First-line Pembrolizumab In Patients Research Articles

Three-Year Overall Survival of Patients With Advanced Non-Small-Cell Lung Cancers With ≥50% PD-L1 Expression Treated With First-Line Pembrolizumab Monotherapy in a Real-World Setting (ESCKEYP GFPC Study).

Outside clinical trials, few data are available on the effect of long-term first-line pembrolizumab in patients with advanced non-small-cell lung cancers with ≥50% of tumor cells expressing programmed cell death ligand 1 (PD-L1). This French, multicenter study included consecutive advanced patients with non-small-cell lung cancer given first-line pembrolizumab alone between May 2017 (authorization date for this indication) and November 2019 (authorization date for pembrolizumab-chemotherapy combination). Information was collected from patients' medical files, with a local evaluation of the response and progression-free survival (PFS). Overall survival (OS) was calculated from pembrolizumab onset using the Kaplan-Meier method. The analysis concerned 845 patients, managed in 33 centers: median age: 65 (range: 59-72) years, 67.8% men, 78.1% Eastern Cooperative Oncology Group performance status 0/1, 38.9%/51.5%/6.6% active, ex or never-smokers, respectively, 10.9%/16.8% taking or recently took corticosteroids/antibiotics, 69.6% nonsquamous histology, 48.9% ≥75% PD-L1-positive, and 20.8% had brain metastases at diagnosis. After a median (95% CI) follow-up of 45 (44.1-45.9) months, respective median (95% CI) PFS and OS lasted 8.2 (6.9-9.2) and 22 (8.5-25.9) months; 3-year PFS and OS rates were 25.4% and 39.4%, respectively. Multivariate analysis retained never-smoker status, adenocarcinoma histology, Eastern Cooperative Oncology Group performance status ≥2, and neutrophil/lymphocyte ratio >4 as being significantly associated with shorter survival, but not brain metastases at diagnosis or <75% PD-L1 tumor-cell expression. These long-term results of pembrolizumab efficacy based on a nationwide "real-world" cohort reproduced those obtained in clinical trials.

1476P Outcomes to first-line pembrolizumab in patients with advanced NSCLC and high PD-L1 expression: A Spanish multicentric study

1476P Outcomes to first-line pembrolizumab in patients with advanced NSCLC and high PD-L1 expression: A Spanish multicentric study

PEOPLE (NTC03447678), a phase II trial to test pembrolizumab as first-line treatment in patients with advanced NSCLC with PD-L1

BackgroundChemoimmunotherapy represents the standard of care for patients with advanced non-small cell lung cancer (NSCLC) and programmed death-ligand 1 (PD-L1) <50%. Although single-agent pembrolizumab has also demonstrated some activity in...

Uptake of second-line anticancer therapy after first-line pembrolizumab in patients with stage IV non–small cell lung cancer with PD-L1 &gt; 50%: Comparison between clinical trials and the real world.

126 Background: In KEYNOTE-024 single agent pembrolizumab was compared to platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC) with PDL1 &gt;50%. Patients treated with pembrolizumab had an improved progression free survival and overall survival (OS). In KEYNOTE-024, 53% of patients treated with pembrolizumab received second line anticancer therapy with a median OS of 26.3 months. The objective of this study is to characterize real-world NSCLC patients who received second line therapy after pembrolizumab. Methods: A retrospective study of stage IV NSCLC patients with PDL1 &gt;50% referred to BC Cancer between 2018-2021 treated with first line pembrolizumab. Patient demographics, treatment received, and outcomes were collected retrospectively. Baseline characteristics were compared using descriptive statistics. Univariate and multivariate analysis was completed. Kaplan-Meier curves was used to calculate OS and compared using the log rank test. Results: Between 2018-2021, 718 Stage IV NSCLC patients received at least 1 cycle of pembrolizumab. Median duration on treatment was 4.4 months and follow up duration was 16.0 months. 567 (80%) had disease progression of which only 21% (n = 119) received second line systemic therapy. Within the subset with disease progression, median duration on treatment was 3.0 months and follow up duration was 11.7 months. Patients who received second line therapy were younger (p &lt; 0.001), better baseline ECOG PS (p &lt; 0.001) and had longer duration on first line pembrolizumab (p &lt; 0.001). There was no difference in sex (p = 0.519), smoking status (p = 0.416) or histology (p = 0.136). In the multivariate model including age (OR 0.95), baseline ECOG PS (PS 0-1, OR 2.59) and duration on pembrolizumab (OR 1.05) each independently impacted receipt of second line therapy, Table. Median OS from date of diagnosis was 9.6 (IQR 8.4-10.9) months in patients who did not receive additional therapy after progression and 25.3 (IQR 22.5-28.1) months in patients who received subsequent therapy, (p &lt; 0.001). Conclusions: In our stage IV NSCLC population, we found that only 21% of patients received second line systemic therapy despite it being associated with improved OS. Compared to KEYNOTE-024, this real-world population found that 60% less patients received second line systemic therapy. Although differences exist between a clinical and non-clinical trial population, these findings suggest significantly undertreating our stage IV NSCLC patients requiring increased rates of offering second line therapy.[Table: see text]

