Importance:The clinical utility of matching therapies to genomic biomarkers based on varying levels of evidence remains uncertain, particularly for patients with rare and refractory cancers. Objective:To assess whether a tiered, evidence-based framework for matching genomic biomarkers to therapies is associated with differential overall survival in patients with advanced solid tumors. Design, Setting, and Participants:This multicenter cohort study was conducted within the Molecular Screening and Therapeutic program, a nationwide precision oncology program in Australia. Patients aged 18 years and older with advanced, refractory solid tumors and adequate Eastern Cooperative Oncology Group Performance Status were enrolled from June 2016 to December 2021, with follow-up through July 2022. Data were analyzed from July 2022 to July 2024. Exposures:Systemic therapy following comprehensive genomic profiling. Therapies were classified as matched or unmatched using the TOPOGRAPH (Therapy-Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals) knowledge base, which stratifies biomarker-drug pairs by level of evidence (tiers 1-3A, prospective trial evidence; tiers 3B/4, investigational/repurposed). Main Outcome and Measures:The primary outcome was overall survival from date of molecular profiling results. The hypothesis was tested using a time-dependent multivariable Cox proportional hazards model, adjusted for age, Eastern Cooperative Oncology Group Performance Status, cancer type, prior therapy, and prior receipt of matched therapy. Results:Of 3383 patients (mean [SD] age 57.1 [14.3] years; 1792 [53.0%] female), 1270 (37.5%) had a clinically active (tiers 1-3A) biomarker. Among patients with a tier 1 to 3A biomarker receiving treatment, those receiving matched therapy had a longer median overall survival than those receiving unmatched therapy (21.2 months [95% CI, 17.1-26.8 months] vs 12.8 months [95% CI, 11.7-13.9 months]; adjusted hazard ratio [aHR], 0.60; 95% CI, 0.44-0.82; P = .001). In contrast, among patients receiving therapy matched to investigational evidence (tiers 3B/4), there was not an associated survival benefit compared with unmatched therapy (14.5 months [95% CI, 12.6-18.4 months] vs 12.8 months [95% CI, 12.0-14.7 months]; aHR, 1.04; 95% CI, 0.84-1.29; P = .71). Patients who received therapies repurposed from other cancer types based solely on a biomarker and lacking direct evidence (tier 3B) did not experience longer survival compared with those receiving unmatched therapy (13.6 months [95% CI, 8.0-16.8 months] vs 12.5 months [95% CI, 11.3-13.5 months]; aHR, 1.40; 95% CI, 1.00-1.96; P = .047). Conclusions and Relevance:In this cohort study of patients with advanced solid tumors, matching therapies to genomic biomarkers was associated with improved survival only when supported by prospective clinical trial evidence. These findings support using an evidence-based framework to prioritize genomically guided therapies.

Genetic and epigenetic modifications of DNA are involved in cancer initiation and progression. Epigenetic modifications change chromatin structure and DNA accessibility and thus affect DNA replication, DNA repair and transcription. Epigenetic modifications are reversible and include DNA methylation, histone acetylation and histone methylation. DNA methylation is catalysed by DNA methyltransferases, histone acetylation and deacetylation are catalysed by histone acetylases and deacetylases, while histone methylation is catalysed by histone methyltransferases. Epigenetic modifications are dysregulated in several cancers, making them cancer therapeutic targets. Epigenetic drugs (epi-drugs) which are inhibitors of epigenetic modifications and include DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi) and bromodomain and extra-terminal motif protein inhibitors (BETi), have demonstrated clinical success as anti-cancer agents. Furthermore, the combination of epi-drugs with standard chemotherapeutic agents has demonstrated promising anti-cancer effects in pre-clinical and clinical settings. In this review, we discuss the role of epi-drugs in cancer therapy and explore their current and future use in combination with other anti-cancer agents used in the clinic. We further highlight the side effects and limitations of epi-drugs. We additionally discuss novel delivery methods and novel tumour epigenetic biomarkers for the screening, diagnosis and development of personalised cancer treatments, in order to reduce off-target toxicity and improve the specificity and anti-tumour efficacy of epi-drugs.

