Integrative evaluation of primary and metastatic lesion spectrum to guide anti-PD-L1 therapy of non-small cell lung cancer: results from two randomized studies

Ma, Si-Cong; Tang, Xixiang; Long, Li-Li; Bai, Xue; Zhou, Jianguo; Duan, Zhijiao; Wang, Jian; Fu, Qiang; Zhu, Hongbo; Guo, Xuejun; Zhang, Yan-Pei; Guo, Ze-Qin; Wu, De‐Hua; Dong, Zhong‐Yi

doi:10.1080/2162402x.2021.1909296

Cited by 13 publications

(11 citation statements)

References 41 publications

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“…S2A), which was congruent with accumulating evidence supporting that adrenal gland or brain metastasis did not influence patients’ survival in the context of PD-(L)1 blockade of NSCLC [ 19 , 20 ]. This was reminiscent of our recent study reporting an upregulated blood-based tumor mutation burden and/or PD-L1 expression for theses metastases [ 20 ], and another study reporting a favorable response rate of adrenal gland metastatic lesions to ICIs [ 18 ]. The “Janus-faced” significance of category I organ metastases has also been recapitulated in liver metastasis, where superior efficacy of immunotherapy over chemotherapy was coupled with a worse prognosis [ 21 – 23 ].…”

Section: Discussionsupporting

confidence: 85%

“…4 A) helped explain the non-significant association of survival prospects with the number of category I organ metastases in the immunotherapy arm (Additional file 5 : Fig. S2A), which was congruent with accumulating evidence supporting that adrenal gland or brain metastasis did not influence patients’ survival in the context of PD-(L)1 blockade of NSCLC [ 19 , 20 ]. This was reminiscent of our recent study reporting an upregulated blood-based tumor mutation burden and/or PD-L1 expression for theses metastases [ 20 ], and another study reporting a favorable response rate of adrenal gland metastatic lesions to ICIs [ 18 ].…”

Section: Discussionsupporting

confidence: 76%

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Organ-specific metastatic landscape dissects PD-(L)1 blockade efficacy in advanced non-small cell lung cancer: applicability from clinical trials to real-world practice

Bai

Guo

et al. 2022

BMC Med

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Background Organ-specific metastatic context has not been incorporated into the clinical practice of guiding programmed death-(ligand) 1 [PD-(L)1] blockade, due to a lack of understanding of its predictive versus prognostic value. We aim at delineating and then incorporating both the predictive and prognostic effects of the metastatic-organ landscape to dissect PD-(L)1 blockade efficacy in non-small cell lung cancer (NSCLC). Methods A total of 2062 NSCLC patients from a double-arm randomized trial (OAK), two immunotherapy trials (FIR, BIRCH), and a real-world cohort (NFyy) were included. The metastatic organs were stratified into two categories based on their treatment-dependent predictive significance versus treatment-independent prognosis. A metastasis-based scoring system (METscore) was developed and validated for guiding PD-(L)1 blockade in clinical trials and real-world practice. Results Patients harboring various organ-specific metastases presented significantly different responses to immunotherapy, and those with brain and adrenal gland metastases survived longer than others [overall survival (OS), p = 0.0105; progression-free survival (PFS), p = 0.0167]. In contrast, survival outcomes were similar in chemotherapy-treated patients regardless of metastatic sites (OS, p = 0.3742; PFS, p = 0.8242). Intriguingly, the immunotherapeutic predictive significance of the metastatic-organ landscape was specifically presented in PD-L1-positive populations (PD-L1 > 1%). Among them, a paradoxical coexistence of a favorable predictive effect coupled with an unfavorable prognostic effect was observed in metastases to adrenal glands, brain, and liver (category I organs), whereas metastases to bone, pleura, pleural effusion, and mediastinum yielded consistent unfavorable predictive and prognostic effects (category II organs). METscore was capable of integrating both predictive and prognostic effects of the entire landscape and dissected OS outcome of NSCLC patients received PD-(L)1 blockade (p < 0.0001) but not chemotherapy (p = 0.0805) in the OAK training cohort. Meanwhile, general performance of METscore was first validated in FIR (p = 0.0350) and BIRCH (p < 0.0001), and then in the real-world NFyy cohort (p = 0.0181). Notably, METscore was also applicable to patients received PD-(L)1 blockade as first-line treatment both in the clinical trials (OS, p = 0.0087; PFS, p = 0.0290) and in the real-world practice (OS, p = 0.0182; PFS, p = 0.0045). Conclusions Organ-specific metastatic landscape served as a potential predictor of immunotherapy, and METscore might enable noninvasive forecast of PD-(L)1 blockade efficacy using baseline radiologic assessments in advanced NSCLC.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 76%

Organ-specific metastatic landscape dissects PD-(L)1 blockade efficacy in advanced non-small cell lung cancer: applicability from clinical trials to real-world practice

Bai

Guo

et al. 2022

BMC Med

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“…Over the past two decades, considerable efforts have been made to identify the molecular mechanisms underlying cancer development 4 . Remarkable advances in the therapeutic regimens of lung cancer have been achieved, in particular, molecularly targeted therapies and immunotherapies such as antiprogrammed cell death ligand 1 antibodies and immune‐checkpoint inhibitors 5,6 . Despite efforts to improve the treatment of NSCLC, the available options remain limited, and patient survival rates have not markedly improved 7,8 .…”

