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. 2025 May 6;10(5):105058. doi: 10.1016/j.esmoop.2025.105058

Durvalumab with or without tremelimumab in combination with chemotherapy in first-line metastatic non-small-cell lung cancer: outcomes by tumor mutational burden in POSEIDON

S Peters 1,∗, KS Oliner 2, A L’Hernault 3, M Ratcliffe 3, H Madison 2,†, Z Lai 4, R Stewart 3, H Mann 3, C Lowery 2, EB Garon 5, T Mok 6, ML Johnson 7
PMCID: PMC12167883  PMID: 40334315

Abstract

Background

In updated analyses from the phase III POSEIDON study, after a median follow-up of >5 years, tremelimumab plus durvalumab and chemotherapy (T + D + CT) showed durable long-term overall survival (OS) benefit versus CT alone in first-line metastatic non-small-cell lung cancer (mNSCLC). In this article, we report the associations of tumor mutational burden (TMB) with outcomes of D with or without T in combination with CT versus CT alone.

Patients and methods

A total of 1013 patients with EGFR/ALK wild-type mNSCLC were randomized (1 : 1 : 1) to T + D + CT, D + CT, or CT, stratified by programmed cell death-ligand 1 (PD-L1) tumor cell (TC) expression ≥50% versus <50%, disease stage (IVA versus IVB) and histology (squamous versus nonsquamous). Patient subgroups were defined by a range of blood TMB (bTMB) values, including at a prespecified cut-off of 20 mutations (mut)/megabase (Mb) and across further subdivisions by PD-L1 TC expression ≥1% or <1% and by tissue TMB (tTMB) values.

Results

At the primary OS data cut-off (12 March 2021), at each bTMB or tTMB cut-off, the magnitude of OS benefit appeared greater among patients in the bTMB- or tTMB-high subgroups for the T + D + CT arm versus the CT arm but was similar between subgroups for the D + CT arm versus the CT arm. Updated OS analyses in the bTMB ≥20 and <20 mut/Mb subgroups, after median follow-up of >5 years (data cut-off 24 August 2023), were similar to those obtained at the primary OS data cut-off.

Conclusions

First-line treatment with T (limited course) plus D (until progression) and four cycles of CT consistently improved clinical outcomes versus CT alone in both bTMB-high and -low subgroups, and also in both high and low tTMB subgroups, in patients with mNSCLC. Benefit appeared greater in the TMB-high versus TMB-low subgroups; the addition of anti-cytotoxic T lymphocyte-associated antigen-4 to anti-PD-L1 and CT seemed to increase the magnitude of this difference.

Key words: durvalumab, tremelimumab, non-small-cell lung cancer, tumor mutational burden, POSEIDON

Highlights

  • •

    OS and PFS benefit for T + D + CT versus CT was observed in both bTMB-high and bTMB-low subgroups at all cut-offs.

  • •

    OS benefit for T + D + CT versus CT was observed in both tTMB-high and tTMB-low subgroups at all cut-offs.

  • •

    The magnitude of benefit appeared greater in the TMB-high compared with TMB-low subgroups.

Introduction

Immunotherapy regimens comprising either a single programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitor, with or without chemotherapy, or dual immunotherapy including inhibitors of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), with or without chemotherapy, are now recommended for the first-line treatment of metastatic non-small-cell lung cancer (mNSCLC).1,2 In the phase III POSEIDON study (NCT03164616), first-line tremelimumab (anti-CTLA-4) plus durvalumab (anti-PD-L1) and platinum-based chemotherapy demonstrated statistically significant improvements in both progression-free survival [PFS; hazard ratio (HR) 0.72, 95% confidence interval (CI) 0.60-0.86; data cut-off 24 July 2019] and overall survival (OS; HR 0.77, 95% CI 0.65-0.92; data cut-off 12 March 2021) versus chemotherapy alone in patients with EGFR/ALK wild-type mNSCLC.3 Based on these findings, tremelimumab plus durvalumab and chemotherapy was approved for the first-line treatment of patients with mNSCLC. Subsequently, after longer follow-up (median >5 years; data cut-off 24 August 2023), tremelimumab plus durvalumab and chemotherapy showed durable long-term OS benefit versus chemotherapy.4

PD-L1 tumor cell (TC) expression is used to help guide treatment decisions but is not always predictive of response to immunotherapy in patients with mNSCLC, especially for combination regimens including both anti-PD-(L)1 and anti-CTLA-4 therapy.3,5, 6, 7 Tremelimumab plus durvalumab and chemotherapy has also shown OS benefit in patient subgroups with harder-to-treat disease such as those with mutations in STK11, KEAP1, or KRAS, or those with PD-L1-negative tumors (defined as PD-L1 expression in <1% of TCs),4 but other biomarkers are needed in this setting.

Tumor mutational burden (TMB), defined as the number of somatic mutations present in DNA derived from blood (bTMB) or tumor tissue (tTMB), has potential as a predictive biomarker for immunotherapy treatment benefit, in particular for combined anti-PD-(L)1 plus anti-CTLA-4 therapy independent of PD-L1 expression.6,8, 9, 10, 11 TMB is a surrogate for tumor neoantigen load,12, 13, 14, 15, 16 and TMB and PD-L1 expression have been shown to be independent predictive variables in relation to response to immunotherapy.14 The KEYNOTE-158 study indicated that tTMB-high status identifies a subgroup of patients who could have a robust tumor response to pembrolizumab monotherapy.17 This led to the approval of the FoundationOne®CDx next-generation sequencing test as a companion diagnostic for high TMB [at the ≥10 mutations per megabase (mut/Mb) cut-off] in patients with solid tumors (with progression following prior treatment and no alternative options) who may benefit from treatment with pembrolizumab.18

