Faculty Bibliography

INTRODUCTION/BACKGROUND:Patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations (EGFRm) have high mortality. The third-generation tyrosine kinase inhibitor (TKI) osimertinib is approved for first-line EGFRm-NSCLC. We used longitudinal US medical oncology databases to evaluate real-world overall survival (rwOS) prognostic risk factor groups in advanced EGFRm-NSCLC treated with first-line osimertinib. METHODS:This retrospective, new-user cohort study used electronic records from ConcertAI, Flatiron Clinical-Genomics, and COTA databases. Patients with advanced/metastatic EGFRm-NSCLC initiating osimertinib monotherapy in first-line between April 1, 2018 and October 30, 2022 were included. Follow-up was until death or October 31, 2023. rwOS was estimated using the Kaplan-Meier method. Risk factors were evaluated using multivariate analysis. RESULTS:1323 patients were included with median follow-up of 20 months. Median age was 70 years (range 35-89). Median rwOS was 28.6 months (95% CI 26.8-30.9). In high-risk subgroups, median rwOS (months) was 18.1 in patients with ECOG score ≥2, 24.3 with brain metastases, 19.3 with liver metastases, and 25.7 with TP53 co-mutation. 95% of patients had ≥1 high risk factor. Prevalence of ECOG ≥2 was 17%, brain metastases 36%, liver metastases 15%, TP53 co-mutation 63%. Risk of death was significantly higher in patients with high-risk factors (p≤0.011 for all). In total, 58% of patients survived to 2 years, 18% to 5 years, and 33% did not receive second-line therapy. CONCLUSION/CONCLUSIONS:Despite advances in TKI treatments, long-term survival of patients with advanced EGFRm-NSCLC remains poor. Nearly all patients had risk factors for mortality and one-third did not receive second-line therapy.

Amivantamab is a fully human bispecific epidermal growth factor receptor (EGFR)-directed and mesenchymal epithelial transition (MET) receptor-directed antibody. Intravenous amivantamab is approved and recommended by treatment guidelines as a first-line treatment (1L) in combination with lazertinib, as a second-line treatment (2L) in combination with chemotherapy in adults with advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitution mutations, and as 2L monotherapy or 1L in combination with chemotherapy in adults with advanced or metastatic NSCLC with exon 20 insertion-mutations. Compared with previous therapies, novel treatments such as amivantamab may be associated with distinct and unique adverse reactions that potentially require optimized prevention and management techniques. Commonly reported adverse reactions associated with amivantamab treatment regimens include cutaneous reactions associated with EGFR inhibition, such as rash, paronychia, and pruritus; those associated with MET inhibition, such as peripheral edema and hypoalbuminemia; and general effects, such as infusion-related reactions. Recommendations are summarized from published guidelines and the authors' clinical experience for the prevention and management of adverse reactions associated with amivantamab. An understanding of the expected adverse events with amivantamab regimens, along with the range of prophylactic and management options available, may facilitate maintenance of ongoing treatment in patients deriving clinical benefit and improve patient quality of life on therapy.

BACKGROUND:)-mutant non-small-cell lung cancer (NSCLC). Zongertinib is an oral, irreversible, HER2-selective tyrosine kinase inhibitor that has been shown to have efficacy in persons with advanced or metastatic solid tumors with HER2 alterations in a phase 1 study. METHODS:-mutant NSCLC. Here we report the primary analysis of zongertinib in previously treated patients: those with tumors harboring a mutation in the tyrosine kinase domain (cohort 1), those with tumors harboring a mutation in the tyrosine kinase domain previously treated with a HER2-directed antibody-drug conjugate (cohort 5), and those with tumors harboring a non-tyrosine kinase domain mutation (cohort 3). In cohort 1, patients were initially randomly assigned to receive zongertinib at a dose of 120 mg or 240 mg once daily. Patients in cohorts 5 and 3 initially received 240 mg daily. After an interim analysis of data from cohort 1, subsequently recruited patients across all cohorts received zongertinib at a dose of 120 mg. The primary end point was an objective response assessed by blinded independent central review (cohorts 1 and 5) or by investigator review (cohort 3). Secondary end points included the duration of response and progression-free survival. RESULTS:In cohort 1, a total of 75 patients received zongertinib at a dose of 120 mg. At the data cutoff (November 29, 2024), 71% of these patients (95% confidence interval [CI], 60 to 80; P<0.001 against a ≤30% benchmark) had a confirmed objective response; the median duration of response was 14.1 months (95% CI, 6.9 to not evaluable), and the median progression-free survival was 12.4 months (95% CI, 8.2 to not evaluable). Grade 3 or higher drug-related adverse events occurred in 13 patients (17%). In cohort 5 (31 patients), 48% of the patients (95% CI, 32 to 65) had a confirmed objective response. Grade 3 or higher drug-related adverse events occurred in 1 patient (3%). In cohort 3 (20 patients), 30% of the patients (95% CI, 15 to 52) had a confirmed objective response. Grade 3 or higher drug-related adverse events occurred in 5 patients (25%). Across all three cohorts, no cases of drug-related interstitial lung disease occurred. CONCLUSIONS:-mutant NSCLC. (Funded by Boehringer Ingelheim; Beamion LUNG-1 ClinicalTrials.gov number, NCT04886804.).

Lung cancer is the leading cause of cancer death in the US and globally. The mortality from lung cancer has been declining, due to a reduction in incidence and advances in treatment. Although recent success in developing targeted and immunotherapies for lung cancer has benefitted patients, it has also expanded the complexity of potential treatment options for health care providers. To aid in reducing such complexity, experts in oncology convened a conference (Bridging the Gaps in Lung Cancer) to identify current knowledge gaps and controversies in the diagnosis, treatment, and outcomes of various lung cancer scenarios, as described here. Such scenarios relate to biomarkers and testing in lung cancer, small cell lung cancer, EGFR mutations and targeted therapy in non-small cell lung cancer (NSCLC), early-stage NSCLC, KRAS/BRAF/MET and other genomic alterations in NSCLC, and immunotherapy in advanced NSCLC.

PURPOSE/OBJECTIVE:-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy. PATIENTS AND METHODS/METHODS:). Key secondary endpoints were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory endpoint. RESULTS:=0.02). Fewer patients in the subcutaneous group experienced infusion-related reactions (13% versus 66%) and venous thromboembolism (9% versus 14%) versus the intravenous group. Median administration time for first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab from 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; end-of-treatment rates were 85% and 35%, respectively. CONCLUSION/CONCLUSIONS:Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced infusion-related reactions, increased convenience, and prolonged survival.

UNLABELLED:Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2-7.6). Median progression-free survival was 6.9 months (95% CI, 5.7-7.4) and median overall survival was 15.9 months (95% CI, 11.8-18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3-4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance. SIGNIFICANCE/UNASSIGNED:Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer. This article is featured in Selected Articles from This Issue, p. 897.

BACKGROUND/UNASSIGNED:-rearranged lung adenocarcinoma. CASE DESCRIPTION/UNASSIGNED:exon 14 skip mutation. The patient was started on dual alectinib and capmatinib therapy, which led to a rapid and durable response. CONCLUSIONS/UNASSIGNED:dependent and independent resistance alterations. Combinatorial therapy may provide a promising effective and safe therapy option for patients who acquire resistance after initial TKI therapy.