Metastatic Non-small Cell Lung Cancer Research Articles

Immune-inflammatory markers and clinical characteristics as predictors of the depth of response and prognosis of patients with PD-L1 ≥50% metastatic non-small cell lung cancer receiving first-line immunotherapy.

Patients with programmed cell death-ligand 1 (PD-L1) ≥50% metastatic non-small cell lung cancer (NSCLC) treated with first-line immunotherapy showed heterogeneous tumor responses. In this study, we investigated the clinical and immune-inflammatory markers distinguishing patients with metastatic NSCLC achieving high depth of tumor response (HDPR) from those with non-high depth of response (NHDPR). The impact of clinical features on the prognosis of patients with PD-L1 ≥50% were further clarified. The clinical characteristics and immune-inflammatory markers of 17 patients with PD-L1 ≥50% metastatic NSCLC at Beijing Tiantan Hospital between July 2020 and December 2023 were retrospectively analyzed. Among the 17 patients, seven (41.2%) patients achieved HDPR (range: -50%, -72%) and 10 (58.8%) patients achieved NHDPR (range: -13%, -45%). Below normal CD4 + T lymphocytes/CD8 + T lymphocytes (CD4/CD8) ratio (p = 0.01) and oncogenes and/or tumor suppressor gene mutations (TP53/KRAS/EGFR) (p = 0.001) were found enriched for NHDPR compared with HDPR. With a median follow-up of 26.0 months (range: 17.2-34.8 months), the median progression-free survival (PFS) following first-line immunotherapy and overall survival (OS) were 9.0 months (95% CI: 5.0-13.0) and not reached (NR), respectively. The neutrophil-to-lymphocyte ratio (NLR) was identified as an independent prognostic factor on first-line PFS. Patients with an NLR ≥4 exhibited a shorter median PFS (7.0 months vs. NR; p = 0.033; 95% CI: 1.2-80.2) than those with an NLR <4 following first-line immunotherapy. Among patients with PD-L1 ≥50% metastatic NSCLC who received first-line immunotherapy, a lower CD4/CD8 ratio and the presence of genes mutations showed a diminished tumor response and a higher NLR ratio exhibited a worse median PFS.

A phase 2 study of mobocertinib as first-line treatment in Japanese patients with non-small cell lung cancer harboring EGFR exon 20 insertion mutations.

Mobocertinib is a novel, synthetic, orally administered tyrosine kinase inhibitor that inhibits many activated forms of epidermal growth factor receptor (EGFR), including those containing exon 20 insertion (ex20ins) mutations. This study aimed to assess the efficacy of mobocertinib in Japanese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR ex20ins mutations. This was a phase 2, open-label study. Patients with NSCLC harboring EGFR ex20ins mutations who had not had previous systemic treatment received mobocertinib 160 mg once daily. The primary endpoint was the confirmed objective response rate. A planned interim analysis was completed for the first 14 patients with a centrally confirmed EGFR ex20ins mutation, with enrollment stopped if the number of patients with an objective response was five or fewer. In total, 33 patients were enrolled into the study (63.6% women; median age: 66 years). At the interim analysis, the objective response rate evaluated by a central independent review committee was 28.6% (4/14, 90% confidence interval: 10.4-54.0); therefore, enrollment was stopped for futility. In the full analysis set, the objective response rate was 18.2% (6/33, 95% confidence interval: 7.0-35.5); of the six responders, one patient (3.0%) had a complete response and five patients (15.2%) had partial responses. The most common treatment-related adverse events were diarrhea, paronychia, stomatitis, and nausea. Although study enrollment was terminated early owing to futility, our results showed modest activity of mobocertinib in Japanese patients with NSCLC with EGFR ex20ins mutations with no additional safety concerns.

Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial

BackgroundWe report 5-year efficacy and safety outcomes from CheckMate 9LA in patients with metastatic non-small cell lung cancer (mNSCLC) and exploratory analyses in key patient subgroups. MethodsAdults with stage IV/recurrent NSCLC and no sensitizing EGFR/ALK alterations were randomized to receive nivolumab plus ipilimumab with chemotherapy (n = 361) or chemotherapy (n = 358). Outcomes were assessed in all randomized patients and subgroups. ResultsWith 57.3 months’ minimum follow-up, patients continued to derive overall survival (OS) benefit with nivolumab plus ipilimumab with chemotherapy over chemotherapy (HR, 0.73; 95% CI, 0.62–0.85; 5-year OS rates, 18% vs. 11%), regardless of tumor programmed death ligand 1 (PD-L1) expression (PD-L1 < 1%, 22% vs. 8%; PD-L1 ≥ 1%, 18% vs. 11%), histology (squamous, 18% vs. 7%; non-squamous, 19% vs. 12%), or presence of baseline brain metastases (20% vs. 6%). Five-year duration of response (DOR) rates were 19% versus 8% with nivolumab plus ipilimumab with chemotherapy versus chemotherapy, with consistent benefit across subgroups. Patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events had a 5-year OS rate of 37%. Five-year progression-free survival and DOR rates in 5-year survivors were 55% versus 38% and 59% versus 46%, respectively. No new safety signals were observed in 5-year survivors, regardless of the number of ipilimumab doses received. ConclusionThis 5-year update supports the long-term, durable OS benefit and improved 5-year survivorship with nivolumab plus ipilimumab with chemotherapy over chemotherapy in patients with mNSCLC, regardless of tumor PD-L1 expression or histology. ClinicalTrials.gov registrationNCT03215706

Real-World Experience of First-Line Osimertinib in EGFR Mutated Non-Small Cell Lung Cancers from a Tertiary Cancer Center, India

Osimertinib is approved in the first line in patients with mutations in the sensitive gene epidermal growth factor receptor (EGFR) mutation. There is lack of real-world evidence to illustrate the effectiveness and safety of osimertinib that can reflect the current medical practice especially in resource-constrained setting. A total of 129 patients with histology-proven metastatic non-small cell lung cancer with EGFR mutation registered at Tata Memorial Hospital between from March 2018 and May 2023 were analyzed. The parameters studied included demographics, outcomes, safety analysis, and secondary mutations. Most common EGFR mutation was exon 19 deletion 58.9% followed by EGFR exon 21 L858R 39.5% and others 1.5%. The overall median progression-free survival was 21.9 months (95% confidence interval [CI]: 16.0–58.1) and median overall survival was 31 months (95% CI: 17.8–45). The median duration of response was 21.3 months (95% CI: 17.1–25.5). Of 129 patients, 77.5% had partial response (PR), 10.1% had stable disease (SD), and 6.2% patients had progressive disease (PD) as the first best response with overall disease control rate was 87.2%. In patients with baseline central nervous system disease, 8.9% had complete response, 75.5% had PR and 8.9% had SD, and 2.2% had PD as best response. The overall intracranial response rate was 84.4% and disease control was 93.3%. Skin toxicities (27.1%) and gastrointestinal toxicities (17%) were most frequently observed toxicities. Overall, 63 patients had progression of disease on osimertinib. Subsequently, 58.7% (n = 37) patients received second line of therapy and 27% (n = 17) patients received third line of therapy. Platinum-based combination chemotherapy was the most common subsequent treatment after progression on osimertinib. Repeat biopsy was done in 33 patients (52.3%) and next-generation sequencing was done in 30 patients (47.6%). The most common resistance alteration detected was TP53 in 30% cases followed by mesenchymal epithelial transition (MET) amplification which was seen in 20% cases. Our study confirms similar efficacy and safety of osimertinib as first-line treatment of mutated non-small cell lung cancer in real-world setting irrespective of the type of common EGFR mutation and similar intracranial activity as well.

Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR-Mutant, Metastatic Nonsquamous Non-Small Cell Lung Cancer.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR-mutant, metastatic non-small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum-based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837). Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS. Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients. Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.

Sintilimab in combination with stereotactic body radiotherapy and granulocyte-macrophage colony-stimulating factor in metastatic non-small cell lung cancer: The multicenter SWORD phase 2 trial

This single-arm, multicenter, phase 2 trial (NCT04106180) investigated the triple combination of sintilimab (anti-PD1 antibody), stereotactic body radiotherapy (SBRT) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic non-small cell lung cancer (NSCLC). With a median follow-up of 32.1 months, 18 (36.7%, 90% CI 25.3%–49.5%) of the 49 evaluable patients had an objective response, meeting the primary endpoint. Secondary endpoints included out-of-field (abscopal) response rate (ASR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). The ASR was 30.6% (95% CI 18.3%–45.4%). The median PFS and OS were 5.9 (95% CI 2.5–9.3) and 18.4 (95% CI 9.7–27.1) months, respectively. Any grade and grade 3 TRAEs occurred in 44 (86.3%) and 6 (11.8%) patients, without grade 4–5 TRAEs. Moreover, in pre-specified biomarker analyses, SBRT-induced increase of follicular helper T cells (Tfh) in unirradiated tumor lesions and patient’s blood, as well as of circulating IL-21 levels, was found associated with improved prognosis. Taken together, the triple combination therapy was well tolerated with promising efficacy and Tfh may play a critical role in SBRT-triggered anti-tumor immunity in metastatic NSCLC.

