Intracranial activity of amivantamab combined with carboplatin and pemetrexed in epidermal growth factor receptor exon 20 insertion-positive non-small cell lung cancer with brain metastases: a report of three cases

Abstract

Background

Epidermal growth factor receptor (EGFR) exon 20 insertion (Ex20ins) mutations in non-small cell lung cancer (NSCLC) are largely insensitive to conventional EGFR tyrosine kinase inhibitors (TKIs) because of steric hindrance in the TKI-binding pocket. Amivantamab, an EGFR-MET bispecific antibody, has been approved for use in combination with chemotherapy as the first-line treatment for EGFR Ex20ins NSCLC. However, intracranial activity remains unknown because monoclonal antibodies are generally thought to have limited central nervous system (CNS) penetration.

Case Description

We report three patients with advanced NSCLC with EGFR Ex20ins and with asymptomatic brain metastases who were treated with carboplatin, pemetrexed, and amivantamab (PAPILLON regimen). Case 1 was a 48-year-old woman with ≥10 asymptomatic brain metastases that developed during prior treatment with carboplatin, pemetrexed, and an investigational TKI targeting their EGFR ex20ins mutations; she achieved intracranial and extracranial partial responses. Case 2 was a 67-year-old man with postoperative recurrence and new brain metastases arising during another investigational EGFR-TKI monotherapy; he achieved a complete intracranial response. Case 3 was a 35-year-old man with previously untreated advanced lung adenocarcinoma and multiple asymptomatic brain metastases, which demonstrated intracranial and extracranial partial responses within two months.

Conclusions

These three cases provide clinical evidence that carboplatin, pemetrexed, and amivantamab may exert clinically meaningful intracranial antitumor activity in patients with EGFR Ex20ins NSCLC harboring small, asymptomatic brain metastases. Amivantamab, a bispecific antibody, combined with carboplatin and pemetrexed may exert clinically meaningful intracranial antitumor activity.

Highlight box.

Key findings

• Three patients with epidermal growth factor receptor (EGFR) exon 20 insertion (Ex20ins)-positive non-small cell lung cancer (NSCLC) and asymptomatic brain metastases achieved intracranial responses following treatment with carboplatin, pemetrexed, and amivantamab.

• In two of three cases, intracranial responses were achieved despite brain metastases having developed during prior EGFR Ex20ins-targeted tyrosine kinase inhibitor (TKI) therapy.

What is known and what is new?

• EGFR Ex20ins mutations confer resistance to conventional EGFR-TKIs. Amivantamab, an EGFR-MET bispecific antibody, combined with carboplatin and pemetrexed, is approved as first-line therapy for EGFR Ex20ins NSCLC based on the phase 3 PAPILLON trial. Monoclonal antibodies are traditionally considered to have limited central nervous system (CNS) penetration due to their large molecular weight, and intracranial therapeutic options for EGFR Ex20ins NSCLC remain limited.

• This case report demonstrates that carboplatin, pemetrexed, and amivantamab can produce clinically meaningful intracranial antitumor activity in patients with EGFR Ex20ins NSCLC harboring small, asymptomatic brain metastases.

What is the implication, and what should change now?

• Amivantamab combined with carboplatin and pemetrexed should be considered as a potential systemic treatment option for patients with EGFR Ex20ins NSCLC presenting with small, asymptomatic brain metastases, potentially delaying or reducing the need for local brain-directed radiotherapy in selected patients.

• Prospective clinical trials specifically designed to evaluate the intracranial efficacy of amivantamab-based regimens in EGFR Ex20ins NSCLC with brain metastases are warranted.

Introduction

Epidermal growth factor receptor (EGFR) mutations are among the most common activating alterations in non-small cell lung cancer (NSCLC), detected in approximately 40–50% of Asian patients and 10–15% of Caucasian patients. Following the two most common subtypes—exon 19 deletions and the exon 21 L858R point mutation—EGFR exon 20 insertion (Ex20ins) mutations represent the third most frequent subtype, accounting for up to 12% of all EGFR-mutated NSCLC cases (1). Because Ex20ins mutations cause steric hindrance at the tyrosine kinase inhibitor (TKI) binding pocket, these tumors are largely insensitive to conventional first-, second-, and third-generation EGFR-TKIs that are effective against tumors with common EGFR mutations.

