Metastatic Non-small Cell Lung Cancer Research Articles

Circulating tumor DNA- and cancer tissue-based next-generation sequencing reveals comparable consistency in targeted gene mutations for advanced or metastatic non-small cell lung cancer.

Molecular subtyping is an essential complementarity after pathological analyses for targeted therapy. This study aimed to investigate the consistency of next-generation sequencing (NGS) results between circulating tumor DNA (ctDNA)-based and tissue-based in non-small cell lung cancer (NSCLC) and identify the patient characteristics that favor ctDNA testing. Patients who diagnosed with NSCLC and received both ctDNA- and cancer tissue-based NGS before surgery or systemic treatment in Lung Cancer Center, Sichuan University West China Hospital between December 2017 and August 2022 were enrolled. A 425-cancer panel with a HiSeq 4000 NGS platform was used for NGS. The unweighted Cohen's kappa coefficient was employed to discriminate the high-concordance group from the low-concordance group with a cutoff value of 0.6. Six machine learning models were used to identify patient characteristics that relate to high concordance between ctDNA-based and tissue-based NGS. A total of 85 patients were enrolled, of which 22.4% (19/85) had stage III disease and 56.5% had stage IV disease. Forty-four patients (51.8%) showed consistent gene mutation types between ctDNA-based and tissue-based NGS, while one patient (1.2%) tested negative in both approaches. Advanced diseases and metastases to other organs would be fit for the ctDNA-based NGS, and the generalized linear model showed that T stage, M stage, and tumor mutation burden were the critical discriminators to predict the consistency of results between ctDNA-based and tissue-based NGS. ctDNA-based NGS showed comparable detection performance in the targeted gene mutations compared with tissue-based NGS, and it could be considered in advanced or metastatic NSCLC.

Pharmacoeconomic evaluation of first-line combination therapy with immunotherapy drugs and platinum-containing chemotherapy in adult patients with metastatic non-squamous non-small cell lung cancer

Objective: to evaluate the pharmacoeconomic efficacy of “atezolizumab + bevacizumab + paclitaxel + carboplatin” drug combination compared to “pembrolizumab + pemetrexed + carboplatin” combination in adult patients with non-small cell lung cancer (NSCLC) in the first line of therapy.Material and methods. The modeling was applied for cost minimization analyzis of using compared therapy regimens with comparable efficacy, and to estimate the impact on the healthcare budget when increasing the proportion of patients in the target population receiving “atezolizumab + bevacizumab + paclitaxel + carboplatin” combination. Published adjusted indirect comparison data were used in modeling. The calculations were based on the registered prices according to the state register of maximum selling prices.Results. The use of “atezolizumab + bevacizumab + paclitaxel + carboplatin” combination instead of “pembrolizumab + pemetrexed + carboplatin” combination will decrease the direct medical costs of therapy per 1 patient for 2 years by 28,165.00 rubles (–0.4%). The budget impact analysis showed that an increase in the proportion of patients receiving “atezolizumab + bevacizumab + paclitaxel + carboplatin” combination from 50% (current therapy practice) to 100% (considered therapy practice) will reduce the budget load for the population of 6,240 patients over 2 years by 256.1 million rubles (–0.64%).Conclusion. The results of pharmacoeconomic analysis demonstrated that the use of “atezolizumab + bevacizumab + paclitaxel + carboplatin” combination in first-line therapy for metastatic NSCLC is economically feasible and reduces the load on the budget compared to “pembrolizu- mab + pemetrexed + carboplatin” scheme.

CXCR6-positive circulating mucosal-associated invariant T cells can identify patients with non-small cell lung cancer responding to anti-PD-1 immunotherapy

BackgroundMucosal-associated invariant T (MAIT) cells have been reported to regulate tumor immunity. However, the immune characteristics of MAIT cells in non-small cell lung cancer (NSCLC) and their correlation with the treatment efficacy of immune checkpoint inhibitors (ICIs) remain unclear.Patients and methodsIn this study, we performed single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence assays to determine the proportion and characteristics of CD8+MAIT cells in patients with metastatic NSCLC who did and did not respond to anti-PD-1 therapy. Survival analyses were employed to determine the effects of MAIT proportion and C-X-C chemokine receptor 6 (CXCR6) expression on the prognosis of patients with advanced NSCLC.ResultsThe proportion of activated and proliferating CD8+MAIT cells were significantly higher in responders-derived peripheral blood mononuclear cells (PBMCs) and lung tissues before anti-PD-1 therapy, with enhanced expression of cytotoxicity-related genes including CCL4, KLRG1, PRF1, NCR3, NKG7, GZMB, and KLRK1. The responders’ peripheral and tumor-infiltrating CD8+MAIT cells showed an upregulated CXCR6 expression. Similarly, CXCR6+CD8+MAIT cells from responders showed higher expression of cytotoxicity-related genes, such as CST7, GNLY, KLRG1, NKG7, and PRF1. Patients with ≥15.1% CD8+MAIT cells to CD8+T cells ratio and ≥35.9% CXCR6+CD8+MAIT cells to CD8+MAIT cells ratio in peripheral blood showed better progression-free survival (PFS) after immunotherapy. The role of CD8+MAIT cells in lung cancer immunotherapy was potentially mediated by classical/non-classical monocytes through the CXCL16-CXCR6 axis.ConclusionCD8+MAIT cells are a potential predictive biomarker for patients with NSCLC responding to anti-PD-1 therapy. The correlation between CD8+MAIT cells and immunotherapy sensitivity may be ascribed to high CXCR6 expression.

