Immunotoxicity of pembrolizumab in patients with metastatic non-small cell lung cancer: A single-centre study

The non-small cell lung cancer (NSCLC) accounts approximately 85% of lung cancers and includes predominantly adenocarcinomas, which is the most common type and squamous cell carcinomas. The treatment options include surgery, radiation therapy, and chemotherapy and the decision depends on the patient’s medical status and stage of disease. From 1970 the standard first line treatment for most patients with unresectable NSCLC and good performance status was the use of a combination of chemotherapy regimens and usually cisplatin-based. The most common combination regimens in use at present are platinum based regimens with gemcitabine, with paclitaxel or docetaxel and with vinorelbine combinations. The addition of the recombinant humanized monoclonal antibody bevacizumab that binds to vascular endothelial growth factor (VEGF) to carboplatin and paclitaxel for the treatment of non-squamous advanced NSCLC has demonstrated to increase response rate (RR), progression free survival (PFS) and overall survival (OS) when compared to chemotherapy alone. Despite recent advances with approval of more active chemotherapeutic and anti-angiogenesis agents for stage IV NSCLC, standard therapy can provide only modest clinical benefits with significant toxicities when used in unselected patients. In 2004, the identification of somatic mutations in the epidermal growth factor receptor (EGFR) gene provided the first glimpse of a possible target for a treatment which could maximize clinical outcome in those patients who could benefit from a personalized therapy. Identifying mutations in oncogenes associated with non-squamous NSCLC can help determine which patients are more likely to benefit from a targeted therapy. Such oncogenes include EGFR, KRAS, and ALK. The presence of an EGFR mutation confers a more favorable prognosis and strongly predicts for sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib. The use of EGFR TKIs is based upon the detection of these mutations. The incidence of EGFR mutations in tumors with non-small-cell histology ranges from ~15% in Caucasians to ~50% in East Asians; 95% of such mutations have been found in adenocarcinomas. Patients bearing EGFR mutations have shown favorable clinical outcomes even with conventional chemotherapy suggesting that EGFR may be a predictive and a prognostic factor. Activation of the EGFR protein stimulates protein tyrosine kinase, which leads to activation of signaling pathways associated with cell growth and survival. Both EGFR overexpression and activating mutations in the tyrosine kinase domain of the EGFR gene lead to tumor growth and progression. Erlotinib, gefitinib and afatinib are examples of EGFR TKIs that can prevent activation of the signaling pathways and improve RRs in selected NSCLC patients. These mutations which are associated with increased sensitivity to EGFR TKIs, predominate in never-smokers, females, and tumors with adenocarcinoma histology. The most common mutations associated with sensitivity to EGFR TKIs include exon 19 deletions and the L858R point mutation and they are associated with RRs of >70%. Other EGFR mutations like T790M and exon 20 insertion, have been associated with much lower response or acquired resistance to TKI’s. The predictive value of EGFR mutations for use of gefitinib has been strengthened by the results of three randomized phase III trials that specifically compared TKIs used as first-line therapy with traditional platinum-based chemotherapy in patients with advanced NSCLC. In 2009 the results of IRESSA Pan-Asia Study were presented. This trial included a big number of Asian ethnicity patients (1,217) who were never smokers or former light smokers with histologic diagnosis of adenocarcinoma. The trial demonstrated an improvement in PFS and RR, with no statistical difference in OS, with the use of gefitinib in EGFR-mutated tumors and better RR and PFS with standard chemotherapy in patients without mutations. The first phase III trial of gefitinib versus chemotherapy as initial treatment of recurrent or advanced NSCLC, based on selection of patients with known activating EGFR mutations was the WJTOG3405 trial, reported in 2010. This trial documented important achievements in RR and PFS with the use of TKIs. Almost the same results were confirmed by another similar Japanese phase III trial, NEJ002, with RR and PFS definitely favoring the use of gefitinib in the first-line setting of metastatic EGFR-mutated NSCLC. Based on the results of the IPASS study, gefitinib was approved for use in Europe for the initial treatment of patients with NSCLC exhibiting EGFR mutations. The positive results of the EURTAC trial, NCT00446225, which was a randomized phase III trial of erlotinib versus standard chemotherapy, suggested that responsiveness in mutation-positive patients was not a function of ethnicity. Afatinib is approved as monotherapy for the treatment of EGFR TKI—naïve adults with locally advanced or metastatic NSCLC with activating EGFR mutations in the EU, and for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test in the US. In two randomized, open-label, multinational phase III trials, progression-free survival was significantly prolonged with afatinib compared with pemetrexed plus cisplatin (LUX-Lung 3) or gemcitabine plus cisplatin (LUX-Lung 6) in treatment-naïve patients with advanced NSCLC with activating EGFR mutations. EGFR-TKIs as a class are generally well tolerated. The two most common toxicities include dermatologic and GI effects, which are mild to moderate, easily managed and reversible. In order to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy, the latest guidelines recommend mutation testing for all patients with advanced NSCLC tumor. The aim of this prospective study is to compare the efficacy of gefitinib, erlotinib and afatinib in patients with advanced NSCLC harboring activating EGFR mutations in first line of treatment. These agents are recommended as first line treatments for NSCLCs with such mutations. The primary endpoint will be the PFS and the secondaries will be the OS and the record of the toxicities. In each of the 3 arms will be participate 20 patients with EGFR mutated tumors. The technique for screening NSCLC patients for driver mutations that it will be used is next-generation sequencing, which overcomes many of the shortcomings of direct sequencing. This massively parallel approach, relying heavily on automation, data storage, and computational processing, allows quantitative analysis of infrequent alleles and simultaneous evaluation of multiple genes or even whole genomes, but is not yet used routinely in clinical practice. In addition, KRAS mutation analysis will be performed in patients with known smoking history in order to determine the correlation of type and mutation frequency with smoking.