In exploratory analyses from the MYSTIC trial, the bTMB cut-off of ≥20 mut/Mb selected for optimal OS benefit, alongside improvements in PFS and objective response rate (ORR), in patients with mNSCLC treated with durvalumab plus tremelimumab versus chemotherapy.6 Although therapeutic activity with first-line durvalumab plus tremelimumab versus chemotherapy in the NEPTUNE trial was in line with expectations based on the previous results from MYSTIC, it did not meet its primary endpoint of a statistically significant improvement in OS in patients with mNSCLC and bTMB ≥20 mut/Mb. Limitations of NEPTUNE included the small size of the primary analysis population caused by late amendment of the study design which also led to imbalances in patients’ baseline characteristics between the treatment arms.9 A systematic review and meta-analysis, in which tumor or blood samples were selected for TMB detection in 21 and 10 datasets, respectively, has shown that, in patients with NSCLC with high TMB, immunotherapy was associated with improved PFS, OS, and ORR when compared with chemotherapy.11 However, limited data are available on the role of TMB as a biomarker for immunotherapy in combination with chemotherapy, although higher TMB appeared to be associated with improved PFS and ORR benefits of nivolumab plus ipilimumab plus chemotherapy versus chemotherapy in the CheckMate 9LA trial. OS benefit was generally similar between subgroups with high and low TMB but a numerically higher benefit was observed in the bTMB ≥20 versus <20 mut/Mb subgroups.19

The objectives of this analysis were to report outcomes in POSEIDON patient subgroups defined by a range of bTMB values (10, 12, and 16 mut/Mb), including at a prespecified cut-off of 20 mut/Mb and across further subdivisions by PD-L1 TC expression (≥1% or <1%), as well as by tTMB values at cut-offs of 10, 13, and 16 mut/Mb.

Patients and methods

Study design, patients, and treatment

POSEIDON (NCT03164616) was an open-label, global phase III study, conducted at 142 sites in 18 countries, which was designed to evaluate the efficacy and safety of first-line tremelimumab plus durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D + CT) versus chemotherapy alone (CT) in patients with mNSCLC. The study methodology has been reported previously.3

In summary, patients were randomly assigned (1 : 1 : 1) with stratification by PD-L1 expression (TC ≥50% versus <50%), disease stage (IVA versus IVB, per the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology version 8),20 and histology (squamous versus nonsquamous) to tremelimumab 75 mg plus durvalumab 1500 mg and chemotherapy for up to four 21-day cycles, followed by durvalumab 1500 mg once every 4 weeks until disease progression (PD), with one additional tremelimumab dose after chemotherapy at week 16/cycle 6 (fifth dose); durvalumab 1500 mg plus chemotherapy for up to four 21-day cycles, followed by durvalumab 1500 mg once every 4 weeks until PD; or chemotherapy for up to six 21-day cycles. Patients with nonsquamous histology who received pemetrexed-platinum doublet could receive pemetrexed maintenance therapy if eligible. Patients continued treatment until PD, unacceptable toxicity, consent withdrawal, or until the maximum duration had been reached (CT arm only).

The study was carried out in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. The protocol and all modifications were approved by relevant ethics committees and regulatory authorities. All patients provided written informed consent.

Endpoints and assessments

The primary endpoints were PFS, evaluated by blinded independent central review (BICR) per RECIST v1.1,21 and OS for D + CT versus CT. Key alpha-controlled secondary endpoints were PFS and OS for T + D + CT versus CT. Investigations of the relationships between PD-L1 TC expression, bTMB, and clinical outcomes were secondary objectives. Investigations of the relationships between tTMB and OS were also secondary objectives. OS, PFS, ORR, and duration of response (DoR) were assessed in patient subgroups with bTMB ≥20 versus <20 mut/Mb, and subgroups defined by additional bTMB cut-offs (≥10 versus <10, ≥12 versus <12, and ≥16 versus <16 mut/Mb cut-offs), and with tTMB at ≥10 versus <10, ≥13 versus <13, and ≥16 versus <16 mut/Mb cut-offs to examine the trends between outcomes and TMB scores. The rationale for the prespecified 20 mut/Mb bTMB cut-off was based on the MYSTIC trial.6 The tTMB 10 mut/Mb cut-off was selected as it was approved by the United States Food and Drug Administration for the use of pembrolizumab in the treatment of adult and pediatric patients with unresectable or metastatic TMB-high solid tumors.22 In the NEPTUNE trial there was a moderate correlation between bTMB (using a 20-mut/Mb cut-off) and tTMB (using a 13-mut/Mb cut-off),9 and the 16-mut/Mb tTMB cut-off was chosen to further evaluate the effects of high TMB in a substantial patient subgroup. For assessment of PD-L1 expression levels and tTMB status, all patients were required to provide formalin-fixed, paraffin-embedded tumor tissue samples (tissue block or 20 unstained sections) collected within 3 months before enrollment. Plasma samples for bTMB profiling were obtained before the start of treatment.

PD-L1 expression testing

Patients’ PD-L1 expression status was assessed at a central laboratory before randomization using the VENTANA PD-L1 (SP263) immunohistochemistry assay, as described previously.3

TMB assessment

The FoundationOne CDx next-generation sequencing platform (Foundation Medicine Inc., Cambridge, MA) which was used to evaluate tTMB was composed of a panel of 315 genes, with a DNA footprint of 1.1 Mb, while the GuardantOMNI sequencing platform (Guardant Health Inc., Palo Alto, CA) used to evaluate bTMB was composed of a panel of 500 genes, with a total DNA footprint of 2.1 Mb but a coding footprint of 1 Mb.

Statistical analyses

The biomarker subgroup analyses reported here were based on data from the primary analysis of POSEIDON with a median follow-up of 10.3 months for PFS (data cut-off 24 July 2019) and 34.9 months for OS (data cut-off 12 March 2021) and a prespecified long-term analysis of OS with a median follow-up of 63.4 months (OS data cut-off 24 August 2023). The bTMB and tTMB biomarker-evaluable populations (BEPs) included all randomized patients who had a plasma or tumor sample available and an evaluable result for bTMB and tTMB testing, respectively.