A Practical Review of Encorafenib and Binimetinib Therapy Management in Patients with BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer.

According to current guidelines, targeted therapy with a combination of BRAF plus MEK inhibitors is the preferred first-line treatment for patients with BRAF V600E-mutant metastatic non-small cell lung cancer (NSCLC). In the open-label, single-arm, phase2 PHAROS trial (NCT03915951), the combination of encorafenib, a potent BRAF inhibitor, and binimetinib, a potent MEK inhibitor, demonstrated durable antitumor activity with a manageable safety profile in this patient population. On the basis of the results of this study, the combination of encorafenib plus binimetinib was approved by the US Food and Drug Administration on October 11, 2023, for patients with BRAF V600E-mutant metastatic NSCLC. In this review, we summarize the efficacy and safety of encorafenib plus binimetinib from the PHAROS study. In addition, we discuss strategies to manage adverse reactions with this combination therapy with the intent of minimizing unnecessary treatment discontinuations in these patients.

Abstract PO2-20-08: Metastatic Lung Cancer Masquerading as Metaplastic Breast Cancer

Abstract Background Metaplastic breast carcinoma (MBC) is an unusual malignancy that presents a diagnostic challenge due to the presence of varying cytomorphologies that can be seen in benign and malignant tumors. We posit that metastatic disease to the breast, itself an uncommon entity, should be considered in the differential diagnosis of MBC. We report a unique case of metastatic non-small cell lung cancer (NSCLC) with an actionable driver mutation that presented as a symptomatic breast mass and was initially considered to represent MBC. Report A 74-year-old woman with a 22-pack-year smoking history presented to the breast clinic complaining of a palpable left breast mass that had grown rapidly over the previous month. Ultrasound-guided biopsy of the breast mass revealed high-grade poorly differentiated carcinoma. On immunohistochemical (IHC) evaluation, tumor cells were strongly positive for epithelial markers CAM5.2 and keratin AE1/AE3, weakly positive for breast cancer (BC) marker TRPS1, and negative for BC marker GATA3, squamous cell carcinoma markers p63 and CK5, and melanoma marker SOX10. Metaplastic triple-negative BC was diagnosed. However, concern remained for metastasis from a non-breast primary tumor due to the patient’s constitutional symptoms such as fatigue, night sweats, and 60-pound unintentional weight loss over the previous year, as well as interval development of a suspicious nodular rash on her right upper extremity. An FDG-PET-CT was obtained and demonstrated a hypermetabolic left lung consolidation (maximum SUV 33.3) measuring 7.2 cm, pulmonary nodules, and extensive thoracic lymphadenopathy. Due to rising suspicion for a primary lung tumor, additional IHC staining on the original breast biopsy was requested. Tumor cells were positive for TTF-1, consistent with metastatic lung adenocarcinoma. Tissue next-generation sequencing (NGS) identified a MET exon 14 skipping mutation, making the patient eligible for treatment with capmatinib, a first-line kinase inhibitor targeted therapy for metastatic NSCLC. At the time of this report, the patient has completed a course of palliative stereotactic body radiation therapy to the left lung and started capmatinib 400 mg BID, which she is tolerating well. Her first restaging scans after treatment initiation will be obtained one week after the time of this report. Conclusion In the absence of heightened suspicion for a non-breast primary tumor, our patient had initially received a diagnosis of triple-negative MBC. This diagnosis would have exposed her to increased treatment-related toxicities from cytotoxic chemotherapy and poor prognosis from MBC without survival benefit from targeted therapy for NSCLC. We advocate for the use of supplemental body imaging, expert and comprehensive IHC evaluation, and multidisciplinary discussion in cases of MBC and undifferentiated breast malignancy to facilitate accurate diagnosis and treatment. Citation Format: Tanmayi Pai, Marte Wasserman, Jason Lewis, Miglena Komforti, James Jakub, Augustine Lee, Yanyan Lou, Pooja Advani, Rohit Rao. Metastatic Lung Cancer Masquerading as Metaplastic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-08.