Triple negative breast cancers (TNBCs) are a heterogenous subcategory of breast cancers which have significantly worse survival outcomes compared to other breast cancer subtypes. However, limited advances have been made towards a targeted TNBC therapeutic and traditional chemotherapies remain the frontline therapy. Therefore, this study aimed to examine the therapeutic potential of a novel TNBC target, Barrier-to-Autointegration Factor 1 (Banf1), including determining Banf1 expression and cellular localisation in non-malignant breast cells and a panel of TNBC cell lines. Bioinformatic analysis of patient samples demonstrated that Banf1 is overexpressed in all breast cancer stages and subtypes. Banf1 depletion inhibited proliferation and induced mitotic arrest in TNBC cells via loss of nuclear envelope integrity and aberrant nuclear morphology, inducing TNBC tumour cell-specific cell death. These findings highlight the significant overexpression and functional involvement of Banf1 in TNBC progression and suggests that it may have potential as a novel anti-cancer target, supporting further investigation.

We present the case of a gentleman who developed oligometastatic colon cancer in his brain one year after completing adjuvant chemotherapy. Subsequent dural metastasis necessitated whole brain radiation therapy (WBRT). Whole exome sequencing (WES) identified a NCOA4-RET fusion and high tumor mutation burden. Treatment with selpercatinib following WBRT for multifocal dural metastases led to an initial treatment response, interrupted by grade 3 transaminitis for two weeks, during which dural metastases progressed. Resuming selpercatinib at 50% dose led to a rapid treatment response and maintained for four months until further brain metastases. Our patient survived 21 months following initial diagnoses of metastatic recurrence including nine months of selpercatinib. This case underscores the importance of molecular tumor board meetings and the use of next-generation sequencing WES to detect rare and targetable mutations, ultimately improving patient outcomes.

INTRODUCTION:Treatment-free survival (TFS) characterizes periods of disease control and durable clinical benefit after treatment discontinuation in patients treated with immunotherapy. In CheckMate 227 Part 1, nivolumab plus ipilimumab reported long-term durable overall survival (OS) benefit versus chemotherapy in patients with metastatic NSCLC. Here, we report updated long-term TFS results. METHODS:This analysis included all patients randomized (tumor programmed death ligand 1 [PD-L1] expression ≥1% and <1%). TFS was estimated as the restricted-mean survival time (between Kaplan-Meier curves for time to treatment discontinuation and time to subsequent systemic therapy or death) over 6 years after randomization. TFS was further divided into periods with or without ongoing toxicity (grade 3 or greater treatment-related adverse events) and estimated over 2 and 6 years after randomization. RESULTS:At 6 years after randomization (minimum follow-up: 73.5 months [∼6.1 years]), the estimated OS rate was 20% with nivolumab plus ipilimumab versus 11% with chemotherapy; 13% versus 2% of patients were treatment free. The 6-year mean TFS was 12.2 versus 5.0 months (difference 7.2 [95% confidence interval: 5.4-9.2]), with 17% versus 7% of the 6-year period spent in TFS. The 6-year mean TFS without grade 3 or greater treatment-related adverse events was 11.6 versus 4.8 months (difference, 6.9 [95% confidence interval: 5.1-8.9]). The proportion of mean TFS time increased from 15% of a 2-year to 17% of a 6-year period with nivolumab plus ipilimumab but decreased from 14% to 7% with chemotherapy. Similar results were observed by tumor PD-L1 expression. CONCLUSIONS:Nivolumab plus ipilimumab improved TFS versus chemotherapy, regardless of tumor PD-L1 expression, supporting its use as an efficacious first-line treatment for metastatic NSCLC.

INTRODUCTION:We describe the safety of sotorasib monotherapy in patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) and discuss practical recommendations for managing key risks. METHODS:Incidence rates of treatment-related adverse events (TRAEs) were pooled from 4 clinical trials: CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883), CodeBreaK 105 (NCT04380753), and CodeBreaK 200 (NCT04303780) and graded according to CTCAE v5.0. Adverse events were deemed sotorasib-related per investigator causality assessment. RESULTS:In the pooled population (n = 549), TRAEs were reported in 388 (70.7%) patients (grade 1: 124 [22.6%]; grade 2: 117 [21.3%]; grade ≥ 3: 147 [26.8%]). Gastrointestinal and hepatic TRAEs, including diarrhea (171 [31.1%]), nausea (80 [14.6%]), elevated alanine aminotransferase (ALT; 68 [12.4%]), and elevated aspartate aminotransferase (AST; 67 [12.2%]) were the most common (≥10%). Dose interruption and dose reduction of sotorasib resulted in the resolution of >90% of diarrhea events; median time to resolution were 18.0 days and 22.0 days, respectively. Similar trends were observed for elevated ALT and AST events. Patients who stopped immunotherapy <3 months before initiating sotorasib had a higher incidence of treatment-related hepatotoxicity (80/240 [33.3%]) than those who stopped immunotherapy ≥3 months before initiating sotorasib (26/188 [13.8%]). Treatment-related pneumonitis/interstitial lung disease (ILD) and corrected QT (QTc) prolongation were observed in 9 (1.6%) and 4 (0.7%) patients, respectively. Two (0.4%) patients died with TRAEs, 1 with ILD whose ultimate cause of death was disease progression, and the other with an unknown cause. CONCLUSIONS:Sotorasib has a well-characterized safety profile in patients with KRAS G12C-mutated advanced NSCLC, and key risks are manageable with dose modification.

