Metastatic Non-squamous Non-small Cell Lung Research Articles

Density patterns of tumor-infiltrating lymphocytes and association with objective response to nivolumab in patients with lung adenocarcinoma from CheckMate 057.

2662 Background: Immune checkpoint inhibitors (ICIs) are currently approved for use as therapy in advanced stage lung adenocarcinoma (LUAD). ICIs can decrease risk of progression by up to 60% when compared to chemotherapy, but only about 20% of patients (pts) show response. Given that high levels of tumor-infiltrating lymphocytes (TILs) have been shown to be associated with better prognosis, here, we assess whether computationally derived TIL density measures on digitized H&E images can predict RECIST derived response to nivolumab in LUAD in Checkmate 057 (CM057). CM057 is a clinical trial designed to compare the overall survival of metastatic non-squamous non-small cell lung cancer subjects treated with either nivolumab or docetaxel after failing platinum-based chemotherapy. Methods: H&E-stained samples of 683 LUAD pts were collected from TCGA (n = 421), University of Bern (UBern) (n = 100), and CM057 (n = 162). Tumor response was assessed using RECIST v1.1. Samples were digitized as whole slide images. 294 pts randomly selected from TCGA formed the training set. The remaining 389 pts were used for validation in response to nivolumab in CM057 and prognosticating overall survival (OS) in UBern and TCGA. Computerized algorithms automatically identified TILs and extracted features related to quantity and compactness of TILs with respect to other surrounding nuclei. The top 6 features, determined by least absolute shrinkage and selection operator, were used to train Cox regression models that assign a death risk score to each patient. Pts with risk scores higher than the training median score were considered “high risk” or “non-responders” while pts with lower scores were considered “low risk” or “responders”. Results: The classifier predicted objective response in CM057 with an AUC = 0.61. Additionally, survival analysis showed that the model was prognostic for OS with hazard ratios of 2.38 (confidence interval (CI): 1.32-4.29, p = 0.01, n = 127) in TCGA and 2.37 (CI: 1.32-4.25, p < 0.01, n = 100) in UBern. Conclusions: A computerized image analysis model based on measurements of TIL density showed association with response to treatment in LUAD pts who received nivolumab and was prognostic of OS. Although the AUC was not high, the results suggest analysis of TILs has potential to identify pts who will respond to treatment. Future work will include training a classifier using response to treatment as endpoint and combining the TIL measures with other biomarkers like TMB or PD-L1.

Potential Process Control Issues with Pemetrexed.

Pemetrexed is a folate analog metabolic inhibitor used in treatment of locally advanced or metastatic nonsquamous non-small cell lung cancer and for mesothelioma. Intra-lot and inter-lot variability in the spectra of ALIMTA® was detected in the Drug Quality Study (DQS) using Fourier transform near-infrared spectrometry (FTNIR). One vial of 12 (8%) sampled from lot S20I013A appeared 3.0 multidimensional SDs from the other vials, suggesting that it represents a different material. Consequently, additional spectra from other lots were analyzed. Spectra of 147 vials from 23 lots in the spectral library contained 14 vials that were outside the main group (26.4 SDs using a subcluster detection test), suggesting that the 14 library vials (9.5% of the total) also contain differing materials.

Carboplatin and nab-paclitaxel chemotherapy with or without atezolizumab as front-line management for treatment-naïve metastatic nonsquamous non-small cell lung cancer with PD-L1 staining: a retrospective study