The primary and key alpha-controlled secondary endpoints in POSEIDON were analyzed in all randomized patients [intention-to-treat (ITT) population] using a stratified log-rank test. The hierarchical multiple testing procedure in POSEIDON allowed for alpha-controlled testings of OS for T + D + CT versus CT in the bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb, and bTMB ≥12 mut/Mb subgroups. However, it did not cross the prespecified threshold of statistical significance in the bTMB ≥20 mut/Mb subgroup, and as a result the bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb subgroups were not tested for significance. As a result, to ensure consistency across the TMB analyses presented here, all HRs and associated CIs were estimated using an unstratified Cox proportional hazards model with the Efron method to control for ties. The Kaplan–Meier method was used to calculate median OS, PFS, and DoR. ORR was analyzed using an unstratified logistic regression model to calculate odds ratios with 95% CIs. SAS® version 9.2 or higher was used for all analyses.

Results

bTMB and tTMB BEPs

Pretreatment plasma samples were available from 958/1013 (94.6%) randomized patients from the ITT population, in which 784/958 patients (81.8%, or 77.4% of randomized patients) were evaluable for bTMB, including 277 in the T + D + CT arm, 266 in the D + CT arm, and 241 in the CT arm. A total of 56 samples (5.9%) failed quality control and 118 (12.3%) did not have detectable somatic mutations (Supplementary Figure S1A, available at https://doi.org/10.1016/j.esmoop.2025.105058). Pretreatment tissue samples for tTMB assessment were available from 895/1013 randomized patients from the ITT population, in which 545/895 (60.9%) were assessable for tTMB, including 184 in the T + D + CT arm, 191 in the D + CT arm, and 170 in the CT arm. A total of 281 samples (31.4%) failed quality control (Supplementary Figure S1B, available at https://doi.org/10.1016/j.esmoop.2025.105058).

Patients’ demographic and disease characteristics in the bTMB and tTMB BEPs were consistent with the ITT population at baseline (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.105058). The proportion of current or former smokers was higher in the bTMB ≥20 mut/Mb subgroup than in the bTMB <20 mut/Mb subgroup (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2025.105058).

Relationship between bTMB and efficacy

In the bTMB BEP, all 784 (100.0%) patients received ≥1 dose of study treatment. At the primary OS analysis data cut-off (12 March 2021), similar OS benefit was observed for the T + D + CT and D + CT arms versus the CT arm in the bTMB BEP (HR 0.73, 95% CI 0.61-0.89 and HR 0.84, 95% CI 0.69-1.01, respectively) and ITT populations (HR 0.77, 95% CI 0.65-0.92 and HR 0.86, 95% CI 0.72-1.02, respectively; Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2025.105058).

Analyses of OS for the T + D + CT arm versus the CT arm showed that, at each bTMB cut-off, the magnitude of the OS benefit appeared greater among patients in the bTMB-high subgroups than in the bTMB-low subgroups (Figure 1A). For D + CT versus CT, the OS benefit was similar to slightly greater in the bTMB-high and bTMB-low subgroups (Figure 1B).

Figure 1.

Figure 1

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Forest plot of overall survival by treatment arm in blood TMB subgroups. OS in bTMB subgroups for (A) T + D + CT versus CT and (B) D + CT versus CT. Data cut-off: 12 March 2021. bTMB, blood tumor mutational burden; CI, confidence interval; CT, chemotherapy; D, durvalumab; HR, hazard ratio; ITT, intention-to-treat; Mb, megabase; mut, mutations; OS, overall survival; PD-L1, programmed cell death-ligand 1; T, tremelimumab. aHRs and 95% CIs were estimated from an unstratified Cox proportional hazards model. ITT analyses were stratified by PD-L1 expression (TC ≥50% versus <50%), histology (squamous versus nonsquamous), and disease stage (IVA versus IVB).

Kaplan–Meier curves for OS using a bTMB cut-off of 20 mut/Mb are shown in Figure 2. The median OS was longer with T + D + CT versus CT in both the bTMB ≥20 mut/Mb subgroup [median OS 13.5 months (95% CI 9.7-19.6 months) versus 10.3 months (95% CI 7.4-13.1 months)] and the bTMB <20 mut/Mb subgroup [median OS 12.6 months (95% CI 10.3-15.1 months) versus 10.9 months (95% CI 9.4-12.9 months)]. The HRs suggested that although OS benefit with T + D + CT versus CT was numerically higher in the bTMB ≥20 mut/Mb subgroup (HR 0.61, 95% CI 0.42-0.88), there was also notable benefit in the bTMB <20 mut/Mb subgroup (HR 0.79, 95% CI 0.63-0.99). Consistent with the ITT results, OS benefit for D + CT versus CT in the bTMB ≥20 and <20 mut/Mb subgroups was smaller than for T + D + CT versus CT, but also slightly higher in the bTMB-high than the bTMB-low subgroup. Updated OS analyses in the bTMB ≥20 and <20 mut/Mb subgroups after median follow-up of >5 years (data cut-off 24 August 2023) were similar to those obtained at the primary OS analysis data cut-off (Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2025.105058).

Figure 2.

Figure 2

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Kaplan-Meier plots of overall survival by treatment arm and blood TMB high/low status. OS by treatment arm in (A) bTMB ≥20 mut/Mb subgroup and (B) bTMB <20 mut/Mb subgroup. Data cut-off: 12 March 2021. HRs and CIs were estimated from an unstratified Cox proportional hazards model. bTMB, blood tumor mutational burden; CI, confidence interval; CT, chemotherapy; D, durvalumab; HR, hazard ratio; Mb, megabase; mut, mutations; OS, overall survival; T, tremelimumab.

At the PFS data cut-off (24 July 2019) there was a trend for PFS HRs in the TMB-high subgroups to improve at TMB cut-offs of 10, 12, and 20 mut/Mb but benefit (HR <1) was also observed within the TMB-low subgroups (Figure 3).

Figure 3.

Figure 3

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Forest plot of progression-free survival by treatment arm in blood TMB subgroups. PFS by BICR in bTMB subgroups for (A) T + D + CT versus CT and (B) D + CT versus CT. Data cut-off: 24 July 2019. BICR, blinded independent central review; bTMB, blood tumor mutational burden; CI, confidence interval; CT, chemotherapy; D, durvalumab; HR, hazard ratio; ITT, intention-to-treat; Mb, megabase; mut, mutations; PD-L1, programmed cell death-ligand 1; PFS, progression-free survival; T, tremelimumab. aHRs and CIs were estimated from an unstratified Cox proportional hazards model. ITT analyses were stratified by PD-L1 (TC ≥50% versus <50%), histology (squamous versus nonsquamous), and disease stage (IVA versus IVB).