Silencing Nrf2 in cisplatin resistant non-small cell lung cancer cells augments sensitivity towards EGFR inhibitor

Recently, non-small cell lung cancer (NSCLC) has been the prime concern of cancer clinicians due to its high mortality rate worldwide. Cisplatin, a platinum derivative, has been used as a therapeutic option for treating metastatic NSCLC for several years. However, acquired, or intrinsic drug resistance to Cisplatin is the major obstacle to the successful treatment outcome of patients. Dysregulation of Nrf2 (nuclear factor erythroid 2-related factor 2) and EGFR (epidermal growth factor receptor) signaling have been associated with cellular proliferation, cancer initiation, progression and confer drug resistance to several therapeutic agents including Cisplatin in various cancers. To dissect the molecular mechanism of EGFR activation in resistant cells, we developed Cisplatin-resistant (CisR) human NSCLC cell lines (A549 and NCIH460) with increasing doses of Cisplatin treatment over a 3-month period. CisR cells demonstrated increased proliferative capacity, clonogenic survivability and drug efflux activity compared to the untreated parental (PT) cells. These resistant cells also showed higher levels of Nrf2 and EGFR expression. Here, we found that Nrf2 upregulates both basal and inducible expression of EGFR in these CisR cells at the transcriptional level. Moreover, genetic inhibition of Nrf2 with siRNA in CisR cells showed increased sensitivity towards the EGFR tyrosine kinase inhibitor (TKIs), AG1478. Our study, therefore suggests the use of Nrf2 inhibitors in combinatorial therapy with EGFR TKIs for the treatment of resistant NSCLC.

Clinical and molecular correlates of tumor aneuploidy in metastatic non-small cell lung cancer

Recent studies have linked elevated tumor aneuploidy to anti-tumor immune suppression and adverse survival following immunotherapy. Herein, we provide supportive evidence for tumor aneuploidy as a biomarker of response to immunotherapy in patients with non-small cell lung cancer (NSCLC). We identify a dose–response relationship between aneuploidy score and patient outcomes. In two independent NSCLC cohorts (n = 659 patients), we demonstrate a novel association between elevated aneuploidy and non-smoking-associated oncogenic driver mutations. Lastly, we report enrichment of TERT amplification and immune-suppressive phenotypes of highly aneuploid NSCLC. Taken together, our findings emphasize a potentially critical role for tumor aneuploidy in guiding immunotherapy treatment strategies.

FDA Approval Summary: Repotrectinib for Locally Advanced or Metastatic ROS1-Positive Non-Small Cell Lung Cancer.

On November 15, 2023, the U.S. Food and Drug Administration (FDA) granted traditional approval to repotrectinib (Augtyro, Bristol Myers Squibb Corporation) for the treatment of adult patients with locally advanced or metastatic receptor tyrosine kinase encoded by the ROS1 gene (ROS1)-positive non-small cell lung cancer (NSCLC). The approval was based on TRIDENT-1, a single-arm trial with multiple cohorts of patients with ROS1 fusion-positive (hereafter "ROS1-positive") NSCLC (NCT03093116), who were either treatment naïve or had received prior ROS1 tyrosine kinase inhibitor (TKI) and/or platinum-based chemotherapy. The primary efficacy outcome measure is objective response rate (ORR) assessed by blinded independent central review (BICR) using response evaluation criteria in solid tumors version 1.1. ORR was assessed in 71 patients who were ROS1 TKI naïve and 56 patients who had received a prior ROS1 TKI. Among the 71 patients who were ROS1 TKI naïve, the ORR was 79% (95% CI, 68-88), median duration of response was 34.1 months (95% CI, 26-NE). In patients who had received a prior ROS1 TKI and no prior chemotherapy, the ORR was 38% (95% CI, 25-52). The median duration of response was 14.8 months (95% CI, 7.6-NE); BICR-assessed responses were observed in CNS metastases in patients in both cohorts and in patients who developed resistance mutations following prior TKI therapy. The most common (>20%) adverse reactions were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. A unique feature of this ROS1 TKI approval is the inclusion of robust evidence of efficacy in patients with ROS1-positive NSCLC who had progressed on prior ROS1 TKIs.