PurposeThe aim of this retrospective review was to compare the efficacy and safety of the atezolizumab plus carboplatin and nab-paclitaxel regimen versus the carboplatin and nab-paclitaxel regimen as front-line management for treatment-naïve, metastatic nonsquamous programmed death-ligand 1 (PD-L1)-positive non-small cell lung cancer (NSCLC) in a selected population.MethodsConsecutive patients with untreated, metastatic nonsquamous PD-L1-positive NSCLC who initially received the atezolizumab plus carboplatin and nab-paclitaxel (ACN) regimen or carboplatin and nab-paclitaxel (CN) regimen were retrospectively identified in two medical institutions from 2017 to 2020. The co-primary end points were overall survival (OS) and progression-free survival (PFS); secondary end point was the rate of key adverse events (AEs).ResultsIn sum, 171 patients were retrospectively analysed, 47 of whom were excluded according to the criteria used in this study, leaving 124 patients (ACN: n = 60, median age 64 years [range 46–75]; CN: n = 64, 63 years [47–72]). The median duration of follow-up was 27 months [range 1–37]. At the final follow-up, the median OS was 19.9 months (95% confidence interval [CI], 16.3–22.5) in the ACN group vs. 14.8 months (95% CI 12.5–17.2) in the CN group (hazard ratio [HR] 0.51, 95% CI 0.33–0.77; p = 0.001). A marked distinction in the median PFS was seen (8.5 months [95% CI 6.7–9.4] in the ACN group vs. in the CN group [5.1 months [95% CI 3.6–6.8; HR 0.60; 95% CI 0.38–0.95; p = 0.005]). The rates of the key AEs (neutropenia and anaemia) were greater in the ACN group than in the CN group (all p < 0.05), but these AEs were manageable.ConclusionAmong selected populations of individuals with treatment-naïve, metastatic nonsquamous PD-L1-positive NSCLC, atezolizumab combined with carboplatin and nab-paclitaxel chemotherapy might have encouraging anticancer activity, with a tolerable safety profile.

POSA418 Real-World Patterns of Biomarker Testing in Metastatic Non-Squamous Non-Small Cell Lung Cancer

POSA418 Real-World Patterns of Biomarker Testing in Metastatic Non-Squamous Non-Small Cell Lung Cancer

Cost-Effectiveness Analysis of Camrelizumab Plus Chemotherapy vs. Chemotherapy Alone as the First-Line Treatment in Patients With IIIB-IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Without EGFR and ALK Alteration from a Perspective of Health - Care System in China.

Objective: The CAMEL clinical trial (412 patients were randomly assigned to either camrelizumab plus chemotherapy (n = 205) or chemotherapy alone (n = 207)) demonstrated that camrelizumab plus chemotherapy (CC) improved the overall survival time (OS) and progression-free survival time (PFS) of patients with metastatic nonsquamous non-small cell lung cancer (non-sq NSCLC) without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations (EGFRm and ALKm) vs. chemotherapy (C) alone. Our objective was to conduct a cost-effectiveness analysis of CC vs. C from a perspective of health - care system in China with a lifetime horizon to identify whether it will be cost-effective. Materials and Methods: A partitioned survival model (PSM) was applied for patients with IIIB–IV non-sq NSCLC without EGFRm and ALKm. Transition parameters and proportions of three health states were derived from the CAMEL trial. The model was designed using a lifetime horizon, a 21-day cycle, and a 5% discount rate of costs and outcomes. It was deemed cost-effective in China if the incremental cost-effectiveness ratio (ICER) value is less than $32,457 per quality adjusted life-year (QALY). Deterministic and probabilistic sensitivity analyses were performed to verify the influence of parameter uncertainty on the results. Results: In the base-case analysis, we found that the ICER of CC compared with C is $-7,382.72/QALY which meant that CC had lower costs and better outcomes. The results of the sensitivity analyses demonstrated that the result was robust for the ICERs never transcending the willingness-to-pay (WTP) threshold. Conclusion: Camrelizumab plus chemotherapy is an obviously cost-effective therapeutic regime for patients of IIIB–IV non-sq NSCLC without EGFRm and ALKm in China at a $32,457 WTP threshold.