Immunophenotypic correlates and response to first-line pembrolizumab among elderly patients with PD-L1-high (≥ 50%) non–small cell lung cancer.

9054 Background: Older age is associated with increased levels of systemic inflammation and altered immunosurveillance in cancer. Whether aging correlates with a distinct immunophenotype or impacts clinical outcomes to first-line pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) of ≥50% is unclear. Methods: We performed a retrospective analysis of patients with NSCLC. Multiplexed immunofluorescence (mIF) for CD8+, PD-1+, PD-1+CD8+ and FOXP3+ was performed to explore tumor immunophenotype. Clinical outcomes were analyzed on a separate cohort of patients with PD-L1-high (TPS of ≥50%) NSCLC (negative for sensitizing genomic alterations in EGFR and ALK) who received treatment with first-line pembrolizumab. Variables demonstrating a univariate signal of association of p &lt; 0.1 were included in the multivariate model. The results were compared in patients &lt; 80 vs ≥80 years old. Results: Among 541 patients with NSCLCs profiled by mIF, the median age was 67 (28-90). When comparing patients &lt; 80y (n = 497) to ≥80y (n = 44), there was no difference in median CD8+ T cells/mm2 (171 vs 148; p = 0.69), PD-1+ immune cells/mm2 (81.1 vs 87.2; p = 0.95), or PD-1+CD8+ T cells/mm2 (18.0 vs 13.1; p = 0.56). NSCLCs from patients ≥80y had a higher median of intratumoral-associated FOXP3+ T cells/mm2 (63.6 vs 91.1; p = 0.03). In a cohort of 271 patients with PD-L1 ≥50% who received first-line pembrolizumab, baseline clinicopathological characteristics were balanced in the &lt; 80y (n = 225) vs ≥80y (n = 46) groups in terms of sex, tobacco use, Eastern Cooperative Oncology Group-Performance Status (ECOG-PS), histology, presence of potentially targetable driver mutations (KRAS, MET, BRAF, HER2, RET), and PD-L1 TPS distribution (50-89% vs ≥90%). Compared to patients &lt; 80y, patients ≥80y had no difference in objective response rate (ORR 39.1% vs 28.2%; p = 0.22) or median progression-free survival (mPFS 6.0 vs 3.0 months; p = 0.16). However, patients ≥80y had a shorter median overall survival (mOS 25.7 vs 7.6 months; p = 0.02), and this result remained significant after adjusting for ECOG-PS. Among those who experienced disease progression on pembrolizumab, patients ≥80y were significantly less likely to receive any second-line systemic therapy compared to patients &lt; 80y (55.6% vs 30.8%; p = 0.008). Conclusions: In patients with NSCLC and PD-L1 ≥50%, the ORR and mPFS to first-line pembrolizumab were similar between patients &lt; vs ≥80 years old. OS was shorter among patients ≥80y, potentially reflecting lower use of second-line therapy in elderly patients after progression on pembrolizumab. The immunophenotypic correlates of NSCLC in older patients need further investigation.

Cancer cachexia as a determinant of efficacy of first-line pembrolizumab in patients with advanced non-small cell lung cancer.