Lazertinib in EGFR-Variant Non–Small Cell Lung Cancer With CNS Failure to Prior EGFR Tyrosine Kinase Inhibitors

EGFR-variant non-small cell lung cancer (NSCLC) is associated with a high rate of central nervous system (CNS) metastases, even with treatment with first-generation or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). To investigate CNS activity with lazertinib, a third-generation EGFR TKI. This multicenter single-arm, phase 2 nonrandomized controlled trial was conducted in South Korea and included patients with EGFR-variant NSCLC who had asymptomatic or mildly symptomatic brain metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs. Data were collected from June 2021 to April 2022, with a data cutoff date of December 15, 2022. Lazertinib, 240 mg, once daily. The primary end point was intracranial objective response rate (iORR) in the evaluable population according to the Response Evaluation Criteria in Solid Tumours version 1.1 assessed by the investigators. Secondary end points included intracranial progression-free survival (iPFS) and iORR in patients with T790M-negative disease and isolated CNS progression as well as overall ORR, duration of response, intracranial duration of response, disease control rate, overall survival, cerebrospinal fluid penetration of lazertinib, and safety. Among 40 included patients, 25 (63%) were women, and the median (range) age was 63 (29-85) years. A total of 38 patients were evaluable for tumor response, including 12 patients with leptomeningeal metastases. At data cutoff, the median (range) follow-up was 13.6 (2.9-17.7) months. The iORR for the evaluable population was 55% (21 of 38; 95% CI, 38.3-71.4); for patients with T790M-positive disease, 80% (4 of 5; 95% CI, 28.4-99.5); for patients with T790M-negative disease, 43% (9 of 21; 95% CI, 21.8-66.0); and for patients with T790M-unknown disease, 67% (8 of 12; 95% CI, 34.9-90.1). The median iPFS was 15.8 months (95% CI, 15.2-not reached) for the evaluable population, 15.2 months (95% CI, 4.2-not reached) for the T790M-positive subgroup, 15.4 months (95% CI, 7.9-not reached) for the T790M-negative subgroup, and 18.0 months (95% CI, 3.9-not reached) for the T790M-unknown subgroup. The cerebrospinal fluid penetration rate of lazertinib was 46.2% (95% CI, 10.0-49.6), providing further support for its mechanism of intracranial response. Most adverse events were grade 1 or 2. In this study, lazertinib had substantial CNS activity, regardless of T790M status, against the progression of intracranial metastases with or without leptomeningeal metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs in patients with metastatic EGFR-variant NSCLC. These results suggest that using lazertinib instead of brain local treatment could be a potential strategy in patients with EGFR-variant NSCLC whose CNS metastases progressed after prior EGFR TKI treatment. ClinicalTrials.gov Identifier: NCT05326425.

Lorlatinib experience in a patient with ALK + non-small cell lung cancer on hemodialysis: A case report.

Lorlatinib is a potent third-generation anaplastic lymphoma kinase/c-ros oncogene 1 (ALK)/ROS1 oral tyrosine kinase inhibitor that has broad coverage of acquired resistance mutations and is currently indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ALK-positive. In this case, we aimed to present the safety and effectiveness of lorlatinib use in a patient diagnosed with ALK-positive metastatic NSCLC who underwent hemodialysis 3 days a week. A 76-year-old female patient has been undergoing regular hemodialysis for about 2 years. A brain magnetic resonance imaging (MRI) was taken due to headache and a mass was detected. She was diagnosed with lung adenocarcinoma as a result of excisional biopsy. Positron emission tomography/ computed tomography (PET/CT) showed a mass in the hilar region of the left lung and multiple lymphadenopathy in the mediastinum. In February 2023, 100 mg lorlatinib was started daily. There was no significant regression in PET-CT and no brain MRI residue during follow-up. The patient has been continuing lorlatinib for approximately 1 year with almost complete response, with no side effects other than hypercholesterolemia. We presented our experience using lorlatinib in a patient with metastatic ALK + NSCLC undergoing hemodialysis. Although the dosage of lorlatinib in hemodialysis patients is still controversial, our case report indicates that 100 mg lorlatinib was safe in this patient.

A phase 2, open-label, single-arm study evaluating the combination of pembrolizumab (pembro), lenvatinib, and chemotherapy in patients (pts) with metastatic non-small cell lung cancer (NSCLC) harbouring a targetable mutation who experienced disease progression on standard tyrosine kinase inhibitors (TKIs).