105P US real-world treatment patterns and outcomes of metastatic nonsquamous non-small cell lung cancer (mNSQ NSCLC) patients (pts) after progression on standard of care (SOC)

The SOC for mNSQ NSCLC pts with no targetable genetic alterations is immunotherapy (IO) or platinum-based chemotherapy (CT) alone in 1L followed by the other in 2L or platinum-based CT and IO in 1L. SOC for pts with targetable genetic alterations (EGFR, ALK, ROS1) is one or more lines of tyrosine kinase inhibitors (TKIs). Data on optimal subsequent treatment after progression(s) on SOC are scarce.

168TiP KEYNOTE-A86: Phase III, randomized, open-label study of first-line subcutaneous (SC) vs intravenous (IV) pembrolizumab with platinum doublet chemotherapy in metastatic squamous or nonsquamous non-small cell lung cancer (NSCLC)

IV pembrolizumab is approved for several tumor types, including squamous and nonsquamous NSCLC. Because most patients prefer SC vs IV dosing, a SC formulation of pembrolizumab was developed, and was found to have similar pharmacokinetics (PK) to the IV formulation in the phase 1 KEYNOTE-555 study. The phase 3, randomized, multicenter, open-label KEYNOTE-A86 study (NCT04956692) evaluates the PK, safety, and efficacy of first-line SC vs IV pembrolizumab plus chemotherapy in metastatic squamous or nonsquamous NSCLC.

Cost-Effectiveness Analysis of Pembrolizumab Plus Pemetrexed and Platinum Versus Chemotherapy Alone as First-Line Treatment in Metastatic Non-Squamous Non-Small Cell Lung Cancer: A Reconstruction of Partitioned Survival Model Based on Time Dependent Pricing Mechanism of Patient Assistance Program.

ObjectivesA new patient assistance program (PAP) for pembrolizumab was started in China in 2021. The researchers aimed to evaluate the economic outcomes of pembrolizumab plus pemetrexed and platinum versus chemotherapy alone in the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer, based on the pricing mechanism of PAP.Material and MethodsSurvival analysis and partitioned survival model were performed to evaluate the incremental cost-effectiveness ratio (ICER) in the pembrolizumab group compared with the chemotherapy group. Survival probabilities were extracted from the data of the KEYNOTE-189 trial. Cost and utility data were gathered from published literature. The pricing mechanism of PAP was set in each cycle in the partitioned survival model, according to the progression-free survival (PFS) data of the KEYNOTE-189 trial, which included PFS-1 and PFS-2. Deterministic sensitivity analysis and probabilistic sensitivity analysis were conducted.ResultsThe ICER of the pembrolizumab group versus chemotherapy group was $65,272/quality-adjusted life year (QALY), which still exceeded the willingness-to-pay threshold of three times per capita gross domestic product (GDP) of China ($33,581.22), although PAP was calculated. Sensitivity analysis implied that the price of chemotherapeutic drugs combined with pembrolizumab was one of the main influencing factors of ICER.ConclusionsDue to various prices set by PAP and the payment for combined chemotherapy, the economic advantage of pembrolizumab plus chemotherapy in the first-line treatment of non-small cell lung cancer (NSCLC) is still not achieved in China.

P24.08 Lung Cancer Diagnosis in Absence of Adequate Tissue Molecular Analysis in Metastatic Disease by NGS Analysis of Plasma cfDNA

Although molecular analysis of tumor material is standard of care in patients with metastatic non-squamous non-small cell lung cancer, this is not always feasible. In daily practice it can be difficult to obtain tumor tissue or there may be insufficient tissue available for molecular investigation. This leaves possible targeted-treatment options unidentified in a subset of patients.

P08.03 Cost-Effectiveness of Pembrolizumab With or Without Chemotherapy for Stage IV Non-Squamous NSCLC with High PD-L1 in Switzerland

Until recently, chemotherapy was the only treatment option for metastatic non-squamous non-small cell lung cancer (NSCLC) without targetable mutations. The introduction of immunotherapies changed the prognosis for patients suffering from this disease. Pembrolizumab can be given as monotherapy or in combination with chemotherapy. So far, it was unclear, if and which of these treatment options is cost-effective for patients with a high programmed death ligand 1 (PD-L1) expression.

