Non-small Cell Lung Cancer Harboring Research Articles

Efficacy of targeted therapy in patients with non-small cell lung cancer harboring very rare mutations in EGFR exon 18.

Somatic mutations in epidermal growth factor receptor (EGFR) exon 18 are classified as uncommon or rare mutations in non-small cell lung cancer (NSCLC), in this context, other than G719X or E709X exon 18 mutations are even more rare and heterogeneous. In such scenario, first line treatment options are still debated. The aim of this study was to investigate the response of NSCLC patients harboring very rare exon 18 mutations to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This retrospective descriptive study included 105 patients with NSCLC harboring mutations in EGFR exon 18 diagnosed at West China Hospital. The clinical response to EGFR-TKIs was evaluated according to different classifications of mutations in 45 NSCLC patients: 39 harboring G719X or E709X mutations and 6 harboring very rare mutations in EGFR exon 18. Among 105 patients, 84% (88/105) harbored rare mutations in EGFR exon 18, including G719X and E709X mutations. The remaining 16% (17/105) had very rare mutations in EGFR exon 18, including E709_710delinsX and G724S. For the subsequent efficacy analysis of EGFR-TKI in 45 NSCLC patients, patients harboring very rare mutations achieved a favorable disease control rate (DCR) of 100% and had a median progression-free survival (PFS) of 17.2 months, which was not significantly different compared to patients harboring G719X or E709X (P=0.59). EGFR-TKIs showed great efficacy in terms of responses and survival in patients harboring exon 18 EGFR rare mutations. This may justify the use of targeted therapies as a potential treatment strategy for these patients.

Abstract 1974: Discovery of TRX-211-399, a potent, CNS-penetrant, highly selective inhibitor of EGFR exon 20 insertion mutations

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for approximately 2 million new cases and 1.8 million deaths annually. Various types of EGFR-activating mutations are one of the most important oncogenic drivers in non-small cell lung cancer (NSCLC). Among NSCLC patients with EGFR mutations, 5-10% of patients have EGFR exon 20 insertion (ex20ins) mutations that are insensitive to clinically available EGFR tyrosine kinase inhibitors (TKIs). Recently, as mobocertinib (EXKIVITY®) failed to improve progression-free survival in Phase 3 clinical trial, there remains a high unmet medical need to develop new drugs with wider therapeutic window to treat NSCLC harboring EGFR ex20ins mutations. Herein, we report a novel EGFR-TKI, TRX-211-399, specifically designed to target ex20ins mutations. TRX-211-399 potently inhibited the proliferation of not only Ba/F3 cells overexpressing near-loop (A767dupASV, S768dupSVD) and far-loop (H773insNPH, H773dupH) mutations but also patient-derived NSCLC cell line. In particular, TRX-211-399 demonstrated high selectivity against wild-type EGFR. With favorable DMPK profiles, once-daily oral administration of TRX-211-399 showed significant tumor regression in multiple Ba/F3 xenograft models carrying different EGFR exon20ins mutations. Furthermore, in a PC-9-luc cell intracranial xenograft model, TRX-211-399 induced substantial anti-tumor effects and prolonged survival without body weight loss. TRX-211-399 is currently undergoing further preclinical evaluation as a potential candidate for clinical development for patients with EGFR exon20ins mutations. Citation Format: Kwangwoo Chun, Sumin Lim, Joohyun Lee, Seulgi Choi, Seongrak Kim, Youngil Choi, Areum Park, Bohee Kim, Yongseo Park, Eunhyun Choi, Sungwon Lee, Koo Lee. Discovery of TRX-211-399, a potent, CNS-penetrant, highly selective inhibitor of EGFR exon 20 insertion mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1974.

1431P The nNGM Preclinical Platform: Preclinical research to generate evidence for patients with non-small cell lung cancer harboring variants of unknown significance

1431P The nNGM Preclinical Platform: Preclinical research to generate evidence for patients with non-small cell lung cancer harboring variants of unknown significance

The treatment of patients with non-small cell lung cancer carrying uncommon EGFR mutations, HER2 mutations, or brain metastases: a systematic review of pre-clinical and clinical findings for dacomitinib.