Evolving Strategies in NSCLC Care: Targeted Therapies, Biomarkers, Predictive Models, and Patient Management

Abstract: Lung cancer, primarily Non-Small Cell Lung Cancer (NSCLC), is a global public health concern responsible for 80-85% of cases, with over two million new cases occurring annually, and 50% of them in Asia. While there has been a gradual reduction in United States (US) cases over the last decade, with 238,340 new cases and 127,070 deaths reported in 2023, managing metastatic NSCLC remains crucial, focusing on prolonging survival and enhancing quality of life. Integration of early palliative care shows promise in this regard. International guidelines recommend personalized treatment guided by genetic mutations (Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase, C-Ros oncogene [1ROS1]) and systemic therapies, including chemotherapy, targeted therapy, and immunotherapy, which play pivotal roles in redefining care. Treatment effectiveness hinges on factors such as cancer stage, patient health, and therapy type, with surgery and radiation therapy common in early stages and advanced stages requiring chemotherapy, targeted therapy, or immunotherapy. Despite advancements in treatment modalities, NSCLC continues to pose a significant challenge globally, particularly in Asia, where a substantial portion of new cases arise. While there has been an uncertain reduction in the incidence of lung cancer in the US over the past decade, the burden of the disease persists, with substantial mortality rates reported annually. Additionally, upon diagnosis, many NSCLC patients present with distant metastases, necessitating effective treatment strategies to improve overall survival and quality of life. The objectives include investigating targeted treatments for NSCLC with specific genetic mutations, examining mechanisms of novel therapies under study, evaluating preclinical and clinical studies for therapy efficacy and safety, identifying genetic and epigenetic biomarkers for diagnosis, prognosis, and treatment selection, developing predictive models for lung cancer recurrence and survival, assessing the efficacy of treatment approaches for early-stage lung cancer, and enhancing patient outcomes through collaborative care and lifestyle interventions. These collective efforts promise to improve patient outcomes and quality of life in the battle against NSCLC.

Molecular Diagnostics and Treatment Patterns in Metastatic Non-small Cell Lung Cancer Patients: Real World Evidence from Greece: LACHESIS Study.

Lung cancer, primarily non-small cell lung cancer (NSCLC), is the leading cause of cancer deaths globally. In Greece in 2020, 8,960 new cases were reported. NSCLC's 5-year survival rates range from 54% (stage I) to less than 2% (stage IV); however, innovative therapies like immune check points inhibitors (ICIs) and targeted treatments have notably enhanced outcomes. The aim of this study was to assess the 1st and 2nd line treatment patterns with the introduction of new treatment modalities. Additionally, we evaluated biomarker testing approaches in NSCLC. LACHESIS was a retrospective multinational study, collecting and analyzing data from adult patients from Russia, Bulgaria, and Greece with metastatic NSCLC either newly diagnosed or relapsed from earlier stages, who had the option to undergo biomarker testing (genetic alterations/programmed death-ligand 1 protein expression levels, PD-L1), and who received 1st line treatment for squamous (SQ) or non-squamous (N-SQ) NSCLC. Subsequent lines of therapy were also reported. The Greek site registered retrospective data from 250 NSCLC patients, of whom 206 were newly diagnosed (ND) metastatic NSCLC patients and 44 were patients relapsed from earlier stages. Seventy-two had SQ NSCLC and 169 had N-SQ NSCLC. For these patients, treatment patterns including immunotherapy±chemotherapy combinations were recorded. Biomarker testing patterns, including genetic alterations and PD-L1 expression levels were also documented. LACHESIS provides treatment patterns and biomarker testing data. Greek patients were treated according to international guidelines, with immunotherapy as a viable option, particularly for PD-L1 levels over 50%. Biomarker testing, crucial for non-squamous (N-SQ) cases, should yield timely results for driver mutations, prioritizing patient benefits.

Retreatment with Immune Checkpoint Inhibitors in the New Scenario of Immunotherapy in Non-Small Cell Lung Cancer

The advent of immunotherapy has transformed the treatment paradigm for metastatic non-small cell lung cancer (NSCLC). In the past few years, several studies have investigated the potential role of immune checkpoint inhibitors (ICIs) in resectable and unresectable locally advanced disease, achieving remarkable results that led to their approval in clinical practice. However, there is limited evidence on immunotherapy rechallenge after recurrence, with the majority of available knowledge coming from retrospective studies which involve heavily pretreated patients with advanced NSCLC. The recent introduction in the curative setting and the potential regulatory restrictions raise questions about the optimal choice of first-line and subsequent therapies for patients with systemic relapse. The role of immunotherapy readministration in this new scenario needs to be clarified, as well as the identification of patients for whom it is more appropriate, including clinical characteristics, duration of response, switching to other ICIs, reasons for discontinuation and immune-related toxicity. Here, we review literature on rechallenge with immunotherapy, including efficacy, safety profile and potential predictive factors of response.