P60.09 Real-World Readiness of US Laboratories to Test Metastatic NSCLC Patients for Rare Actionable Genomic Variants by NGS

Various rare driver genomic variants have been investigated in metastatic non-squamous non-small cell lung cancer (mNSCLC). Individually they are considered rare (<3% prevalence), however, studies have shown collectively they represent up to 14.5% of the mNSCLC mutation profile. While multiple targeted therapies for rare variants such as NTRK fusions, MET exon14 skipping and RET fusions have been approved in the US for 1st line therapy in mNSCLC, other variants such as HER2 exon20ins, EGFR exon20ins, and FGFR-alterations are also gaining traction.

Incorporation of plasma-based next-generation sequencing to improve guideline-concordant molecular testing in patients with newly diagnosed metastatic nonsquamous non-small cell lung cancer.

14 Background: Current NCCN guidelines recommend comprehensive molecular profiling for all newly diagnosed patients with metastatic non-squamous NSCLC to enable the delivery of personalized medicine. We have previously demonstrated that incorporation of plasma based next-generation gene sequencing (NGS) improves detection of clinically actionable mutations in patients with advanced NSCLC (Aggarwal et al, JAMA Oncology, 2018). To increase rates of comprehensive molecular testing at our institution, we adapted our clinical practice to include concurrent use of plasma (P) and tissue (T) based NGS upon initial diagnosis. P NGS testing was performed using a commercial 74 gene assay. We analyzed the impact of this practice change on guideline concordant molecular testing at our institution. Methods: A retrospective cohort study of patients with newly diagnosed metastatic non-squamous NSCLC following the implementation of this practice change in 12/2018 was performed. Tiers of NCCN guideline concordant testing were defined, Tier 1: complete EGFR, ALK, BRAF, ROS1, MET, RET, NTRK testing, Tier 2: included above, but with incomplete NTRK testing, Tier 3: &gt; 2 genes tested, Tier 4: single gene testing, Tier 5: no testing. Proportion of patients with comprehensive molecular testing by modality (T NGS vs. T+P NGS) were compared using one-sided Fisher’s exact test. Results: Between 01/2019, and 12/2019, 170 patients with newly diagnosed metastatic non-Sq NSCLC were treated at our institution. Overall, 98.2% (167/170) patients underwent molecular testing, Tier 1: n = 100 (59%), Tier 2: n = 39 (23%), Tier 3/4: n = 28 (16.5%), Tier 5: n = 3 (2%). Amongst these patients, 43.1% (72/167) were tested with T NGS alone, 8% (15/167) with P NGS alone, and 47.9% (80/167) with T+P NGS. A higher proportion of patients underwent comprehensive molecular testing (Tiers 1+2) using T+P NGS: 95.7% (79/80) compared to T alone: 62.5% (45/72), p &lt; 0.0005. Prior to the initiation of first line treatment, 72.4% (123/170) patients underwent molecular testing, Tier 1: n = 73 (59%), Tier 2: n = 27 (22%) and Tier 3/4: n = 23 (18%). Amongst these, 39% (48/123) were tested with T NGS alone, 7% (9/123) with P NGS alone and 53.6% (66/123) with T+P NGS. A higher proportion of patients underwent comprehensive molecular testing (Tiers 1+2) using T+P NGS, 100% (66/66) compared to 52% (25/48) with T NGS alone (p &lt; 0.0005). Conclusions: Incorporation of concurrent T+P NGS testing in treatment naïve metastatic non-Sq NSCLC significantly increased the proportion of patients undergoing guideline concordant molecular testing, including prior to initiation of first-line therapy at our institution. Concurrent T+P NGS should be adopted into institutional pathways and routine clinical practice.