Pembrolizumab, either as a type of monotherapy or in combination with cytotoxic anticancer agents, is effective in the treatment of advanced non-small cell lung cancer (NSCLC). However, the development of cancer cachexia may adversely affect anticancer drug therapy. The present study investigated the effect of cancer cachexia on clinical outcomes in patients with advanced NSCLC who received first-line pembrolizumab. The data of patients with advanced NSCLC receiving first-line monotherapy or combination therapy with pembrolizumab were retrospectively analyzed. The primary endpoint was time to treatment failure (TTF), and the secondary endpoints were overall survival (OS) and incidence of adverse events (AEs). Clinical outcome was compared between patients with and without cancer cachexia. A total of 53 patients were analyzed. Among all patients, median TTF and OS were significantly shorter in patients with cancer cachexia than in those without [TTF: 5.8 vs. 10 months; hazard ratio (HR): 2.13; 95% confidence interval (CI): 1.07-4.24; P=0.016; OS: 12.1 months vs. not reached; HR: 5.85; 95% CI: 2.0-17.1; P=0.001]. In addition, TTF in the pembrolizumab monotherapy group was significantly shorter in patients with cancer cachexia than in those without, but no significant difference was detected in patients receiving pembrolizumab combination therapy. The incidence of AEs did not significantly differ between patients with and without cancer cachexia, except with regard to hypothyroidism. In conclusion, although cancer cachexia is prognostic of a poor outcome in patients with advanced NSCLC who receive first-line pembrolizumab, cancer cachexia might not affect therapeutic efficacy in combination therapy with pembrolizumab and cytotoxic anticancer agents.

Low peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is associated with increased tumor T-cell infiltration and favorable outcomes to first-line pembrolizumab in non-small cell lung cancer

BackgroundAn elevated peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is a negative prognostic marker for patients with non-small cell lung cancer (NSCLC) receiving chemotherapy and immune checkpoint inhibitors. Whether dNLR is...

Programmed Death-Ligand 1 Tumor Proportion Score and Overall Survival From First-Line Pembrolizumab in Patients With Nonsquamous Versus Squamous NSCLC

IntroductionFor patients with NSCLC receiving immune checkpoint inhibitors, programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) has been validated as a predictive biomarker for improved overall survival (OS). Nevertheless, its histology-specific predictive value in patients with advanced squamous versus nonsquamous cancers remains unclear. To evaluate the differential value of PD-L1 TPS as a predictive biomarker for OS after first-line pembrolizumab in patients with squamous versus nonsquamous NSCLC. MethodsRetrospective, observational study of patients diagnosed with having advanced NSCLC who were treated between October 2015 and April 2019 at community oncology clinics and academic medical centers in a deidentified electronic health record–derived database. Included patients were diagnosed with having advanced or metastatic NSCLC, received treatment with first-line, single-agent pembrolizumab, and had documentation of PD-L1 testing with a numeric result. Exclusion criteria included alterations in EGFR, ALK, and ROS1. The primary end point was OS from start of first-line pembrolizumab therapy by squamous or nonsquamous histology and PD-1 expression level measured by TPS (low, <50% or high, ≥50%). ResultsThe cohort of 1460 patients with NSCLC who received pembrolizumab as a first-line therapy had a mean age of 72 years. Histology was 28% squamous and 72% nonsquamous. PD-L1 expression was low in 13% and high in 87%. No meaningful differences in age, sex, or smoking history were observed by PD-L1 TPS or histology type. A generalized gamma model adjusting for sex and stage at diagnosis found that for patients with nonsquamous histology, high PD-L1 TPS was significantly associated with improved OS by a median OS difference of 8.4 months (p < 0.001). In contrast, for patients with squamous histology, there was no evidence of association between PD-L1 expression level and OS (p = 0.283). PD-L1–related incremental differences in median OS between the patients with squamous and nonsquamous tumors were significantly different (p = 0.034). ConclusionsAmong patients with NSCLC treated with first-line pembrolizumab, high PD-L1 TPS is associated with OS among patients with nonsquamous NSCLC, but not among patients with squamous NSCLC.

