newly diagnosed peritoneal mesothelioma will be randomized 1:1 using a dynamic allocation Pocock-Simon procedure to receive carboplatin, pemetrexed and bevacizumab, with or without atezolizumab, every 21 days for four cycles. Patients who are eligible to proceed with surgery after four cycles of therapy will then do so. Pts who are not eligible to proceed with surgery may receive maintenance bevacizumab and atezolizumab, or second-line atezolizumab with bevacizumab until progression of disease or toxicity. The primary objective is to determine if frontline treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab results in a superior best response rate (RR) to carboplatin, pemetrexed and bevacizumab as determined by RECIST. With 31 eligible pts per arm (62 eligible total), this randomized design has 80% power to detect an improvement in the RR from 20% to 45%, with a 1-sided significance level of 0.10 where an interim futility analysis will be conducted after 32 pts are enrolled. Stratification factors include eligibility for cytoreductive surgery at diagnosis and histologic subtype. Secondary endpoints include progression-free survival, overall survival and adverse events. As integrated biomarkers, we will determine if soluble mesothelin-related peptides and megakaryocyte potentiating factor correlate with responses. This trial was recently approved by the National Cancer Institute Central IRB and is activating at sites across the country. Clinical trial information: NCT05001880 .

TPS8602 Background: Sarcomatoid mesothelioma is the most aggressive form of pleural mesothelioma and is associated with the worst prognosis of the histologic variants of this disease. In the Checkmate 743 clinical trial the patients with sarcomatoid mesothelioma who received ipilimumab and nivolumab had survival outcomes that were similar to those of patients with epithelioid mesothelioma. In comparison, the patients with sarcomatoid mesothelioma who received chemotherapy had the worst outcomes in this trial, highlighting the known limited efficacy of chemotherapy against this histologic variant. Checkmate 743 demonstrated that ipilimumab and nivolumab is a new standard of care for non-epithelioid mesothelioma. Surgery typically has not been offered to this group of patients given their historically poor outcomes. With the significant survival gains seen patients with sarcomatoid mesothelioma treated with immunotherapy, we hypothesized that surgery may extend the benefits seen with immunotherapy. Methods: Alliance for Clinical Trials in Oncology A082101 is a prospective, phase 2 nonrandomized clinical trial for patients with sarcomatoid mesothelioma. The co-primary objectives are to determine the percentage of patients with potentially resectable sarcomatoid mesothelioma able to proceed with surgery after neoadjuvant ipilimumab and nivolumab, and the progression-free survival (PFS) at 12 months (12-month PFS). For sample size determination, we assumed that if the true rate of surgery is 75% or greater, it would indicate that neoadjuvant immunotherapy is feasible to be given prior to surgery. On the other hand, if the true rate of surgery is 50% or less it would indicate that neoadjuvant immunotherapy is not worthy of further investigation. Twenty-six (26) eligible patients will be needed to receive neoadjuvant immunotherapy. If 16 or fewer of the 26 eligible patients proceed to surgery, it will be concluded that the experimental therapy is not worthy of further investigation. Otherwise, it will be concluded that the experimental therapy is worthy of further investigation. Safety monitoring will be done through a 6-week run-in for the first 10 patients to assess for pre-operative and post-operative toxicities and complications. Sequential boundaries will be used to monitor severe toxicity and complication rates. Accrual will be halted if excessive numbers of severe toxicity and complications in pre-operative and post-operative phases are seen. Tumor and blood-based biomarkers will be included as exploratory biomarkers. Clinical trial information: NCT05647265 .

3109 Background: WSD0922-Fu is an oral, central nervous system (CNS)-penetrant, small molecule, ATP non-competitive, reversible EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). We report initial results of a first-in-human phase 1 dose-escalation trial (NCT04197934) in patients with EGFR aberrant recurrent HGA and NSCLC. Methods: Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR mutant and/or EGFR amplified HGA were enrolled. WSD0922-Fu was orally administered, and dose escalated in cohorts based on a standard 3+3 design to determine the maximum tolerated dose (MTD). Toxicities were graded per CTCAE v5.0 and preliminary efficacy was based on modified RANO criteria or RECIST 1.1 as appropriate. Results: 25 patients (17 HGA, 8 NSCLC) were enrolled and treated in six cohorts (40 mg once daily to 320 mg twice daily, 28-day cycles). The median age was 57 years (range 39-75 years). 24% were female and 36% were ECOG 0. For patients with HGA, all patients were previously treated with radiation and temozolomide; the median number of prior lines of systemic therapy was 1 (range 1-4). For patients with NSCLC, all patients were previously treated with an EGFR inhibitor (prior osimertinib 88%); the median number of prior lines of systemic therapy was 1.5 (range 1-6). The median duration of exposure to WSD0922-Fu among all patients was 54 days (range 2-258 days). The most common (≥25%) treatment-related adverse events included fatigue (68%), acneiform rash (68%), diarrhea (52%), nausea (48%) and pruritis (28%). The frequency of severe AEs was dose dependent. The most common Grade 3+ AEs (≥10%) included lymphopenia (16%), acneiform rash (12%), headache (12%) and diarrhea (12%). The MTD was defined as 160 mg twice daily. At Cycle 1 Day 15 for patients treated at this dose level, the mean terminal elimination half-life (%CV) in the plasma was 31.6 h (102%) (median 14.5 h; range 6.2-78.7 h). The mean Cmax, Tmax, oral clearance at steady state, and AUC (0-12 h) (%CV) were 4513 ng/mL (50%), 2.0 hr (69%), 6.9 L/hr/m2 (42%), and 28084 h*ng/mL (52%), respectively. Oral clearance at steady state was inversely related with dose, suggesting either inhibition or saturation of clearance processes. Among patients treated at MTD or higher dose levels and with available response data, 100% (5/5) of patients with NSCLC demonstrated clinical benefit (SD + PR) while 60% of patients had partial responses (intracranial and extracranial). Furthermore, prolonged stable disease (9 cycles) was observed in a patient with EGFRvIII mutant GBM. Conclusions: The MTD for WSD0922-Fu monotherapy is 160 mg BID. Preliminary efficacy was observed in patients with osimertinib-resistant NSCLC and EGFRvIII mutant HGA. Enrollment to expansion cohorts is ongoing. Clinical trial information: NCT04197934 .

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 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.