198 Background: Pts with metastatic NSCLC harbouring a targetable mutation who progressed on standard TKIs often receive chemotherapy as the next line of treatment. We report efficacy and safety of a novel combination of pembro, lenvatinib and chemotherapy for these pts. Methods: This was a phase 2, open-label, single-centre, single-arm study enrolling pts with metastatic NSCLC with sensitizing EGFR, ALK or ROS1 mutation who progressed on standard TKIs. Eligible pts had measurable disease, no untreated brain metastasis and ECOG PS ≤1. Pts received pembro 200 mg, pemetrexed 500 mg/m2 and carboplatin AUC 5 every 3 weeks for 4 cycles plus lenvatinib 8 mg QD. The maintenance regimen without carboplatin was continued as tolerated for up to 2 years. The primary endpoint was objective response rate (ORR) by independent radiology review (IRR) as per RECIST 1.1. The secondary endpoints were PFS, overall survival (OS) and safety. Results: At the data cutoff date (2nd February 2024), 24 pts were screened and 19 were enrolled: median age 64 years (range 29–77); 10 (53%) female. Four pts were excluded at screening due to untreated brain metastasis. All enrolled pts were evaluated for safety while 15 pts were evaluable for response. All pts had adenocarcinoma with targetable mutation: EGFR mutation in 18 (95%) pts and ALK fusion in 1 (5%) pt. The median follow-up time was 11.3 months. Treatment was ongoing in 8 pts on the date of analysis, while 6 pts permanently discontinued due to disease progression and 1 pt permanently discontinued due to a treatment-related adverse event (TRAE). The ORR was 40% (6/15, 95% CI 19.8%–64.3%). All responses were partial responses. The median PFS was 11.9 months (range 3.5–20.3). The OS was not reached. TRAEs of any grade (Gr) occurred in 74% (14/19) of the pts. Most of the TRAEs were Gr 1–2, which occurred in 63% (12/19) of the pts. The most common TRAEs were hypothyroidism (31.6%), nausea (26.3%), neutropenia (26.3%), thrombocytopenia (26.3%), anorexia (21.1%), hypertension (15.8%), anaemia (10.5%), pruritus (10.5%) and rash (10.5%). G1 diarrhoea was reported in 1 pt (5.3%) and G1 adrenal insufficiency in 1 pt (5.3%). Gr 3 TRAEs were neutropenia in 2 pts, anaemia in 1 pt and thrombocytopenia in 1 pt. The only Gr 4 TRAE was thrombocytopenia. No treatment related death was observed. Conclusions: The combination of pembro, lenvatinib and chemotherapy demonstrated a favourable ORR and safety in treating metastatic NSCLC pts with a targetable mutation who progressed on standard TKIs. Clinical trial information: NCT04989322 .

Real-world outcomes of atypical EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) treated with osimertinib (osi) vs. Afatinib or erlotinib

ObjectivesLimited data are available comparing the efficacy of osi versus earlier generation TKIs for mNSCLC with atypical EGFR mutations (AMs) such as L861Q, G719X, S768I and exon20. MethodsWe performed a single-institution retrospective analysis of patients with EGFR-mutated mNSCLC treated from 2007 to 2023 with 1L TKIs, comparing outcomes for AM patients treated with osi, afatinib, and erlotinib. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the electronic medical record and compared between TKIs using independent sample t-tests and chi-square analyses. Median progression free survival (mPFS) and overall survival (mOS) were compared via Kaplan-Meier log-rank analysis and Cox multivariable regression. ResultsAmong 355 patients with EGFR-mutated mNSCLC, 36 (10 %) harbored AMs in G719X (N=21; 6 %), Exon 20 (N=11; 3 %), L861Q (N=7; 2 %), S768I (N=4; 1 %), C797S (N=1; 0.3 %); 6 patients had compound mutations. Patients with classical mutations (CMs) vs AMs had similar baseline demographic and disease characteristics and usage of TKIs (p = 0.124). Among AM patients, osi yielded superior mPFS (22 m) vs afatinib (12 m; p = 0.005) or erlotinib (9 m; p = 0.001). mOS was likewise superior for osi (32 m) vs afatinib (21 m; p = 0.032) or erlotinib (17 m; p = 0.011). Dose-reduction rates due to AEs were lower for osi (19 %) vs afatinib (24 %; p = 0.003) or erlotinib (23 %; p = 0.002). Discontinuation rates due to AEs were lower for osi vs afatinib (1 % vs 2 %; p < 0.001) or erlotinib (2 %; p = 0.004). ConclusionsIn a large real-world analysis, osi demonstrated superior progression-free and overall survival and improved tolerability compared to afatinib or erlotinib for atypical EGFR-mutated mNSCLC.