Accumulating evidence has shown that dacomitinib has potential activities for patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations, human epidermal growth factor receptor 2 (HER2) mutations, or central nervous system (CNS) metastases. This study aimed to give a systematic review on its potential applications in the above settings by searching MEDLINE/PubMed, Embase, Cochrane Library, American Society of Clinical Oncology.org, European Society for Medical Oncology.org, and ClinicalTrials.gov. The literature search yielded 649 publications in total. According to our findings, dacomitinib exhibited promising efficacy in patients with major uncommon EGFR mutations (including G719X, S768I, and L861Q). Both EGFR exon 20 insertional mutation (Ex20ins) and HER2 Ex20ins demonstrated significant internal heterogeneity in response to dacomitinib, among which specific subtypes (including EGFR D770delinsGY, A763_Y764insFQEA, and HER2 M774delinsWLV) were highly sensitive. Other uncommon EGFR mutations including 18del and L747P have also been shown responsive to dacomitinib. Interestingly, limited studies suggested dacomitinib application on certain first or third generation tyrosine kinase inhibitors (TKIs)' resistant secondary mutations. Last but not least, both pre-clinical and clinical data indicated that dacomitinib has an encouraging intracranial tumor control ability, regardless of uncommon mutations. Dacomitinib demonstrated good disease control on patients with NSCLC harboring major uncommon EGFR mutations and specific EGFR or HER2 mutation subtypes, and selective clinical application of dacomitinib is considerable in this setting, especially for those with intracranial metastases.

Clinical characteristics, response to poly (adenosine phosphate-ribose) polymerase inhibitors and platinum chemotherapy in patients with lung cancer harboring BRCA mutations.

e21036 Background: BRCA1/2 are tumor suppressor genes involved in DNA double-strand break repair. Tumors harboring BRCA1/2 pathogenic mutations (BPM) are highly responsive to treatment with poly (adenosine phosphate-ribose) polymerase inhibitors (PARPi) and exhibit increased sensitivity to platinum-based chemotherapy (platinum). Somatic BPM are found in 1-2% of all cases of non-small cell lung cancer (NSCLC), the majority of which are not associated with germline variants. While platinum remains the backbone of first-line treatment of NSCLC, PARPi have not demonstrated efficacy in treatment of NSCLC and testing for BRCA mutations in NSCLC is not routine. We present the clinical characteristics and outcomes of patients with NSCLC harboring BPM treated with platinum and PARPi as part of clinical practice at our center. Methods: We retrospectively evaluated the onco-genetic and pathology data bases for patients with locally advanced or metastatic NSCLC who were treated at Hadassah Medical Center (HMC), underwent somatic molecular or genetic testing, and were found to have somatic BPM (according to ClinVar or Varsom). We compared the clinical outcomes to a matched cohort (age, gender, smoking, and performance status) of non-BPM NSCLC patients treated at HMC. Results: Since 2013 we evaluated 642 patients with locally advanced or metastatic NSCLC using comprehensive somatic or germline molecular panels. Twenty-two patients were found to have somatic BPM of which, 18 (81.8%) were found to be carriers of corresponding germline BRCA1/2 variants. This included 14 (63.6%) carriers of classical Ashkenazi-Jewish variants (10 - BRCA2 617delT, 2- BRCA1 185delAG and 2- BRCA1 5382incC) and representing less than 1% of all BRCA1/2 carriers at HMC. Median age of diagnosis was 67 yeas old (range 40–78). Eleven (50%) patients had a history of smoking, and 8 (36.3%) patients had a history of other malignancies, mainly breast cancer. Pathology for all patients revealed adenocarcinoma and 8 (36.6%) patients had additional actionable mutations ( EGFR, ALK, BRAF or ERBB2). Sixteen (72.7%) patients were treated with platinum, with an objective response rate (ORR) of 75% and a median progression free survival (mPFS) of 14 months (range 4-29), compared to ORR of 45% and mPFS of 8.5 months (range 3-18) in a matched cohort of non-BPM NSCLC patients treated with platinum. Six (27.7%) patients were treated with second or third line PARPi with ORR of 83.3%, mPFS of 21 months (range 6-34). Median overall survival (OS) for the entire cohort was 28 months (range 4-103) with 8 (36.4%) patients surviving for more than 3 years. Conclusions: In this cohort, patients with NSCLC harboring BPM show a durable response to platinum and PARPi with prolonged OS. The results support testing BRCA1/2 in NSCLC patients and treatment with platinum and PARPi for patients with BPM.

