Asian Subgroup Analysis of Patients in the Phase 2 DeLLphi-301 Study of Tarlatamab for Previously Treated Small Cell Lung Cancer.

Introduction: Tarlatamab is a bispecific T-cell engager (BiTE) immunotherapy that binds delta-like ligand 3 on the surface of small cell lung cancer (SCLC) cells and CD3 on T cells, facilitating T cell-mediated cancer cell lysis. In the primary analysis of the phase 2 DeLLphi-301 study (NCT05060016), tarlatamab showed a favourable benefit-to-risk profile with durable objective responses and promising survival outcomes in patients with previously treated SCLC. Here, phase 2 data for the Asia region subgroup are presented.

Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells.

Non-small cell lung cancers (NSCLCs) treated with tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) almost invariably relapse in the long term, due to the emergence of subpopulations of resistant cells. Through a DNA barcoding approach, we show that the clinically approved drug sorafenib specifically abolishes the selective advantage of EGFR-TKI-resistant cells, while preserving the response of EGFR-TKI-sensitive cells. Sorafenib is active against multiple mechanisms of resistance/tolerance to EGFR-TKIs and its effects depend on early inhibition of MAPK-interacting kinase (MKNK) activity and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and later down-regulation of MCL1 and EGFR.

Atezolizumab and bevacizumab, with or without radiotherapy, versus docetaxel in patients with metastatic non-small cell lung cancer previously treated with a checkpoint inhibitor and chemotherapy: results from the randomized, phase Ib/II MORPHEUS-Lung study.

Background: Options remain limited for patients requiring later lines of therapy for metastatic non-small cell lung cancer (mNSCLC) due to poor prognosis and potential toxicities. Therefore, trials of novel combinations of existing therapeutic candidates are warranted. Here, we report robust interim analysis results from the MORPHEUS-Lung study in immune checkpoint inhibitor (CPI)-exposed patients with non-squamous mNSCLC and without targetable gene mutations.

Subcutaneous versus intravenous amivantamab, both in combination with lazertinib, in refractory EGFR-mutated non-small cell lung cancer: Patient satisfaction and resource utilization results from the PALOMA-3 study.

Introduction: Intravenous anticancer treatments present challenges for patients and healthcare professionals (HCPs), prompting the development of subcutaneous formulations. In the phase 3 PALOMA-3 study, subcutaneous amivantamab demonstrated noninferior pharmacokinetics and response rates versus intravenous amivantamab (both with lazertinib), with substantially faster administration, a 5-fold reduction in infusion-related reactions, reduced venous thromboembolism, and numerically prolonged survival.

Methods: Participants with EGFR-mutated NSCLC and progression on osimertinib and chemotherapy were randomized to subcutaneous (n = 206) or intravenous amivantamab (n = 212), plus lazertinib.

Evolving roles of MET as a therapeutic target in NSCLC and beyond.

Alterations in the proto-oncogene MET are associated with tumour development, invasion and metastasis across various solid cancers. Therapeutically actionable MET alterations include MET exon 14 skipping (METex14) mutations, MET amplification and/or MET overexpression and MET fusions, which vary in incidence by tumour type. In contrast to rare de novo MET alterations, acquired MET amplification and/or MET overexpression is a relatively common phenomenon that is associated with distinct clinical implications and responses to treatment.

Lazertinib Versus Osimertinib in Previously Untreated EGFR-Mutant Advanced NSCLC: A Randomized, Double-Blind, Exploratory Analysis From MARIPOSA.

Introduction: Lazertinib is a central nervous system-penetrant, third-generation EGFR tyrosine kinase inhibitor (TKI) that was selected for combination with amivantamab due to its relatively low rates of wild-type EGFR toxicities. In the phase 3 MARIPOSA study, amivantamab plus lazertinib (amivantamab-lazertinib) significantly improved progression-free survival (PFS; p < 0.001) versus osimertinib in participants with treatment-naive EGFR-mutant advanced NSCLC.

A Pooled Analysis of Datopotamab Deruxtecan in Patients With EGFR-Mutated NSCLC.

Background: This exploratory analysis assessed datopotamab deruxtecan (Dato-DXd) in pretreated patients with advanced or metastatic NSCLC and EGFR mutations.

Methods: Data were pooled from the phase II TROPION-Lung05 (NCT04484142) and phase III TROPION-Lung01 (NCT04656652) trials. Patients with EGFR-mutated advanced or metastatic NSCLC, who had received previous targeted therapies and platinum-based chemotherapy, received Dato-DXd 6 mg/kg (TROPION-Lung05) or were randomized to Dato-DXd 6 mg/kg or docetaxel 75 mg/m (TROPION-Lung01) once every 3 weeks.

