EGFR-MET bispecific antibody treatment in a patient with EGFR ex20ins–positive NSCLC and bone metastases

Two weeks after commencing amivantamab treatment, the patient’s CEA level decreased to 6.8 ng/mL; this reduced further to 6.0 ng/mL at week 4.

After 1 month of amivantamab, the patient’s bone pain resolved, and analgesics were discontinued. Follow-up PET-CT at 3 months revealed metabolic quiescence of bone metastases. (Figure 1B) At 4 months, the patient’s CEA level dropped to a minimum level of 1.2 ng/mL, and her ALP level was 72 U/L.

The patient experienced mild adverse events (AEs) during ami­vantamab treatment, which were adequately managed with conserva­tive therapies. These AEs included grade 1 oral mucositis after the first dose, which was controlled with an oral rinse, grade 1 rash on the face following the second dose, which was controlled with minocycline and topical hydrocortisone, and grade 1 paronychia during the third cycle and grade 1 scalp lesions in the fifth cycle, which were controlled with antibiotics.

By the end of August 2023, the 8^th cycle of amivantamab was admin­istered. The patient was asymptom­atic, with ECOG PS of 1. Her ALP level was normal (80 U/L), whereas her CEA level was slightly elevated at 2.4 ng/mL. She continued to receive amivantamab.

Discussion
International guidelines recommend genetic testing to identify ac­tionable mutations in patients with advanced NSCLC.^3-5 In our clinic, a small-panel genetic test with an ar­ray of actionable mutations (BRAF, KRAS, EGFR variants, etc) is routinely used at diagnosis in advanced NSCLC patients. Tissue biopsy spec­imens are primarily used, with liquid biopsy as an alternative when tissue samples are unavailable.

Compared with common EGFR (cEGFR) mutations, EGFR ex20ins mutations are associated with poor prognosis. In a retrospec­tive study involving 3,014 EGFR-mutant NSCLC patients, those with EGFR ex20ins had a 75 percent higher risk of death (adjusted hazard ratio [HR], 1.75; p<0.0001) and a 93 per­cent higher risk of disease progres­sion or death (adjusted HR, 1.93; p<0.0001) vs those with cEGFR mutations.⁶ No­tably, EGFR ex20ins mutations have steric hindrance in the drug-binding pocket, which may cause resistance to earlier-generation EGFR tyrosine kinase inhibitors (TKIs).^7-9

Amivantamab is the EGFR-MET bispecific antibody that overcomes TKI resistance by binding to extracel­lular domains of both receptors.^2,10 In the open-label phase I CHRYSALIS study, amivantamab demonstrated robust and durable responses with tolerable safety in patients with EGFR ex20ins–positive NSCLC progressing on platinum-based chemotherapy.^11,12

Preliminary results at a medi­an follow-up of 9.7 months showed that in the efficacy population (n=81), amivantamab was associated with an overall response rate (ORR) of 36 per­cent by investigator assessment and 40 percent by blinded independent central review. Median duration of re­sponse (DoR) was 11.1 months, me­dian progression-free survival (PFS) was 8.3 months, and median over­all survival (OS) was 22.8 months.¹¹ (Table)

In a longer-term follow-up of CHRYSALIS (median, 19.2 months; n=114), investigator-assessed ORR was 37 percent, median DoR was 12.5 months, median PFS was 6.9 months, and median OS was 23.0 months.¹² (Table)

Among the 114 patients, 48 (42 percent) had received amivantamab for ≥12 cycles. Notably, amivantamab treatment was ongoing in 15 patients (13 percent; free of progression, n=7; beyond progression, n=8) who had received the agent for a median of 2.6 years. These results indicated that amivantamab may provide sus­tained clinical benefit to patients with EGFR ex20ins–positive NSCLC.¹²

Amivantamab is more likely to benefit EGFR ex20ins–positive NS­CLC than other treatments, includ­ing EGFR TKIs. Data from CHRYSA­LIS were compared with an external cohort of patients derived from six real-world data sources who met the CHRYSALIS eligibility criteria. After patient-level data adjustment, results were consistently in favour of amivantamab vs EGFR TKIs in terms of investigator-assessed ORR (relative risk, 8.08; 95 percent con­fidence interval [CI], 2.05–31.90), investigator-assessed PFS (HR, 0.50; 95 percent CI, 0.33–0.75), and OS (HR, 0.42; 95 percent CI, 0.28–0.65) in the real-world setting.¹³

Most common treatment-related AEs (TRAEs) reported in the safety population (n=114) of CHRYSALIS were rash (86 percent), IRRs (66 per­cent) and paronychia (45 percent), the majority of which were grade 1/2 (83 percent, 63 percent, 44 per­cent, respectively). Grade ≥3 TRAEs occurred in 16 percent of patients, and no grade 5 TRAEs were report­ed. Rates of treatment-related dose reductions and treatment-related discontinuation were 13 percent (n=15) and 4 percent (n=5), respectively.¹¹ No new safety signals were found in longer-term follow-up.¹²

IRRs usually occur with the first exposure to amivantamab and are mostly of grade 1/2. A descriptive analysis of CHRYSALIS (data cut-off, 30 March 2021; n=380) showed that IRRs occurred in 67 percent of patients receiving IV amivantam­ab at the recommended dose (ie, 1,050 mg for patients weighing <80 kg; 1,400 mg for patients weighing ≥80 kg). In this cohort, 66 percent of patients had IRRs on day 1 of cycle 1, and 65 percent of the patients had grade 1 or 2 events. To reduce IRR risk, the first dose of amivantamab should be administered as a 2-day split dose. Premedication with anti­histamines, antipyretics and glucocorticoids should be given.^2,14

In the above patient with body weight of 69 kg, the IV infusion of amivantamab 1,050 mg was well tolerated. She received steroid, antihistamine and antipyretic premedi­cation before the first dose. AEs, in­cluding oral mucositis after the first dose, were mild and manageable. Importantly, her back pain resolved 1 month after amivantamab com­mencement. She now enjoys a better quality of life.

Both clinical trial data and this patient’s case demonstrate amivan­tamab’s efficacy and manageable safety profile in advanced NSCLC with EGFR ex20ins mutation after progression on platinum-based chemotherapy.