Background: KRAS G12D and G12C mutations have distinct biological traits influencing treatment response. This study examines real-world demographics, clinical characteristics, and first-line treatment outcomes in metastatic non-small-cell lung cancer (NSCLC) patients with these mutations. Methods: This retrospective, multi-institution observational study used data from the AURORA database. Patients aged 18 years or older, diagnosed with metastatic KRAS G12D or G12C NSCLC between January 1, 2010, and April 30, 2024, were included. Descriptive statistics compared patient characteristics, and time-to-event outcomes were assessed using Cox proportional hazards regression. Results: A total of 298 (216 KRAS G12C and 82 KRAS G12D) patients were included. The KRAS G12D group had a higher proportion of never smokers (15 % vs. 1 %, p < 0.01) and PD-L1 < 1 % (36 % vs. 21 %, p = 0.06). No significant differences were observed in overall survival (OS) (HR 1.09, 95 % CI 0.80-1.48, p = 0.60) or real-world progression-free survival (rwPFS) (HR 1.21, 95 % CI 0.92-1.59, p = 0.18) between mutation groups. In KRAS G12C, monotherapy immunotherapy (HR 0.61, 95 % CI 0.39-0.97, p = 0.04) and chemo-immunotherapy (HR 0.59, 95 % CI 0.37-0.94, p = 0.03) improved OS compared to chemotherapy. For KRAS G12D, neither immunotherapy (HR 0.74, 95 % CI 0.29-1.89, p = 0.53) nor chemo-immunotherapy (HR 0.73, 95 % CI 0.34-1.57, p = 0.42) improved OS compared to chemotherapy alone. Conclusion: KRAS G12C and G12D mutations demonstrate distinct clinical characteristics and treatment responses, with poorer immunotherapy outcomes in KRAS G12D patients. Prospective studies are needed to validate these findings.

BackgroundMucosal head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage, where the prognosis is poor due to the high rates of recurrence and metastasis. With approximately one million new cases projected in 2024, worldwide mortality of HNSCC is estimated to reach 50% of detected cases the same year. Patients with early-stage tumours showed a 50-60% five-year survival rate in the US. Immune checkpoint inhibitors (ICIs) have shown promising results in prolonging survival in a subset of patients with recurrent or metastatic disease. However, challenges remain, particularly the limited efficacy of PD-1/PD-L1 blockade therapies. PD-L1 protein expression has been shown to be limited in its predictive power for ICI therapies. Emerging evidence shows that intricate characterisation of the tumour microenvironment (TME) is fundamental to understand interacting cells. This study aims to bridge the gap in understanding the tumor microenvironment by identifying distinct spatial patterns of PD-1/PD-L1 interactions and their association with immunotherapy responses in head and neck squamous cell carcinoma (HNSCC).MethodsIn this study, we sought to apply a more nuanced approach to understanding cellular interactions by mapping PD-1/PD-L1 interactions across whole-slide HNSCC tissue samples collected prior to ICI therapy. We used a combination of spatial proteomics (Akoya Biosciences) and an in situ proximity ligation assay (isPLA, Navinci Diagnostics) to visualise PD-1/PD-L1 interactions across cell types and cellular neighbourhoods within the tumour TME.ResultsOur findings indicate the existence of isPLA+ PD-1/PD-L1 interactions between macrophages/CD3 T cell-enriched neighbourhoods and tumour cells at the tumour-stroma boundaries in ICI-resistant tumours. The presence of these dense macrophage-tumour layers, which are either absent or dispersed in responders, indicates a barrier that may restrict immune cell infiltration and promote immune escape mechanisms. In contrast, responders had abundant B and T cell aggregates, predominantly around the tumour edges linked to enhanced immune responses to ICI therapy and better clinical outcomes.ConclusionThis study highlights the utility of isPLA in detecting distinct tumour-immune interactions within the TME, offering new cellular interaction metrics for stratifying and optimising immunotherapy strategies.