The Glasgow Prognostic Score Predicts Survival in Patients with Advanced Non-Small Cell Lung Cancer Harboring Sensitive Epidermal Growth Factor Receptor Mutations Who Are Treated with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors

Introduction: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with sensitive EGFR mutations. The Glasgow prognostic score (GPS) is an inflammation-assessing score based on C-reactive protein and albumin concentrations. Information regarding the association between the GPS and EGFR-TKI treatment effectiveness is limited; hence, we investigated whether the GPS can predict the response of NSCLC to EGFR-TKIs. Methods: We evaluated 340 patients with NSCLC harboring sensitive EGFR mutations who received EGFR-TKI monotherapy between March 2009 and July 2021. The Kaplan-Meier method and Cox proportional hazards models were used to assess progression-free survival (PFS) and overall survival (OS). Results: After a median follow-up of 26.6 months, patients with a GPS of 0, 1, and 2 had PFS of 15.7, 10.0, and 6.3 months, respectively, and OS of 40.1, 25.8, and 14.4 months, respectively; patients with a GPS of 0 had significantly better PFS and OS than those with a GPS of 1 (p = 0.03, p = 0.001, respectively) or 2 (p < 0.001, p < 0.001, respectively). Multivariate analysis identified poor performance status, stage 4 at diagnosis, type of EGFR-TKI (gefitinib/erlotinib vs. afatinib), and GPS = 2 as predictors of a short PFS. Meanwhile, poor performance status, gefitinib/erlotinib administration, and GPS = 2 were predictors of a short OS. Conclusion: The GPS predicted the survival of NSCLC patients harboring sensitive EGFR mutations who were undergoing EGFR-TKI treatment. The GPS might be ideal for routine use in clinical practice, given that it is an easily calculated parameter.

85P The impact of adjuvant EGFR-TKIs and 14-gene molecular assay on patients with stage I non-small cell lung cancer harboring sensitive EGFR mutations

85P The impact of adjuvant EGFR-TKIs and 14-gene molecular assay on patients with stage I non-small cell lung cancer harboring sensitive EGFR mutations

Rationale and protocol design of a phase II study of first-line osimertinib treatment for patients with poor performance status and EGFR mutation-positive non-small cell lung cancer (OPEN/TORG2040)

BackgroundCancer chemotherapy indications for patients with poor performance status and advanced lung cancer are limited. Molecular targeted drugs, including epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors, can be used in patients with poor performance status owing to their high efficacy and safety. The third-generation EGFR-tyrosine kinase inhibitor osimertinib has demonstrated effectiveness in the initial treatment of advanced EGFR mutation-positive non-small cell lung cancer in patients with good performance status; however, no evidence exists of the drug’s effectiveness in patients with poor performance status in a prospective study. We designed a study that aims to investigate the efficacy and safety of first-line osimertinib treatment in patients with advanced non-small cell lung cancer harboring sensitive EGFR mutations and with poor performance status.MethodsThe OPEN/TORG2040 study is a multicenter, single-arm, phase II trial for patients with unresectable, advanced EGFR mutation-positive non-small cell lung cancer with a poor performance status (≥ 2). Eligible patients will receive osimertinib until disease progression or unacceptable toxicity. The primary endpoint is the objective response rate of the first-line osimertinib treatment. Considering a threshold value of 45%, expected value of 70% for objective response rate, one-sided significance level of 5%, statistical power of 80%, and ineligible patients, the sample size was set to 30. The secondary endpoints are disease control rate, performance status improvement rate, and safety and patient-reported outcomes using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Quality of Life Questionnaire and Lung Cancer 13. Time to treatment failure, progression-free survival, and overall survival will also be assessed.DiscussionOur study can determine the clinical benefits of osimertinib treatment in patients with poor performance status, since the clinical outcomes of patients with EGFR mutation-positive non-small cell lung cancer with poor performance status treated with this drug as a first-line treatment have not been sufficiently evaluated.Trial registrationJapan Registry of Clinical Trials: jRCTs041200100 (registration date: February 12, 2021).

State of the Art: onkogen alteriertes nichtkleinzelliges Lungenkarzinom im Stadium IV

BackgroundTwo decades ago, stage IV non-small-cell lung cancer (NSCLC) was associated with a poor median overall survival (mOS) of 7–9 months following chemotherapy. Due to revolutionary developments in recent years and the approval of modern targeted therapies, new therapeutic options with remarkable survival times have broadened the therapeutic armamentarium for patients with NSCLC.ObjectivesThis article provides a systematic overview of the latest therapeutic standards in the treatment of stage IV NSCLC, especially concerning targeted therapies, mechanisms of resistance, and future developments.Materials and methodsAn up-to-date analysis of the literature was performed.ResultsMolecular testing is essential to offer individualized targeted therapies tailored to corresponding genetic alterations. Besides tyrosine kinase inhibitors (TKI) of EGFR and ALK alterations that have been widely adopted in routine practice for at least a decade, new inhibitors for KRAS G12C, ROS1, BRAF V600, MET exon 14 skipping, NTRK or RET alterations were approved in recent years.ConclusionDue to consistent testing and the use of targeted therapies, prolonged overall survival and improvement in quality of life in patients with NSCLC harboring driver alterations could be achieved. Future developments focus on individualization of targeted therapies, optimization of therapeutic concepts, and identification of new targets.