Identifying key circulating tumor DNA parameters for predicting clinical outcomes in metastatic non-squamous non-small cell lung cancer after first-line chemoimmunotherapy

Circulating tumor DNA (ctDNA) provides valuable tumor-related information without invasive biopsies, yet consensus is lacking on optimal parameters for predicting clinical outcomes. Utilizing longitudinal ctDNA data from the large phase 3 IMpower150 study (NCT02366143) of atezolizumab in combination with chemotherapy with or without bevacizumab in patients with stage IV non-squamous Non-Small Cell Lung Cancer (NSCLC), here we report that post-treatment ctDNA response correlates significantly with radiographic response. However, only modest concordance is identified, revealing that ctDNA response is likely not a surrogate for radiographic response; both provide distinct information. Various ctDNA metrics, especially early ctDNA nadirs, emerge as primary predictors for progression-free survival and overall survival, potentially better assessing long-term benefits for chemoimmunotherapy in NSCLC. Integrating radiographic and ctDNA assessments enhances prediction of survival outcomes. We also identify optimal cutoff values for risk stratification and key assessment timepoints, notably Weeks 6–9, for insights into clinical outcomes. Overall, our identified optimal ctDNA parameters can enhance the prediction of clinical outcomes, refine trial designs, and inform therapeutic decisions for first-line NSCLC patients.

Real-world effectiveness and safety of recombinant human endostatin plus PD-1 inhibitors and chemotherapy as first-line treatment for EGFR/ALK-negative, advanced or metastatic non-small cell lung cancer

BackgroundThis study aimed to evaluate the effectiveness and safety of recombinant human endostatin (Rh-endostatin) plus programmed cell death 1 (PD-1) inhibitors and chemotherapy as first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) in a real-world setting.MethodsThis was a retrospective study on patients with EGFR/ALK-negative, advanced or metastatic NSCLC. Patients received Rh-endostatin plus PD-1 inhibitors and chemotherapy every three weeks for 4 to 6 cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.ResultsA total of 68 patients were included in this retrospective analysis. As of data cutoff (December 13, 2022), the median follow-up of 21.4 months (interquartile range [IQR], 8.3-44.4 months). The median PFS and OS was 22.0 (95% confidence interval [CI]: 16.6-27.4) and 31.0 months (95% CI: 23.4-not evaluable [NE]), respectively. The ORR was 72.06% (95% CI: 59.85-82.27%), and DCR was 95.59% (95% CI: 87.64-99.08%). Patients with stage IIIB/IIIC NSCLC had significantly longer median PFS (23.4 vs. 13.2 months), longer median OS (not reached vs. 18.0 months), and higher ORR (89.2% vs. 51.6%) than those with stage IV NSCLC (all p ≤ 0.001). The ORR was higher in patients with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%) than in those with low PD-L1 expression or positive PD-L1 expression (75% vs. 50%, p = 0.025). All patients experienced treatment-related adverse events (TRAEs), and ≥ grade 3 TRAEs occurred in 16 (23.53%) patients.ConclusionsRh-endostatin combined with PD-1 inhibitors plus chemotherapy as first-line treatment yielded favorable effectiveness with a manageable profile in patients with advanced or metastatic NSCLC, representing a promising treatment modality.

Successful treatment of PD1-inhibitor induced psoriasiform dermatitis using IL-17 blockade without compromising immunotherapy efficacy.