8526 Background: The treatment paradigm for metastatic non-small cell lung cancer (mNSCLC) without actionable genomic alterations does not differentiate between histologic subtypes for the use of checkpoint inhibitors. However, there is growing recognition of differences between squamous (SQ) and non-squamous (NSQ) lung cancer that may impact response to treatment. For example, in the RELATIVITY-104 study, addition of the LAG-3 inhibitor relatlimab to anti-PD-1 + platinum-doublet chemotherapy (PDCT) showed improved clinical benefit among patients with PD-L1 ≥1%, which was further enriched with NSQ histology. There is an unmet need to understand differences in tumor biology between NSQ and SQ histologies in patients with mNSCLC to inform on mechanisms underlying differences in clinical activity of anti-PD-1 + PDCT, alone or in combination with a LAG-3 inhibitor. Methods: Data were obtained from molecular profiling of baseline tumor samples of treatment-naive patients enrolled in the phase 3 CheckMate 227 (NCT02477826) study. PD-L1 (N=1739) and LAG-3 expression (N=540) were evaluated using immunohistochemistry. Somatic mutations and copy number alterations were assessed using the FoundationOne panel (N=1368). Gene expression, analyzed through RNA sequencing (N=465), was used to characterize differences in tumor immunobiology, including differential gene expression, pathway enrichment, and calculation of cell type-specific scores representing different immune and stromal cell types. Results: Transcriptional and mutational analyses revealed clear differences between NSQ and SQ tumors. NSQ tumors showed enrichment of immune pathways (e.g., antigen presentation and T cells), while SQ tumors exhibited enrichment of pathways consistent with rapid cell growth and numerous oncogenic alterations (e.g., p53 and PIK3CA). Differences in the relationship between tumor PD-L1 expression and the tumor microenvironment by histology were observed; PD-L1 expression was positively correlated with immune infiltration scores in NSQ but not SQ tumors, suggesting that drivers of PD-L1 expression may differ by histology. Consistent with previously published reports for mNSCLC, PD-L1 expression enriched for 1L anti-PD-1 + PDCT benefit in NSQ but not SQ tumors (CheckMate 227 Part 2). Differences in LAG-3 ligand expression by histology and PD-L1 expression were noted. Both canonical LAG-3 ligands, MHC-II and FGL-1, were expressed at higher levels in NSQ tumors. Within NSQ tumors, relative expression of each ligand varied by PD-L1 expression, with high MHC-II expression specifically in NSQ, PD-L1 ≥1% tumors. Conclusions: These data provide a supporting mechanistic rationale for the use of tumor histology in addition to PD-L1 expression to identify patients who would benefit from the addition of a LAG-3 inhibitor to PD-1 inhibitor + PDCT. Clinical trial information: NCT02477826 .

TPS8127 Background: Atigotatug is an innate immune inducer monoclonal antibody that binds fucosyl-monosialoganglioside-1 (fuc-GM1) with high affinity and specificity, thereby inducing immune-mediated tumor cell death. Fuc-GM1, a cell surface target, is expressed in 50%–90% of SCLC tumors. In a randomized, open-label phase 2 study, atigotatug combined with nivolumab and chemotherapy vs nivolumab and chemotherapy alone has shown a promising trend in overall survival (OS) with median OS of 15.6 mo vs 11.4 mo, respectively (HR 0.71; 95% CI 0.44–1.16), as a first-line treatment in ES-SCLC. Based on these results, a confirmatory trial comparing this regimen to the standard of care is warranted. TIGOS (NCT06646276) is a randomized, double-blind, multicenter phase 3 trial to compare the efficacy and safety of atigotatug + nivolumab fixed-dose combination with chemotherapy vs atezolizumab with chemotherapy. Methods: Approximately 530 eligible patients will be randomized 1:1 to receive either atigotatug + nivolumab fixed-dose combination with carboplatin and etoposide Q3W (induction) followed by atigotatug + nivolumab fixed dose combination (maintenance) Q4W or atezolizumab with carboplatin and etoposide Q3W (induction) followed by atezolizumab (maintenance) Q4W. Patients will be stratified by ECOG performance status (PS) 0–1, presence of liver metastases, and presence of brain metastases at baseline. Treatment will continue until disease progression, unacceptable toxicity, death, or withdrawal of consent. Eligible patients must be ≥18 years old, have histologically or cytologically documented SCLC, ≥1 measurable lesion outside the central nervous system (CNS), any previous limited-stage SCLC treatment completed ≥6 months prior to study treatment initiation, and an ECOG PS of 0–1. Key exclusion criteria include prior treatment for ES-SCLC, untreated symptomatic CNS metastases, and prior treatment targeting T-cell co-stimulation, checkpoint pathways, and/or fuc-GM1. The primary endpoint is OS, and the secondary endpoints are time to definitive deterioration, safety, objective response, duration of response, and progression-free survival, as assessed by the investigator. Assessment of pre- and on-treatment changes in biomarkers will be part of an exploratory analysis. This study will be conducted in 180 locations, with a primary completion date expected in April 2028. Clinical trial information: NCT06646276 .

