NON-SMALL CELL LUNG CANCER (NSCLC)
Globally, lung cancer is the most prevalent cancer type and the leading cause cancer-related mortality, of which, non-small cell lung cancer is responsible for 80% to 85% of all lung cancers per the American Cancer Society. An estimated 2% to 3% of individuals with non-small cell lung cancer will have epidermal growth factor receptor (EGFR) exon 20 insertion mutations, which are a group of mutations on a protein that result in rapid cell proliferation and ensuing cancer spread. EGFR exon 20 insertion mutations are the third most prevalent type of EGFR mutation (FDA, 2021).
AMIVANTAMAB-VMJW (RYBREVANT)
Amivantamab-vmjw is available as Rybrevant (Janssen Biotech, Inc.) and is a low-fucose human immunoglobulin GI-based bispecific antibody that binds the extracellular domains of epidermal growth receptor factor (EGFR) and mesenchymal-epithelial transition (MET). In in vitro and in vivo studies, amivantamab-vmjw was able to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 20 insertion mutation models, degradation of EGFR and MET. Tumor cells with EGFR and MET on their surface are targeted for destruction by immune effector cells through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms. Amivantamab-vmjw is produced by mammalian cell line (Chinese Hamster Ovary [CHO] using recombinant DNA technology (Janssen, 2021a).
On May 21, 2021, the U.S. Food and Drug Administration (FDA) approved Rybrevant (amivantamab-vmjw) for the treatment of adult individuals with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. The FDA granted accelerated approval based on Priority Review and Breakthrough Therapy designation for the non-small cell lung cancer indication. The FDA approval was based on supporting data from the ongoing Phase I CHRYSALIS study (Janssen, 2021).
Per the prescribing information, amivantamab-vmjw (Rybrevant) carries the following warnings and precautions:
- Infusion-related reactions (IRR): In clinical trial, IRR was noted in 66% of individuals treated with Rybrevant and 97% of the reported IRRs were Grade 1 to 2, 2.2% were Grade 3, and 0.4% were Grade 4;
- Interstitial lung disease (ILD)/pneumonitis: In clinical trial, ILD/pneumonitis was noted in 3.3% of individuals treated with Rybrevant, with 0.7% of individuals experiencing Grade 3 ILD/pneumonitis;
- Dermatologic adverse reactions: In clinical trial, rash was noted in 74% of individuals treated with Rybrevant, including Grade 3 rash in 3.3% of individuals;
- Ocular toxicity: The occurrence of ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis has been noted with Rybrevant therapy; keratitis occurred in 0.7% of individuals and uveitis occurred in 0.3% of individuals with all events being Grade 1 to 2;
- Embryo-fetal toxicity.
The most frequent adverse reactions (≥20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting (Janssen, 2021a).
The most frequent Grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium(Janssen, 2021a).
PEER-REVIEWED LITERATURE
NSCLC
The Phase I CHRYSALIS study consisted of a multicenter, open-label, multi-cohort clinical trial which included individuals with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Rybrevant was administered as an intravenous infusion at 1050 mg (for individual baseline body weight < 80 kg) or 1400 mg (for individual baseline body weight ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. The efficacy of Rybrevant was evaluated in a population of 81 individuals with NSCLC with EGFR exon 20 insertion mutation with measurable disease who received prior platinum-based chemotherapy. The primary efficacy outcome measure was overall response rate (ORR) with an additional efficacy outcome measure as duration of response (DOR). The confirmed ORR was 40% (95% confidence interval [CI], 29% to 51%), with 3.7% achieving complete responses (CR) and 36% having partial responses (PR). The median DOR was 11.1 months (95% CI, 6.9 months to not estimable) with 63% of individuals having a DOR of 6 months or more (Janssen, 2021a).
Combined Amivantamab and Lazertinib for the Treatment of EGFR Mutation-Positive Non-Small-Cell Lung Cancer
Cho et al. (2022) stated that 3rd-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, have shown effectiveness in individuals with EGFR-mutant NSCLC; however, almost all individuals will eventually relapse. Amivantamab is an EGFR-MET bi-specific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations and MET mutations and amplifications. In the ongoing CHRYSALIS Trial, amivantamab in combination with lazertinib, a potent, brain-penetrant 3rd-generation EGFR TKI, demonstrated anti-tumor activity in the treatment-naive and osimertinib-relapsed setting. These researchers presented the methodology for the MARIPOSA Trial, a randomized, multi-center, phase-III clinical trial designed to compare the safety and effectiveness of amivantamab and lazertinib combination therapy versus single-agent osimertinib as 1st-line treatment for EGFR-mutant NSCLC.
Gastro-Esophageal Cancer
Maron et al. (2022) noted that subset analyses from phase-III clinical trials of EGFRi suggested improved outcomes in individuals with EGFR-amplified gastro-esophageal adenocarcinoma (GEA); however, large-scale analyses are lacking. In a multi-center analysis , these investigators examined the role of EGFRi in the largest cohort of individuals with EGFR-amplified GEA to-date. A total of 60 individuals from 15 tertiary cancer centers in 6 countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments (CLIA)-approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing (NGS), plasma circulating tumor DNA NGS, and/or fluorescence in-situ hybridization (FISH) carried out by a CLIA- approved laboratory. Treatment patterns and outcomes analysis was also carried out using a de-identified clinic-genomic database (CGDB). A total of 60 individuals with EGFR-amplified GEA received EGFRi, including 31 of 60 individuals (52 %) with concurrent chemotherapy. Across treatment lines, individuals achieved a 43 % ORR with a median progression-free survival (PFS) of 4.6 months (95 % CI: 3.5 to 6.4). Individuals receiving EGFRi in 1st-, 2nd-, and 3rd-line therapy achieved a median overall survival (OS) of 20.6 months (95 % CI: 13.5 to not reached [NR]), 9 months (95 % CI: 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95 % CI: 8.7 to 14.2) median OS from 1st-line initiation of non-EGFRi therapy in individuals with EGFR-amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011 to December 2020) suggested that only 5 % of individuals with EGFR-amplified GEA received EGFRi. The authors concluded that individuals with EGFR-amplified GEA derived significant benefit from EGFRi. Moreover, these researchers stated that further prospective investigation of EGFRi in a well-selected individual population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.
SUMMARY
Amivantamab-vmjw (Rybrevant), a bispecific epidermal growth factor receptor (EGFR) and MET receptor-directed antibody, was approved by the U.S. Food and Drug Administration (FDA) in May 2021 for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, in individuals whose disease has progressed on or after platinum-based chemotherapy. This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval of amivantamab for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and efficacy of amivantamab was evaluated in a phase 1, open-label study of individuals with metastatic or unresectable NSCLC and EGFR exon 20 mutations whose disease had progressed on or after platinum based chemotherapy (CHRYSALIS, NCT02609776). Included individuals (median age, 62 years) received amivantamab 1050 mg (baseline body weight less than 80 kg) or 1400 mg (baseline body weight 80 kg or greater) once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. Amivantamab produced an overall response rate (ORR) of 40% (complete response, 3.7%) in cohort individuals with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations who had progressed on or after platinum-based chemotherapy (n=81) from the CHRYSALIS trial. The median duration of response (DOR) was 11.1 months, with 63% of individuals having a DOR of 6 months or longer. Individuals had adenocarcinoma (95%), had received prior immunotherapy (46%), had previously treated brain metastases (22%), and received a median of 2 prior therapies (range, 1 to 7). National Comprehensive Cancer Network (NCCN) Guidelines for Non-Small Cell Lung Cancer (Version 7.2021) contain recommendations for the use of amivantamab in NSCLC.