Tumoral PD-L1 does not impact time to treatment discontinuation in EGFR mutated non-small cell lung cancer patients treated with EGFR tyrosine kinase inhibitor-a Danish cohort study.

BackgroundNot all non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations respond equally to therapy with tyrosine kinase inhibitors (TKIs). Programmed death ligand-1 (PD-L1) has previously been speculated as a possible biomarker for treatment outcome because of its positive correlation with these mutations in cell lines, but clinical studies have yielded conflicting results. We investigate the predictive potential of this surface protein in relation to clinical benefit in patients as measured by time to treatment discontinuation (TTD).MethodsWe screened 516 Danish patients with EGFR mutations for inclusion based on a history of TKI treatment and a PD-L1 status that was assessed no earlier than three months prior to treatment initiation. Patients were stratified according to their expression of the potential biomarker as either negative (0%), low (1–49%) or high (≥50%). We employed the Kaplan-Meier method and the log rank test to test for a difference in treatment duration according to PD-L1 expression.ResultsWe included 111 Danish patients. The median follow-up time from inclusion until death or censoring at the end of the study was 670 days (range, 32–1,664 days, 95% CI: 502–897 days). Fifty-seven patients (51%) categorized as PD-L1 expression negative, 32 (29%) as low and 22 (20%) as high. We tested for differences in treatment duration between the three groups. Our tests did not yield statistically significant P values.ConclusionsIn our cohort of 111 Danish patients with NSCLC harboring mutations in the epidermal growth factor receptor gene, expression levels of PD-L1 did not significantly impact the duration of clinical benefit from tyrosine kinase treatment.

Extracellular Vesicles from EGFR T790M/L858R-mutant Non-small Cell Lung Cancer Promote Cancer Progression.

Tyrosine kinase inhibitors (TKIs) are the first-line therapy for non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. Unfortunately, most patients quickly develop an acquired resistance to EGFR-TKIs. However, the effects of NSCLC harboring EGFR-T790M mutation on aggressive NSCLC phenotypes is still unclear. This study aimed to investigate the extracellular vesicles (EVs) involvement in promoting the aggressiveness of NSCLC cells. EVs were isolated from the culture media of TKI-sensitive (HCC827) and TKI-resistant (H1975) NSCLC cells using ultracentrifugation. Cell viability, proliferation, migration, and invasion were examined following incubation with indicated EVs. HCC827 and H1975 cells showed time-dependent uptake of PKH67 dye labeled EVs. Incubation of EVs derived from H1975 cells (EV-H1975) did not alter the TKI sensitivity of HCC827 cells. Interestingly, EV-H1975 significantly increased HCC827 cells proliferation, invasion, and migration. By a phospho-kinase array, EV-H1975 increased phosphorylation of several proteins related to cell proliferation, invasion, and migration, including FAK, AKT, and ERK1/2, in HCC827 cells. EGFR-T790M NSCLC cells promote TKI-sensitive NSCLC cell aggressiveness, at least partially, through mechanisms associated with EVs.

Exposure–response analyses for the MET inhibitor tepotinib including patients in the pivotal VISION trial: support for dosage recommendations