1842P Molecular testing in older patients treated for an advanced or metastatic non-squamous non-small cell lung cancer

In the last years, tumor genomic testing has drastically changed the prognosis of patients especially in those treated for an advanced/metastatic nonsquamous non–small-cell lung cancer (NSCLC). Lung cancer is associated with older age. However considering the heterogeneity of this population it remains unclear whether older patients are screened in the same proportion as younger patients. This study aims to compare the proportion of molecular testing performed in advanced or metastatic nonsquamous NSCLC at diagnosis between patients aged ≥ 70 years old, and their younger counterparts.

Nivolumab induced hypophysitis in a patient with recurrent non-small cell lung cancer

Nivolumab is a programmed death receptor-1 blocking monoclonal antibody which has been approved by United States Food and Drug Administration for patients with metastatic non-squamous non-small cell lung cancer. Endocrinopathies like thyroid dysfunction and adrenal insufficiency are its known immune related adverse effects. Hypophysitis is very rare and usually presents with minimal symptoms. We report development of hypophysitis in an 84-year-old female patient who developed a range of symptoms (fatigue, headache, nausea) as well as laboratory confirmation of both central hypothyroidism and central adrenal deficiency which is unusual in cases of nivolumab induced hypophysitis. The patient had well differentiated adenocarcinoma of the left upper lobe of the lung. She underwent wedge resection followed by chemotherapy and was started on nivolumab due to recurrence. After 14 cycles of nivolumab, she started complaining of intense fatigue. She was found to have central thyroid deficiency and was started on levothyroxine. But her symptoms did not improve. Then she underwent adrenocorticotropic hormone stimulation test which showed central adrenal deficiency, but her brain magnetic resonance imaging did not reveal any pituitary or sellar changes. A diagnosis of nivolumab induced hypophysitis was made, based on clinical grounds and hormonal profile and she was started on oral steroids. She responded dramatically to this steroidal therapy within four weeks of its initiation and her immunotherapy with nivolumab was restarted.

Abstract 442: Pemetrexed and platinum plus pembrolizumab in patients with metastatic non-squamous non-small cell lung cancer by tumor burden at baseline: A post-hoc efficacy analysis of KEYNOTE-189

Abstract Background: Pemetrexed (pem) and platinum (plat) plus pembrolizumab (pembro) showed clinical improvement in metastatic nonsquamous (NSQ) non-small-cell lung cancer (NSCLC). The aim of this analysis was to assess the clinical benefit of pem+plat+pembro in patients by tumor burden at baseline. Methods: The intention-to-treat population was analysed. Patients were randomized pem+plat+pembro (n=410) or pem+plat+placebo (n=206). The data cut-off date was May 20, 2019. OS, PFS, PFS-2, and ORR were evaluated by Kaplan-Meier and univariate Cox methods within subgroups identified by extent of distant metastasis (M1a vs. M1b), median number (≤3 vs. &amp;gt;3) of organ systems with lesions, and severity score of patient-reported symptoms (below median vs. above median) at baseline. These subgroup analyses were also replicated within PD-L1 TPS subgroups (&amp;lt;1%, 1-49%, ≥50%). Results: A consistent benefit in OS, PFS, PFS-2 and ORR was observed in the pem+plat+pembro treatment arm, compared to the pem+plat+placebo arm, irrespective of staging (M1a vs. M1b), number (≤ 3 vs. 3) of organ systems with lesions and severity of patient-reported symptoms (Table 1). Results by PD-L1 expression in the subgroups were generally consistent regardless of the level of expression. Conclusions: Pem+plat+pembro demonstrated consistent clinical benefit across all subgroups analysed regardless of baseline tumor burden. These results continue to support pem+plat+pembro as a standard of care in metastatic NSQ-NSCLC. TABLE 1.OS, PFS, PFS-2, and ORR in subgroups by tumor burden at baselineTreatment armsNaOSPFSPFS-2ORRHRHRHROdds ratioM1aPembro1230.540.480.572.66Placebo53M1bPembro2850.580.510.504.21Placebo152≤ 3b organ systems with lesionsPembro2350.490.410.436.00Placebo118&amp;gt; 3b organ systems with lesionsPembro1750.670.590.601.80Placebo88≤ medianc severity score of symptomsPembro1700.510.490.432.72Placebo82&amp;gt; medianc severity score of symptomsPembro1870.600.480.554.04Placebo97a.There were 3 patients with missing data for M1a and M1bb.Median number of organ systems with lesions was 3. Lesions include the primary tumorc.Median score = 122.2, based on six questions from the patient-reported LC-13 instrument Citation Format: Shirish Gadgeel, Jhanelle Grey, Maria Teresa Rizzo, Patrick Peterson, Jongseok Kim, Delvys Rodríguez-Abreu. Pemetrexed and platinum plus pembrolizumab in patients with metastatic non-squamous non-small cell lung cancer by tumor burden at baseline: A post-hoc efficacy analysis of KEYNOTE-189 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 442.