NSCLC frequently metastasizes to the brain; approximately 25% of patients with EGFR-mutated NSCLC present with brain metastases at diagnosis, and more than 50% develop them during the course of their disease (2,3). For patients with common EGFR mutations, small-molecule TKIs such as osimertinib and lazertinib—which efficiently penetrate the blood-brain barrier (BBB)—have demonstrated remarkable intracranial activity and are now standard of care for asymptomatic or non-emergent brain metastases in this population. However, intracranial therapeutic options for EGFR Ex20ins NSCLC remain limited.

Amivantamab is a bispecific monoclonal antibody targeting both EGFR and MET receptors, exerting antitumor activity through ligand blocking, receptor endocytosis and degradation, and immune cell-directing activities including antibody-dependent cell-mediated cytotoxicity (ADCC) and trogocytosis (4). The phase 3 PAPILLON trial demonstrated that carboplatin, pemetrexed, and amivantamab significantly prolonged progression-free survival (PFS) compared with chemotherapy alone in patients with EGFR Ex20ins NSCLC [median PFS, 11.4 vs. 6.7 months; hazard ratio (HR), 0.395; P<0.001] (5). In the CHRYSALIS study, amivantamab monotherapy in platinum-treated Ex20ins NSCLC was associated with infrequent intracranial-only first progression (11%), suggesting some degree of central nervous system (CNS) disease control (6).

Monoclonal antibodies are traditionally considered unlikely to penetrate the intact BBB because of their large molecular weight. Here, this report describes three patients with EGFR Ex20ins NSCLC and asymptomatic brain metastases who received carboplatin, pemetrexed, and amivantamab and achieved intracranial responses, which were retrospectively assessed according to RECIST version 1.1 in routine clinical practice. These cases suggest potential intracranial activity of an amivantamab combined with carboplatin and pemetrexed in this patient population. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0096/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Verbal informed consent was obtained from each patient for the publication of this case report and accompanying images.

Case 1

A 46-year-old woman with no history of smoking was diagnosed with lung adenocarcinoma harboring an EGFR Ex20ins mutation (A767_V769dup; detected by Oncomine Dx) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 80%, presenting with multiple bone and pulmonary metastases (cT4N3M1c, stage IVB). As first-line treatment, she enrolled in a clinical trial and received carboplatin, pemetrexed, and an investigational EGFR Ex20ins-targeted TKI starting in December 202X. Brain magnetic resonance imaging (MRI) revealed new multiple asymptomatic brain metastases (more than 10 lesions; maximum diameter, 6 mm) in July 202X+2. At the age of 48 years, the patient had a good performance score of 0 and was otherwise clinically stable (Table 1).

Table 1. Summary of three cases of EGFR Ex20ins NSCLC with brain metastases treated with carboplatin, pemetrexed, and amivantamab.

Variable	Case 1	Case 2	Case 3
Age†/sex	48/F	67/M	35/M
Smoking history	Never	Former (12 pack-years)	Current (15 pack-years)
Medical history	Breast cancer (age 37 years)	Hypertension, dyslipidemia	None
Histology	Lung adenocarcinoma	Lung adenocarcinoma	Lung adenocarcinoma
EGFR mutation	Ex20ins A767_V769dupOncomine Dx test	Ex20ins H773_V774dupOncomine Dx test	Ex20insAmoy Dx Pan Lung Cancer PCR Panel
Treatment line with amivantamab-containing regimen	Second line	Second line	First line
Prior therapies	Carbo/Pem + investigational EGFR TKI	Investigational EGFR TKI	None
Intracranial tumor burden	13 lesions, with maximum 6 mm	2 lesions, with maximum 5 mm	4 lesions, with maximum 3 mm
Intracranial response	Intracranial non-CR or non-PD as non-target lesions (with tumor shrinkage)	Intracranial CR as non-target lesions	Intracranial CR as non-target lesions
Extracranial response	PR	PR	PR

^†, age refers to the patient's age at initiation of carboplatin, pemetrexed, and amivantamab therapy. CR, complete response; Ex20ins, exon 20 insertion; F, female; PCR, polymerase chain reaction; M, male; PD, progressive disease; Pem, pemetrexed; PR, partial response; TKI, tyrosine kinase inhibitor.

