History, prior treatment and presentation
A 37-year-old female non-smoker was diagnosed in 2023 with stage IV non-small-cell lung cancer (NSCLC) harbouring EGFR exon 21 L858R mutation. Lymph node (LN), lung and bone metastases were present, and her Eastern Cooperative Oncology Group (ECOG) performance status was 0. Initially, the patient’s response to standard-of-care first-line osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), was good.1 A PET scan after 6–8 months showed that the metastases had shrunk in response to treatment. However, oligoprogression was also observed at the primary lung tumour site, which was treated with radiotherapy.
Eight months after she had started osimertinib treatment, the patient developed progressive vision blurring in her left eye. MRI and a PET scan revealed choroidal metastasis in the ocular orbit, with no brain metastases. The PET scan also showed disease progression in multiple bone sites, LNs and liver. (Figure 1) To salvage the patient’s vision, radiotherapy to the eye was performed. A switch in systemic therapy was urgently needed to control the rapid disease progression. Typically, tissue rebiopsy is recommended to determine the mechanism of resistance to osimertinib to guide treatment after progression.1 However, while lung and liver metastases are relatively easy to rebiopsy, patients with bone or small LN metastases are not eligible for rebiopsy.
Treatment and response
With no suitable site and a long waiting time for rebiopsy, the patient’s treatment was switched to amivantamab (an EGFR-MET bispecific antibody) plus chemotherapy in December 2023.
The patient had a complete response to amivantamab plus chemotherapy, returned to work with no evidence of disease, and was doing well at her last follow-up in June 2025. (Figure 1)
She reported treatment-related adverse events (AEs) of facial and scalp rash, poor nail condition, and ankle oedema, which were all of grade 1 severity. These were managed with doxycycline, steroid shampoo once weekly for the scalp rash, nail care, steroid cream, and compression stockings.
Discussion
Amivantamab plus chemotherapy was chosen because of the patient’s rapid disease progression, meaning that she could not afford to wait for a rebiopsy, and required a treatment regimen with high response rates.
Amivantamab binds the extracellular domains of EGFR and MET receptors to target both EGFR-dependent and MET-dependent mechanisms of osimertinib resistance.2,3 Given that the waiting time for rebiopsy in the Hong Kong public healthcare setting could be months, patients may not be able to wait for this procedure. In addition, as the incidence of emergence of an actionable genomic alteration such as MET amplification remains low (approximately 20 percent), most patients may not benefit from rebiopsy.
In the randomized phase III MARIPOSA-2 trial, amivantamab plus chemotherapy significantly improved progression-free survival (PFS) vs chemotherapy alone (hazard ratio [HR], 0.48; 95 percent confidence interval [CI], 0.36–0.64; p<0.001) in patients with EGFR-mutated NSCLC.3 Notably, early separation of PFS curves was observed.3 (Figure 2)
Objective response rate (ORR) was 64 vs 36 percent in the amivantamab vs chemotherapy group.3 Among confirmed responders, median duration of response (DoR) was 6.9 vs 5.6 months.3 On the basis of the high-quality evidence from this trial, most patients are expected to demonstrate rapid improvement with this treatment combination after osimertinib failure.
Amivantamab plus chemotherapy can also prevent or delay central nervous system (CNS) progression in patients with TKI resistance, an important benefit given the high proportion of patients who develop brain metastases (44 percent in MARIPOSA-2). The median intracranial PFS was significantly longer with amivantamab plus chemotherapy than chemotherapy alone in MARIPOSA-2 (12.5 vs 8.3 months; HR, 0.55; 95 percent CI, 0.38–0.79).3 For this reason, amivantamab plus chemotherapy is a good choice for patients with no or small, asymptomatic brain metastases.
Common AEs observed with amivantamab include infusion-related reactions during the first treatment cycle, skin-related AEs (eg, rash and stomatitis), cytopenia, and peripheral oedema, but most of these can be easily managed with close follow-up and supportive care. In MARIPOSA-2, the majority of these AEs were of grade 1 or 2.3 Although cytopenia is common, it is typically mild and infection rates are low. Infusion-related reactions can be managed with corticosteroid premedication and, if required, by interrupting the infusion before slow resumption.3,4 Skin-related AEs can be managed with prophylactic steroid shampoo, sun protection, good dental hygiene including the use of saline or chlorhexidine mouthwash, and topical doxycycline to prevent facial rash. Ankle oedema emerges over time due to MET inhibition and can be managed with lifestyle advice such as elevation and use of compression stockings. The manageable safety profile of this combination is reflected in the low rate of treatment discontinuations in MARIPOSA-2, making amivantamab plus chemotherapy suitable for most patients after osimertinib failure unless they are too frail to tolerate these AEs.3
The use of immune checkpoint inhibitors (ICIs) was investigated in numerous studies in patients with advanced EGFR-mutant NSCLC due to their potential to provide a more durable response than chemotherapy.5 However, several studies have shown that ICIs given after TKI failure do not significantly improve outcomes in patients with EGFR-mutated NSCLC, possibly because of the noninflammatory tumour microenvironment in these patients.5-7 The addition of VEGF inhibitors to the ICI-chemotherapy combination improved outcomes compared with platinum-based chemotherapy in some studies, but not others.8,9
In conclusion, amivantamab plus chemotherapy has demonstrated significant improvements in median PFS, ORR, DoR, and intracranial PFS compared with chemotherapy in patients with osimertinib-resistant EGFR-mutated advanced NSCLC.3 MARIPOSA-2 established amivantamab plus chemotherapy as a new standard of care for patients with EGFR-mutant NSCLC after progression on TKIs. After switching to amivantamab plus chemotherapy to control the rapid disease progression that occurred during osimertinib treatment, our patient had a complete response and was able to return to work with no evidence of disease. Her mild skin-related symptoms and ankle oedema were adequately managed with supportive care.
