Faculty Bibliography

BACKGROUND:)-mutant non-small-cell lung cancer (NSCLC). Zongertinib is an oral, irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing wild-type epidermal growth factor receptor (EGFR), thereby minimizing associated toxic effects. METHODS:-mutant NSCLC. Here, we evaluated zongertinib at a dose of 120 mg once daily in patients who had not previously received treatment (cohort 2). The primary end point was objective response as assessed by blinded independent central review. Secondary end points included duration of response and progression-free survival. In addition, zongertinib was evaluated in patients with active brain metastases (exploratory cohort 4). RESULTS:In cohort 2, a total of 74 previously untreated patients received zongertinib at a dose of 120 mg. As of August 21, 2025, the percentage of patients with a confirmed objective response was 76% (95% confidence interval [CI], 65 to 84); the median duration of response was 15.2 months (95% CI, 9.8 to not evaluable), and the median progression-free survival was 14.4 months (95% CI, 11.1 to not evaluable). Adverse events of any grade occurred in 73 patients (99%), including events of grade 3 or higher in 33 patients (45%). Treatment-related adverse events occurred in 67 patients (91%), including events of grade 3 or higher in 14 patients (19%). In cohort 4, a total of 30 patients with active brain metastases received zongertinib at a dose of 120 mg; of these, 47% (95% CI, 30 to 64) had a confirmed intracranial objective response according to Response Assessment in Neuro-Oncology Brain Metastases criteria. In this cohort, treatment-related adverse events of grade 3 or higher occurred in 5 patients (17%). CONCLUSIONS:-mutant NSCLC. Treatment-related adverse events were predominantly low-grade. (Funded by Boehringer Ingelheim; Beamion LUNG-1 ClinicalTrials.gov number, NCT04886804.).

PURPOSE/OBJECTIVE:Amivantamab is an EGFR-MET bispecific antibody approved as an intravenous formulation for EGFR-mutated advanced non-small cell lung cancer (NSCLC). Intravenous delivery is frequently associated with infusion-related reaction (IRRs), which require adopting slow infusion rates and splitting the first dose over 2 days. The PALOMA study assessed the safety and feasibility of subcutaneous amivantamab administration and identified the formulation and recommended phase II doses (RP2Ds) for multiple dosing schedules. PATIENTS AND METHODS/METHODS:PALOMA is a phase Ib dose-escalation study in 158 participants with advanced solid malignancies. Primary objectives included pharmacokinetics, safety, and determining RP2Ds for every-2-week (Q2W), every-3-week (Q3W), and every-4-week (Q4W) administration. RESULTS:The safety profile of subcutaneous amivantamab was largely consistent with intravenous monotherapy; most common toxicities reflected on-target EGFR/MET inhibition. Subcutaneous amivantamab resulted in meaningfully shorter administration time (≤ 10 minutes vs. 2.3 hours for intravenous beyond cycle 3) and lower incidence and severity of IRRs versus historical intravenous data, which eliminates the need for split-dose administration. Pharmacokinetic analyses and population pharmacokinetic modeling/simulation were used to estimate subcutaneous amivantamab RP2Ds of 1600 mg (2240 mg, ≥ 80 kg), 2400 mg (3360 mg, ≥ 80 kg), and 3520 mg (4640 mg, ≥ 80 kg) for Q2W, Q3W, and Q4W schedules, respectively. The observed efficacy was consistent with intravenous amivantamab monotherapy. CONCLUSION/CONCLUSIONS:Subcutaneous amivantamab administration substantially reduced IRRs, obviating the need for prolonged infusions and 2-day split-dosing at first administration. The identified RP2Ds for subcutaneous amivantamab are implemented in ongoing studies evaluating amivantamab regimens in NSCLC, colorectal cancer, and head and neck squamous cell carcinoma.

www.clinicaltrials.gov identifier is NCT06119581. EudraCT: 2023-503412-33-00.

Human epidermal growth factor receptor 2 (HER2) has been identified as a distinct molecular drug target in patients with non-small cell lung cancer (NSCLC), with mutations detected in approximately 1.8-5.6% of tumors. While HER2-directed agents have revolutionized treatment algorithms in breast and gastric cancers, there remains an unmet need for patients with HER2-mutant NSCLC. Currently, no first-line HER2-directed agents are available and, until recently, trastuzumab deruxtecan, a HER2-targeting antibody-drug conjugate, was the only approved HER2-directed treatment option in the previously treated setting. In the current review, we summarize the development of treatment options for HER2-mutant NSCLC, including antibody-drug conjugates and tyrosine kinase inhibitors.