There were trends toward improved benefits in OS (Figure 4A) and PFS (Figure 4B) with higher bTMB in subgroups with either PD-L1 TC <1% or ≥1% for the T + D + CT and D + CT arms versus the CT arm.

Figure 4.

Figure 4

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Kaplan-Meier plots of overall survival and progression-free survival by blood TMB high/low status and PD-L1 expression. (A) OSa and (B) PFSb by bTMB-high/low status and PD-L1 expression in the T + D + CT versus CT and D + CT versus CT arms. bTMB, blood tumor mutational burden; CI, confidence interval; CT, chemotherapy; D, durvalumab; HR, hazard ratio; Mb, megabase; mut, mutations; OS, overall survival; PD-L1, programmed cell death-ligand 1; PFS, progression-free survival; T, tremelimumab; TC, tumor cell. aData cut-off: 12 March 2021. bData cut-off: 24 July 2019. HRs and CIs were estimated from an unstratified Cox proportional hazards model.

Tumor response and DoR in the bTMB ≥20 and <20 mut/Mb subgroups are summarized in Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2025.105058. Confirmed ORRs were higher in the T + D + CT arm versus the CT arm in both bTMB ≥20 and <20 mut/Mb groups (42.7% versus 21.3%, and 38.3% versus 23.8%, respectively). Corresponding confirmed ORRs for the D + CT arm in the bTMB ≥20 and <20 mut/Mb groups were 49.4% and 39.1%, respectively. Median DoR was also longer in the T + D + CT arm and D + CT arm versus the CT arm in the bTMB ≥20 mut/Mb and bTMB <20 mut/Mb subgroups. The proportions of patients with ongoing response at 12 months were higher in the T + D + CT arm and D + CT arm than in the CT arm in the bTMB ≥20 mut/Mb and bTMB <20 mut/Mb subgroups.

Relationship between tTMB and efficacy

In the tTMB BEP, all 545 (100.0%) patients received ≥1 dose of study treatment. At the primary OS analysis data cut-off (12 March 2021), similar OS benefit for the T + D + CT and D + CT arms versus the CT arm was observed in the tTMB BEP (HR 0.79, 95% CI 0.63-1.00 and HR 0.76, 95% CI 0.60-0.95, respectively) and ITT populations (HR 0.77, 95% CI 0.65-0.92 and HR 0.86 95% CI 0.72-1.02, respectively; Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2025.105058).

Analyses of OS at tTMB cut-offs of 10, 13, and 16 mut/Mb showed that HRs for the T + D + CT arm compared with the CT arm in the high versus low tTMB subgroups at each cut-off were 0.63 (95% CI 0.44-0.91) versus 0.94 (95% CI 0.70-1.27); 0.53 (95% CI 0.32-0.87) versus 0.90 (95% CI 0.69-1.17); and 0.43 (95% CI 0.24-0.79) versus 0.90 (95% CI 0.70-1.16), respectively (Figure 5). In addition, the median OS in the T + D + CT arm increased with higher cut-offs for tTMB-high but did not increase in the CT arm (Figure 5). Corresponding OS HRs for the D + CT arm compared with the CT arm in the high versus low tTMB subgroups at each cut-off were 0.62 (95% CI 0.42-0.90) versus 0.87 (95% CI 0.65-1.16); 0.69 (95% CI 0.43-1.11) versus 0.78 (95% CI 0.60-1.01); and 0.61 (95% CI 0.34-1.09) versus 0.79 (95% CI 0.62-1.02), respectively (Figure 5). However, higher tTMB cut-offs had little impact on median OS for the comparison of the D + CT arm versus the CT arm (Figure 5).

Figure 5.

Figure 5

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Kaplan-Meier plots of overall survival by treatment arm and tissue TMB high/low status. OS in tTMB (A) ≥10 and <10, (B) ≥13 and <13, and (C) ≥16 and <16 mut/Mb subgroups for T + D + CT versus CT and D + CT versus CT. Data cut-off: 12 March 2021. HR and CI were estimated from an unstratified Cox proportional hazards model. CI, confidence interval; CT, chemotherapy; D, durvalumab; HR, hazard ratio; Mb, megabase; mOS, median OS, mut, mutations; NE, not estimable; OS, overall survival; T, tremelimumab; tTMB, tissue tumor mutational burden.

There were indications of improved benefits in OS and PFS (Supplementary Figure S4A and B, respectively, available at https://doi.org/10.1016/j.esmoop.2025.105058) with higher tTMB in subgroups with either PD-L1 TC <1% or ≥1% for the T + D + CT and D + CT arms versus the CT arm. However, with the exception of PFS in the tTMB ≥10 mut/Mb PD-L1 TC ≥1% subgroup, the upper 95% CIs of the OS and PFS HRs approached or crossed 1.

Discussion

These prespecified analyses from the phase III POSEIDON study tested whether bTMB is predictive of treatment benefit with T + D + CT and D + CT versus CT. Although bTMB did appear to be slightly predictive, the magnitude of benefit improvement was incremental and low bTMB did not necessarily define lack of benefit.

Evaluation of bTMB via liquid biopsy allows for rapid, less invasive testing compared with tissue-based approaches, typically resulting in a larger BEP than evaluation of tTMB, and its feasibility has been demonstrated in clinical trials.6,23, 24, 25, 26 It also might provide a more holistic view of mutation burden across primary and metastatic tumor sites, which may be missed when testing a single biopsy sample for tTMB analysis.