Atezolizumab in first-line treatment of metastatic nonsquamous non-small cell lung cancer in the real-world setting.

e21112 Background: The phase III IMpower150 study showed efficacy benefits with atezolizumab in combination with bevacizumab, carboplatin and paclitaxel (ABCP; arm B) as first-line (1L) treatment for patients (pts) with metastatic non-squamous (nsq) NSCLC. The FDA approved this regimen for these pts (with no EGFR or ALK mutations [WT]) on December 2018. However, to date there is limited evidence on its use in real life. This study aimed to explore the use of ABCP in the real-world setting and to describe the characteristics of early adopters (those who received ABCP in 1L). Methods: Data were extracted from the Flatiron Health database (US population). Pts with advanced stage IIIB/IV nsq NSCLC at diagnosis receiving ABCP regimen in any line were eligible for the study. Finally, early adopters were selected. Results: A total of 67 pts received the ABCP regimen in 1L. Baseline characteristics for these pts and comparisons with the IMpower150 population are summarized in Table. Real-world (rw) response in the WT group ( n = 49; 6 pts were excluded due to EGFR mutations and 12 because minimum follow-up was not reached) was similar to that of the IMpower150 series (rwRR: 55.1% [40.2-69.3] vs. 63.5% [58.2-68.5]), despite the WT population being older with a higher proportion of ECOG PS = 1. In patients who would have met the IMpower150 inclusion criteria ( n = 24), rwRR was 70.8% (48.9-87.4). Conclusions: The ABCP regimen has been adopted in the real-world setting. In terms of efficacy, response rates and current PFS data were in line with trial results, despite the population being unselected and having a worse clinical profile. Longer follow-up is required for rwOS data. vs. arm B IMpower150 results.[Table: see text]

185TiP A phase Ib dose-escalation study evaluating trastuzumab deruxtecan (T-DXd) and durvalumab in combination with chemotherapy as first-line treatment in patients with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) and HER2 overexpression (DESTINY-Lung03)

Background: In patients (pts) with metastatic NSCLC without EGFR/ALK/ROS1 genomic aberrations, platinum doublet chemotherapy (ctx) + anti–PD-1/L1 immunotherapy is the current first-line standard of care. HER2 overexpression, an established target for treatments in breast and gastric cancers, is observed in up to 30% of pts with NSCLC. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload.