FP13.04 KEYNOTE-042 3-Year Survival Update: 1L Pembrolizumab vs Platinum-Based Chemotherapy for PD-L1+ Locally Advanced/Metastatic NSCLC

In the KEYNOTE-042 study (NCT02220894), pembrolizumab significantly improved OS vs platinum-based chemotherapy as first-line treatment for locally advanced/metastatic NSCLC without sensitizing EGFR/ALK alterations with PD-L1 tumor proportion score (TPS) ≥1%. We present updated data from KEYNOTE-042 with >3 years follow-up from randomization, including an exploratory analysis of time to progression on next-line therapy (PFS-2). Outcomes in patients who completed 35 cycles of pembrolizumab and in those who received second-course treatment are also reported. Patients were randomized 1:1 to pembrolizumab 200 mg Q3W for 35 cycles or chemotherapy (carboplatin area under the curve 6/5 plus paclitaxel 200 mg/m2 or pemetrexed 500 mg/m2) Q3W for 4‒6 cycles with optional pemetrexed maintenance (nonsquamous only). Randomization was stratified by region (East Asia vs non–East Asia), histology (squamous vs nonsquamous), ECOG PS (0 vs 1), and PD-L1 TPS (≥50% vs 1%–49%). The primary endpoint was OS in prespecified TPS groups (≥50%, ≥20%, and ≥1%). Secondary endpoints included PFS, ORR, and safety. Patients randomized to pembrolizumab who completed 35 treatment cycles with SD or better or stopped treatment after confirmed CR could receive second-course pembrolizumab after PD if eligibility criteria were met. No alpha was assigned to these analyses. 1274 patients were randomized (pembrolizumab, n=637; chemotherapy, n=637). As of February 21, 2020, median (range) time from randomization to database cutoff was 46.9 (35.8‒62.1) months. Efficacy results are summarized in the Table. Treatment-related grade 3‒5 AEs occurred in 120 (18.9%) vs 256 patients (41.6%) in the pembrolizumab vs chemotherapy groups. 102 patients completed 35 cycles (∼2 years) of pembrolizumab. 86/102 (84.3%) had CR (n=2) or PR (n=84) as best response. 80/102 (78.4%) patients were alive at time of analysis. 1-year OS after completion of 35 cycles was 91.1% in patients with PD-L1 TPS ≥1%. Among 26 patients who received second-course pembrolizumab; ORR after initiation of second-course treatment was 15.4% (all PR), and the disease-control rate (CR+PR+SD) was 76.9%. 21/26 (80.8%) patients were alive at data cutoff.TableEfficacyPD-L1 TPS ≥50%PD-L1 TPS ≥20%PD-L1 TPS ≥1%Pembro (N=299)Chemo (N=300)Pembro (N=413)Chemo (N=405)Pembro (N=637)Chemo (N=637)Median OS,a,b mo (95% CI)20.0 (15.9‒24.2)12.2 (10.4‒14.6)18.0 (15.5‒21.5)13.0 (11.6‒15.3)16.4 (14.0‒19.6)12.1 (11.3‒13.3)HR (95% CI)0.68 (0.57‒0.82)0.75 (0.64‒0.88)0.80 (0.71‒0.90)3-y OS rate,a % (95% CI)31.3 (26.1‒36.6)18.4 (14.2‒23.0)28.3 (24.1‒32.8)18.8 (15.1‒22.8)25.3 (22.0‒28.7)16.7 (13.8‒19.7)Median PFS,a,b, c mo (95% CI)6.5 (5.9‒8.6)6.5 (6.2‒7.6)6.2 (5.1‒7.4)6.8 (6.3‒8.1)5.5 (4.3‒6.2)6.8 (6.4‒7.7)HR (95% CI)0.85 (0.72‒1.02)0.95 (0.82‒1.10)1.05 (0.93‒1.18)3-y PFS rate,a % (95% CI)14.5 (10.5‒19.0)5.3 (3.0‒8.7)13.2 (10.0‒16.9)4.7 (2.7‒7.5)11.0 (8.6‒13.7)4.1 (2.6‒6.2)Median PFS-2,a,d mo (95% CI)15.0 (11.6‒19.2)10.1 (8.9‒11.2)12.9 (10.9‒15.5)10.2 (9.0‒11.3)11.3 (10.1‒12.9)9.3 (8.6‒10.2)HR (95% CI)0.62 (0.52‒0.74)0.66 (0.57‒0.77)0.73 (0.65‒0.82)ORR,b %39.1 (33.6‒44.9)32.3 (27.1‒37.9)33.2 (28.6‒37.9)29.1 (24.8‒33.8)27.3 (23.9‒31.0)26.7 (23.3‒30.3)Median DOR,a mo (95% CI)27.3 (2.1+ to 56.0+)10.8 (1.8+ to 49.6+)22.3 (2.1+ to 56.0+)10.8 (1.8+ to 49.6+)22.3 (2.1+ to 56.0+)8.4 (1.8+ to 49.6+)Chemo, chemotherapy; Pembro, pembrolizumab. “+” indicates no progressive disease at the time of last disease assessment. aKaplan-Meier estimate. bOS and PFS were calculated from the time of randomization. cPer RECIST v1.1 by blinded independent central review. dPFS-2 was defined as time from randomization to subsequent disease progression after initiation of new anticancer therapy, or death from any cause, whichever occurred first. Open table in a new tab Chemo, chemotherapy; Pembro, pembrolizumab. “+” indicates no progressive disease at the time of last disease assessment. aKaplan-Meier estimate. bOS and PFS were calculated from the time of randomization. cPer RECIST v1.1 by blinded independent central review. dPFS-2 was defined as time from randomization to subsequent disease progression after initiation of new anticancer therapy, or death from any cause, whichever occurred first. With long-term follow-up, first-line pembrolizumab monotherapy continued to show improved OS, ORR and PFS-2 outcomes compared with platinum-based chemotherapy in patients with locally advanced/metastatic PD-L1–positive NSCLC without sensitizing EGFR/ALK alterations, with a manageable safety profile. Patients who completed 35 cycles of pembrolizumab had durable responses, and second-course pembrolizumab was feasible and associated with antitumor activity. These findings continue to support first-line pembrolizumab in patients with locally advanced/metastatic PD-L1–positive NSCLC without sensitizing EGFR/ALK alterations.