In this study, plasma and tissue samples for analysis of bTMB or tTMB were evaluable from 77.4% and 53.8% of the ITT population, respectively. Patients’ demographic and disease characteristics and outcomes in the bTMB and tTMB BEPs were broadly representative of the ITT population. The higher proportion of current/former smokers in the bTMB ≥20 versus <20 mut/Mb group was likely a reflection of the DNA-damaging effects of smoking as there is an established dose–response relationship between smoking history and TMB in advanced NSCLC,27 and was consistent with previous reports.6,9,28

OS and PFS benefit for T + D + CT versus CT was observed in both bTMB-high and bTMB-low subgroups at all cut-offs, although the magnitude of benefit appeared greater in the bTMB-high compared with bTMB-low subgroups. This was in line with expectations from mechanistic studies, which have indicated that higher TMB is correlated with more tumor neoantigens,12,14 and previous clinical trials of regimens combining tremelimumab and durvalumab in first-line treatment of patients with mNSCLC.6,9

bTMB and tTMB have been shown to be moderately correlated,9 whereas previous reports have indicated that there is no association between PD-L1 expression and TMB.6,9,28, 29, 30 Patients with PD-L1-negative tumors, or those with low levels of PD-L1 expression, are more likely to show primary resistance to anti-PD-(L)1 therapy than those with high levels of PD-L1 expression.31,32 In this analysis from POSEIDON, there were trends toward improved OS and PFS benefit with T + D + CT versus CT with higher TMB in patients with either PD-L1 TC <1% or ≥1%. In our analysis, within the PD-L1 TC <1% subgroup, T + D + CT, but not D + CT, provided OS and PFS benefit in bTMB-low patients, while for bTMB-high patients both D + T + CT and D + CT provided similar benefits compared with CT in both PD-L1 TC <1% and ≥1% subgroups. The second-line OAK study of atezolizumab versus docetaxel suggested that using both PD-L1 expression and TMB together may be a better predictor of outcomes with anti-PD-(L)1 monotherapy than either biomarker in isolation.33 However, the results of our analysis were in line with the concept that addition of anti-CTLA-4 therapy to anti-PD-(L)1 is able to provide increased benefit in the PD-L1 TC <1% subgroup, consistent with the finding in the first-line CheckMate 227 study that PFS benefit was greater with a combination of nivolumab plus ipilimumab than with chemotherapy in tTMB-high and -low patients with either PD-L1 TC <1% or ≥1%.10 In POSEIDON, despite T + D + CT appearing to provide benefit across all tested combinations of TMB and PD-L1 expression, addition of tremelimumab to durvalumab plus chemotherapy was associated with improvement in OS HR in the bTMB ≥20 mut/Mb subgroup in particular. The association of TMB-high with the treatment benefits of combining anti-CTLA-4, anti-PD-(L)1, and chemotherapy in our study was consistent with that seen with nivolumab plus ipilimumab plus chemotherapy in CheckMate 9LA.19

High tTMB (≥10 mut/Mb) has previously been found to be predictive of PFS benefit with anti-PD-(L)1 plus anti-CTLA-4 immunotherapy in patients with mNSCLC, although OS benefit was similar in patients with high and low tTMB.5,10,34 In KEYNOTE-042, tTMB with a cut-off of 175 mut/exome was associated with improved OS and PFS with pembrolizumab monotherapy versus chemotherapy. However, it was suggested that combining pembrolizumab with chemotherapy may reduce the predictive value of tTMB,30 in line with findings from the KEYNOTE-189 and -407 trials in which patients both below and above the 175 mut/exome cut-off derived PFS and OS benefit from pembrolizumab plus chemotherapy.29 In POSEIDON, there was a trend toward higher OS benefit for T + D + CT (versus CT) in TMB-high subgroups based on increasing tTMB cut-offs which was not clearly observed with D + CT, but, due to the small subgroup sizes, these findings should be interpreted with caution.

Potential limitations of these secondary and exploratory biomarker analyses include the fact that not all study patients were evaluable for TMB and the relatively small size of the subgroups at each TMB cut-off. Small differences between tTMB and bTMB were most likely due to qualitative differences in mutation detection and/or differences in evaluable patient populations. Although previous results have demonstrated a quantitative correlation between bTMB and tTMB scores in patients with mNSCLC, this does not necessarily imply qualitative concordance in the mutations identified by blood and tissue assays9,35,36; this has potential implications for the relative utility of each assay type across different patient subgroups.

Conclusions

In patients with mNSCLC, first-line treatment with a limited course of tremelimumab plus durvalumab (until progression) and four cycles of chemotherapy consistently improved clinical outcomes versus chemotherapy alone in both bTMB-high and -low subgroups, and also in both high and low tTMB subgroups. Benefit appeared greater in the TMB-high compared with TMB-low subgroups; the addition of anti-CTLA-4 to anti-PD-L1 and chemotherapy seemed to increase the magnitude of this difference. However, in view of the limited benefit, TMB testing is not warranted in this setting.

Acknowledgements

The POSEIDON study (NCT03164616) was funded by AstraZeneca. The authors thank the patients, their families, and caregivers, and all investigators involved in this study. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Simon Lancaster, BSc of Ashfield MedComms (Macclesfield, UK), an Inizio company, and funded by AstraZeneca.

Funding

This work was funded by AstraZeneca (no grant number).