In patients with renal failure and hemodialysis, there are difficulties in drug selection and dose adjustment for cancer treatment. The use of immune checkpoint inhibitors (ICIs), including pembrolizumab, approved by the U.S. Food and Drug Administration (FDA) for patients with metastatic non-small cell lung cancer (NSCLC) in 2015, has become an important option for the treatment of metastatic NSCLC. However, data regarding the dosage and schedule for long-term use of ICIs, especially pembrolizumab, in hemodialysis patients are limited. We present the case of a patient with metastatic squamous NSCLC who demonstrated a long-term partial response to pembrolizumab monotherapy for 45 months during hemodialysis and showed no immune-related adverse events (irAEs). To our knowledge, this is the longest remission to be reported without irAEs after discontinuation of pembrolizumab in a NSCLC patient undergoing HD. In addition, we reviewed previously reported lung cancer patients who used ICI during dialysis, comparing them with our case in clinical aspect. We believe that this report will provide clinical insights into the long-term efficacy and safety of pembrolizumab in lung cancer patients undergoing hemodialysis.

WS05.03 Treatment of Advanced and Metastatic NSCLC without Oncogenic Drivers: Balancing Cost and Efficacy

Introduction: EGFR exon 20 insertion mutations occur in approximately 2% of non-small cell lung cancer (NSCLC) and overall account for approximately 9% of all the EGFR mutations in NSCLC (Robichaux et al., 2021). Current first-line standard of care for NSCLC patients with these mutations is platinum-based chemotherapy (NCCN NSCLC, 2023). Furmonertinib is an oral, highly brain penetrant, broadly active mutant-selective EGFR inhibitor that targets EGFR exon 20 insertions and other EGFR mutations (Musib et al., NACLC 2022). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the first line treatment of patients with advanced NSCLC with EGFR ex20ins based on the data from the FAVOUR study. Promising preliminary clinical activity was observed in the FAVOUR study testing furmonertinib (240 mg daily [QD]) in patients with treatment naïve locally advanced or metastatic NSCLC, with EGFR exon 20 insertion (ex20ins) mutations showing confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) with a preliminary median DOR of 15.2 months (Han et al., WCLC 2023). In previously treated patients both the 240 mg and 160 mg QD dose levels were active with confirmed ORR of 46.2% (n=26) and 38.5% (n=26) respectively, and included patients harboring near and far loop mutations.Furmonertinib showed a generally well-tolerated safety profile with expected EGFR-TKI class toxicities. Additional furmonertinib preclinical data in uncommon EGFR mutations, including P-loop and αC-helix Compressing (PACC) and ex20ins mutations will be presented at the AACR 2024 Annual Meeting (Nilsson et al., AACR 2024 Abstract #4174). Methods: The FURVENT (FURMO-004) study is a registrational global, phase 3, randomized, multicenter, open-label study. Eligible patients havetreatment-naïve, locally advanced or metastatic non-squamous NSCLC with EGFR exon 20 insertion mutations. Key inclusion criteria include documented EGFR exon 20 insertion mutation and measurable disease per RECIST 1.1. Key exclusion criteria include prior systemic anticancer therapy in the locally advanced or metastases setting or any prior EGFR TKI therapy. Approximately 375 patients will be randomized 1:1:1 to receive furmonertinib 160 mg QD, furmonertinib 240 mg QD, or platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed for 4 cycles followed by pemetrexed maintenance therapy). Stratification factors include the history or presence of central nervous system metastases at baseline, geographic region, and sex at birth. Patients from the platinum-based chemotherapy arm with documented disease progression are eligible to participate in the crossover phase of this trial to furmonertinib therapy. The primary endpoint is progression-free survival comparing between the treatment arms (furmonertinib 160 mg or 240 mg vs chemotherapy) based on BICR assessment. The key secondary endpoint is overall survival. Study enrollment is ongoing. Clinical trial information: NCT05607550. Citation Format: Alexander Spira, Byoung Chul Cho, Enriqueta Felip, Edward Garon, Koichi Goto, Melissa Lynne Johnson, Natasha B. Leighl, Antonio Passaro, David Planchard, Sanjay Popat, James Yang, Xiaoqian Lu, Yong Jiang, Jack Huang, Morgan Lam, Marcin Kowanetz, Shirley Wang, John Le, Jerry Hsu, Caicun Zhou. FURVENT, Phase 3 trial testing furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions (FURMO-004) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT280.