A real-world pharmacovigilance study of amivantamab-related cardiovascular adverse events based on the FDA adverse event reporting system (FAERS) database

Amivantamab is the first dual-specificity antibody targeting EGFR and MET, which is approved for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations. Cardiovascular toxicities related to amivantamab have not been reported in the CHRYSALIS study. However, the occurrence of cardiovascular events in the real world is unknown. To comprehensively investigate the clinical characteristics, onset times, and outcomes of cardiovascular toxicities associated with amivantamab. The Food and Drug Administration Adverse Event Reporting System (FAERS) database from 1st quarter of 2019 to the 2nd quarter of 2023 was retrospectively queried to extract reports of cardiovascular adverse events (AEs) associated with amivantamab. To perform disproportionality analysis, the reporting odds ratios (RORs) and information components (ICs) were calculated with statistical shrinkage trans-formation formulas and a lower limit of the 95% confidence interval (CI) for ROR (ROR025) > 1 or IC (IC025) > 0 with at least 3 reports was considered statistically significant. A total of 20,270,918 eligible records were identified, among which 98 records were related to cardiovascular events associated with amivantamab. 4 categories of cardiovascular events exhibited positive signals: venous thrombotic diseases, abnormal blood pressure, arrhythmia, and pericardial effusion. Venous thrombotic diseases and abnormal blood pressure were the two most common signals. The median time to onset (TTO) for cardiovascular AEs was 33 days. The cumulative incidence within 90 days was 100% for cardiac failure, 75% for stroke, 63.16% for arrhythmia, 50% for sudden death, and 44.18% for venous thrombotic diseases. Death accounted for 16.3% of all cardiovascular AEs associated with amivantamab. The mortality rates for Major Adverse Cardiovascular Events (MACE) were up to 60%. This pharmacovigilance study systematically explored the cardiovascular adverse events of amivantamab and provided new safety signals based on past safety information. Early and intensified monitoring is crucial, and attention should be directed towards high-risk signals.

Recent updates in the therapeutic uses of Pembrolizumab: a brief narrative review.

Treatment of cancer has been improved with the discovery of biological drugs that act as immune checkpoint inhibitors. In 2017, FDA designated pembrolizumab, an immune checkpoint inhibitor employed in immunotherapy, as the first tissue-agnostic cancer treatment. To review pembrolizumab's use in oncology, gather and examine the latest discoveries regarding the effectiveness of pembrolizumab in cancer treatment. A literature review was conducted through PubMed(Medline) from January 2015 to December 2023 using "pembrolizumab", "cancer" and "treatment" as search terms. Pembrolizumab demonstrated effectiveness as primary treatment for metastatic nonsmall cell lung cancer, unresectable esophageal cancer, head and neck squamous cell carcinoma and alternative treatment for notable triple-negative breast cancer, biliary, colorectal, endometrial, renal cell, cervical carcinoma, and high microsatellite instability or mismatch repair deficiencies tumors. Pediatric applications include treatment for refractory Hodgkin lymphoma. Evolving research on pembrolizumab allows a deeper clinical understanding, despite challenges as variable patient responses. Pembrolizumab has emerged as a pivotal breakthrough in cancer treatment, improving patient outcomes and safety.

Mutational Profiling by Next-Generation Sequencing in Patients with Metastatic Non-Small Cell Lung Carcinoma: Our Experience

Introduction According to GLOBOCAN 2020, overall lung cancer is the second most common cancer in both sexes (11.4%) accounting for highest cancer-related mortality (18%).1 Adenocarcinoma subtype of non-small cell lung cancer (NSCLC) is the most common subtype and is divided into further molecular subtypes based on oncogenic driver mutations. Overall survival in these patients is poor with the use of conventional platinum-based double chemotherapy and various recent studies on targeted therapy studies have showed improved survival. Therefore, broad panel-based testing like next-generation sequencing (NGS) is strongly recommended to identify these targetable driver mutations. Aims and Objectives The aim of this study was to evaluate the mutational profile in patients with metastatic NSCLC (mNSCLC) by NGS method. Materials and Methods A hospital-based prospective observational study done on 88 patients under the Department of Medical Oncology, State Cancer Institute during a period of 1 year. All patients above 18 years of age diagnosed as mNSCLC having Eastern Cooperative Oncology Group performance status 0 to 2 and evaluated for mutational profiling by NGS method were included. Five gene panel tests including endothelial growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK), BRAF, mesenchymal epithelial transition (MET), and ROS proto-oncogene 1 (ROS1) were used. Results and Observations Majority of mNSCLC cases were in the age group of 41 to 50 years (n = 30, 34.1%) with average age at presentation being 53.74 years. Male: female ratio was 1.14:1 and most patients were nonsmokers. Adenocarcinoma subtype of mNSCLC cases had the highest mutational burden (n = 55, 62.5%). EGFR (n = 32, 56.14%) was the most common mutation followed by EML4-ALK (n = 19, 33.33%). Most common EGFR mutation was in Exon 19. Other rare mutations were ROS1 (n = 4), BRAF V600E (n = 1), and MET (n = 1). Skeleton was the most common site of metastasis across all driver mutations. Conclusion EGFR and EML4-ALK were the commonest targetable mutations detected in the study. As there is very limited data from North Eastern region of India regarding mutational status in mNSCLC, this study opens up possibilities for further studies targeting multiple mutations to give us more comprehensive understanding of the mutational landscape of mNSCLC in this era of precision medicine.