Disclosure

SP has received education grants, provided consultation, attended advisory boards, and/or provided lectures for the following organizations, from whom she received honoraria (all fees to institution): consultation/advisory role: AbbVie, Amgen, Arcus, AstraZeneca, Bayer, Beigene, BioNTech, BerGenBio, Bicycle Therapeutics, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genmab, Genzyme, Gilead, GSK, Hutchmed, Illumina, Incyte, Ipsen, iTeos, Janssen, Qlucore, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Nuvation Bio, Nykode Therapeutics, Novartis, Novocure, Pharma Mar, Promontory Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda, and Zymeworks; talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Foundation Medicine, GSK, Illumina, Ipsen, Merck Sharp and Dohme, Mirati, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, and Takeda; receipt of grants/research support: principal investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, Arcus, AstraZeneca, Beigene, Bristol-Myers Squibb, Eli Lilly, GSK, iTeos, Merck Sharp and Dohme, Mirati, Pharma Mar, Promontory Therapeutics, Roche/Genentech, and Seattle Genetics. KSO is an employee of, and owns stocks in, AstraZeneca. AL'H is an employee of, and owns stocks in, AstraZeneca. MR is a consultant for AstraZeneca. HMad was an employee of AstraZeneca during the conduct of the study. ZL is an employee of, and owns stocks in, AstraZeneca. RS is an employee of, and owns stocks in, AstraZeneca. HMan is an employee of, and owns stocks in, AstraZeneca. CL is an employee of, and owns stocks in, AstraZeneca. EBG has received research grants, provided consultation, attended meetings for the following organizations: consultation/advisory role: AbbVie, Arcus, AstraZeneca, Arrivent, Atreca, Black Diamond Therapeutics, BridgeBio, Bristol Myers Squibb, EMD Serono, Eli Lilly, Gilead, Hookipa, I-Mab, iTeos, LianBio, Merck, Merus, Novartis, Nuvalent, Pfizer, Regeneron, Sanofi, Seagan, Sensei, Sumitomo, Strata, Summit, and Synthekine; support for attending meetings and/or travel: A2 Bio; receipt of grants/research support: ABL-Bio, Arrivent, AstraZeneca, BridgeBio, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck, Mirati, Novartis, Prelude, Regeneron, Synthekine, and TILT Biotherapeutics; TM owns stocks/shares, has provided consultation, attended advisory boards, board membership, and has received honoraria and consulting fees, grants or funds and travel support from the following organizations: ownership of stock/shares: Alentis Therapeutics AG, AstraZeneca, Aurora Tele-Oncology Ltd., Biolidics Ltd., HutchMed, Prenetics, D3 Bio, and Lunit Inc.; advisory role: AbbVie Inc., ACEA Pharma, Alentis Therapeutics AG, Amgen, AstraZeneca, BerGenBio ASA, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim, Bowtie Life Insurance Co Ltd., Bristol Myers Squibb, C4 Therapeutics Inc., Covidien LP, CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Daiichi Sankyo Inc., Eisai, Fishawack Facilitate Ltd., G1 Therapeutics Inc., Gilead Sciences Inc., Gritstone Oncology, Inc., Guardant Health, geneDecode Co. Ltd. (uncompensated), Hengrui Therapeutics Inc., HutchMed, Ignyta Inc., Incyte Corporation, Imagene AI Ltd., Inivata, IQVIA, Janssen, Lakeshore Biotech, Lily, Loxo-Oncology Inc., Lunit, Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., MiRXES Group, Novartis, OrigiMed, Pfizer, Prenetics, Puma Biotechnology Inc., Roche/Genentech, Regeneron Pharmaceuticals Inc., Sanofi-Aventis R&D, SFJ Pharmaceutical, Simcere of America Inc., Simcere Zaiming, Inc., Summit Therapeutics, Inc., Takeda, Vertex Pharmaceuticals, Virtus Medical Group, and Yuhan Corporation; board of directors: AstraZeneca PLC, HutchMed, Aurora, Insighta, and Epoch; honoraria: AbbVie Inc., ACEA Pharma, Adagene, Alentis Therapeutics AG, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AnHeart Therapeutics, AstraZeneca (before 1 January 2019), AVEO Pharmaceuticals, Inc., Bayer Healthcare Pharmaceuticals Ltd., BeiGene, BerGenBio ASA, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines Corporation, BMS, Bowtie Life Insurance Company Ltd., Bridge Biotherapeutics Inc., Covidien LP, C4 Therapeutics Inc., Cirina Ltd., CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, F. Hoffmann-La Roche Ltd., Genentech, GLG’s Healthcare, Fishawack Facilitate Ltd., G1 Therapeutics Inc., geneDecode Co., Ltd, Gilead Sciences, Inc. Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., HutchMed, Ignyta, Inc., Illumina, Inc., Incyte Corporation, Inivata, InxMed (Hong Kong) Limited, IQVIA, Janssen, Johnson & Johnson, Lakeshore Biotech Ltd, Lilly, Lunit USA, Inc., Loxo-Oncology, Lucence Health Inc., Medscape LLC/WebMD, Medtronic, Merck Serono, MSD, Mirati Therapeutics Inc., MiRXES, MoreHealth, New Frontier Group, Ningbo NewBay Technology Development Co., Ltd., Novartis, Novocure GmbH, Omega Therapeutics Inc., OrigiMed, OSE Immunotherapeutics, Phanes Therapeutics, Inc., PeerVoice, Pfizer, PrIME Oncology, Prenetics, Puma Biotechnology Inc., Qiming Development (HK) Ltd., Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Schrödinger, Inc., SFJ Pharmaceutical Ltd., Simcere of America Inc., Summit Therapeutics Sub, Inc., Synergy Research, Takeda Pharmaceuticals HK Ltd., Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, XENCOR, Inc., and Yuhan Corporation; consulting fees: AbbVie Inc., ACEA Pharma, Adagene, Alentis Therapeutics AG, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AnHeart Therapeutics, AstraZeneca (before 1 January 2019), AVEO Pharmaceuticals, Inc., Bayer Healthcare Pharmaceuticals Ltd., BeiGene, BerGenBio ASA, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines Corporation, BMS, Bowtie Life Insurance Company Limited, Bridge Biotherapeutics Inc., Covidien LP, C4 Therapeutics Inc., Cirina Ltd., CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, F. Hoffmann-La Roche Ltd., Genentech, GLG’s Healthcare, Fishawack Facilitate Ltd., G1 Therapeutics Inc., geneDecode Co., Ltd, Gilead Sciences, Inc. Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., HutchMed, Ignyta, Inc., Illumina, Inc., Incyte Corporation, Inivata, InxMed (Hong Kong) Ltd., IQVIA, Janssen, Johnson & Johnson, Lakeshore Biotech Ltd, Lilly, Lunit USA, Inc., Loxo-Oncology, Lucence Health Inc., Medscape LLC/WebMD, Medtronic, Merck Serono, MSD, Mirati Therapeutics Inc., MiRXES, MoreHealth, New Frontier Group, Ningbo NewBay Technology Development Co., Ltd., Novartis, Novocure GmbH, Omega Therapeutics Inc., OrigiMed, OSE Immunotherapeutics, Phanes Therapeutics, Inc., PeerVoice, Pfizer, PrIME Oncology, Prenetics, Puma Biotechnology Inc., Qiming Development (HK) Ltd., Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Schrödinger, Inc., SFJ Pharmaceutical Ltd., Simcere of America Inc., Summit Therapeutics Sub, Inc., Synergy Research, Takeda Pharmaceuticals HK Ltd., Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, XENCOR, Inc., and Yuhan Corporation; support for attending meetings and/or travel: AstraZeneca, MiRXES, Daiichi Sankyo, Novartis, Roche, AbbVie, Pfizer, Liangyihui, Zai Lab, and MSD; receipt of grants/research support (all fees to institution): AstraZeneca, BMS, G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, and XCovery. MLJ has received grants and provided consultation for the following organizations (all fees to institution): consultation/advisory role: AbbVie, Alentis Therapeutics, Amgen, Arcus Biosciences, Arrivent, AstraZeneca, Biohaven Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, D3 Bio Limited, Daiichi Sankyo, Fate Therapeutics, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Gritstone Oncology, Hookipa Biotech, Immunocore, Janssen, Jazz Pharmaceuticals, Lilly, Merck, Mirati Therapeutics, ModeX Therapeutics, Normunity, Novartis, Novocure, Pfizer, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, Sanofi-Aventis, SeaGen, Synthekine, Takeda Pharmaceuticals, and Zai Laboratory; receipt of grants/research support: AbbVie, Adaptimmune, Amgen, Arcus Biosciences, Array BioPharma, ArriVent BioPharma, Artios Pharma, AstraZeneca, Bayer, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Carisma Therapeutics, City of Hope National Medical Center, Conjupro Biotherapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Immuneering Corporation, Immunitas Therapeutics, Immunocore, Impact Therapeutics, Incyte, Janssen, Kartos Therapeutics, LockBody Therapeutics, Loxo Oncology, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, NextPoint Therapeutics, Novartis, Numab Therapeutics, Nuvalent, OncoC4, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Summit Therapeutics, Syndax Pharmaceuticals, Systimmune, Taiho Oncology, Takeda Pharmaceuticals, TCR2 Therapeutics, Tempest Therapeutics, TheRas, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, Vividion, Vyriad, and Y-mAbs Therapeutics.