A cost-effectiveness analysis of pembrolizumab with or without chemotherapy for the treatment of patients with metastatic, non-squamous non-small cell lung cancer and high PD-L1 expression in Switzerland

IntroductionPembrolizumab monotherapy or in combination with chemotherapy are two new treatment options for patients with metastatic non-squamous non-small cell lung cancer (NSCLC) and high (≥ 50%) programmed death ligand 1 (PD-L1) expression. We conducted a cost-effectiveness analysis for Switzerland comparing these two options but also pembrolizumab to chemotherapy.MethodsWe constructed a 3-state Markov model with a time horizon of 10 years. Parametric functions were fitted to Kaplan–Meier overall survival (OS) and progression-free survival (PFS) using 2-year follow-up data from the KN-024 and KN-189 registration trials. We included estimated costs for further treatment lines and costs for best supportive care. Costs were assessed from the Swiss healthcare payer perspective. We used published utility values.ResultsCombination therapy resulted in an expected gain of 0.17 quality-adjusted life years (QALYs) per patient and incremental costs of Swiss Francs (CHF) 81,085 as compared to pembrolizumab. These estimates led to an incremental cost-effectiveness ratio (ICER) of CHF 475,299/QALY. Pembrolizumab in comparison to chemotherapy was estimated to generate mean incremental QALYs of 0.83 and incremental costs of CHF 56,585, resulting in an ICER of CHF 68,580/QALY. Results were most sensitive to changes in costs of 1L pembrolizumab and combination therapy, together with changes in PFS. In the probabilistic sensitivity analysis, we estimated combination therapy was cost-effective in 4.9% of the simulations and pembrolizumab monotherapy in 82.9%, assuming a willingness-to-pay threshold of CHF 100,000 per QALY gained.ConclusionsPembrolizumab is likely to be cost-effective from the Swiss healthcare payer perspective, whereas pembrolizumab plus chemotherapy is not.

CLO21-020: Pembrolizumab in Metastatic Non-Squamous and Squamous Non-Small Cell Lung Cancer (NSCLC): Real World Data Results

CLO21-020: Pembrolizumab in Metastatic Non-Squamous and Squamous Non-Small Cell Lung Cancer (NSCLC): Real World Data Results

P72.09 Study of Relationship Between Proportion of CTLA-4 Positive Tregs in Tumor Infiltrating Lymphocytes and PD-L1 TPS

KEYNOTE-189 regimen shows a good treatment outcome in patients with previously untreated metastatic non-squamous non-small cell lung cancer (NSCLC) without sensitizing EGFR or ALK mutation. The problem with this regimen is that patients with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of less than 50% have poorer outcomes than those with a PD-L1 TPS of more than 50%. In 2020, FDA approved CheckMate 9LA regimen as first-line treatment of metastatic or recurrent NSCLC. This regimen is promising because similar therapeutic results were reported regardless of PD-L1 TPS. However, in subgroup analysis, the treatment outcome in the group with a PD-L1 TPS of 50% or more was similar to KEYNOTE-189 regimen. Furthermore, ipilimumab may cause a high frequency of adverse events. Biomarkers are desired for appropriate patient selection. Tumor mutation burden has been attracting attention as a biomarker for predicting the effect of ipilimumab, but it is currently considered negative according to the results of CheckMate 227 study. We focused on cytotoxic T-lymphocyte antigen 4 (CTLA-4) positive regulatory T cells (Tregs), which are considered to be the main therapeutic target of ipilimumab. Tumor tissues resected from 55 patients with NSCLC were homogenized using gentleMACS™ Dissociator (Miltenyi Biotec, Germany), and tumor infiltrating lymphocytes were collected using autoMACS® (Miltenyi Biotec, Germany). Patients with sensitizing EGFR or ALK mutation were excluded. CTLA-4+ CD45RA- forkhead box P3++ Tregs were measured by flow cytometry. Then, we statistically examined the relationship between the proportion of those cells and PD-L1 TPS. The patient background did not vary depending on the PD-L1 TPS. The proportion of CTLA-4+ CD45RA- forkhead box P3++ Tregs in CD8 T cells was constant regardless of PD-L1 TPS (P=0.4857). Lymphocyte counts in peripheral blood did not differ depending on the PD-L1 TPS (P=0.1797). This result suggests that a certain proportion of patients are expected to benefit from CheckMate 9LA regimen, regardless of PD-L1 TPS. Further biomarker study is needed in order to provide appropriate treatment to individual patients.