SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer. Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21.
Epidermal Growth Factor Receptor (EGFR) plays an important role in regulating cell proliferation, survival and differentiation, and is overexpressed in a variety of epithelial malignancies. EGFR targeted Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib target the EGFR signaling cascade. However, patients eventually will develop drug resistance due to new EGFR mutations. Another important cause of drug resistance to TKIs is due to the activation of parallel RTK (Receptor Tyrosine Kinase) pathways such as Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition factor (HGF/MET) pathway, thereby bypassing EGFR TKI inhibitors. These patients are often treated with platinum-based chemotherapy as the next line of therapy, resulting in a median Progression Free Survival of 5 months.
Amivantamab (RYBREVANT®) is a fully-human bispecific antibody directed against EGFR and MET receptors. Amivantamab binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, Amivantamab downregulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, Amivantamab can bypass primary and secondary TKI resistance at the active site. Amivantamab also engages effector cells such as Natural Killer cells, monocytes, and macrophages via its optimized Fc domain. Amivantamab demonstrated activity against a wide range of activating and resistance mutations in EGFR-mutated NSCLC, and in patients with MET exon 14 skip mutations, and is approved for the treatment of patients with EGFR exon 20 insertion mutations, whose disease progressed on or after platinum-based chemotherapy.
Lazertinib is a highly selective, third-generation TKI that penetrates the CNS, with demonstrated efficacy in activating EGFR mutations and acquired T790M “gatekeeper” point mutation. Combining Amivantamab with Lazertinib has been shown to provide a synergistic benefit by targeting the extracellular and catalytic EGFR domains. In early phase studies, Amivantamab plus chemotherapy and Amivantamab, Lazertinib plus chemotherapy demonstrated an Objective Response Rate of 44% and 50% in advanced and refractory NSCLC, and in patients whose disease had progressed on prior TKIs, respectively.
MARIPOSA-2 is a global, randomized, Phase 3 trial, conducted to assess the efficacy and safety of Amivantamab plus chemotherapy and Amivantamab, Lazertinib plus chemotherapy versus chemotherapy alone, in patients with EGFR-mutated advanced NSCLC, whose disease had progressed on or after Osimertinib monotherapy. Amivantamab is a large molecule and was not expected to readily cross the blood-brain barrier. This was one of the main reasons for the addition of Lazertinib, a known CNS-active TKI, to Amivantamab plus chemotherapy. A total of 657 patients (N=657) with EGFR-mutated (exon 19 deletions or L858R substitution mutations) locally advanced or metastatic NSCLC, after disease progression on Osimertinib, were randomized 2:2:1 to receive either Amivantamab along with Lazertinib and chemotherapy (N=263), chemotherapy alone (N=263), or Amivantamab plus chemotherapy (N=131). Patients received Amivantamab 1400 mg IV (1750 mg for body weight 80 kg or greater) weekly for the first 4 weeks, then 1750 mg (2100 mg for body weight 80 kg or greater) every 3 weeks starting at cycle 3 (week 7). The first Amivantamab infusion was split over 2 days, with 350 mg IV on cycle 1, day 1 and the remainder on cycle 1, day 2. Lazertinib was administered at 240 mg orally daily. Chemotherapy consisted of Carboplatin AUC5 IV, starting on day 1 every 3 weeks for the first 4 cycles along with Pemetrexed 500 mg/m2 IV every 3 weeks until disease progression. The median age was 62 years, 48% of patients were Asian, about 45% of patients had a history of brain metastases, and approximately 70% of patients had Osimertinib as first line treatment and 30% had Osimertinib as second line treatment. Randomization was stratified by Osimertinib line of therapy (first or second), race (Asian or non-Asian), and history of brain metastasis (yes or no). All three treatment groups were well balanced. The dual Primary endpoints were Progression Free Survival (PFS) of Amivantamab plus chemotherapy and Amivantamab, Lazertinib plus chemotherapy, versus chemotherapy alone. Secondary endpoints included Objective Response Rate (ORR), Duration of Response, Overall Survival (OS) and Safety.
At a median follow-up of 8.7 months, the PFS was significantly longer for Amivantamab plus chemotherapy and Amivantamab, Lazertinib plus chemotherapy versus chemotherapy alone (HR for disease progression or death=0.48 and 0.44, respectively; P<0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively). The Objective Response Rate was significantly higher for Amivantamab plus chemotherapy and Amivantamab, Lazertinib plus chemotherapy versus chemotherapy alone (64% and 63% versus 36%, respectively; P<0.001 for both). The median intracranial PFS was 12.5 and 12.8 versus 8.3 months for Amivantamab plus chemotherapy and Amivantamab, Lazertinib plus chemotherapy versus chemotherapy alone (HR for intracranial disease progression or death=0.55 and 0.58, respectively). The researchers postulated that the mechanism by which Amivantamab improves intracranial PFS could either be through direct antitumor effects or indirectly through immune-based mechanisms. The most common adverse events with the Amivantamab combinations were cytopenias, infusion-related reactions and venous thromboembolism. The researchers recommend prophylactic anticoagulation.
It was concluded that Amivantamab plus chemotherapy, as well as Amivantamab, Lazertinib plus chemotherapy, significantly improved Progression Free Survival (PFS) and intracranial PFS, compared with chemotherapy alone, in patients with EGFR-mutated advanced NSCLC with disease progression on or after Osimertinib. The authors added that MARIPOSA-2 is the first study to demonstrate improved PFS versus chemotherapy, after disease progression on Osimertinib.
Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: Primary results from the phase 3 MARIPOSA-2 study. Passaro A, Wang J, Wang Y, et al. Annals of Oncology. 2023. DOI:https://doi.org/10.1016/j.annonc.2023.10.117