PD-L1 tumor proportion score and clinical benefit from first-line pembrolizumab in patients with advanced nonsquamous versus squamous non-small cell lung cancer (NSCLC).

9539 Background: The predictive value of PD-L1 tumor proportion score (TPS) on NSCLC tumor cells as a biomarker for response to PD-(L)1 inhibitors is well established. However, its histology specific value in advanced (a) squamous (Sq) versus nonsquamous (NS) cancers remains unclear. Here, we used real world data to assess the differential value of PD-L1 TPS as a predictive biomarker for overall survival (OS) after first-line pembrolizumab (P) in patients (pts) with Sq versus NS NSCLC. Methods: Inclusion criteria for this analysis of the Flatiron Health EHR-derived de-identified database required that pts were diagnosed with aNSCLC, tested for PD-L1 TPS and received a numerical result, had no alteration in EGFR, ALK, or ROS, and received first-line, single agent P. The primary endpoint was overall survival (OS) from the first dose of P in patients with TPS ≥ 50% (H) compared to patients with TPS &lt; 50% (L). Due to the violation of the proportional hazards assumption, a generalized gamma model of OS was used, adjusting for demographic variables and estimated median OS and their confidence intervals with the bootstrap method. The PD-L1-histology interaction was examined by comparing the differences in median OS (H vs. L) between Sq and NS patients. Results: Of 1560 pts with NSCLC treated from 1/2011 – 5/2019, 1055 had NS and 405 Sq. No meaningful differences in age, gender, or smoking history were seen between PD-L1 H and L pts with either histology. Among NS pts, H had significantly longer OS than L, with unadjusted hazard ratio (HR) of 0.71 (95% CI: 0.53 - 0.94; p = 0.018). Among Sq pts, H was not associated with longer OS than L, with unadjusted HR 0.89 (95% CI: 0.64 - 1.25; p = 0.514). Based on the generalized gamma model, PD-L1 H in Sq patients was associated with a 0.19 year improvement in median OS (95% CI: -0.22-0.49, P = 0.283), whereas PD-L1 H in the NS group was associated with a 0.70 year improvement in OS (95% CI: 0.34-1.05, P &lt; 0.001). The median improvements between the Sq and NS patients were significantly different (P = 0.034), after adjusting for demographic variables. Conclusions: PD-L1 TPS of ≥ 50% predicted longer OS in pts with NS NSCLC treated with first-line P compared to pts whose tumors had a TPS of &lt; 50%. However, no relationship between PD-L1 TPS and OS after first-line P was seen in patients with Sq NSCLC. These data suggest that PD-L1 may not be an appropriate predictive biomarker for checkpoint inhibitor use in NSCLC with squamous histology.