Phase I and II Clinical Studies of the STING Agonist Ulevostinag with and without Pembrolizumab in Participants with Advanced or Metastatic Solid Tumors or Lymphomas.

Purpose: We report results from two clinical trials of the cyclic dinucleotide stimulator of IFN genes (STING) agonist ulevostinag.

Patients And Methods: In a phase I study (NCT03010176) with an accelerated titration design/modified toxicity probability interval method, participants with advanced/metastatic solid tumors or lymphomas received intratumoral ulevostinag (±intravenous pembrolizumab). In an expansion phase, participants with head and neck squamous cell carcinoma (HNSCC) or triple-negative breast cancer received the combination.

LEAP-008: Lenvatinib Plus Pembrolizumab for Metastatic NSCLC That Has Progressed After an Anti-Programmed Cell Death Protein 1 or Anti-Programmed Cell Death Ligand 1 Plus Platinum Chemotherapy.

Background: LEAP-008 (NCT03976375) was an open-label, randomized, phase 3 study of lenvatinib plus pembrolizumab versus docetaxel for metastatic NSCLC that progressed on anti‒programmed cell death protein 1 or anti‒programmed cell death ligand 1 therapy and platinum-containing chemotherapy.

Methods: Participants were randomized 4:4:1 to once-daily lenvatinib 20 mg plus pembrolizumab 200 mg every 3 weeks (maximum 35 cycles), docetaxel 75 mg/m every 3 weeks, or once-daily lenvatinib 24 mg. Primary end points were overall survival (OS) and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.

ORCHARD: Osimertinib Plus Necitumumab in Patients With Epidermal Growth Factor Receptor-Mutated Advanced Non-Small Cell Lung Cancer With a Secondary Epidermal Growth Factor Receptor Alteration Whose Disease Had Progressed on First-Line Osimertinib.

Purpose: ORCHARD (ClinicalTrials.gov identifier: NCT03944772) is a phase II, biomarker-directed platform study designed to characterize resistance mechanisms and evaluate novel drug combinations in patients with epidermal growth factor receptor ()-mutated advanced non-small cell lung cancer who have progressed on first-line osimertinib. We report final results of the module assessing the efficacy and safety of osimertinib plus necitumumab (a monoclonal antibody that blocks EGFR) in patients with ≥one of the following: amplification or select secondary alterations (L718 or G724 mutation, or exon 20 insertion).

Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy.

Background: Tarlatamab, a bispecific delta-like ligand 3-directed T-cell engager immunotherapy, received accelerated approval for the treatment of patients with previously treated small-cell lung cancer. Whether tarlatamab is more effective than chemotherapy in the treatment of patients whose small-cell lung cancer has progressed during or after initial platinum-based chemotherapy is not known.

Methods: We conducted a multinational, phase 3, open-label trial to compare tarlatamab with chemotherapy as second-line treatment in patients with small-cell lung cancer whose disease had progressed during or after platinum-based chemotherapy.

Intracranial and systemic progression on amivantamab in platinum-treated epidermal growth factor receptor exon 20 insertion-mutated advanced non-small cell lung cancer.

Background: Amivantamab, an epidermal growth factor receptor (EGFR)-MET bispecific antibody, is approved as monotherapy and as combination therapy for patients with advanced non-small cell lung cancer (NSCLC) harboring various EGFR mutations in first-line and refractory settings. Sites of progressive disease on amivantamab monotherapy are not well understood and could be instructive for treatment management.

Methods: CHRYSALIS (NCT02609776) enrolled participants with NSCLC, including those with treated brain metastases.

Lenvatinib Plus Pembrolizumab, Pemetrexed, and a Platinum as First-Line Therapy for Metastatic Nonsquamous NSCLC: Phase 3 LEAP-006 Study.

Introduction: We present the LEAP-006 (NCT03829319) phase 3 study evaluating the addition of lenvatinib to first-line pembrolizumab plus chemotherapy in metastatic nonsquamous NSCLC.

Methods: Adults with previously untreated stage IV nonsquamous NSCLC without targetable genetic alterations were randomized 1:1 to lenvatinib 8 mg/d or placebo once daily plus pembrolizumab 200 mg every 3 weeks with pemetrexed and carboplatin or cisplatin for 4 cycles, followed by pembrolizumab (≤35 total cycles) and pemetrexed until disease progression or intolerable toxicity. Primary end points were progression-free survival and overall survival (OS).