Pembrolizumab is a monoclonal PD-1 inhibitor used in the treatment of lung cancer in addition to several other malignancies. Psoriasiform dermatitis is a well-documented adverse effect. We present a 68 year-old-male with a 50-year smoking history and a 30-year remote history of plaque psoriasis, limited to the knees and elbows, who presented with metastatic non-small cell lung cancer. He was started on a chemotherapy regimen of carboplatin, paclitaxel, and pembrolizumab. One month later, he presented to dermatology with diffuse erythematous scaly papules coalescing into plaques on 80% of body surface area (BSA). Pembrolizumab treatment was paused. The patient was prescribed triamcinolone 0.1% twice daily, but still had significant BSA at one-month and was started on an Il-17 inhibitor, ixekizumab, clearing the psoriasiform dermatitis. He was rechallenged with pembrolizumab every 3 weeks and repeat PET/CT demonstrated excellent tumor response. This case prompted a literature review to further characterize the use of IL-17 inhibitors for psoriasiform dermatitis in the setting of ICI therapy. All six cases demonstrated improvement of psoriasiform dermatitis, with two cases showing partial response and four cases showing complete resolution. In three of the six cases, the patients exhibited clinical response to the primary malignancy after rechallenging with ICI, while remaining on an IL-17 inhibitor. Our case, in conjunction with the other reported cases, seems to suggest that IL-17 blockade can maintain a fine balance in this challenging clinical scenario by treating psoriasiform dermatitis without compromising the efficacy of immunotherapy.

Association of TP53 Mutation Status and Sex with Clinical Outcome in NSCLC Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study.

Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC. Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of TCGA and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed. In SNUBH cohort, no statistically significant difference was observed in disease control rate per the TP53 mutation status (p=0.503); however, female patients with TP53 mutated (MT) had a significantly prolonged median progression-free survival (PFS) compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). PD-L1 high (≥50%) expression was significantly enriched in female patients with TP53 MT (p=0.001). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p<0.001). In TCGA analysis, expression of immune-related genes, and TMB score in TP53 MT females were higher than in males without TP53 MT. Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

Patient-centric thresholding of Cobas® EGFR mutation Test v2 for surveillance of EGFR-mutated metastatic non-small cell lung cancer

Cobas EGFR mutation Test v2 was FDA-approved as qualitative liquid biopsy for actionable EGFR variants in non-small cell lung cancer (NSCLC). It generates semiquantitative index (SQI) values that correlate with mutant allele levels, but decision thresholds for clinical use in NSCLC surveillance are lacking. We conducted long-term ctDNA monitoring in 20 subjects with EGFR-mutated NSCLC; resulting in a 155 on-treatment samples. We defined optimal SQI intervals to predict/rule-out progression within 12 weeks from sampling and performed orthogonal calibration versus deep-sequencing and digital PCR. SQI showed significant diagnostic power (AUC 0.848, 95% CI 0.782–0.901). SQI below 5 (63% of samples) had 93% (95% CI 87–96%) NPV, while SQI above 10 (25% of samples) had 69% (95% CI 56–80%) PPV. Cobas EGFR showed perfect agreement with sequencing (Kappa 0.860; 95% CI 0.674–1.00) and digital PCR. SQI values strongly (r: 0.910, 95% 0.821–0.956) correlated to mutant allele concentrations with SQI of 5 and 10 corresponding to 6–9 (0.2–0.3%) and 64–105 (1.1–1.6%) mutant allele copies/mL (VAF) respectively. Our dual-threshold classifier of SQI 0/5/10 yielded informative results in 88% of blood draws with high NPV and good overall clinical utility for patient-centric surveillance of metastatic NSCLC.

Estimation of the Clinical, Economic, and Social Burden of Stage IV Non-Small Cell Lung Cancer in Mexico.

Lung cancer continues to be the leading cause of death among cancer patients worldwide. This study aimed to estimate the clinical, economic, and social burdens of stage IV non-small cell lung cancer (NSCLC) in private and public healthcare centers in Mexico, utilizing real-world evidence. The study population included patients >18 years of age diagnosed with stage IV NSCLC who received cancer treatment at the Centro Médico Nacional Siglo XXI (IMSS), the Centro Médico Nacional "20 de Noviembre" (ISSSTE), the Mexican Institute of Respiratory Diseases (INER), and the Medical Center ABC (American British Cowdray) from 1 January 2019 to 31 December 2020. The analysis included evaluation of epidemiological data, treatment regimens, and clinical outcomes, and emphasized pharmacological and non-pharmacological treatments, including detailed follow-up investigations, as part of comprehensive clinical management. Additionally, the study assessed the social burden through variables such as working-age absenteeism and presenteeism and caregiver productivity loss, as well as economic burden, considering both clinical and social components, with costs adjusted to 2022 Mexican pesos (MXN) values. A total of 188 patients with metastatic NSCLC were studied. The main type of NSCLC tumor found in the sample was adenocarcinoma (81%). Treatment regimens included pharmacological treatments (78%), non-pharmacological treatments (25%), and palliative care (24%). Complications were present in 73% of the cohort, while 60% presented adverse events. Clinical management costs of up to MXN1,001,579 per patient in the public sector and MXN2,140,604 in the private sector were reported. It was estimated that working-age patients lose 84-335 days yearly due to absenteeism and presenteeism, while caregivers report a productivity loss equivalent to 13-30 days due to the management of NSCLC patients. These indirect costs of NSCLC contribute to the social burden. A working-age patient with stage IV disease is associated with an average indirect cost of MXN49,731-178,287 in public institutions, while in private institutions, the cost elevates to MXN438,103. This study highlights the substantial clinical, economic, and social burdens of stage IV NSCLC in Mexico, revealing significant disparities between public and private healthcare sectors. It underscores the urgent need for standardized practices and equitable care across all systems.