Cost-effectiveness of additional serplulimab to chemotherapy in metastatic squamous non-small cell lung cancer patients.

To estimate the cost-effectiveness of adding serplulimab to chemotherapy for metastatic squamous non-small cell lung cancer (NSCLC) patients in a first-line setting from a Chinese perspective. A three-health state partitioned survival model was constructed to simulate disease development. The clinical data used in the model were derived from the ASTRUM-004 clinical trial. Only direct medical costs were included, and the utilities were derived from published literature. The quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were employed to evaluate health outcomes. Additionally, a sensitivity analysis was performed to verify the robustness of the results. Compared with chemotherapy alone, the addition of serplulimab resulted in an increase of 0.63 QALYs with an incremental cost of $5,372.73, leading to an ICER of $8,528.14 per QALY. This ICER was significantly lower than 3 times China's per capita GDP. The one-way sensitivity analysis suggested that the utility of PFS was the most sensitive factor on ICERs, followed by the price of serplulimab. The combination of serplulimab and chemotherapy has been shown to be a cost-effective initial treatment option for patients with metastatic squamous NSCLC with the commonly accepted willingness-to-pay threshold of 3 times the GDP per capita per QALY in China.

Response to lorlatinib rechallenge in a case of ALK-rearranged metastatic NSCLC with a resistance mutation to second generation TKIs.

Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have been developed for the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged non-small cell lung cancer (NSCLC), with the newer generation agents brigatinib, alectinib and lorlatinib showing prolonged responses. With the increasing number of target therapies available, the optimal sequence is yet to be defined, as resistance profiles may evolve over time and in response to sequential ALK inhibitors. Therefore, ALK-targeted strategies may be personalized based upon the presence of specific ALK resistance mutations. Here, we report on the case of a patient who has been treated with a sequence of three ALK TKIs after receiving diagnosis of ALK-rearranged metastatic NSCLC in 2015 and gained further benefit upon lorlatinib rechallenge after the acquisition of the G1202R resistance mutation to second generation TKIs. In this case, the first ALK resistance mutation detected after progression on first line TKI, the I1171N, is a common resistance mutation after alectinib and confers sensitivity to brigatinib, that the patient received afterwards with a long-term disease stability. The second ALK resistance mutation detected after a chemotherapy interval, the G1202R, is the most common resistance mutation after second generation ALK TKIs and has been associated with sensitivity to third generation TKIs, such as lorlatinib. This case of a patient with EML4-ALK-rearranged NSCLC shows that sequential treatment with next-generation ALK TKIs, including rechallenge, can induce profound remissions, even in heavily pretreated patients, and that ALK-targeted strategies may be personalized by considering the presence of distinct ALK resistance mutations.

Treatment selection and real-world analysis of immunotherapy with or without chemotherapy in PD-L1-high metastatic non-small cell lung cancer.

Lung cancer is the leading cause of cancer death in Australia. Immunotherapy has improved outcomes in patients with metastatic non-small cell lung cancer (NSCLC). Pembrolizumab is approved in first-line treatment as single-agent immunotherapy (SAI) or combination chemoimmunotherapy (CIT). In metastatic NSCLC programmed death-ligand 1 (PD-L1) ≥50% either regimen may be used. We aim to identify patient and tumour characteristics that influence treatment selection. This is a retrospective observational study. Pharmacy records identified patients with metastatic/recurrent NSCLC receiving pembrolizumab at two metropolitan centres in Victoria, Australia, since 2018. Demographics, tumour characteristics, Charlson Comorbidity Index (CCI) and treatment data were collected. Descriptive and multivariate analyses were performed. Sixty-one patients had metastatic NSCLC PD-L1 ≥50% and received pembrolizumab with median age of 65.6 years, Eastern Cooperative Oncology Group 0-1 in 82%. CIT was administered to 23% (14) with no difference in rate of delivery between centres (P = 0.808). CCI mean score differed (3.38 SAI vs 2.36 CIT, P = 0.042). Patients with high CCI score (≥2) were less likely to receive CIT (OR = 0.15, P = 0.003, 95% confidence interval (CI) 0.04-0.57). Primary tumours over 5 cm were more likely to receive CIT (OR = 3.74, P = 0.043, 95% CI = 1.04-13.42). Site-specific metastases of liver, brain and pericardial effusion were not associated with CIT. Patients with higher comorbidity score were less likely to receive CIT, suggesting chemotherapy avoidance in comorbid patients. Larger tumours are associated with CIT use, indicating that oncologists may use tumour size as a surrogate of disease burden. Limitations include small sample size and data cut-off. Future prospective studies could incorporate comorbid status and a validated disease burden score to stratify patients.

