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

Dr. Tim-Shing Choy
Specialist in Clinical Oncology
Private practice
Hong Kong
03 Oct 2023
EGFR-MET bispecific antibody treatment in a patient with EGFR ex20ins–positive NSCLC and bone metastases

History
A 64-year-old Chinese woman with hyperlipidaemia was diagnosed with non-small-cell lung cancer (NSCLC) in June 2020. She had a 2.2 cm lesion in the right lower lobe of the lung.

The patient underwent right low­er lobectomy in June 2020, which was uneventful. Pathology confirmed pT1cN0M0, stage IA moderately differentiated adenocarcinoma with EGFR exon 20p.Ala767_Val769dup insertion (ex20ins) and a PD-L1 score of <1 percent.1 No further adjuvant treatment was given.

In May 2022, the patient began to experience back pain. X-ray showed lytic bone lesions in lumbar spine. Subsequent MRI in mid-July 2022 revealed multiple bone metastases, and PET-CT demonstrated metastat­ic activities in bone, including pelvis (ilium), lumbar vertebrae (L3–L5) and thoracic vertebrae (T9). No intratho­racic recurrence was detected.

In late July 2022, the patient received first-line chemotherapy with carboplatin and pemetrexed, together with denosumab. Although her bone pain was relieved after the therapy, PET-CT in late November 2022 showed new bone lesions, with increased metastatic activities in the pel­vis, lumbar vertebrae and thoracic vertebrae. (Figure 1A) She experienced progressive pain in the left side of the pelvis and required as-needed paracetamol.

The patient had completed 7 cy­cles of platinum-based chemother­apy before she was referred to our clinic in early February 2023.

Presentation, treatment and response
In early February 2023, the pa­tient’s carcinoembryonic antigen (CEA) level was 14.6 ng/mL, and al­kaline phosphatase (ALP) level was 183 U/L. She weighed 69 kg, with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1.

Due to failure of platinum-based chemotherapy for bone metasta­ses and presence of EGFR ex20ins in the primary tumour at diagnosis, the patient was commenced on an EGFR-MET bispecific antibody, ami­vantamab, at 1,050 mg intravenously weekly for 4 weeks, followed by bi­weekly. In week 1, the first dose was split over 2 days to avoid infusion-related reaction (IRR), with dexa­methasone, chlorpheniramine and paracetamol premedication given.2

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 8th 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.

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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)

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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.

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