Programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) is the primary clinically-available biomarker of response to immunotherapy in non-small-cell lung cancer (NSCLC), but factors ...associated with PD-L1 expression are not well understood.
Consecutive nonsquamous NSCLCs with successful PD-L1 assessment and targeted next-generation sequencing were included in this retrospective study. Clinicopathological characteristics, gene mutations, and copy number changes in gene and chromosomal arms were compared among three PD-L1 expression groups: negative (TPS < 1%), low (TPS 1%–49%), and high (TPS ≥ 50%). A Q-value <0.25 was considered significant after multiple comparisons correction.
A total of 909 nonsquamous NSCLCs were included. High PD-L1 expression compared with low and negative PD-L1 expression was associated with increased tobacco exposure (median pack-years: 25 versus 20 versus 20, respectively; P = 0.01), advanced stage at diagnosis (76% versus 67% versus 61% with advanced stage of disease, respectively; P < 0.001), and higher tumor mutational burden (TMB) (median 12.2 versus 10.6 versus 10.6 mutations/megabase, respectively; P < 0.001). Negative PD-L1 expression when compared with high PD-L1 expression was associated with: mutations in STK11 (19% versus 5%; Q < 0.001), EGFR (22% versus 11%; Q < 0.001), CTNNB1 (4.3% versus 0.4%; Q = 0.04), APC (5% versus 1%; Q = 0.17), and SMARCA4 (9% versus 4%; Q = 0.20); copy number loss of CD274 (PD-L1, 28% versus 6%; Q < 0.001), PDCD1LG2 (PD-L2, 28% versus 6%; Q < 0.001), and JAK2 genes (27% versus 7%; Q < 0.001), loss of chromosomal arm 9p (23% versus 10%; Q = 0.04), and gain of 1q (46% versus 21%; Q < 0.001). High PD-L1 expression compared with negative PD-L1 expression was associated with copy number gain of CD274 (11% versus 3%; Q = 0.01) and PDCD1LG2 (11% versus 3%; Q = 0.01). NSCLCs with CD274 loss, compared with those without loss, had a lower response rate (23% versus 9%; P = 0.006) and shorter progression-free survival (3.3 versus 2.0 months; P = 0.002) on immunotherapy.
PD-L1 expression is associated with specific genomic alterations and clinicopathologic characteristics in nonsquamous NSCLC.
•PD-L1 expression is highly variable in nonsquamous NSCLC and is associated with distinct clinicopathological and genomic features.•Tobacco exposure, stage at diagnosis, and tumor mutational burden are associated with PD-L1 expression.•PD-L1 expression ≥50% is associated with copy gain of CD274 (PD-L1), PDCD1LG2 (PD-L2), JAK2, and the 9p24.1 locus.•PD-L1 negativity is associated with STK11, EGFR, CTNNB1, APC, and SMARCA4 mutations, as well as loss of CD274, PDCD1LG2, JAK2, and the 9p24.1 locus.•CD274 copy loss is associated with lower response rate and shorter progression-free survival to immune checkpoint inhibitors in NSCLC.
In non-small-cell lung cancers with programmed death-ligand 1 (PD-L1) expression on ≥50% of tumor cells, first-line treatment with the PD-1 inhibitor pembrolizumab improves survival compared with ...platinum-doublet chemotherapy. Whether higher PD-L1 levels within the expression range of 50%–100% predict for even greater benefit to pembrolizumab is currently unknown.
In this multicenter retrospective analysis, we analyzed the impact of PD-L1 expression levels on the overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients who received commercial pembrolizumab as first-line treatment of non-small-cell lung cancer (NSCLC) with a PD-L1 expression of ≥50% and negative for genomic alterations in the EGFR and ALK genes.