This multicenter, first-in-human Phase 1 study (NCT04956640) evaluated olomorasib (LY3537982), a next-generation KRAS G12C inhibitor designed to enhance target occupancy at low absolute exposures. In total, data from 195 patients are reported: Phase 1a dose escalation (n = 112) assessed olomorasib monotherapy at 50, 100, 150 or 200 mg BID across KRAS G12C-mutant advanced solid tumors; the primary objective was to determine the recommended Phase 2 dose (RP2D) based on dose-limiting toxicities (DLTs). No DLTs occurred, and 150 mg BID was selected as the RP2D. The primary objective for the Phase 1b dose expansion (n = 83) was to evaluate the safety and tolerability of olomorasib in specific KRAS G12C-mutant tumor types. Olomorasib was well tolerated, with predominantly grade 1-2 treatment-related adverse events (TRAEs) and infrequent grade 3 TRAEs; no grade 4/5 TRAEs occurred. Secondary objectives evaluated the antitumor activity of olomorasib. Among 168 efficacy-evaluable patients, the ORR and median PFS were both higher in non-CRC solid tumors compared to CRC, including in patients with NSCLC who previously received a KRAS G12C inhibitor. Intracranial responses were observed in patients with untreated, active brain metastases. This may support the potential of next-generation KRAS G12C inhibitors to overcome limitations of earlier agents and justify further investigation of combination therapy.

BACKGROUND:Epidermal growth factor receptor (EGFR) exon 20 insertions (Ex20ins) are the third most common type of EGFR mutation, occurring in up to 12% of EGFR-mutated non-small cell lung cancers (NSCLC). Ex20ins-mutated NSCLC can be resistant to most approved tyrosine kinase inhibitors (TKIs). The Phase III PAPILLON trial (NCT04538664) demonstrated that amivantamab plus chemotherapy significantly improves progression-free survival (PFS) compared to chemotherapy alone, leading to its approval as a first-line treatment for patients with Ex20ins NSCLC. PAPILLON further evaluated patient-reported outcomes (PROs) and time to symptomatic progression (TTSP). METHODS:The open-label, multicenter trial randomized 308 treatment-naïve patients with advanced or metastatic NSCLC harboring Ex20ins to receive either amivantamab plus carboplatin-pemetrexed (n = 154) or chemotherapy alone (n = 154). TTSP was defined as the time to onset or worsening of lung cancer-related symptoms necessitating treatment change or clinical intervention, or death. PROs were assessed using the PROMIS PF8c and EORTC QLQ-C30. RESULTS:At 12 months, 77 % of patients in the amivantamab-chemotherapy arm remained free of symptomatic progression versus 60 % in the chemotherapy arm (HR, 0.67; 95 % CI, 0.46-0.98; p = 0.04). Physical functioning and global health status PROs were maintained in both arms, with a higher proportion of patients treated in the amivantamab-chemotherapy arm reporting stable or improved quality of life at 6 and 12 months. CONCLUSIONS:Amivantamab plus chemotherapy significantly delays symptomatic progression without compromising health-related quality of life, reinforcing its role as a first-line treatment for Ex20ins-mutated NSCLC.

INTRODUCTION/BACKGROUND:In advanced non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitution mutations (Ex19del/L858R), intravenous amivantamab is approved for first-line treatment with lazertinib, and second-line treatment with carboplatin-pemetrexed. Subcutaneous amivantamab demonstrated noninferior pharmacokinetics and comparable efficacy with improved safety outcomes versus intravenous amivantamab in the PALOMA-3 trial. Venous thromboembolism (VTE) was also reduced when combined with prophylactic anticoagulation. In the COCOON trial, an enhanced prophylactic dermatologic regimen with intravenous amivantamab plus lazertinib treatment lowered grade ≥ 2 dermatologic adverse events (AEs). There are no studies combining subcutaneous administration with supportive care advancements in diverse participants with EGFR-mutated NSCLC. COPERNICUS (NCT06667076), an open-label, phase 2b study aims to evaluate the efficacy and safety of subcutaneous amivantamab with lazertinib (cohort 1) or with chemotherapy (cohort 2) while preventing and proactively managing VTE and dermatologic AEs in a multinational, clinically representative population with EGFR-mutated NSCLC. METHODS:Eligible participants are adults with EGFR Ex19del/L858R NSCLC. A pragmatic study approach will be used to eliminate potential barriers to enrollment and increase diversity. Cohort 1 will enroll participants without prior systemic therapy to receive subcutaneous amivantamab and oral lazertinib. Cohort 2 will enroll participants with disease progression on EGFR-tyrosine kinase inhibitors to receive subcutaneous amivantamab and chemotherapy (carboplatin-pemetrexed). Both cohorts will receive enhanced dermatologic management; cohort 1 will receive prophylactic anticoagulation for the first 4 months of treatment. The primary endpoint is investigator-assessed progression-free survival. RESULTS:COPERNICUS is currently enrolling, with a planned enrollment in the United States of 300 and 30 participants in cohorts 1 and 2, respectively, plus 150 participants for cohort 1 in Europe. CONCLUSION/CONCLUSIONS:COPERNICUS uses a pragmatic study design to evaluate the efficacy and safety of subcutaneous amivantamab regimens combined with advancements in supportive care to prevent and proactively manage AEs in a diverse participant population. Supplementary file1 (MP4 117333 KB).