Data Sharing

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data-sharing policy described at: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Data for studies directly listed on Vivli can be requested through Vivli at: https://vivli.org/.

Data for studies not listed on Vivli could be requested through Vivli at: https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/.

The AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.

Supplementary data

Supplementary Material
mmc1.pdf (934.4KB, pdf)

References

  • 1.Hendriks L.E., Kerr K.M., Menis J., et al. Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(4):358–376. doi: 10.1016/j.annonc.2022.12.013. [DOI] [PubMed] [Google Scholar]
  • 2.Shields M.D., Marin-Acevedo J.A., Pellini B. Immunotherapy for advanced non-small cell lung cancer: a decade of progress. Am Soc Clin Oncol Educ Book. 2021;41:1–23. doi: 10.1200/EDBK_321483. [DOI] [PubMed] [Google Scholar]
  • 3.Johnson M.L., Cho B.C., Luft A., et al. Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non-small-cell lung cancer: the Phase III POSEIDON Study. J Clin Oncol. 2023;41(6):1213–1227. doi: 10.1200/JCO.22.00975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Peters S., Cho B.C., Luft A.V., et al. Durvalumab with or without tremelimumab in combination with chemotherapy in first-line metastatic NSCLC: five-year overall survival outcomes from the phase 3 POSEIDON trial. J Thorac Oncol. 2024;20(1):76–93. doi: 10.1016/j.jtho.2024.09.1381. [DOI] [PubMed] [Google Scholar]
  • 5.Hellmann M.D., Paz-Ares L., Bernabe Caro R., et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381(21):2020–2031. doi: 10.1056/NEJMoa1910231. [DOI] [PubMed] [Google Scholar]
  • 6.Rizvi N.A., Cho B.C., Reinmuth N., et al. Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: the MYSTIC phase 3 randomized clinical trial. JAMA Oncol. 2020;6(5):661–674. doi: 10.1001/jamaoncol.2020.0237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Paz-Ares L., Ciuleanu T.E., Cobo M., et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):198–211. doi: 10.1016/S1470-2045(20)30641-0. [DOI] [PubMed] [Google Scholar]
  • 8.Carbone D.P., Reck M., Paz-Ares L., et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017;376(25):2415–2426. doi: 10.1056/NEJMoa1613493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.de Castro G., Jr., Rizvi N.A., Schmid P., et al. NEPTUNE: phase 3 study of first-line durvalumab plus tremelimumab in patients with metastatic NSCLC. J Thorac Oncol. 2023;18(1):106–119. doi: 10.1016/j.jtho.2022.09.223. [DOI] [PubMed] [Google Scholar]
  • 10.Hellmann M.D., Ciuleanu T.E., Pluzanski A., et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093–2104. doi: 10.1056/NEJMoa1801946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Meng G., Liu X., Ma T., Lv D., Sun G. Predictive value of tumor mutational burden for immunotherapy in non-small cell lung cancer: a systematic review and meta-analysis. PLoS One. 2022;17(2) doi: 10.1371/journal.pone.0263629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Jardim D.L., Goodman A., de Melo Gagliato D., Kurzrock R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell. 2021;39(2):154–173. doi: 10.1016/j.ccell.2020.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Maleki Vareki S. High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J Immunother Cancer. 2018;6(1):157. doi: 10.1186/s40425-018-0479-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Moeckel C., Bakhl K., Georgakopoulos-Soares I., Zaravinos A. The efficacy of tumor mutation burden as a biomarker of response to immune checkpoint inhibitors. Int J Mol Sci. 2023;24(7):6710. doi: 10.3390/ijms24076710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Ricciuti B., Wang X., Alessi J.V., et al. Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels. JAMA Oncol. 2022;8(8):1160–1168. doi: 10.1001/jamaoncol.2022.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Budczies J., Kazdal D., Menzel M., et al. Tumour mutational burden: clinical utility, challenges and emerging improvements. Nat Rev Clin Oncol. 2024;21(10):725–742. doi: 10.1038/s41571-024-00932-9. [DOI] [PubMed] [Google Scholar]
  • 17.Marabelle A., Fakih M., Lopez J., et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353–1365. doi: 10.1016/S1470-2045(20)30445-9. [DOI] [PubMed] [Google Scholar]
  • 18.FDA FoundationOne®CDx (F1CDx) FDA Summary of Safety and Effectiveness Data (SSED) 2020. PMA P170019/S170016. https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170019S016B.pdf Available at.
  • 19.Paz-Ares L., Ciuleanu T.E., Cobo M., et al. 98O First-line nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles chemotherapy (chemo) vs 4 cycles chemo in advanced non-small cell lung cancer (aNSCLC): association of blood and tissue tumor mutational burden (TMB) with efficacy in CheckMate 9LA. J Thorac Oncol. 2021;16(4):S750–S751. [Google Scholar]