In Italy, the management of metastatic non-small cell lung cancer and melanoma leads to significant healthcare challenges, necessitating cost-effective treatment strategies and offering valuable insights for healthcare policymakers and stakeholders. This study was designed to assess the costs, quality-adjusted life-years (QALYs) and disability-adjusted life-years (DALYs) associated with the health and economic outcomes of (1) pembrolizumab-combined chemotherapy administered as a first-line treatment for metastatic non-squamous and squamous non-small cell lung cancer (NSCLC) where the tumour presents with a programmed death-ligand 1 expression level <50% and of (2) adjuvant pembrolizumab treatment for stage III melanoma. Three cost-effectiveness models developed by MSD were investigated for each treatment indication. A unique model was built to assess the overall effect of pembrolizumab versus chemotherapy or watchful waiting in patients with lung cancer or melanoma, respectively. Theoretical cohorts of patients with metastatic squamous and non-squamous NSCLC were followed over time using a partitioned survival model with weekly cycles. A weekly cycle Markov model was employed for melanoma. The analysis was conducted from the Italian National Health Service perspective, considering a time horizon of 40 years (lifetime). A single closed cohort of treatable patients was followed over time for each indication (4000, 7000 and 900 for NSCLC squamous, non-squamous and melanoma, respectively). The costs evaluated included those for adverse drug events, non-drug disease management, subsequent treatment and terminal care. Drug acquisition and administration costs were excluded. For each treatment indication assessed, pembrolizumab produced downstream direct cost offsets (- €122,498,568, -€133,369,076 and -€32,993,242 for NSCLC squamous, non-squamous and melanoma indications, respectively), increased quality of life (+2088, +5317 and +2307 QALYs for NSCLC squamous, non-squamous and melanoma indications, respectively) and reduced disability (-2658, -7202 and -3029 DALYs for NSCLC squamous, non-squamous and melanoma indications, respectively). Across indications, the total cost offsets of pembrolizumab were -€288,860,885, with 9712 QALYs gained and 12,889 DALYs avoided. The analysis demonstrated that, compared with chemotherapy, pembrolizumab is more cost effective in Italy as a first-line treatment in patients with metastatic squamous or non-squamous NSCLC and, if compared with watchful waiting, as adjuvant treatment in patients with stage III melanoma. The present analysis suggested that pembrolizumab use could lead to important health benefits for patients while offsetting a portion of cancer care costs.