BACKGROUND:In the PAPILLON study, first-line amivantamab-chemotherapy in epidermal growth factor receptor (EGFR) exon 20 insertion-mutated non-small cell lung cancer demonstrated significantly prolonged progression-free survival and favorable overall survival over chemotherapy; a consistent benefit was also observed across some secondary endpoints. However, the complete clinical benefit of first-line amivantamab-chemotherapy is not fully understood, nor is the survival advantage in the presence of per-protocol crossover from chemotherapy to amivantamab after progression. OBJECTIVE:We aimed to assess time to treatment discontinuation (TTD) and time to subsequent therapy (TTST), at the time of primary analysis for progression-free survival, and the effect of the crossover design on overall survival at the time of interim analysis. METHODS:In the phase III PAPILLON study, 308 participants were randomized (amivantamab-chemotherapy, n = 153; chemotherapy, n = 155). Intravenous amivantamab was administered every 3 weeks. Chemotherapy was administered as carboplatin for four cycles and pemetrexed until disease progression. TTD and TTST were evaluated using Kaplan-Meier and Cox proportional hazards models. Crossover-adjusted survival estimates were generated using three established statistical methods. RESULTS:At a median follow-up of 14.9 months, median TTD was 13.2 versus 7.5 months for amivantamab-chemotherapy versus chemotherapy (hazard ratio [HR] 0.38 [95% confidence interval 0.28-0.51]; nominal p < 0.0001). Median TTST was 17.7 versus 9.9 months (HR 0.35 [95% confidence interval 0.25-0.49]; nominal p < 0.0001). A total of 65/155 participants crossed over from chemotherapy to amivantamab after progression. The crossover-adjusted overall survival continued to demonstrate a favorable survival benefit for amivantamab-chemotherapy versus chemotherapy with HRs of 0.52-0.60, which is more pronounced than the planned interim intention-to-treat overall survival (HR of 0.67; 95% confidence interval 0.42-1.09). CONCLUSIONS:In PAPILLON, TTD and TTST were substantially longer for amivantamab-chemotherapy versus chemotherapy at primary analysis (cut-off on 3 May 2023). Crossover-adjusted analyses of the planned interim overall survival demonstrated a greater benefit for amivantamab-chemotherapy versus chemotherapy, further supporting amivantamab-chemotherapy as the first-line standard of care in EGFR exon 20 insertion-mutated non-small cell lung cancer. CLINICAL TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov Identifier: NCT04538664.

Clinical practice guidelines for nonsmall cell lung cancer (NSCLC) and small cell lung cancer include recommendations based on high-level clinical trial evidence, but complex clinical questions are frequently seen in real-world practice that are not clearly answered by prospective trial data. To address these questions, the Bridging the Gaps Lung Cancer Consensus Conference 2024 (BtG LCCC 2024) convened to develop US-focused expert guidance for clinical situations in which level 1 evidence is lacking. At BtG LCCC 2024, a multidisciplinary expert panel discussed ongoing clinical issues in small cell lung cancer management, targeted therapy in EGFR-mutated NSCLC, management of early stage NSCLC, identification and management of non-EGFR oncogene-driven NSCLC, and use of immunotherapy in advanced/metastatic NSCLC. By using a modified Delphi process, 12 consensus recommendations were developed with the goal of providing guidance on the use of novel diagnostic methods and treatments for clinicians who manage lung cancer. This report reviews these areas of consensus and discusses ongoing questions about ways to apply current clinical evidence.