Among 187 patients included in this analysis, the ORR was 44.4% 95% confidence interval (CI) 37.1% to 51.8%, the mPFS was 6.5 months (95% CI 4.5–8.5), and the mOS was not reached. The median PD-L1 expression level among patients who experienced a response to pembrolizumab was significantly higher than among patients with stable or progressive disease (90% versus 75%, P < 0.001). Compared with patients with PD-L1 expression of 50%–89% (N = 107), patients with an expression level of 90%–100% (N = 80) had a significantly higher ORR (60.0% versus 32.7%, P < 0.001), a significantly longer mPFS 14.5 versus 4.1 months, hazard ratio (HR) 0.50 (95% CI 0.33–0.74), P < 0.01, and a significantly longer mOS not reached versus 15.9 months, HR 0.39 (95% CI 0.21–0.70), P = 0.002.
Among patients with NSCLC and PD-L1 expression of ≥50% treated with first-line pembrolizumab, clinical outcomes are significantly improved in NSCLCs with a PD-L1 expression of ≥90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design.
Immune checkpoint inhibitors (ICIs) are standard therapies for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. ...Tumor mutation burden (TMB) also predicts response to ICIs but is often not available in real time for decision making in the first-line setting. Smoking exposure can be a proxy for TMB in NSCLC. The impact of smoking status on efficacy of PD-1 blockade in NSCLC patients with PD-L1 TPS ≥50% has not been well defined.
To investigate the relationship between smoking and activity of ICIs in NSCLC, we retrospectively studied 315 patients with NSCLC and PD-L1 TPS ≥50% at five USA academic medical centers. Objective response rates (ORRs), progression-free survival (PFS), and duration of response (DOR) were compared between never (<100 lifetime cigarettes), light (≤10 pack-years), and heavy (>10 pack-years) smokers. A subset of patients underwent next-generation sequencing to estimate TMB.
We identified 36 (11%) never, 42 (13%) light, and 237 (75%) heavy smokers with NSCLC and PD-L1 TPS ≥50% treated with ICIs. Objective responses were observed in 27%, 40%, and 40% of never, light, and heavy smokers, respectively (P = 0.180 never versus heavy; P = 1.000 light versus heavy). Median PFS and median DOR were numerically shorter in never and light smokers compared with heavy smokers (PFS 3.0 versus 4.0 versus 5.4 months; median DOR 6.9 versus 10.8 versus 17.8 months), but were not statistically different PFS: hazard ratio (HR) 1.37, P = 0.135 and HR 1.24, P = 0.272; DOR: HR 1.92, P = 0.217 and HR 1.79, P = 0.141.
PD-(L)1 inhibitors are associated with antitumor activity in NSCLC with PD-L1 TPS ≥50% regardless of smoking status. Nevertheless, there is a signal of potentially decreased durability among never and light smokers that should be further evaluated. Distinct immunobiologic features may affect initial response versus durability of antitumor immunity to programmed cell death 1 (PD-1) blockade.
•In patients with NSCLC and PD-L1 ≥50%, TMB is lower in never and light smokers compared with heavy smokers.•PD-(L)1 inhibitors are active in a significant subset of never and light smokers with NSCLC and PD-L1 ≥50%.•Nonetheless, we observed numerically shorter PFS/DOR among never and light smokers compared to heavy smokers.•Distinct immunobiologic features may underlie initial response versus durability of response to PD-1 inhibitors in NSCLC.
Prior antibiotic therapy (pATB) is known to impair efficacy of single-agent immune checkpoint inhibitors (ICIs), potentially through the induction of gut dysbiosis. Whether ATB also affects outcomes ...to chemo-immunotherapy combinations is still unknown.
In this international multicentre study, we evaluated the association between pATB, concurrent ATB (cATB) and overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in patients with non-small-cell lung cancer (NSCLC) treated with first-line chemo-immunotherapy at eight referral institutions.