Outcomes to first-line pembrolizumab in patients with PD-L1-high (≥50%) non-small-cell lung cancer and a poor performance status.

9568 Background: Patients with non-small cell lung cancer (NSCLC) and a poor Eastern Cooperative Oncology Group performance status (ECOG PS) have been excluded from immunotherapy clinical trials. We sought to evaluate clinical outcomes to first-line pembrolizumab in patients with advanced NSCLC, a PD-L1 tumor proportion score (TPS) of ≥50%, and an ECOG PS of 2. Methods: We performed a multicenter retrospective analysis of patients with metastatic NSCLC and a PD-L1 tumor proportion score (TPS) of ≥50% (negative for genomic alterations in EGFR and ALK) who received treatment with first-line commercial pembrolizumab. Clinical outcomes were compared in patients based on ECOG PS. Results: Among 234 patients, 83.3% (N = 195) had an ECOG PS of 0 or 1, and 16.7% (N = 39) had an ECOG PS of 2. The baseline clinicopathological characteristics were balanced between the ECOG PS 0-1 vs 2 groups in terms of age, sex, tobacco use, histology, KRAS mutation status, presence of other potentially targetable driver mutations ( BRAF, MET, HER2, RET), history of central nervous system (CNS) disease, and PD-L1 TPS distribution. Compared to patients with an ECOG PS of 0-1, patients with an ECOG PS of 2 had a significantly lower objective response rate (ORR 43.1% vs 25.6%; P = 0.04), a numerically shorter median progression free survival (mPFS 6.6 months vs 4.0 months; P = 0.09), and a significantly shorter median overall survival (mOS 20.3 months vs 7.4 months; P &lt; 0.001). Upon disease progression, patients with an ECOG PS of 2 were significantly less likely to receive second-line systemic therapy compared to patients with an ECOG PS of 0-1 (55.5% vs 14.3%, P &lt; 0.001). Conclusions: Although a subset of patients with an ECOG PS of 2 can respond first-line pembrolizumab, clinical outcomes in this population are poor, and use of second-line systemic therapy is infrequent.

Real-World Efficacy of First-Line Pembrolizumab in Patients With Advanced or Recurrent Non–Small-Cell Lung Cancer and High PD-L1 Tumor Expression

BackgroundIn clinical trials, first-line treatment with pembrolizumab improved overall survival (OS) in patients with advanced non–small-cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score of ≥ 50%. However, data on the efficacy of this treatment between clinical trials and actual clinical practice are inconsistent. Patients and MethodsNinety-five patients with histologically diagnosed advanced or recurrent NSCLC and a PD-L1 tumor proportion score of ≥ 50% who received pembrolizumab as first-line treatment were consecutively enrolled onto this multicenter retrospective study from February 2017 to December 2018. Clinical data were collected from electronic medical records. We assessed the objective response rate, progression-free survival (PFS), OS, and immune-related adverse events (irAE), and determined their associations with clinical characteristics. ResultsThe objective response rate was 40.0%. The median PFS was 6.1 months, and OS did not reach the median. Multivariate analyses revealed that nonadenocarcinoma histology (hazard ratio, 1.78; 95% confidence interval, 1.05-3.03; P = .015) and ≥ 3 metastatic sites (hazard ratio, 3.97; 95% confidence interval, 1.97-8.01; P < .001) were independently correlated with poor PFS. Patients with irAE and patients without interstitial lung disease had significantly longer PFS (14.0 and 4.9 months, respectively; P = .011) than patients without irAE or patients with interstitial lung disease. ConclusionThe outcome of patients receiving first-line pembrolizumab treatment was worse in those with nonadenocarcinoma and with a large number of metastatic sites. Patients with irAE and without interstitial lung disease had a more favorable outcome.