Introduction: EGFR-mutant NSCLC is associated with low mutation burden and low levels of PD-L1 expression. We conducted a phase 2 trial to determine the efficacy of durvalumab, tremelimumab, and platinum-pemetrexed in EGFR-mutant NSCLC after progression with EGFR tyrosine kinase inhibitors (TKIs). Methods: Participants were treated with induction durvalumab, tremelimumab, and platinum-pemetrexed, followed by durvalumab-pemetrexed maintenance. Participants were divided into two cohorts: (1) EGFR exon 20 T790M negative (T790M-, progressing on either first-line osimertinib, or on a single line of first/second generation TKI), and (2) T790M positive (T790M+, progressing on greater than or equal to 1 lines of TKI, including osimertinib). The primary endpoint was the confirmed objective response rate (ORR) assessed Results: One hundred participants from Australia and Taiwan were enrolled. Median follow-up was 26 months with 88% and 96% experiencing progression events for T790Mand T790M+, respectively. The ORR for T790Mwas 31% (95% confidence interval: 20-45), including two complete responses. The ORR for T790M+ was 21% (95% confidence interval: 12-34). Median durations of response were 9.5 months and 6.3 months for T790Mand T790M+, respectively; median progression-free survival rates were 6.5 months and 4.9 months, respectively. For T790M-, ORR was 27% for 50% or higher PD-L1 (n = 22) and 0% for less than 50% PD-L1 (n = 10), respectively. For T790M+, ORR was 17% for 50% or higher PD-L1 (n = 24). The safety profile was consistent with previous reports. Conclusions: Durvalumab, tremelimumab, and platinumpemetrexed had modest anti-tumor activity in EGFR-mutant NSCLC after progression on TKI. The T790Mcohort had higher ORR and a longer duration of response. Immune adverse events were not increased with tremelimumab. The clinical registration number of this trial is NCT03994393. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

OX40 may stimulate T-cell activation, potentially enhanced with checkpointinhibition. Results are from the dose-escalation part of an ongoing, multicenter, open-label study (NCT04215978, registered 30 December 2019) investigating OX40 agonist BGB-A445 alone or with anti-PD-1 antibody tislelizumab in patients with advanced solid tumors. Adults ≥18 years with previously treated advanced solid tumors, measurable by RECIST v1.1, enrolled. Dose-escalation A: 8 cohorts received increasing doses of IV BGB-A445 as monotherapy (20, 60, 150, 300, 600, 1200, 2400, 3600 mg); dose-escalation B: 6 cohorts received increasing doses of IV BGB-A445 (150, 300, 600, 1200, 2400, 3600 mg) + IV tislelizumab 200 mg. Primary objectives were safety and tolerability; secondary objectives included overall response rate (ORR) and pharmacokinetics. 112 patients were treated (A, n=63; B, n=49); 34/112 (30.4

