History, prior treatment and presentation
A 37-year-old female non-smoker was diagnosed in 2023 with stage IV non-small-cell lung cancer (NSÂCLC) 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. IniÂtially, the patient’s response to standard-of-care first-line osimertinib, a third-genÂeration 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 obÂserved at the primary lung tumour site, which was treated with radiotherapy.
Eight months after she had started osimertinib treatment, the patient develÂoped 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 mulÂtiple bone sites, LNs and liver. (Figure 1) To salvage the patient’s vision, radiotherÂapy to the eye was performed. A switch in systemic therapy was urgently needÂed to control the rapid disease progresÂsion. Typically, tissue rebiopsy is recomÂmended to determine the mechanism of resistance to osimertinib to guide treatÂment 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 paÂtient’s treatment was switched to amivantamab (an EGFR-MET bispeÂcific antibody) plus chemotherapy in December 2023.
The patient had a complete reÂsponse to amivantamab plus chemoÂtherapy, returned to work with no eviÂdence 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 manÂaged with doxycycline, steroid shamÂpoo once weekly for the scalp rash, nail care, steroid cream, and comÂpression 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 extraÂcellular domains of EGFR and MET receptors to target both EGFR-dependent and MET-dependent mechanisms of osimertinib resisÂtance.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 inÂcidence of emergence of an actionÂable genomic alteration such as MET amplification remains low (approxÂimately 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 NSÂCLC.3 Notably, early separation of PFS curves was observed.3 (Figure 2)
Objective response rate (ORR) was 64 vs 36 percent in the amiÂvantamab vs chemotherapy group.3 Among confirmed responders, meÂdian 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 chemotheraÂpy can also prevent or delay central nervous system (CNS) progression in patients with TKI resistance, an important benefit given the high proÂportion of patients who develop brain metastases (44 percent in MARIPOÂSA-2). The median intracranial PFS was significantly longer with amiÂvantamab plus chemotherapy than chemotherapy alone in MARIPOÂSA-2 (12.5 vs 8.3 months; HR, 0.55; 95 percent CI, 0.38–0.79).3 For this reason, amivantamab plus chemoÂtherapy is a good choice for patients with no or small, asymptomatic brain metastases.
Common AEs observed with amiÂvantamab include infusion-related reactions during the first treatment cycle, skin-related AEs (eg, rash and stomatitis), cytopenia, and peÂripheral 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 typicalÂly mild and infection rates are low. Infusion-related reactions can be managed with corticosteroid preÂmedication and, if required, by inÂterrupting the infusion before slow resumption.3,4 Skin-related AEs can be managed with prophylactic steÂroid 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 comÂpression stockings. The manageable safety profile of this combination is reflected in the low rate of treatment discontinuations in MARIPOSA-2, making amivantamab plus chemoÂtherapy suitable for most patients afÂter 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 chemotherÂapy.5 However, several studies have shown that ICIs given after TKI failÂure do not significantly improve outcomes in patients with EGFR-mutated NSCLC, possibly because of the noninflammatory tumour miÂcroenvironment 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 mediÂan PFS, ORR, DoR, and intracranial PFS compared with chemotherapy in patients with osimertinib-resistant EGFR-mutated advanced NSCLC.3 MARIPOSA-2 established amivanÂtamab plus chemotherapy as a new standard of care for patients with EGFR-mutant NSCLC after proÂgression on TKIs. After switching to amivantamab plus chemotherapy to control the rapid disease progresÂsion that occurred during osimertinib treatment, our patient had a comÂplete response and was able to return to work with no evidence of disease. Her mild skin-related symptoms and ankle oedema were adequately manÂaged with supportive care.