Section: Introductionmentioning

confidence: 99%

ACT001 inhibits the proliferation of non‐small cell lung cancer cells by upregulating NKTR expression

2022

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Background Lung cancer, the primary cause of cancer‐related deaths worldwide, is diagnosed at an advanced stage and has a poor prognosis. Non‐small cell lung cancer (NSCLC) is a major histological type of lung malignancy. This study investigated the effect of ACT001, a novel sesquiterpene lactone derivative, on the proliferation of NSCLC cells and explored the underlying mechanism. Methods The effect of ACT001 on cell proliferation was examined by clone formation and MTT assay. Differentially expressed genes and enrichment pathways were analyzed by RNA‐seq. Flow cytometry and cell cycle‐related protein expression analysis were performed to study the cell cycle. Phosphorylated AKT was detected to explore the mechanism in natural killer cell triggering receptor (NKTR) KD cells with AKT activator and/or inhibitor. The therapeutic effect of ACT001 in vivo was studied in the xenograft tumor model. Results ACT001 inhibited the proliferation and G1/S transition in NSCLC cell lines. By RNA‐seq analysis, NKTR may be the target of ACT001. Moreover, knockdown NKTR promoted cell proliferation and reversed the effects of ACT001. In addition, ACT001 inhibited AKT phosphorylation, but NKTR knockdown promoted AKT phosphorylation. Conclusion Our results suggested NKTR may be the target of ACT001 in NSCLC. ACT001 holds promise as a novel method for the treatment of NSCLC.

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“…With the unprecedented progress of immune checkpoint inhibitors (ICIs), immunotherapy has altered the treatment paradigm and gradually become the mainstay of the treatment for advanced cancers, especially melanoma (5,6). Identifying marker of significance to predict responses to ICI therapy has become a key challenge in study and clinical practice of immunotherapy because of the heterogeneity of ICI effectiveness seen among patients in the clinical work (7)(8)(9)(10)(11). Given the relatively modest predictive power of the routinely applied immunotherapeutic biomarkers, such as PD-L1, growing studies have been committed to search for clues from gene mutation (8,(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

De Novo Mutation in Non-Tyrosine Kinase Domain of ROS1 as a Potential Predictor of Immune Checkpoint Inhibitors in Melanoma

Zhu

Wang

et al. 2021

Front. Oncol.

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PurposeDespite the success of targeted therapy in c-ros oncogene 1 (ROS1)-rearranged cancers, especially non-small cell lung cancer (NSCLC), the clinical significance of ROS1 de novo mutation has not yet been understood. We sought to elucidate the predictive effect of ROS1 mutation for immune checkpoint inhibitor (ICI) therapy in melanoma.MethodsThe Cancer Genome Atlas [TCGA (n = 10967)] and Memorial Sloan Kettering Cancer Center [MSK (n = 10,945)] datasets, as well as two clinical cohorts of melanoma received ICI [CA209-038 (n = 73) and MEL-IPI (n = 110)], were included to explore the prevalence, prognostic effect, and immunotherapeutic predictive effect of ROS1 mutation in melanoma. Overall survival (OS) was defined as the primary outcome.ResultsOverall, melanoma accounted for the highest proportion of ROS1 mutation (~20%) which made up the majority (~95%) of the ROS1-alterated cases. Remarkably, ROS1 mutation yielded longer OS from ICI than the wild-type counterpart in the MSK melanoma population [hazard ratio (HR) 0.47, 95% confidence interval (CI) 0.30–0.74], and two external melanoma cohorts (CA209-038: HR 0.42, 95% CI 0.20–0.89; MEL-IPI: HR 0.55, 95% CI 0.34–0.91), without affecting the prognosis of patients. Elevated tumor mutational burden and enrichment of DNA damage repair was observed in ROS1 mutated patients, providing an explanation for the favorable responses to ICI therapy. Precisely, ROS1 mutation in non-protein tyrosine kinase (PTK) domain but not PTK mutation was responsible for the immunotherapy-specific responses of the ROS1 mutated patients in melanoma.ConclusionsCollectively, ROS1 mutation, specifically the non-PTK mutation, is a potential predictor of ICI therapy in melanoma, which is distinct from the well-established role of ROS1 rearrangement for targeted therapy in NSCLC.

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Integrative evaluation of primary and metastatic lesion spectrum to guide anti-PD-L1 therapy of non-small cell lung cancer: results from two randomized studies

Cited by 13 publications

References 41 publications

Organ-specific metastatic landscape dissects PD-(L)1 blockade efficacy in advanced non-small cell lung cancer: applicability from clinical trials to real-world practice

Organ-specific metastatic landscape dissects PD-(L)1 blockade efficacy in advanced non-small cell lung cancer: applicability from clinical trials to real-world practice

ACT001 inhibits the proliferation of non‐small cell lung cancer cells by upregulating NKTR expression

De Novo Mutation in Non-Tyrosine Kinase Domain of ROS1 as a Potential Predictor of Immune Checkpoint Inhibitors in Melanoma

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