TPS8668 Background: EGFR exon 20 insertion mutations (ex20ins) occur in approximately 2% of non-small cell lung cancer (NSCLC) and overall account for approximately 9% of all the EGFR mutations in NSCLC (Robichaux et al., 2021). Current first-line standard of care for NSCLC patients with these mutations is platinum-based chemotherapy (NCCN NSCLC, 2023). Furmonertinib is an oral, highly brain penetrant, broadly active mutant-selective EGFR inhibitor that targets EGFR exon 20 insertions and other EGFR mutations (1). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the first line treatment of patients with advanced NSCLC with EGFR ex20ins based on the data from the FAVOUR study. In FAVOUR, treatment naïve patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations showed preliminary clinical activity with a confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) with a preliminary median DOR of 15.2 months when treated with 240 mg daily [QD] of furmonertinib (2). In previously treated patients both the 240 mg and 160 mg QD dose levels were active with confirmed ORR of 46.2% (n=26) and 38.5% (n=26) respectively and included patients harboring near and far loop mutations. Furmonertinib showed a generally well-tolerated safety profile with expected EGFR-TKI class toxicities. Methods: The FURVENT (FURMO-004) study is a registrational global, phase 3, randomized, multicenter, open-label study. Eligible patients have treatment-naïve, locally advanced or metastatic non-squamous NSCLC with EGFR exon 20 insertion mutations. Key inclusion criteria include documented EGFR ex20ins mutation and measurable disease per RECIST 1.1. Key exclusion criteria include prior systemic anticancer therapy in the locally advanced or metastatic setting or any prior EGFR TKI therapy. Approximately 375 patients will be randomized 1:1:1 to receive furmonertinib 160 mg QD, furmonertinib 240 mg QD, or platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed for 4 cycles followed by pemetrexed maintenance therapy). Stratification factors include the history or presence of central nervous system metastases at baseline, geographic region, and sex at birth. Patients from the platinum-based chemotherapy arm with documented disease progression can crossover to furmonertinib cohort. The primary endpoint is progression-free survival comparing between the treatment arms (furmonertinib 160 mg or 240 mg vs chemotherapy) based on BICR assessment. The key secondary endpoint is overall survival. Study enrollment is ongoing. 1. Musib et al., NACLC 2022. 2. Han et al., WCLC 2023. Clinical trial information: NCT05607550 .

The Challenges of Third-Generation EGFR Tyrosine Kinase Inhibitors in the Therapy of Advanced NSCLC

Lung cancer is one of the most common malignant cancers in most countries, and non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. Checkpoint inhibitor immunotherapy is the preferred therapy for metastatic NSCLC patients who do not exhibit EGFR exon 19 deletion or L858R or ALK, RET, or ROS1 rearrangements. A recent clinical study (PERLA, NCT04581824) reports that dostarlimab has comparable effectiveness to pembrolizumab and presents clinical reliability as a first-line treatment for patients with metastatic non-squamous NSCLC. Our study employed a partitioned survival model (PSM) to evaluate the cost-effectiveness of dostarlimab plus chemotherapy compared to pembrolizumab plus chemotherapy as a first-line treatment of metastatic NSCLC from the perspective of healthcare payers in China. We found that when the time horizon was 10 years, dostarlimab plus chemotherapy was not cost-effective at the willingness to pay (WTP) threshold of 287,247 Chinese yuan (CNY)/QALY (35,057 EUR/QALY at an exchange rate of 1 CNY = 0.122 EUR).

Recent phase III studies indicate that patients with metastatic non–small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) gene

PC02.04 IO Should Be Given with Chemo

ObjectivesEvaluating the cost-effectiveness of pembrolizumab plus standard chemotherapy in the first-line setting for patients with metastatic non-small cell lung cancer (NSCLC) from the US payer perspective.DesignA Markov model was constructed...

Immunotherapy plays an important role in cancer treatment. Biomarkers that can predict response, including tumor-infiltrating lymphocytes (TILs), are in the spotlight of many studies. This cohort study was designed to evaluate the role of CD4+ and CD8+ TILs as predictive factors for response to anti PD-1 treatment in patients with metastatic non-small cell lung cancer (NSCLC) or metastatic melanoma. We evaluated the expression of CD4+ and CD8+ TILs in tissue samples of 56 patients with metastatic NSCLC or melanoma treated with anti-PD1 immunotherapy. The study included 30 patients with melanoma and 26 with NSCLC. An association was found between CD8+/CD4+ TILs ratio and response to anti-PD1 treatment in both cancers. Regarding melanoma patients, ratios of CD8+/CD4+ lower than 2 predicted lack of response to treatment (0%) (p=0.006), while CD8+/CD4+ ratios higher than 2.7 had an 81.3% response rate (p=0.0001). In addition, we found that the presence of more than 1900/mm2 of CD8+ lymphocytes in the melanoma tumor predicted a 90% response to therapy. In the metastatic NSCLC group, tumors with CD8+ lymphocyte count under 886/mm2 showed low response rates (16.7%, p=0.046). When the CD8+ lymphocyte count was in the range of 886-1899/mm2, the response rate was high (60%, p=0.017). In CD8+/CD4+ ratios lower than 2, the response rate was low (13.3%), and in ratios higher than 2, response rates ranged between 43 and 50% (p=0.035). The use of CD8+/CD4+ TILs ratios in tumor biopsies may predict response to anti-PD1 treatment in metastatic melanoma and NSCLC.