PurposeTepotinib is a highly selective MET inhibitor approved for treatment of non-small cell lung cancer (NSCLC) harboring METex14 skipping alterations. Analyses presented herein evaluated the relationship between tepotinib exposure, and efficacy and safety outcomes.MethodsExposure–efficacy analyses included data from an ongoing phase 2 study (VISION) investigating 500 mg/day tepotinib in NSCLC harboring METex14 skipping alterations. Efficacy endpoints included objective response, duration of response, and progression-free survival. Exposure–safety analyses included data from VISION, plus four completed studies in advanced solid tumors/hepatocellular carcinoma (30–1400 mg). Safety endpoints included edema, serum albumin, creatinine, amylase, lipase, alanine aminotransferase, aspartate aminotransferase, and QT interval corrected using Fridericia’s method (QTcF).ResultsTepotinib exhibited flat exposure–efficacy relationships for all endpoints within the exposure range observed with 500 mg/day. Tepotinib also exhibited flat exposure–safety relationships for all endpoints within the exposure range observed with 30–1400 mg doses. Edema is the most frequently reported adverse event and the most frequent cause of tepotinib dose reductions and interruptions; however, the effect plateaued at low exposures. Concentration-QTc analyses using data from 30 to 1400 mg tepotinib resulted in the upper bounds of the 90% confidence interval being less than 10 ms for the mean exposures at the therapeutic (500 mg) and supratherapeutic (1000 mg) doses.ConclusionsThese analyses provide important quantitative pharmacologic support for benefit/risk assessment of the 500 mg/day dosage of tepotinib as being appropriate for the treatment of NSCLC harboring METex14 skipping alterations.Registration NumbersNCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992.

Favorable immune checkpoint inhibitor outcome of patients with melanoma and NSCLC harboring FAT1 mutations

Immune checkpoint inhibitors (ICIs) are most commonly used for melanoma and non-small cell lung cancer (NSCLC) patients. FAT atypical cadherin 1 (FAT1), which frequently mutates in melanoma and NSCLC. In this study, we aim to investigate the association of FAT1 mutations with ICI response and outcome. We collected somatic mutation profiles and clinical information from ICI-treated 631 melanoma and 109 NSCLC samples, respectively. For validation, a pan-cancer cohort with 1661 patients in an immunotherapy setting was also used. Melanoma and NSCLC samples from the Cancer Genome Atlas were used to evaluate the potential immunologic mechanisms of FAT1 mutations. In melanoma, patients with FAT1 mutations had a significantly improved survival outcome than those wild-type patients (HR: 0.67, 95% CI: 0.46–0.97, P = 0.033). An elevated ICI response rate also appeared in FAT1-mutated patients (43.2% vs. 29.2%, P = 0.032). Associations of FAT1 mutations with improved prognosis and ICI response were confirmed in NSCLC patients. In the pan-cancer cohort, the association between FAT1 mutations and favorable ICI outcome was further validated (HR: 0.74, 95% CI: 0.58–0.96, P = 0.022). Genomic and immunologic analysis showed that a high mutational burden, increased infiltration of immune-response cells, decreased infiltration of immune-suppressive cells, interferon and cell cycle-related pathways were enriched in patients with FAT1 mutations. Our study revealed that FAT1 mutations were associated with better immunogenicity and ICI efficacy, which may be considered as a biomarker for selecting patients to receive immunotherapy.

Abstract 5351: LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion

Abstract Background: CLIP1-LTK was recently discovered as a novel oncogenic gene fusion in non-small cell lung cancer (NSCLC). Lorlatinib, an ALK/ROS1 inhibitor, can inhibit CLIP1-LTK constitutive kinase activity, and showed dramatic and promising efficacy in a patient with NSCLC harboring CLIP1-LTK fusion. However, acquired resistance to lorlatinib will be inevitably developed, especially by mutations in LTK gene, as 50-60% of oncogenic driver-positive NSCLC develop resistance to kinase inhibitors by acquired mutations in the target gene. The aim of this study is to identify the LTK mutations responsible for resistance to lorlatinib in CLIP1-LTK fusion positive NSCLC, and to explore compounds that can overcome resistance. Methods: As LTK and ALK share nearly 80% protein sequence identity in their respective kinase domains, we established Ba/F3 cells expressing CLIP1-LTK (Ba/F3-CLIP1-LTK) with six different LTK mutations (I565N, F568C, L590M, L592F, G596R, and G663A), all of which are analogous to reported ALK mutations responsible for resistance to lorlatinib. Ba/F3 cells expressing CLIP1-LTK with these different LTK mutations, as well as CLIP1-LTK-wild type (WT) were treated with several concentrations of lorlatinib. Then, the efficacy of other compounds including crizotinib, alectinib, ceritinib, brigatinib, entrectinib, giltertinib, repotorectinib was assessed to detect which compounds can overcome lorlatinib resistance. Results: All LTK mutations tested showed resistance to lorlatinib, with IC50s of lorlatinib ranging 2.7 to 31.3 nM, which were higher than that in Ba/F3-CLIP-LTK-WT (1.0 nM) in cell viability assay. An IC50 of giltertinib in Ba/F3-CLIP1-LTK-F568C was lower than that of lorlatinib (0.9 vs 2.7 nM). Moreover, an IC50 of giltertinib in Ba/F3-CLIP1-LTK-G663A was lower than that of lorlatinib (2.7 vs 19.4 nM). Ba/F3-CLIP1-LTK-L592F was rather sensitive to crizotinib compared with Ba/F3-CLIP1-LTK-WT (IC50, &amp;lt;0.1 vs 16.5 nM). Similarly, Ba/F3-CLIP1-LTK-G596R was similar to repotorectinib compared with WT (IC50, 10.4 vs 11.3 nM). The results of western blotting assay evaluating phosphorylation of CLIP1-LTK were in accordance with that obtained cell viability assay. Conclusion: We identified that several LTK mutations, analogous to ALK resistant mutations, were responsible for lorlatinib resistance, some of which can be overcome by existing compounds. Further validation and exploration are warranted to establish resistance mechanism-based precision medicine following lorlatinib treatment in CLIP1-LTK fusion-positive NSCLC. Citation Format: Shunta Mori, Hiroki Izumi, Jie Liu, Kosuke Tanaka, Shogo Kumagai, Takuma Hayashida, Yosuke Kagawa, Yuji Shibata, Shingo Matumoto, Koichi Goto, Susumu Kobayashi. LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5351.