Development of crizotinib-associated renal cyst in a non-small cell lung cancer patient with ALK fusion: a case report and review of the literature

BackgroundCrizotinib, an oral first-generation tyrosine kinase inhibitor (TKI), is superior to systemic chemotherapy for the treatment of non-small cell lung cancer (NSCLC) with positive rearrangement of anaplastic lymphoma kinase (ALK). However, an increased incidence of renal and hepatic cysts has been reported in the patients on crizotinib treatment.Case presentationHere, we describe a case of a 71-year-old Chinese women developed multiple cystic lesions in kidney and liver during crizotinib treatment for the primary and metastatic NSCLC. The renal and hepatic cysts were noted by CT scan 3 months after crizotinib treatment, which were spontaneously and significantly regressed after stopping crizotinib.ConclusionsBased on literature review and our experience in this case report, we concluded that crizotinib-associated renal cyst (CARCs) has features of malignancy and abscess in radiographic imaging, and thus, pathological confirmation is necessary to avoid inappropriate treatment decision. In addition, to benefit the patients with progress-free survival (PFS), switching from crizotinib to alectinib is recommended for the treatment of NSCLC patients who developed CARCs.

The effect of food on the pharmacokinetics of Sutetinib maleate capsule, an irreversible EGFR tyrosine kinase inhibitor, in healthy Chinese subjects.

Sutetinib is an irreversible inhibitor of epidermal growth factor receptor (EGFR) and showed favorable efficacy and safety in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring nondrug-resistant rare EGFR mutations. To evaluate the potential food effect, eighteen healthy Chinese subjects were enrolled in a single-centre, randomized, open-label, two-sequence, two-period crossover study. Sutetinib was administered as a single oral 100mg under fasting or fed conditions, and pharmacokinetic sampling was performed following each dose and analysed by a validated liquid chromatography/mass spectrometry method. Safety and tolerability were also evaluated. Food intake slightly decreased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUC0 - inf) of sutetinib (geometric least-squares mean [GLSM] ratio, 80.94% and 86.11%; 90% confidence interval [CI], 68.43-95.72 and 75.88-97.73) and its active metabolite sutetinib N-Oxide (GLSM ratio, 75.58% and 84.00%; 90% CI, 65.69-86.95 and 75.42-93.56), respectively. In addition, the time to maximum plasma concentration (Tmax) of both sutetinib and its metabolite has been prolonged by 2h under fed conditions. A total of 31 adverse events (AEs) occurred during the study, with no serious adverse events (SAE) reported, and no obvious difference was observed between the fasting and fed groups. Our results demonstrated that a high-fat and high-calorie diet caused a significant delay in drug absorption and a marginal reduction in drug exposure. Sutetinib was generally well tolerated in healthy Chinese subjects. (This trial was registered at http://www.chinadrugtrials.org.cn . The registration No. is CTR20201933, and the date of registration is 2020-10-16).

Abstract CT280: FURVENT, Phase 3 trial testing furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions (FURMO-004)

Abstract 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.

Abstract CT277: BGB-LC-201 (NCT05635708): A phase 2, open-label, multi-arm study of tislelizumab (TIS; anti-PD-1) in combination with investigational agents +/- chemotherapy as first-line treatment for patients with locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC)