7062 Background: Pemetrexed (pem, Alimta) is a multitargeted antifolate approved for second-line treatment of metastatic non-small cell lung cancer (NSCLC). Treatment failure with chemoradiotherapy (CRT) is frequently due to development of distant metastasis suggesting a potential need for more effective systemic therapy. The primary objective was to determine whether pem based CRT allows administration of systemically active chemotherapy doses. Methods: Patients (pts) with locally advanced or metastatic (dominant local symptoms) NSCLC or esophageal cancer (ca) were enrolled in a phase I dose-escalating study with chemotherapy delivered on day 1, every 21 days for 2 cycles. Schedule 1 was pem (200–600 mg/m2) with concurrent radiotherapy (RT) 40–66Gy (2 Gy/d). Schedule 2 was pem fixed at recommended single-agent dose (500 mg/m2) and escalating carboplatin doses (AUC 4–6) + concomitant RT (40–66Gy). Results: 30 pts (18 locally advanced, 12 metastatic disease) were enrolled. ECOG performance status was 0 (8 pts, 26.7%), 1 (21 pts, 70.0%), and 2 (1 pt, 3.3%). Schedule 1 enrolled 18 pts (15 NSCLC, 3 esophageal ca); all dose levels were tolerable. One DLT (Grade [Gr] 4 esophagitis) was reported. One pt developed Gr 4 pulmonary embolism (PE) at the end of therapy. Gr 3 toxicities were leukopenia (n=3), dysphagia (1), and dehydration (1). Schedule 2 enrolled 12 NSCLC pts; all dose levels were tolerated. One DLT (Gr 4 PE) was reported at 500 mg/m2 + AUC 6. One pt had Gr 4 leukopenia at 500 mg/m2 + AUC 5. Treatment-related grade 3 toxicities were leukopenia (n=3), dehydration (1), and fatigue (1). Overall responses for Schedule 1 were PR (n=5), SD (5), PD (6), and unknown (2); for Schedule 2, pts had CR (1), PR (3), SD (4), PD (1), and unknown (3). Study is on-going. 3 pts had Gr 1/2 radiation pneumonitis (8 d - 8 w) after RT. Several pts underwent curative intent surgery. In-field responses are being assessed. Conclusions: The combination of pemetrexed (500 mg/m2) with carboplatin (AUC 6) day 1 every 21 days for 2 cycles with concurrent radiotherapy is feasible, allows administration of systemically active doses, and warrants examination in a phase II trial. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly Eli Lilly

Simple SummaryNext-generation sequencing (NGS) has revolutionized care for patients with advanced and metastatic non-small cell lung cancer through the identification of specific oncogenic driver mutations and pairing with matched targeted therapies. The application of NGS technologies also has the potential to improve outcomes in patients with earlier-stage disease who undergo surgery as their first line of treatment. We review clinically relevant topics in this patient cohort, for whom NGS technologies have spearheaded our understanding of tumor heterogeneity, the underlying genomic features associated with lung adenocarcinoma histologic subtypes, the prediction of recurrence after surgery, the identification of minimal residual disease by circulating tumor DNA, the discernment of intrapulmonary metastases versus synchronous or metachronous disease, and the identification of patients with early-stage non-small cell lung cancer who are likely to benefit from induction or adjuvant therapies.During the last two decades, next-generation sequencing (NGS) has played a key role in enhancing non-small cell lung cancer treatment paradigms through the application of “targeted therapy” in advanced and metastatic disease. The use of specific tyrosine kinase inhibitors in patients with oncogenic driver alterations, such as EGFR, ALK, ROS1, BRAF V600E, MET, and NTRK mutations, among others, has changed treatment approaches and improved outcomes in patients with late-stage disease. Although NGS technology has mostly been used in the setting of systemic therapy to identify targets, response to therapy, and mechanisms of resistance, it has multiple potential applications for patients with earlier-stage disease, as well. In this review, we discuss the emerging role of NGS technologies to better understand tumor biology in patients with non-small cell lung cancer who are undergoing surgery with curative intent. In this patient cohort, we examine tumor heterogeneity, the underlying tumor genomics associated with lung adenocarcinoma subtypes, the prediction of recurrence after complete surgical resection, the use of plasma circulating tumor DNA for detection of early cancers and monitoring for minimal residual disease, the differentiation of separate primaries from intrapulmonary metastases, and the use of NGS to guide induction and adjuvant therapies.

New Horizons in Chemotherapy: Platforms for Combinations in First-Line Advanced Non-small Cell Lung Cancer