Background and Objective: Approximately 16,000 new cases of lung cancer are diagnosed each year in Australia and Aotearoa New Zealand, and it is the leading cause of cancer death in the region. Unwarranted variation in lung cancer care and outcomes has been described for many years, although clinical quality indicators to facilitate benchmarking across Australasia have not been established. The purpose of this study was to establish clinical quality indicators applicable to lung and other thoracic cancers across Australia and Aotearoa New Zealand. Methods: Following a literature review, a modified three round eDelphi consensus process was completed between October 2022 and June 2023. Participants included clinicians from all relevant disciplines, patient advocates, researchers and other stakeholders, with representatives from all Australian states and territories and Aotearoa New Zealand. Consensus was set at a threshold of 70%, with the first two rounds conducted as online surveys, and the final round held as a hybrid in person and virtual consensus meeting. Results: The literature review identified 422 international thoracic oncology indicators, and a total of 71 indicators were evaluated over the course of the Delphi consensus. Ultimately, 27 clinical quality indicators reached consensus, covering the continuum of thoracic oncologic care from diagnosis to first line treatment. Indicators benchmarking supportive care were poorly represented. Attendant numeric quality standards were developed to facilitate benchmarking. Conclusion: Twenty-seven clinical quality indicators relevant to thoracic oncology care in Australasia were developed. Real world implementation will now be explored utilizing a prospective dataset collected across Australia.

Background 5-Fluorouracil (5-FU) remains a core component of systemic therapy for colorectal cancer (CRC). However, response rates remain low, and development of therapy resistance is a primary issue. Combinatorial strategies employing a second agent to augment the therapeutic effect of chemotherapy is predicted to reduce the incidence of treatment resistance and increase the durability of response to therapy. Methods Here, we employed quantitative proteomics approaches to identify novel druggable proteins and molecular pathways that are deregulated in response to 5-FU, which might serve as targets to improve sensitivity to chemotherapy. Drug combinations were evaluated using 2D and 3D CRC cell line models and an ex vivo culture model of a patient-derived tumour. Results Quantitative proteomics identified upregulation of the mitosis-associated protein Aurora B (AURKB), within a network of upregulated proteins, in response to a 24 h 5-FU treatment. In CRC cell lines, AURKB inhibition with the dihydrogen phosphate prodrug AZD1152, markedly improved the potency of 5-FU in 2D and 3D in vitro CRC models. Sequential treatment with 5-FU then AZD1152 also enhanced the response of a patient-derived CRC cells to 5-FU in ex vivo cultures. Conclusions AURKB inhibition may be a rational approach to augment the effectiveness of 5-FU chemotherapy in CRC.

Importance Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma. Objective To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor. Design, Setting, and Participants This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months’ follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023. Intervention Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m 2 ) or placebo. All patients received intravenous pemetrexed (500 mg/m 2 ) and platinum (75-mg/m 2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months. Main Outcomes and Measures The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only. Results Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo). Conclusions and Relevance In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology. Trial Registration ClinicalTrials.gov Identifier: NCT02709512

INTRODUCTION:Nivolumab plus ipilimumab-based treatment regimens have shown long-term, durable efficacy benefits in patients with metastatic NSCLC. Here we report clinical outcomes from a pooled analysis of patients with metastatic NSCLC and tumor programmed death-ligand 1 (PD-L1) lower than 1% treated with first-line nivolumab plus ipilimumab with or without two cycles of chemotherapy versus up to four cycles of chemotherapy in the randomized phase 3 CheckMate 227 and CheckMate 9LA studies. METHODS:Patients were aged 18 years or older and had stage IV or recurrent NSCLC with no sensitizing EGFR/ALK alterations. Assessments included overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety. RESULTS:In patients with tumor PD-L1 lower than 1% in the nivolumab plus ipilimumab with or without chemotherapy (n = 322) versus chemotherapy (n = 315) arms, median OS was 17.4 versus 11.3 months, respectively, (hazard ratio [HR] = 0.64, 95% confidence interval [CI]: 0.54-0.76; 5-y OS rate, 20% versus 7%) at a median follow-up of 73.7 months. The OS benefit was observed across key subgroups, including difficult-to-treat populations such as those with baseline brain metastases (HR = 0.44, 95% CI: 0.26-0.75) or squamous NSCLC (HR = 0.51, 95% CI: 0.36-0.72). In the overall pooled population, the median PFS was 5.4 versus 4.9 months (HR = 0.72, 95% CI: 0.60-0.87; 5-y PFS rate, 9% versus 2%), the objective response rate was 29% versus 22%, and the median duration of response was 18.0 versus 4.6 months. No new safety signals were observed. CONCLUSION:Nivolumab plus ipilimumab with or without chemotherapy provides a long-term, durable clinical benefit in patients with metastatic NSCLC and tumor PD-L1 lower than 1%, supporting the use of this strategy as a first-line treatment option in this population with high unmet need. CLINICAL TRIAL REGISTRATIONS:NCT02477826, NCT03215706.