Abstract Background: Prognosis for locally advanced, unresectable, or metastatic NSCLC remains poor despite advances in the use of immune checkpoint inhibitors (ICI) with or without histology-appropriate chemotherapy (chemo), partly due to innate or adaptive resistance to ICI. Combination therapies aim to overcome resistance to anti-programmed cell death protein-1 or programmed death-ligand-1 (PD-1/PD-L1) therapy and thus improve anticancer activity. This phase 2 study will determine whether adding investigational agents BGB-A445 (OX40 agonistic monoclonal antibody [mAb]), LBL-007 (anti-lymphocyte activation gene-3 mAb), or BGB-15025 (hematopoietic progenitor kinase 1 [HPK1] inhibitor) improves the therapeutic benefit of TIS (anti-PD-1 mAb) +/- chemo in patients with locally advanced, unresectable, or metastatic NSCLC. Methods: The umbrella design allows for the use of multiple investigational drugs, administered alone or in combination, in patients with untreated locally advanced, unresectable, or metastatic NSCLC without actionable driver mutations. Approximately 400 patients aged ≥18 years will be enrolled in 1 of 2 Substudies based on PD-L1 expression and randomized 2:1 to either the experimental or reference arm within each Substudy. Patients in Substudy 1 (PD-L1 ≥50%) will be randomized to receive either TIS (200 mg intravenously [IV] every 3 weeks [Q3W]) in combination with BGB-A445 (2400 mg IV Q3W), LBL-007 (600 mg IV Q3W), or BGB-15025 (experimental arms) or TIS monotherapy (reference arm). Those in Substudy 2 (PD-L1 <50%) will receive TIS + chemo in combination with BGB-A445 (2400 mg IV Q3W), LBL-007 (300 mg, 600 mg, or 1200 mg IV Q3W), or BGB-15025 (experimental arms) or TIS + chemo (reference arm). Patients will receive up to 36 cycles (each cycle lasting 3 weeks) or until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint is investigator-assessed confirmed overall response rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; secondary endpoints include investigator-assessed progression-free survival, duration of response, clinical benefit rate, disease control rate (per RECIST v1.1), pharmacokinetics, immunogenicity, and safety. Exploratory endpoints include overall survival, time to response, and relevant biomarker associations with response or resistance to study treatments. Enrollment is ongoing at 66 sites in China, Asia-Pacific, the United States, and the European Union. Citation Format: George Blumenschein, Benjamin Besse, Justin F. Gainor, DingZhi Huang, Steven Kao, Se-Hoon Lee, Luis Paz-Ares, Xin Chen, Wanyu He, Sridharan Gururangan, Kathy Zhang, Caicun Zhou. BGB-LC-201 (NCT05635708): A phase 2, open-label, multi-arm study of tislelizumab (TIS; anti-PD-1) in combination with investigational agents +/- chemotherapy as first-line treatment for patients with locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) [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 CT277.

Abstract LB107: Association of circulating free DNA (cfDNA) maximum variant allele frequency (mVAF) levels with clinical outcomes in patients (pts) with metastatic nonsquamous non-small cell lung cancer (NSCLC) treated with pembrolizumab (pembro) + chemotherapy (chemo) in the phase 2 KEYNOTE-782 trial

Abstract Background: The phase 2 KEYNOTE-782 trial (NCT03664024) was designed to prospectively evaluate plasma-derived biomarkers of response to first-line pembro + chemo in pts with metastatic nonsquamous NSCLC. This exploratory analysis of KEYNOTE-782 evaluated the association of cfDNA mVAF levels with clinical outcomes. Methods: Adults with untreated stage IV nonsquamous NSCLC received pembro 200 mg Q3W + chemo (pemetrexed + carboplatin or cisplatin). cfDNA was isolated from plasma samples collected at baseline (BL) and cycle 2 (C2) and sequenced using a targeted NGS-based assay previously used to assess blood tumor mutational burden from cfDNA for the primary analysis. cfDNA mVAF was quantified for each patient. The associations of BL cfDNA mVAF (all pts) and change in cfDNA mVAF from BL at C2 (pts with ≥1 detectable variant at BL; cfDNA+) as continuous variables with ORR, PFS, and OS were evaluated; 1-sided α was prespecified at 0.05 after multiplicity adjustment. ORR, PFS, and OS were also descriptively evaluated by cfDNA bins (BL mVAF, >0 vs 0; mVAF change from BL, ≥median vs <median). Results: Of 101 pts with evaluable cfDNA samples at BL, 83 (82.2%) were cfDNA+; 74 of these 83 pts had evaluable cfDNA samples at C2. Low BL mVAF was associated with improved ORR, PFS, and OS (P <0.01, each). The area under the receiver operating characteristic curve (AUROC) for discriminating response was 0.61 (95% CI, 0.50-0.72). Among pts with BL mVAF >0 (n = 83) vs 0 (n = 18), ORR (95% CI) was 38.6% (28.1-49.9) vs 55.6% (30.8-78.5), median PFS (95% CI) was 6.6 mo (4.9-9.0) vs 19.7 mo (9.8-not reached [NR]), and median OS (95% CI) was 13.6 mo (9.4-22.5) vs 31.6 mo (20.1-NR). Larger reductions in mVAF from BL at C2 were associated with improved ORR, PFS, and OS (P <0.05, each). The AUROC for discriminating response was 0.69 (95% CI, 0.57-0.82). After adjustment for best overall response, change in mVAF from BL at C2 was not associated with PFS or OS (P >0.05). In a descriptive evaluation for pts with a mVAF change from BL at C2 ≥median of 0.15 (n = 37) vs <median (n="37)," orr="" (95%="" ci)="" was="" 18.9%="" (8.0-35.2)="" vs="" 64.9%="" (47.5-79.8),="" median="" pfs="" 5.1="" mo="" (4.2-11.1)="" 7.2="" (6.2-21.7),="" and="" os="" 12.8="" (7.9-18.1)="" 25.9="" (15.3-nr).="" conclusions:="" in="" pts="" with metastatic nonsquamous NSCLC treated with pembro + chemo, low cfDNA mVAF levels at BL and larger reductions in cfDNA mVAF levels were associated with improved clinical outcomes. However, after correction for clinical response, the prognostic value of cfDNA mVAF reduction was not significant. Further studies are warranted to elucidate the utility of cfDNA for disease monitoring in this setting. Citation Format: Jair Bar, Emilio Esteban, Delvys Rodríguez-Abreu, Santiago Ponce-Aix, Zsuzsanna Szalai, Enriqueta Felip, Maya Gottfried, Mariano Provencio Pulla, Andrew Robinson, Andrea Fülöp, Suman Bannur Rao, D. Ross Camidge, Giovanna Speranza, Nathan Hunkapiller, Robert McDaniel, Byoungsok Jung, David Burkhardt, Ruth Mauntz, Cai Chen, Carol Pena, Razvan Cristescu, Elisha J. Dettman, Steven M. Townson, Julie Kobie, Tibor Csőszi. Association of circulating free DNA (cfDNA) maximum variant allele frequency (mVAF) levels with clinical outcomes in patients (pts) with metastatic nonsquamous non-small cell lung cancer (NSCLC) treated with pembrolizumab (pembro) + chemotherapy (chemo) in the phase 2 KEYNOTE-782 trial [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 LB107.