Abstract 2380: The effect of metabolic alterations on chemo-immunotherapy response in non-small-cell lung cancer model

Abstract Introduction: Lung cancer is one of the leading cause of cancer death worldwide, with an estimate incidence of about 2 million new cases per year. Among all lung cancers, non-small-cell lung cancer (NSCLC) is the most frequent (nearly 85%) with a 5-year survival of about 25% when all stages are considered.NSCLCs are frequently mutated in KRAS or STK11/LKB1 and co-mutation is often reported. Considering the key role of STK11/LKB1 in controlling cell metabolism, we hypothesized that NSCLC harboring mutations in this gene could be vulnerable to metabolic stresses. Different studies in the last years have highlighted how is possible to interfere with cancer metabolism using metformin and caloric restriction.Our work aimed at investigating the role of metabolic stress in determining response to chemotherapy and immunotherapy in LKB1 mutated NSCLC model. Methods: For isolation of cell lines with the genetic backgrounds, nodules from lungs of KRASG12D/LKB1wt and KRASG12D/LKB1mut transgenic mice were used. Stabilized cell lines were then inoculated intramuscularly in immunocompetent mice and treated with chemotherapy alone (cisplatin) or in combination with metformin and caloric restriction. Caloric restriction consisted of 36 hours of fasting every week for three weeks. Metformin was administered daily for the entire experiment while cisplatin was given once a week for three weeks. Results: We started our in vivo experiments comparing the response of the tumors characterized by the mutation in KRASG12D or the co-mutation KRASG12D/LKB1mut. The results indicate that the addition of metformin and caloric restriction improve the activity of cisplatin in both tumors but a stronger effect was detected in tumors presenting the deletion of LKB1. In fact, only in the latter group, the effect of the combination lasted beyond the end of the treatment slowing down the tumor growth. The different combinations were well tolerated. Molecular analysis on tumor samples run in parallel are in progress. Conclusion: Our in vivo preliminary studies confirm our hypothesis that the addition of the caloric restriction and metformin is able to improve the antitumor activity of the cisplatin without increasing the treatment toxicity in tumors characterized by the co-mutations of KRASG12D/LKB1mut. Further investigations are ongoing on the role of metabolic stress in addition to the immunotherapy (using anti PD-1 antibody as immunocheckpoint inhibitor). Citation Format: Gloriana Ndembe, Mirko Marabese, Ilenia Intini, Alessandra Fabbri, Massimo Moro, Mario Occhipinti, Elisa Sottotetti, Giuseppe Lo Russo, Monica Ganzinelli, Massimo Broggini. The effect of metabolic alterations on chemo-immunotherapy response in non-small-cell lung cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2380.

Dacomitinib for Advanced Non-small Cell Lung Cancer Patients Harboring Major Uncommon EGFR Alterations: A Dual-Center, Single-Arm, Ambispective Cohort Study in China.

