Virtual Library
Start Your Search
Peter Szlosarek
Author of
-
+
ES03 - BAP-1 and Other Novel Molecular and Metabolic Targets in Mesothelioma (ID 6)
- Event: WCLC 2019
- Type: Educational Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Michele Carbone, Miyako Satouchi
- Coordinates: 9/08/2019, 10:30 - 12:00, Tokyo (1982)
-
+
ES03.04 - Pegargiminase to Treat Mesothelioma (Now Available) (ID 3164)
10:30 - 12:00 | Presenting Author(s): Peter Szlosarek
- Abstract
- Presentation
Abstract
Treatments based on targeting metabolism remain central to the management of malignant mesothelioma, an intractable malignancy with a median overall survival (OS) of ~12 months. The standard of care since 2003 is an antifolate drug (pemetrexed or raltitrexed) paired with a platinum salt which provides a 2-3 month median survival benefit. Arginine metabolism is dysregulated in mesothelioma with deficiency of the rate limiting enzyme argininosuccinate synthetase 1 (ASS1) three-fold higher in sarcomatoid and biphasic compared to epithelioid tumours. ASS1 inactivation via promoter methylation diverts the precursor aspartate for enhanced pyrimidine synthesis via carbamoyl-phosphate synthetase 2 (CAD), accounting in part for increased tumorigenesis. However, loss of ASS1 generates a collateral dependence on exogenous arginine for growth (auxotrophy) that may be exploited with arginine-degrading enzymes, such as arginine deiminase and arginase.
A randomised phase 2 trial of pegargiminase (ADI-PEG20, pegylated arginine deiminase) monotherapy delivered as a weekly intramuscular (IM) injection (36mg/m2) in patients with ASS1-deficient mesothelioma (ADAM study; NCT01279967) revealed a 1.2 month progression-free survival benefit over best-supportive care (BSC) only (3.2 versus 2.0 months; hazard ratio of 0.56; and p=0.03). The restricted mean survival for OS, calculated due to early survival curve cross-over, was 15.7 months for the pegargiminase group versus 12.1 months for the BSC group, for a difference of 3.6 months (p=0.13). Pegargiminase was well-tolerated with a 13.6% grade 3-4 allergic rate, including anaphylactoid reactions and serum sickness, which were readily reversible and a low frequency of grade 1-2 reactions, mostly local skin irritation and discomfort due to the IM therapy. Pharmacodynamically, pegargiminase suppressed arginine plasma levels (measured on the day of and prior to drug dosing) for 4 weeks before a return to baseline with a reciprocal change in the degradation product, citrulline, a consequence of the production of drug-neutralising antibodies. Partial metabolic responses were documented by FDG-PET in almost 50% of patients by the third week of pegargiminase administration. Thus, while the PFS primary endpoint was modest, the ADAM trial is the first proof of principle study to show a survival benefit using an ASS1 biomarker-directed strategy.
More recent efforts in the arginine deprivation field have focused on rational drug combinations. Preclinically, pegargiminase reduces intracellular thymidine pools via inhibition of enzymes involved in de novo synthesis, specifically thymidylate synthetase and dihydrofolate reductase, and pyrimidine salvage via thymidine kinase 1, collectively enhancing pemetrexed cytotoxicity in arginine-auxotrophic tumour cell lines, including mesothelioma. This was tested in the phase 1 TRAP study (NCT02029690) combining pegargiminase with pemetrexed and cisplatin (ADIPemCis) in patients with ASS1-deficient mesothelioma (n=5) and non-squamous non-small cell lung cancer (NSCLC, n=4). The dose-escalation portion of the study revealed ADIPemCis was safe with a 78% (n=7/9) partial response rate and an overall 100% disease control rate. Moreover, partial responses were seen in biphasic and sarcomatoid mesothelioma considered to be largely chemorefractory. The overall PFS and OS in this small study was 7.5 and 13.9 months, respectively. A dose expansion cohort in mesothelioma at the maximum tolerated dose confirmed a similarly high disease control rate of 93.5% (29/31) and, with two-thirds of patients with non-epithelioid mesothelioma (10 biphasic and 10 sarcomatoid), an overall median PFS of 5.6 and OS of 10.1 months was observed. Although, a small series there was a 3 fold-higher survival at 12 months for patients with sarcomatoid mesothelioma compared with historical controls (30% versus 10% survival). These data supported the opening of a randomised double-blind phase 2/3 trial called ATOMIC-meso and the first to focus on the most aggressive subtypes of mesothelioma that is expected to report initial results by 2020 (NCT02709512).
Mesothelioma therapeutics are at a crossroads with increasing evidence for a key role of immunotherapy in a subset of patients. Objective responses of 10-30% have been reported in several phase 1-2 studies of PD1/PD-L1 antagonists with or without CTLA4 blockade in patients with mesothelioma. Pegargiminase increases PD-L1 expression on mesothelioma cells and leads to an influx of T cells in immunocompetent murine tumour models. Furthermore, urea cycle dysregulated cancers with increased aspartate flux and pyrimidine synthesis are hypothesized to generate genomic signatures more amenable to immune checkpoint blockade. Preliminary results of a phase 1 study of pegargiminase and pembrolizumab reveal activity in arginine auxotrophic cancers with good safety and tolerability (NCT03254732). Similarly, a first-in-man trial of platinum, pemetrexed combined with pegargiminase and atezolizumab (iTRAP study) is planned to start in 2019 focusing on patients with ASS1-deficient non-squamous NSCLC (NCT03498222). Pending these early data, and further ASS1 and PD-L1 biomarker analyses, additional studies are planned in patients with mesothelioma.
Recent preclinical work in our laboratory has revealed that arginine deprivation has a key role in remodulating the tumour microenvironment with an increase in macrophages involved in resistance to pegargiminase. Mesothelioma cells co-cultured with macrophages released several proinflammatory cytokines including IL-1alpha and the CXCR-2 dependent chemokines IL-8, CXCL2 and CXCL8 with a co-ordinate increase in ASS1 and ASL in macrophages and tumour cells, respectively bypassing sensitivity to pegargiminase. Moreover, analysis of blood from the ADAM study revealed an increase in argininosuccinate in the plasma of early metabolic progressors and paired biopsies from the TRAP mesothelioma expansion cohort revealed an influx of macrophages consistent with the preclinical work. Thus, re-education of macrophages with chemokine or “don’t’ eat me” inhibitors may be a viable strategy in mitigating stromal resistance to pegargiminase. Further optimisation of pegargiminase for the treatment of mesothelioma may come from manipulation of additional resistance pathways. Thus, antimalarial agents such as chloroquine inhibit autophagy, a common escape mechanism to nutrient deprivation, and have enhanced the effect of arginine depletion in various ASS1 negative tumour cell lines including mesothelioma. Lastly, synthetic lethal approaches targeting polyamine metabolism in ASS1-negative mesothelioma cells, also merit clinical investigation in combination with pegargiminase and may lead to deeper and more durable metabolic responses.
In summary, bench-to-bedside studies of pegargiminase have progressed to a phase 2/3 trial in mesothelioma. Combinations of pegargiminase with immune checkpoint blockade and modulators of resistance pathways appear promising areas for further development.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