Given the development of brain metastases during prior EGFR-targeted therapy, second-line treatment with carboplatin, pemetrexed, and amivantamab was initiated in August 202X+2. Pre-existing grade 1 paronychia and lower limb edema persisted without worsening. Contrast-enhanced brain MRI approximately 6 weeks after treatment initiation demonstrated a marked reduction in the size of brain metastases, with most lesions having disappeared. Computed tomography (CT) imaging also showed extracranial PR. The patient continued treatment with ongoing disease control (Figure 1).

Figure 1.

Imaging before and after initiation of carboplatin, pemetrexed, and amivantamab in case 1. (A) Baseline contrast-enhanced CT showing a lung metastasis. (B-D) Baseline brain contrast-enhanced MRI demonstrating multiple asymptomatic brain metastases. (E) Follow-up (after approximately 6 weeks) CT images and (F-H) MRI, demonstrating intracranial and extracranial responses. The red arrows indicate metastatic lung cancer lesions. CT, computed tomography; MRI, magnetic resonance imaging.

Case 2

A 67-year-old man underwent right upper lobectomy for lung adenocarcinoma with an EGFR Ex20ins mutation (H773_V774dup; Oncomine Dx) and PD-L1 TPS of 5% (pT2aN1M0, stage IIB) in May 202X. He received adjuvant cytotoxic chemotherapy consisting of four cycles of cisplatin and vinorelbine, followed by one cycle of atezolizumab. However, grade 3 liver dysfunction developed following atezolizumab administration, and the patient was subsequently managed with observation alone. Disease recurrence was identified as right pleural dissemination and right axillary lymph node metastasis. The patient enrolled in a clinical trial and was treated with another investigational EGFR Ex20ins-targeted TKI. Approximately 28 months after trial treatment initiation, disease progression occurred with new brain metastases, worsening pleural dissemination, and axillary lymph node enlargement (Table 1).

Carboplatin, pemetrexed, and amivantamab were started in December 202X+2. Approximately 10 months after treatment initiation, follow-up brain MRI demonstrated complete radiographic disappearance of all brain metastases. Extracranial lesions also showed a partial response. However, 13 months after starting amivantamab-based therapy, malignant right pleural effusion developed, indicating disease progression. Brain MRI performed concurrently revealed re-emergence of previously resolved lesions and two new brain metastases, suggesting that the intracranial recurrence was concurrent with systemic progression (Figure 2).

Figure 2.

Imaging before and after initiation of carboplatin, pemetrexed, and amivantamab in case 2. (A) CT images and (B) brain MRI before initiation of carboplatin, pemetrexed, and amivantamab in case 2. The red arrows indicate metastatic lung cancer lesions. (C) CT images showing partial response and (D) brain MRI showing a complete response at 10 months. CT, computed tomography; MRI, magnetic resonance imaging.

Case 3

A 35-year-old man was diagnosed with lung adenocarcinoma harboring an EGFR Ex20ins mutation detected by AmoyDx lung cancer polymerase chain reaction (PCR) panel and high PD-L1 expression. He presented with multiple asymptomatic brain, liver, bone, and lymph node metastases (cT4N3M1c, stage IVB). The patient’s performance status score was 1. He received carboplatin, pemetrexed, and amivantamab starting in October 202X as first-line therapy (Table 1). Two months after treatment initiation, follow-up imaging demonstrated complete radiographic disappearance of all brain metastases on brain MRI, along with an extracranial partial response on CT. The patient continued treatment with ongoing systemic and intracranial disease control (Figure 3).

Figure 3.

Imaging before and after initiation of carboplatin, pemetrexed, and amivantamab in case 3. (A) CT images and (B,C) brain MRI before initiation of carboplatin, pemetrexed, and amivantamab in case 3. The red arrows indicate metastatic lung cancer lesions. (D) CT images showing partial response and (E,F) brain MRI showing a complete response at 2 months. CT, computed tomography; MRI, magnetic resonance imaging.