Objective: Dacomitinib has been approved for non-small-cell lung cancer (NSCLC) patients harboring classical epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on major uncommon EGFR mutations is currently limited. Materials and methods: This was a dual-center, single-arm, ambispective cohort study in China. Patients with histologically confirmed metastatic or recurrent NSCLC harboring major uncommon EGFR mutations were eligible for the study. The objective response rate and disease control rate were determined by RECIST 1.1 every 1–2 months. Adverse events were assessed by CTCAE 5.0. Results: In total, 32 NSCLC patients were enrolled between July 2020 and January 2022, and 18 (56.3%) patients received dacomitinib as first-line therapy. Median age was 64 years, and 20 (62.5%) were female. The mutations identified were G719X (n = 24; 75%), followed by L861X (n = 10; 31.3%), and S768I (n = 8; 25%). In the first-line setting, 72.2% of patients (13/18) had a confirmed partial response and 100% (18/18) had disease control, and the median progression-free survival (PFS) and overall survival (OS) were unreached. In the whole cohort, 56.3% of patients (18/32) had a confirmed partial response and 90.6% (29/32) had disease control, and the median PFS was 10.3 months (95% confidence interval, 6.1–14.5) and the median OS was 36.5 months. Except for one case not available for brain re-evaluation, control of the intracranial metastases was observed in 13 patients (13/14, 92.9%). No grade 4–5 adverse events (AEs) occurred, but all patients had grade 1–2 AEs, and 12.5% (4/32) patients required a dosage reduction due to intolerable AEs. Conclusions: Dacomitinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring major uncommon EGFR mutations.

Crizotinib in MET Exon 14-Mutated or MET-Amplified in Advanced Disease Non-Small Cell Lung Cancer: A Retrospective, Single Institution Experience

Introduction: Non-small cell lung cancer (NSCLC) accounts for most lung cancers and is a leading cause of cancer-related deaths in the USA. Alterations in c-MET, a tyrosine kinase receptor, have been involved in many cases of NSCLC progression and metastasis. Crizotinib and other tyrosine kinase inhibitors (TKIs) have been used in NSCLC treatment with limited success. Methods: In this retrospective observational study, we analyzed data from patients diagnosed with lung cancer at Soroka University Medical Center between January 2015 and January 2020. We investigated patient characteristics, including disease-associated mutation type and median survival in response to different TKI treatments. Results: A total of 780 patients with lung cancer were included in the study, 134 of whom had small cell lung cancer and 646 had NSCLC. Of the NSCLC patients, 403 were diagnosed with advanced or metastatic disease, and 374 underwent molecular testing. We identified 16 patients with either c-MET mutations or amplifications who were treated with crizotinib. Of these patients, 7 expressed a c-MET exon 14 skipping mutation while the remaining 9 patients expressed c-MET amplification. Among the patients with a c-MET exon 14 skip mutation, the overall survival was 22.8 months and the median progression-free survival (PFS) on crizotinib treatment was 12.4 months. Of the patients with c-MET amplification, the median overall survival was 5.4 months and the median PFS with crizotinib treatment was 2.6 months. Discussion and Conclusions: We analyzed the data of a series of cases describing patients diagnosed with different stages of NSCLC, having either a c-MET exon 14 skipping mutation or an amplification mutation, and treated with various TKIs, including crizotinib. We investigated the characteristics of these patient groups in accordance with mutation types and compared median survival between patient groups. Crizotinib was found to be an optimal treatment for NSCLC harboring c-MET exon 14 skipping mutations.

Efficacy of dacomitinib in patients with non-small cell lung cancer carrying complex EGFR mutations: a real-world study.

BackgroundDacomitinib is a first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on NSCLC with complex EGFR mutations is limited.MethodsPatients harboring complex (common mutations co-existing with uncommon mutations), or common (comparison cohort) EGFR mutations, who were treated with dacomitinib, were retrospectively evaluated in the Chinese National Cancer Center and the China PLA hospital between August 2019 and August 2021.ResultsIn total, 72 patients with NSCLC harboring complex (C+U group, n=18) or common (C group, n=54) EGFR mutations and being treated with dacomitinib were enrolled. In the C+U group, 16 cases (88.9%) harbored L858R mutations co-existing with uncommon mutations located from exon 18 to exon 25 of EGFR (mostly E709X), and two cases harbored exon 19 deletion co-existing with G724S or K754E. Among the 15 evaluable patients, the objective response rate (ORR) was 40% (6/15), and the disease control rate (DCR) was 73.3% (11/15). The median progression-free survival (PFS) was 7.5 months [95% confidence interval (CI), 4.4–10.6 months]. Except for the application line of dacomitinib (P=0.039), no significant statistical differences were found in other characteristics and adverse events between the two groups. The Kaplan-Meier method revealed no significant differences in PFS (P=0.889) and overall survival (OS) (P=0.703). However, the stratified analysis found worse PFS in the C+U group than that observed in the C group when receiving 1st and ≥3rd line dacomitinib treatment, while its OS was worse than that of group C when receiving ≥3rd line treatment. Furthermore, in a multivariate analysis, complex mutation status was an independent prognostic factor for OS (P=0.038) in the entire cohort.ConclusionsThis study indicated a worse response and prognosis of patients with NSCLC harboring complex EGFR mutations than those harboring common EGFR mutations when treated with dacomitinib. Further studies and data are needed to confirm this conclusion.