  • 20.Rami-Porta R. 2nd ed. Editorial Rx Press for the International Association for the Study of Lung Cancer (IASLC); 2016. Staging Manual in Thoracic Oncology.https://www.iaslc.org/research-education/publications-resources-guidelines/staging-manual-thoracic-oncology-2nd-edition Available at. [Google Scholar]
  • 21.Eisenhauer E.A., Therasse P., Bogaerts J., et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45(2):228–247. doi: 10.1016/j.ejca.2008.10.026. [DOI] [PubMed] [Google Scholar]
  • 22.Marcus L., Fashoyin-Aje L.A., Donoghue M., et al. FDA approval summary: pembrolizumab for the treatment of tumor mutational burden–high solid tumors. Clin Cancer Res. 2021;27(17):4685–4689. doi: 10.1158/1078-0432.CCR-21-0327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Herbst R.S., Giaccone G., de Marinis F., et al. Atezolizumab for first-line treatment of PD-L1–selected patients with NSCLC. N Engl J Med. 2020;383(14):1328–1339. doi: 10.1056/NEJMoa1917346. [DOI] [PubMed] [Google Scholar]
  • 24.Aggarwal C., Thompson J.C., Chien A.L., et al. Baseline plasma tumor mutation burden predicts response to pembrolizumab-based therapy in patients with metastatic non-small cell lung cancer. Clin Cancer Res. 2020;26(10):2354–2361. doi: 10.1158/1078-0432.CCR-19-3663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Kim E.S., Velcheti V., Mekhail T., et al. Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: the phase 2 B-F1RST trial. Nat Med. 2022;28(5):939–945. doi: 10.1038/s41591-022-01754-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Peters S., Dziadziuszko R., Morabito A., et al. Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial. Nat Med. 2022;28(9):1831–1839. doi: 10.1038/s41591-022-01933-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Wang X., Ricciuti B., Nguyen T., et al. Association between smoking history and tumor mutation burden in advanced non-small cell lung cancer. Cancer Res. 2021;81(9):2566–2573. doi: 10.1158/0008-5472.CAN-20-3991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Willis C., Bauer H., Au T.H., et al. Real-world survival analysis by tumor mutational burden in non-small cell lung cancer: a multisite U.S. study. Oncotarget. 2022;13:257–270. doi: 10.18632/oncotarget.28178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Garassino M.C., Gadgeel S., Novello S., et al. Associations of tissue tumor mutational burden and mutational status with clinical outcomes with pembrolizumab plus chemotherapy versus chemotherapy for metastatic NSCLC. JTO Clin Res Rep. 2023;4(1) doi: 10.1016/j.jtocrr.2022.100431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Mok T.S.K., Lopes G., Cho B.C., et al. Associations of tissue tumor mutational burden and mutational status with clinical outcomes in KEYNOTE-042: pembrolizumab versus chemotherapy for advanced PD-L1-positive NSCLC. Ann Oncol. 2023;34(4):377–388. doi: 10.1016/j.annonc.2023.01.011. [DOI] [PubMed] [Google Scholar]
  • 31.Fernandez A.I., Gavrielatou N., McCann L., et al. Programmed death-ligand 1 and programmed death-ligand 2 mRNAs measured using closed-system quantitative real-time polymerase chain reaction are associated with outcome and high negative predictive value in immunotherapy-treated NSCLC. J Thorac Oncol. 2022;17(9):1078–1085. doi: 10.1016/j.jtho.2022.06.007. [DOI] [PubMed] [Google Scholar]
  • 32.Sun D., Liu J., Zhou H., et al. Classification of tumor immune microenvironment according to programmed death-ligand 1 expression and immune infiltration predicts response to immunotherapy plus chemotherapy in advanced patients with NSCLC. J Thorac Oncol. 2023;18(7):869–881. doi: 10.1016/j.jtho.2023.03.012. [DOI] [PubMed] [Google Scholar]
  • 33.Gandara D.R., Paul S.M., Kowanetz M., et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24(9):1441–1448. doi: 10.1038/s41591-018-0134-3. [DOI] [PubMed] [Google Scholar]
  • 34.Ready N., Hellmann M.D., Awad M.M., et al. First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568): outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers. J Clin Oncol. 2019;37(12):992–1000. doi: 10.1200/JCO.18.01042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Si H., Kuziora M., Quinn K.J., et al. A blood-based assay for assessment of tumor mutational burden in first-line metastatic NSCLC treatment: results from the MYSTIC study. Clin Cancer Res. 2021;27(6):1631–1640. doi: 10.1158/1078-0432.CCR-20-3771. [DOI] [PubMed] [Google Scholar]
  • 36.Sturgill E.G., Misch A., Jones C.C., et al. Discordance in tumor mutation burden from blood and tissue affects association with response to immune checkpoint inhibition in real-world settings. Oncologist. 2022;27(3):175–182. doi: 10.1093/oncolo/oyab064. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

Supplementary Material
mmc1.pdf (934.4KB, pdf)

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