Discussion

This report describes three patients with EGFR Ex20ins NSCLC and asymptomatic brain metastases who achieved an intracranial response following treatment with carboplatin, pemetrexed, and amivantamab. These cases provide clinical evidence that amivantamab combined with carboplatin and pemetrexed may have meaningful intracranial antitumor activity in this population.

Amivantamab is a bispecific antibody with a large molecular weight (~148 kDa) that has traditionally been considered a barrier to CNS penetration. Several mechanisms may account for the intracranial activity observed. First, brain metastases physically disrupt the BBB, and the resulting blood tumor barrier (BTB) exhibits heterogeneous permeability with variable efflux transporter activity, which may facilitate delivery of large molecules such as amivantamab to CNS lesions (7,8). Second, immune cell–directing activity by amivantamab, including ADCC and trogocytosis, is mediated through engagement of macrophages, monocytes, and natural killer cells within intracranial lesions (4). This mechanism is conceptually similar to immune checkpoint inhibitors such as pembrolizumab and nivolumab, which demonstrate intracranial activity despite their large molecular weight (9).

Clinical evidence regarding the intracranial activity of amivantamab remains limited because patients with active brain metastases were excluded from most clinical trials, and only those with treated, asymptomatic, and clinically stable brain metastases were eligible for investigation. In the CHRYSALIS study, amivantamab monotherapy in platinum-treated Ex20ins NSCLC was associated with infrequent intracranial-only first progression (11%), and the 12-month cumulative probability of intracranial-only progression was only 9.0% (6). In the phase 3 MARIPOSA-2 study (common EGFR mutations post-osimertinib), amivantamab plus chemotherapy reduced the risk of intracranial disease progression or death by 45% compared with chemotherapy alone (median intracranial PFS, 12.5 vs. 8.3 months; HR, 0.55; P<0.001) (10). Our cases extend these observations to the Ex20ins population treated with the PAPILLON regimen in real-world practice. Beyond brain parenchymal metastases, a recent case report described a durable complete intracranial response to amivantamab monotherapy in a patient with leptomeningeal seeding of NSCLC who had progressed on first-line therapy, raising the hypothesis that amivantamab may have broader CNS activity (11).

Notably, in two of three cases (cases 1 and 2), brain metastases developed during prior EGFR Ex20ins-targeted TKI therapy, reflecting acquired resistance with CNS involvement. Despite this, both patients achieved intracranial responses with amivantamab-based therapy, suggesting that the extracellular domain-targeting mechanism of amivantamab may overcome at least some TKI-resistance mechanisms relevant to CNS disease. This represents a clinically important finding, as therapeutic options for TKI-resistant CNS disease in EGFR Ex20ins NSCLC remain extremely limited.

Local brain-directed therapies such as stereotactic radiosurgery (SRS) were not performed initially in our three patients, because their brain metastases were small, asymptomatic, and multiple, and systemic therapy was prioritized. The observed intracranial responses to amivantamab-based therapy in our patients are clinically significant because they suggest that this approach may delay or reduce the need for local brain-directed radiotherapy in selected patients with small, asymptomatic brain metastases.

This series has important limitations. First, it represents our institution's consecutive experience with carboplatin, pemetrexed, and amivantamab in patients with active brain metastases—three patients who responded—but we also encountered one additional patient with EGFR Ex20ins NSCLC and leptomeningeal carcinomatosis in whom this regimen did not produce an intracranial response, suggesting variability in CNS efficacy. This finding underscores that while intracranial activity is possible, it is not universal. Second, all three responding patients had asymptomatic, small brain metastases and had not received prior brain radiotherapy; whether the regimen provides intracranial benefit for larger, symptomatic brain metastases remains unclear. Third, biopsy of brain metastases was not feasible, precluding elucidation of resistance mechanisms. Finally, the contribution of concomitant platinum-pemetrexed chemotherapy to the observed intracranial response cannot be excluded.

Conclusions

This report describes three cases of NSCLC with EGFR Ex20ins, in which carboplatin, pemetrexed, and amivantamab produced intracranial responses in patients with small, asymptomatic brain metastases. These findings suggest that amivantamab-containing regimens may exert clinically meaningful intracranial antitumor activity in this patient population.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Verbal informed consent was obtained from each patient for the publication of this case report and accompanying images.