Clinical value of serum albumin level in patients with non-small cell lung cancer and anaplastic lymphoma kinase (ALK) rearrangement.

There are few data on the clinical value of serum albumin (Alb) level as a prognostic indicator in advanced non-small cell lung cancer (NSCLC) patients with positive anaplastic lymphoma kinase (ALK) rearrangement. Thus, we retrospectively analyzed the clinicopathological features of advanced, ALK-positive NSCLC patients diagnosed and treated at our institution to investigate the effects of pretreatment serum Alb on outcome in this patient setting. We selected 261 consecutive patients with newly diagnosed pathologically or cytologically confirmed NSCLC harboring ALK rearrangement between May 2016 and February 2018. The target-independent and dependent variables were Serum albumin level measured in patients before anticancer treatment and progression-free survival (PFS). Pre-treatment serum Alb levels and demographic, clinical, and histological characteristics, as well as outcome variables were recorded and analyzed. Serum albumin level was estimated before treatment and at every visit. The pretreatment and the lowest serum albumin level during treatment were recorded. The mean pretreatment Alb level was 42.185 g/L. Before the treatment initiation, low Alb level (<40 g/L) was measured in 74 (28.4%) patients and normal Alb (≥40 g/L) was measured in 187 (71.6%) participants. Low pretreatment Alb (<40 g/L) was more highly prevalent in those with pleural effusion (P=0.013). Pretreatment hypoalbuminemia was significantly associated with shorter progression-free survival (PFS) [8.0 months, 95% confidence interval (CI): 4.56-11.44 vs. 12.0 months, 95% CI: 9.85-14.15; P=0.046]. Crizotinib-treated participants had a significantly prolonged PFS compared to those treated with chemotherapy, regardless of Alb level [normal Alb level: 19.0 (95% CI: 12.72-25.28) vs. 8.0 (95% CI: 6.22-9.78), P<0.001; low Alb level: 12.0 months (95% CI: 10.13-13.87) vs. 6.0 months (95% CI: 2.95-9.05), P=0.006]. Multivariate analyses indicated that poor Eastern Cooperative Oncology Group performance status (ECOG PS) [hazard ratio (HR) =1.66; 95% CI: 1.16-2.38; P=0.005] and presence of pleural effusion (HR =2.43; 95% CI: 1.55-3.82; P<0.001) were significantly independent predictive factors for PFS in ALK-positive NSCLC. Pretreatment hypoalbuminemia is associated with poor outcome of NSCLC patients harboring ALK rearrangement. However, the role of the pretreatment serum Alb level as predictive biomarker requires further investigation.

First-line osimertinib for poor performance status patients with EGFR mutation-positive non-small cell lung cancer: A prospective observational study.

The clinical outcomes of poor performance status (PS) patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who are treated with osimertinib as a first-line treatment have not been sufficiently evaluated. This study aimed to assess the efficacy and safety of osimertinib in chemotherapy-naive and poor PS (2 or more) patients with NSCLC harboring sensitive EGFR mutations. We assessed the clinical effects of osimertinib as a first-line treatment for patients with poor PS NSCLC with an exon 19 deletion or exon 21 L858R mutation in EGFR. All patients were administered osimertinib (80mg/day) as the initial treatment. Sixteen patients (nine women and seven men) who were treated between August 2018 and July 2021 were included in this study; their median age was 78years. The overall objective response rate was 56.3%. The median progression-free survival (PFS) of the entire patient population was 10.5months and the PS score improved in 8 of 16 patients (50%). The most common adverse event was acneiform rash (42%), followed by diarrhea (36%) and paronychia (36%); none of these were of grade ≥ 3. Interstitial lung disease occurred in 2 patients (12.5%); however, no treatment-related deaths occurred. Considering the findings of this study, osimertinib appears to be an effective and safe treatment option for patients with poor PS and advanced NSCLC harboring sensitive EGFR mutations. To obtain conclusive results, further studies with larger cohorts are warranted.