Amivantamab in Participants With Advanced NSCLC and MET Exon 14 Skipping Mutations: Final Results From the CHRYSALIS Study.

Introduction: Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity. We assessed the safety and efficacy of amivantamab in participants with advanced NSCLC harboring primary MET exon 14 skipping mutations (METex14).

Methods: CHRYSALIS enrolled participants with METex14 NSCLC who progressed after or declined standard-of-care therapy.

Lazertinib for Patients with NSCLC Harboring Uncommon EGFR Mutations: A Phase II Multicenter Trial.

Introduction: Uncommon EGFR mutations comprise 10% to 20% of all EGFR mutations in NSCLC and generally report reduced responsiveness to EGFR tyrosine kinase inhibitors (TKIs). Lazertinib, a third-generation EGFR-TKI, has found efficacy in common EGFR mutations, but its potential in uncommon mutations remains unexplored. This study investigated the efficacy and safety of lazertinib in patients with NSCLC with uncommon EGFR mutations.

Association of thyroid radiation dose with thyroid dysfunction in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy followed by maintenance immunotherapy.

Background And Purpose: We investigated whether incidental irradiation to the thyroid increased the risk of thyroid dysfunction among patients with non-small cell lung cancer (NSCLC) undergoing concurrent chemoradiotherapy (CCRT) followed by maintenance immunotherapy (IO).

Materials And Methods: This was a retrospective study of 250 patients diagnosed with locally advanced NSCLC during 2014-2022 who were treated with definitive CCRT followed by maintenance IO. The primary endpoint was the incidence of thyroid dysfunction, which we compared between patients with irradiation of the supraclavicular fossa (the SCFi group) and those without (the non-SCFi group).

D3S-001 in advanced solid tumors with KRAS mutations: a phase 1 trial.

D3S-001 is a next-generation KRAS-G12C inhibitor (G12Ci) designed to enhance target engagement efficiency and overcome growth factor-induced nucleotide exchange. D3S-001 was evaluated in a phase 1a dose-escalation study in patients with advanced solid tumors harboring KRAS mutation (N = 42) and a phase 1b expansion cohort of patients with non-small-cell lung cancer (NSCLC) whose disease progressed after prior G12Ci therapy (N = 20). The primary endpoints were safety and determination of the maximum tolerated dose.

Amivantamab plus lazertinib versus osimertinib as first-line treatment in EGFR-mutated advanced non-small cell lung cancer: MARIPOSA Asian subset.

Introduction: The incidence of epidermal growth factor receptor (EGFR) mutations is higher among Asian patients with advanced non-small cell lung cancer than the general advanced non-small cell lung cancer population. We evaluated the efficacy and safety of amivantamab in combination with lazertinib versus osimertinib in Asian participants from the phase 3 MARIPOSA study who had treatment-naïve advanced non-small cell lung cancer with common EGFR mutations.

Methods: Participants were randomized 2:2:1 to receive amivantamab-lazertinib, osimertinib alone, or lazertinib alone.

A phase 1b study of cofetuzumab pelidotin monotherapy in patients with PTK7-expressing recurrent non-small cell lung cancer.

Background: Protein tyrosine kinase 7 (PTK7) overexpression in lung cancer is associated with tumor progression. Cofetuzumab pelidotin (Cofe-P) is an antibody-drug conjugate comprising an anti-PTK7 antibody conjugated to a microtubule inhibitor. Herein, we report the results of a phase 1b study evaluating Cofe-P safety, efficacy, and pharmacokinetics in patients with recurrent non-small cell lung cancer (NSCLC).

Population-Adjusted Indirect Treatment Comparisons of Repotrectinib Among Patients with NSCLC.

Background: Head-to-head evidence comparing repotrectinib against other approved ROS1 tyrosine kinase inhibitors (TKIs) is not currently available. The objective of this study was to indirectly compare progression-free survival (PFS), the objective response rate (ORR), and the duration of response (DoR) for repotrectinib vs. crizotinib and vs.

Osimertinib long-term tolerability in patients with EGFRm NSCLC enrolled in the AURA program or FLAURA study.

Introduction: This post-hoc analysis of the registrational FLAURA study and AURA program reports long-term safety data in epidermal growth factor receptor-mutated (EGFRm), advanced non-small cell lung cancer (NSCLC) treated with osimertinib for ≥ 36 months.

Methods: Patients from FLAURA who received first-line osimertinib and from the AURA program (AURA, AURA2, AURA3) who received ≥ second-line osimertinib were included. Patients received osimertinib 80 mg once daily.