P1.16-10 Real-World Efficacy of First-Line Pembrolizumab in Patients with Advanced PD-L1 High Non-Small Cell Lung Cancer in Argentina

Pembrolizumab monotherapy is a standard first-line (1L) treatment regimen for patients (pts) with non-small cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) ≥ 50%. We aimed to study the clinical efficacy and toxicity of this approach in the real-world setting in Argentina. We conducted a retrospective, multicenter study. Patients with metastatic NSCLC and a PD-L1 TPS ≥ 50% treated in 1L with at least one dose of pembrolizumab monotherapy, from December 2016 to February 2019, were included. Data was collected from clinical records, overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were estimated. Cox regression model was performed for uni- and multivariate analysis. A total of 53 pts were included. Median age (range) was 68 years (35-88), 33 (62.3%) were male, and 46 pts (86.7%) were smokers. Most tumors were lung adenocarcinoma (N=47, 88.7%), median (IQR) PD-L1 TPS was 79% (60-87.5) and 22 tumors (41.5%) had a TPS ≥75%. EGFR/ALK/ROS1 mutations/fusions were not detected. Brain (N=10; 18.9%), liver (N=5 (9.4%) and bone (N=15; 28.3%) metastasis were present at baseline. Performance status (PS) score was 0-1 in 46 pts (86.8%) and 7 pts (13.2%) had PS 2. Six pts received baseline corticosteroid treatment. The ORR with pembrolizumab was 41.5% (95% CI: 28.1-55.8), median PD-L1 TPS (mTPS) was significantly higher in responders (mTPS 74% vs 67%, P = 0.04). Grade ≥3 immune-related adverse events occurred in 7 pts (13.2%) and 10 (18.9%) required systemic therapy with steroids. With a median-follow up of 12.9 months (95% CI: 8.4-17.6), median PFS and median OS were not reached. The estimated percentage of patients alive and without progression at 6 and 12 months was 64.8% and 55.8%. The estimated percentage of patients alive at 6 and 12 months was 77.5% and 69.4%. Median PFS and OS for patients with PS 2 was 2.4 months (95% CI: 1.7-3.1) and 4.5 months (95% CI: 3.1-6.0), respectively. After adjusting for PS, a PDL1 TPS score ≥75% was independently associated with improved PFS in multivariate analysis [HR 0.28 (95% CI: 0.09-0.92); P = 0.03) but not with OS. PS score equal to 2 was independently associated with decreased OS [HR 4.52 (95% CI: 1.06-19.28); P = 0.04] in multivariate analysis. Pembrolizumab monotherapy is tolerable and confers durable clinical benefit for patients with tumors expressing high levels of PD-L1 in the real world clinical setting. The optimal first-line immunotherapy approach for patients with PS 2 in this setting warrants further studies.

Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression.

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.

P1.01-69 Blood Serum Amyloid A as Potential Predictor of Response to First-Line Pembrolizumab in Patients with Advanced Non-Small-Cell Lung Cancer