Among 302 patients with stage IV NSCLC, 216 (71.5%) and 61 (20.2%) patients were former and current smokers, respectively. Programmed death-ligand 1 tumour expression in assessable patients (274, 90.7%) was ≥50% in 76 (25.2%), 1%-49% in 84 (27.9%) and <1% in 113 (37.5%). Multivariable analysis showed pATB-exposed patients to have similar OS {hazard ratio (HR) = 1.42 95% confidence interval (CI): 0.91-2.22; P = 0.1207} and PFS HR = 1.12 (95% CI: 0.76-1.63); P = 0.5552, compared to unexposed patients, regardless of performance status. Similarly, no difference with respect to ORR was found across pATB exposure groups (42.6% versus 57.4%, P = 0.1794). No differential effect was found depending on pATB exposure duration (≥7 versus <7 days) and route of administration (intravenous versus oral). Similarly, cATB was not associated with OS HR = 1.29 (95% CI: 0.91-1.84); P = 0.149 and PFS HR = 1.20 (95% CI: 0.89-1.63); P = 0.222 when evaluated as time-varying covariate in multivariable analysis.
In contrast to what has been reported in patients receiving single-agent ICIs, pATB does not impair clinical outcomes to first-line chemo-immunotherapy of patients with NSCLC. pATB status should integrate currently available clinico-pathologic factors for guiding first-line treatment decisions, whilst there should be no concern in offering cATB during chemo-immunotherapy when needed.
Tumor mutational burden (TMB) is a biomarker that measures the number of somatic mutations in a tumor’s genome. TMB has emerged as a predictor of response to immune checkpoint inhibitors (ICIs) in ...various cancer types, and several studies have shown that patients with high TMB have better outcomes when treated with programmed death-ligand 1-based therapies. Recently, the Food and Drug Administration has approved TMB as a companion diagnostic for the use of pembrolizumab in solid tumors. However, despite its potential, the use of TMB as a biomarker for immunotherapy efficacy is limited by several factors. Here we review the limitations of TMB in predicting immunotherapy outcomes in patients with cancer and discuss potential strategies to optimize its use in the clinic.
•TMB has been proposed as a biomarker of ICI efficacy across cancers, but its use in the clinic remains elusive.•Technical and biological factors limit the accuracy of TMB for the prediction of ICI efficacy in patients with cancer.•Cancer-specific thresholds should be considered to identify patients who are most likely to benefit from ICI.•TMB standardization and integration with other biomarkers can improve its predictive accuracy in patients with cancer.
Programmed death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy in ...non-small-cell lung cancer (NSCLC). Data on their variation across multiple samples are limited.
Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation.
In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ = 0.53, P < 0.0001) and high for TMB (ρ = 0.80, P < 0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS ≥ +50%) and decreases (ΔTPS ≤ −50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P = 0.02). Acquired copy number loss of CD274, PDCD1LG2, and JAK2 were associated with major decrease in PD-L1 (q < 0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and overall survival to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment.
Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment before ICI initiation when feasible.
•Intrapatient paired PD-L1 TPS and TMB assessments have good concordance.•Variations in PD-L1 TPS and TMB with clinical implications may occur.•Intervening ICI therapy is associated with decrease in PD-L1 TPS.•Copy number loss in CD274, PDCD1LG2, and JAK2 genes are strongly associated with major decrease in PD-L1 TPS (−50% to −100%).•Variations in PD-L1 TPS and TMB have significant impact on outcomes to a subsequent ICI-based therapy.
KEAP1 mutations have been associated with reduced survival in lung adenocarcinoma (LUAD) patients treated with immune checkpoint inhibitors (ICIs), particularly in the presence of STK11/KRAS ...alterations. We hypothesized that, beyond co-occurring genomic events, clonality prediction may help identify deleterious KEAP1 mutations and their counterparts with retained sensitivity to ICIs.
