Plain language summary of PAPILLON: amivantamab plus chemotherapy in untreated EGFR-mutated non-small-cell lung cancer.

What is this summary about? This is a plain language summary of an article that describes the first results of the phase 3 PAPILLON study in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with Exon 20 insertion (Ex20ins) mutations in the epidermal growth factor receptor (EGFR) gene who had not had any cancer treatment before. Researchers looked at how safe and effective the bispecific antibody amivantamab (brand name: RYBREVANT^®) plus chemotherapy was in comparison to chemotherapy alone.Amivantamab was approved by the US Food and Drug Administration (FDA) in May 2021 for patients with the same type of cancer who got worse after chemotherapy. In March 2024, amivantamab was approved in combination with chemotherapy for previously untreated patients with the same type of cancer. The National Comprehensive Cancer Network^® (NCCN^®) recommends amivantamab plus chemotherapy as a preferred first treatment option for these patients.What were the results? 308 patients were randomly selected to receive amivantamab plus chemotherapy or chemotherapy alone. Patients who received amivantamab plus chemotherapy lived longer without having their disease get worse compared to those who had chemotherapy. Patients who had amivantamab plus chemotherapy also had the risk of their disease getting worse or dying reduced by 60% compared to chemotherapy. After 18 months of treatment, 31% of patients on amivantamab plus chemotherapy did not have their cancer grow or spread compared to 3% with chemotherapy. More than 7 in 10 patients who had amivantamab plus chemotherapy had tumors that shrank by at least 30% or were no longer detectable. This only happened in less than 5 in 10 patients who had chemotherapy alone.All patients had side effects, with the most common being neutropenia (occurring in 59% of patients), paronychia (56%), and rash/red skin bumps (54%/31%) for those treated with amivantamab plus chemotherapy, and anemia (55%), neutropenia (45%), and nausea (42%) for those treated with chemotherapy. Few patients (7%) stopped taking amivantamab due to side effects.What do the results mean? Amivantamab plus chemotherapy worked well to extend the time that patients' cancer did not worsen. Patients had a 60% lower risk of death or having their cancer worsen compared to those who had chemotherapy. These benefits were seen in groups of patients with different characteristics.Amivantamab plus chemotherapy works well, is well tolerated, and is a good treatment option for untreated patients who have advanced NSCLC with EGFR Ex20ins mutations.

Subcutaneous versus Intravenous Amivantamab, both in Combination with Lazertinib, in Refractory EGFR-mutated NSCLC: Primary Results from the Phase 3 PALOMA-3 Study.

PURPOSE: Phase 3 studies of intravenous amivantamab demonstrated efficacy across EGFR-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy. PATIENTS AND METHODS: Patients with EGFR-mutated advanced NSCLC who progressed following osimertinib and platinum-based chemotherapy were randomized 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Co-primary pharmacokinetic noninferiority endpoints were trough concentrations (Ctrough; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUCD1-D15). Key secondary endpoints were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory endpoint. RESULTS: Overall, 418 patients underwent randomization (subcutaneous group, n=206; intravenous group, n=212). Geometric mean ratios of Ctrough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04-1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27-1.61) at cycle-4-day-1; the cycle-2 AUCD1-D15 was 1.03 (90% CI, 0.98-1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42-0.92; nominal P=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: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced infusion-related reactions, increased convenience, and prolonged survival.

Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer.

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: 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.

Combinatorial therapy is a safe and durable treatment option in ALK-rearranged non-small cell lung cancer with an acquired MET exon 14 skipping mutation mediated resistance to alectinib: a case report.

Background: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard first line treatment for ALK-rearranged non-small cell lung cancer (NSCLC) and have demonstrated high and durable response rates. Despite these initial responses, patients eventually develop resistance through ALK dependent and ALK independent alterations. These resistance mechanisms have made treatment decisions increasingly more complex. Here we describe a case of an acquired mesenchymal epithelial transition factor (MET) exon 14 skipping (METex14) mutation mediated resistance to alectinib in a patient with ALK-rearranged lung adenocarcinoma. Case Description: We present a 72-year-old male with a 2-pack year smoking history and end-stage renal disease on hemodialysis diagnosed with metastatic lung adenocarcinoma harboring an echinoderm microtubule-associated protein 4 (EML4)-ALK fusion gene mutation. The patient was initially treated with alectinib with good response. However, the patient eventually developed resistance. Next generation sequencing of a liquid biopsy at time of progression revealed a MET exon 14 skip mutation. The patient was started on dual alectinib and capmatinib therapy, which led to a rapid and durable response. Conclusions: This is the first case report of the successful treatment of METex14 mutation mediated resistance to alectinib with combination therapy of alectinib and capmatinib, which led to a rapid and durable response in our patient. This case highlights the importance of resequencing patients at the time of progression to identify potential actionable ALK 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.