22 Association of a germline single nucleotide polymorphism (SNP) in the interleukin-7 (IL7) gene with immune-related adverse events (irAEs)

Abstract Background Adverse events (AEs) can limit treatment immune checkpoint inhibitors (ICI) efficacy and worsen patient outcomes. Our group recently identified a germline IL7 SNP as a potential biomarker for prediction of irAEs (Groha, Nat Med 2022). In the current study, we sought to replicate the association between this IL7 SNP (rs16906115) and AEs in two clinical trials of patients with cancer treated with ICI regimens. Methods In the CheckMate-025 (CM025) trial (NCT01668784), involving patients with metastatic renal cell carcinoma (mRCC) randomized to either nivolumab (NIVO) or everolimus (EVE), whole-exome sequencing (WES) data from tumor and peripheral blood samples were analyzed. The Cancer Genome Analysis pipeline was utilized to identify somatic alterations, and the STITCH pipeline was employed to determine SNP carrier status. In the BinTA-0037 (BTA-0037) trial (NCT03631706), focusing on patients with metastatic non-small cell lung cancer (mNSCLC), the carrier status of a surrogate SNP rs16906062 (R2=0.66) was determined from tumor WES in the pembrolizumab (PEMBRO) arm. Within each treatment arm, time to incident AEs were compared between carriers (SNP+) and non-carriers (SNP-) via multivariable Cox regression, controlling for age, sex, race, ECOG and sample purity. A SNP´treatment interaction term was also included in the entire CM025 cohort. Censoring for AEs occurred at death or last follow-up. A recurrent event analysis for AEs was conducted using the Andersen-Gill model, controlling for the same variables. Additionally, overall survival (OS) and progression-free survival (PFS) were also assessed. Results In total, 534 pts were included (NIVO: n=189, PEMBRO: n=152, EVE: n=193), among which 82 (15.4%) were SNP+. There were no differences in clinical and pathological characteristics between SNP+ and SNP-, except for sex (SNP+ 16.1% vs. SNP- 30.1% in females, P=0.046). Similarly, no differences in somatic alterations, including single nucleotide and copy number variants were seen between SNP+ and SNP- in CM025. SNP carrier status had no effect on OS nor PFS in all treatment arms (all P≥0.22). The rate of grade 2+ AEs was significantly higher in SNP+ vs. SNP- in the NIVO arm (Figure A, HR=2.91[1.48-5.72]), but not in the EVE (Figure B, control, non-ICI) arm (HR=0.63[0.3-1.29], SNP´treatment Pinteraction=0.002). Similarly, the rate of all grade AEs in the PEMBRO arm of BTA-0037 was higher in SNP+ vs. SNP- (Figure C, HR=2.30[1.60-4.60]). The rate of recurrent grade 2+ AEs was also significantly higher in SNP+ vs. SNP- in the NIVO arm (HR=3.43[1.83-6.43]), whereas a trend for fewer recurrent grade 2+ AEs was seen in SNP+ vs. SNP- in the EVE arm (HR=0.46[0.17-1.25], SNP´treatment Pinteraction=0.0005). Figure: Kaplan-Meier curves showing the cumulative rate of adverse events in the NIVO (A) and EVE (B) arms of CM025, as well as the PEMBRO arm of BTA0037 (C), in SNP- and SNP+. Conclusions The IL7 SNP (rs16906115) is associated with significantly higher rates of grade 2+ AEs, including recurrent events, in pts with mRCC or mNSCLC treated with single agent PD-1 inhibitors but not with non-ICI regimens, with no effect on survival and efficacy outcomes. These results confirm the SNP’s predictive potential as a biomarker for irAEs to guide therapeutic decisions in pts treated with ICIs.