Beta-binomial modelling of sequencing read counts was used to infer KEAP1 clonal inactivation by combined somatic mutation and loss of heterozygosity (KEAP1 C-LOH) versus partial inactivation KEAP1 clonal diploid-subclonal (KEAP1 CD-SC) in the Memorial Sloan Kettering Cancer Center (MSK) MetTropism cohort (N = 2550). Clonality/LOH prediction was compared to a streamlined clinical classifier that relies on variant allele frequencies (VAFs) and tumor purity (TP) (VAF/TP ratio). The impact of this classification on survival outcomes was tested in two independent cohorts of LUAD patients treated with immunotherapy (MSK/Rome N = 237; DFCI N = 461). Immune-related features were studied by exploiting RNA-sequencing data (TCGA) and multiplexed immunofluorescence (DFCI mIF cohort).
Clonality/LOH inference in the MSK MetTropism cohort overlapped with a clinical classification model defined by the VAF/TP ratio. In the ICI-treated MSK/Rome discovery cohort, predicted KEAP1 C-LOH mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAP1 wild-type cases (PFS log-rank P = 0.001; OS log-rank P < 0.001). Similar results were obtained in the DFCI validation cohort (PFS log-rank P = 0.006; OS log-rank P = 0.014). In both cohorts, we did not observe any significant difference in survival outcomes when comparing KEAP1 CD-SC and wild-type tumors. Immune deconvolution and multiplexed immunofluorescence revealed that KEAP1 C-LOH and KEAP1 CD-SC differed for immune-related features.
KEAP1 C-LOH mutations are associated with an immune-excluded phenotype and worse clinical outcomes among advanced LUAD patients treated with ICIs. By contrast, survival outcomes of patients whose tumors harbored KEAP1 CD-SC mutations were similar to those with KEAP1 wild-type LUADs.
•Variant allele frequency and tumor purity frame deleterious KEAP1 mutations in LUAD.•Clonal KEAP1 mutations with LOH (KEAP1 C-LOH) define a subset of LUAD patients unresponsive to immunotherapy.•Preserved immunotherapy efficacy was noticed in tumors with clonal diploid/subclonal KEAP1 mutations (KEAP1 CD-SC).•Immune-related pathways and markers were differentially represented across KEAP1 C-LOH, KEAP1 CD-SC, and wild-type tumors.
Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRASMUT) non-small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in ...underlying biology shaped by co-mutations. In contrast to KRASG12C NSCLC, KRASG12D NSCLC is associated with low/never-smoking status and is largely uncharacterized.
Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype.
Of 2327 patients with KRAS-mutated (KRASMUT) NSCLC, 15% (n = 354) harbored KRASG12D. Compared to KRASnon-G12D NSCLC, KRASG12D NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRASG12D had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRASnon-G12D (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRASG12D had lower intratumoral and total CD8+PD1+ T cells (P < 0.05). Among 850 patients with advanced KRASMUT NSCLC who received PD-(L)1-based therapies, KRASG12D was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003, and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09 compared to KRASnon-G12D.
KRASG12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRASG12D lung cancers will have to take these differences into account.
•Among KRAS NSCLC, KRASG12D NSCLC defines a subset with a lower pack-year smoking history, lower PD-L1 TPS, and lower TMB.•The smoking history among KRASG12D NSCLC is bimodal—those with a greater smoking history have higher PD-L1 TPS and TMB.•KRASG12D NSCLC is associated with diminished infiltration of CD8+ T cells.•Patients with KRASG12D NSCLC experience worse clinical outcomes to PD-(L)1 inhibition compared to KRASnon-G12D NSCLC.•KRASG12D NSCLC may respond better to chemotherapy added to PD-1 blockade, especially with a low smoking history/unknown PD-L1/TMB.
Ricciuti B, Genova C, Crinò L, Libra M, Leonardi GC.Onco Targets Ther. 2019;12:3171-3179. Lucio Crinò has advised that affiliation 3 is incorrect. Thecorrect affiliation 3 should be as ...follows:Department of Medical Oncology, Istituto ScientificoRomagnolo per lo Studio e la Cura dei Tumori (IRSTIRCCS), Meldola, Italy.Read the original article
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