Abstract CT082: Phase I study of autologous CD8+ and CD4+ transgenic T cells expressing high-affinity KRAS G12V mutation-specific T cell receptors (FH-A11KRASG12V-TCR) in patients with metastatic pancreatic, colorectal and non-small cell lung cancers with KRAS G12V mutations

Abstract Background: KRAS, the most common driver oncogene in human malignancies, has predictable mutations. 85% of RAS mutations occur at the Glycine (G) 12 position with G12V being amongst the most common. Cancers driven by mutant KRAS include pancreatic (PDAC), colorectal (CRC), and non-small cell lung (NSCLC) malignancies. The prognosis of patients with activating KRAS mutations remains poor. Preliminary anti-tumor activity has been observed in the clinic with T cell receptor (TCR) T cell therapies targeting KRAS mutations, but durable clinical benefit is lacking. Rationale: FH-A11KRASG12V-TCR is an autologous CD8+ and CD4+ transgenic T cell product expressing (1) an HLA-A11-restricted, high affinity KRASG12V mutation-specific T cell receptor (TCR) and (2) the wildtype CD8α/β coreceptor enabling CD4+ T cell recognition of KRAS G12V presented on an MHC class I allele mediating helper T cell activity and cytotoxicity. The TCR sequence is derived from the peripheral blood of a healthy HLA-A11+ adult based on a strong pre-clinical dataset. Methods: This is an ongoing, investigator-initiated, Phase 1, first-in-human, single-center, open-label dose escalation study of FH-A11KRASG12V-TCR. The aims are to evaluate the safety, tolerability, maximum tolerated dose (MTD), and preliminary anti-tumor activity of FH-A11KRASG12V-TCR in patients with advanced PDAC, CRC, and NSCLC who express the HLA-A11-restricted KRAS G12V mutation. Dose modification will be guided by the Bayesian Optimal Interval design (BOIN). Patients will initially be treated in cohorts of 3 at each dose level (DL). BOIN will be used to identify the recommended dose for subsequent patients. The planned target doses are 5 x 109 transgenic TCR T cells in DL 1 with dose escalation up to 15 x 109 transgenic TCR T cells in DL 3. This study enrolls patients who are 18 years or older, HLA-A*11:01-positive, with KRAS G12V mutated metastatic PDAC, CRC, or NSCLC. Patients must have progressed on or be intolerant of at least two lines of prior therapies including any targeted therapies indicated for their current malignancy. Patients undergo leukapheresis prior to treatment and receive lymphodepleting chemotherapy with either cyclophosphamide intravenously (IV) and fludarabine IV on days -6, -5, -4, and -3 or bendamustine IV on days -4 and -3. FHA11KRASG12V-TCR is administered IV on day 0. The dose-limiting toxicity observation period is 28 days. Patients may receive an additional FHA11KRASG12V-TCR IV infusion at the same or lower dose as soon as 28 days or up to 1 year after the first infusion. One patient enrolled to date and the study is actively recruiting (NCT06043713). Citation Format: Elena Gabriela Chiorean, Andrew Coveler, Rachael Safyan, Stacey Cohen, Sylvia Lee, Cecilia Yeung, Mary Redman, Thomas Schmitt, Aude Chapuis, Philip D. Greenberg. Phase I study of autologous CD8+ and CD4+ transgenic T cells expressing high-affinity KRAS G12V mutation-specific T cell receptors (FH-A11KRASG12V-TCR) in patients with metastatic pancreatic, colorectal and non-small cell lung cancers with KRAS G12V mutations [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 CT082.