The selection of patients (pts) deriving clinical benefit from immune checkpoint agents represents the modern challenge for clinicians. Tumor-derived Serum Amyloid A (SAA) inhibits the immune response through the expansion of IL-10-secreting neutrophils in pts with melanoma. We investigated the predictive value of blood SAA monitoring in a cohort of Advanced Non-Small-Cell Lung Cancer (ANSCLC) pts receiving up-front Pembrolizumab (P). Pts with ANSCLC (PD-L1≥50%) receiving upfront P, were prospectively evaluated for blood SAA and radiological response at baseline and every 9 weeks during the treatment. The primary endpoint was response rate (RR) according Immune-related Response Evaluation Criteria in Solid Tumors (IrRECIST); the secondary endpoints were progression-free survival (PFS) and overall survival (OS). The most accurate SAA cut-off to predict response was established with a ROC-analysis. Forty-two patients were enrolled. Pts characteristics: male/female (71/29%), number of sites 1/2/3/≥ 4 (5/38/40/17%), ECOG PS 0/≥ 1 (38/62%); never or former/current smokers (12/78%); median age 70.5 (range 35-86) years. The overall RR was 38% (95%CI 25-53%). After a median follow-up of 13.5 months (m), baseline SAA ≤ the ROC-derived cut-off (29.9 mg/L, AUC 0.74, 95% CI 0.59-0.87, p=0.002; 14 [33%] pts) was significantly associated with a higher RR (53.6vs 7.1%, OR 15, 95% CI 1.72-130.7, p<0.01), longer PFS (17.4 vs 2.1 m, HR 0.18, 95%CI 0.06-0.51, p<0.0001) and OS (not reached [NR]vs7.2 m, HR 0.08, 95%CI 0.02-0.39, p<0.0001) compared with SAA >29.9 mg/L. Multivariate analysis confirmed pre-treatment low SAA as independent predictor of longer PFS (p=0.029) and OS (p=0.018). Considering SAA at baseline and the dynamic monitoring (pts=40), the median PFS was 17.4 m (95% CI 10.7-14.7) when SAA remained low (n=14) compared with 2.1 m (95%CI 1.3-5.6) when SAA remained high (n=12) (p<0.0001).The SAA monitoring was also significantly associated with OS (p=0.0002), with a median OS of 7.2 m (95% CI 5.6-13.4) in pts maintaining high SAA versus NR median at 18-m for pts with SAA remained low or changed. No deaths occurred in the permanently low-SAA group at the current data-lock. Baseline low SAA predicts good outcomes of 1stline P and the SAA monitoring throught simple blood test could help to easily identify patients who derived the greatest benefit from immunotherapy. The strong relationship with RR and the known immunosuppressive activity support a potential predictive value of this serum marker. A multi-institutional validation set is currently ongoing to confirm the role of SAA in this setting.

Outcomes to first-line pembrolizumab in patients with non-small cell lung cancer and a PD-L1 tumor proportion score ≥90%.

9111 Background: In non-small cell lung cancers with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of ≥50%, first-line treatment with the PD-1 inhibitor pembrolizumab improves survival compared to platinum-doublet chemotherapy. Whether higher PD-L1 expression levels within the TPS range of 50-100% predict for even greater benefit to pembrolizumab is currently unknown. Methods: 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 for advanced NSCLC with a PD-L1 TPS of ≥50%. Results: Among 196 patients with NSCLC treated with first-line pembrolizumab, the ORR was 43.8% (95%CI: 36.8-51.1). At a median follow-up of 12.6 months (95%CI: 11.6-13.7), the mPFS was 6.2 months (95% CI: 4.2-8.2) and the mOS was not reached. The median PD-L1 TPS among patients who experienced a response to pembrolizumab was significantly higher than in patients with stable or progressive disease (TPS 90% vs 70%, P &lt; 0.001), so a TPS cut point of 90% was chosen for further analysis. Baseline clinicopathological characteristics were well-balanced between patients with a PD-L1 TPS of 50-89% vs 90-100%. Compared to patients with a PD-L1 TPS of 50-89% (N = 114, 58.2% of the cohort), patients with a TPS of 90-100% (N = 82, 41.8% of the cohort) had a significantly higher ORR (61.0% versus 31.6%, P &lt; 0.001), a significantly longer mPFS (13.2 versus 3.7 months, HR: 0.48 [95% CI: 0.33-0.71], P &lt; 0.001), and a significantly longer mOS (NR versus 16.0 months, HR: 0.38 [95% CI: 0.21-0.70], P = 0.002). After adjusting for ECOG performance status and smoking history, PD-L1 TPS of 90-100% was significantly associated with improved mPFS (HR: 0.51 [95% CI: 0.34-0.75], P &lt; 0.001) and mOS (HR: 0.38 [95% CI: 0.21-0.70], P = 0.001). Conclusions: Among patients with NSCLC and a PD-L1 TPS ≥50%, clinical outcomes are improved in the subgroup of patients with a PD-L1 TPS of ≥90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design.