3L EGFR-MET bispecific antibody in a patient with EGFR ex20ins–positive NSCLC after haemorrhagic stroke

Background, presentation and investigation
This was a 60-year-old woman with a history of diabetes and end-stage kidney disease (ESKD) re­quiring haemodialysis three times a week. She was admitted to the hos­pital in June 2022 due to shortness of breath and chest tightness lasting for 1 month. Her Eastern Cooperative Oncology Group performance status (ECOG PS) was 2. (Table)

Investigations showed primary tu­mour as well as pericardial effusion, pleural effusion and multiple nodules in the left lung. Cytology of the pleu­ral fluid confirmed stage IV lung ade­nocarcinoma. Her carcinoembryonic antigen (CEA) level was 23.6 μg/L. (Table)

EGFR hotspot panel testing of the pleural fluid detected no muta­tions in exon 18 (G719A/C/S), exon 20 (S768I) and exon 21 (L861Q), and no exon 20 insertions (ex20ins). No common EGFR mutations (ie, exon 19 deletions, exon 21 L858R muta­tion, exon 20 T790M mutation) were found in the hotspot panel or through molecular testing.¹ (Table)

Treatment before stroke
Since no EGFR mutations or other targetable lesions were detected, the patient was started on first-line che­motherapy with paclitaxel and carbo­platin in early July 2022 (pemetrexed was not used as she was on renal dialysis). The pretreatment CEA lev­el was 50.5 μg/L. She suffered from bone marrow suppression after che­motherapy and therefore carboplatin was stopped and was replaced with bevacizumab after 2 cycles.

The patient showed partial re­sponse (PR) to bevacizumab and paclitaxel. Her CEA level gradually dropped to 27.5 μg/mL in late Octo­ber 2022. (Table) CT in early Novem­ber 2022 revealed a paramediastinal mass in the left upper lobe of the lung (LUL) measuring 1.7 x 2.6 x 3.1 cm and multiple nodules in the lungs.

After 6 cycles, a PR was achieved and the patient continued with bev­acizumab as maintenance treatment. Over 6 months of maintenance beva­cizumab, her disease remained sta­ble, and her CEA levels fluctuated be­tween 22.2 and 26.7 μg/L. Her ECOG PS was maintained at 1. (Table)

Stroke and subsequent treatment
On 19 June 2023, during a routine haemodialysis session, the patient experienced a sudden surge in sys­tolic blood pressure (>200 mm Hg) and loss of consciousness. Subse­quent CT confirmed a large cerebellar and intraventricular haemorrhage and hydrocephalus. She underwent blood clot evacuation and right ventricular drain insertion, which provided tem­porary improvement, but experienced rebleeding after 5 days, necessitating another operation with left ventricular drain insertion. She was in intensive care unit for 3 weeks and stayed in hospital for a total of 6 weeks before discharge.

During this period, bevacizum­ab was stopped and her disease progressed. PET-CT thorax in Sep­tember 2023 showed that the para­mediastinal mass in the LUL had en­larged to 3.0 x 4.0 x 4.9 cm, while the number of lung nodules (>20) and left pleural effusion had increased. (Figure 1A) Her CEA level increased to 37.4 μg/L. The patient was mostly bedbound and required feeding as­sistance. Her body weight was 59 kg, and her ECOG PS deteriorated to 3. (Table)

Despite the poor PS and dismal prognosis, the patient’s family was still keen for further active treatment. After discussion with the patient’s family, next-generation sequencing (NGS) was performed in September 2023, revealing an EGFR ex20ins variant (A767_V769dup) in the pleural fluid sample. Given her genetic profile and disease history, in early October 2023, the patient was started on the EGFR-MET bispecific antibody, ami­vantamab, at 700 mg intravenously. Premedication with antihistamines, antipyretics, antiemetics, and gluco­corticoids was given.² (Table)

The patient achieved a PR to ami­vantamab. Her CEA level decreased from 72.7 μg/L in October 2023 to 49 μg/L in December 2023 and further dropped to 22 μg/L in July 2024. CT Thorax showed the primary LUL mass reduced to 3.0 x 3.3 x 3.6 cm in March 2024 and 2.9 x 3.1 x 3.4 cm in June 2024, with decrease in number of lung nodules and reduction of left pleural ef­fusion. (Figure 1B and 1C)

During the first dose of amivantam­ab, the patient experienced grade 2 infusion-related reaction (IRR), neces­sitating temporary infusion interruption. After her symptoms improved, the in­fusion was resumed. Apart from IRRs during the first infusion, the patient did not experience other adverse events (AEs) with amivantamab.

The patient and her family were sat­isfied with the treatment. After 6 weeks, she was able to eat independently and walk at home despite residual weak­ness from haemorrhagic stroke. Her body weight increased to 60 kg. She attended our clinic and hospital visits in a wheelchair, with an ECOG PS of 1. She had completed 21 doses of ami­vantamab, with the last treatment given on 6 August 2024, and the CEA level was 20 μg/L. The patient achieved a progression-free period of more than 10 months, and amivantamab treat­ment will be continued.

Discussion
At our clinic, EGFR hotspot testing is a routine workup for diagnosing non-small-cell lung cancer (NSCLC). While tissue biopsy is typically preferred, it can be challenging to obtain tumour tissue in NSCLC patients with small nodules, such as ours. In these cases, malignant pleural fluid may contain high content of cell-free tumour DNA and can be more amenable to genomic analysis than both tissue and plasma samples.³

After initial negative EGFR muta­tion findings, our patient had PR on bevacizumab-containing treatment un­til experiencing haemorrhagic stroke during haemodialysis. As bevacizumab is contraindicated in patients with se­vere bleeding or major surgery within 28 days, treatment was discontinued.⁴ This resulted in disease progression shortly afterwards.

To identify targeted therapy for ad­vanced NSCLC after haemorrhagic stroke, the patient’s family opted for NGS testing, which revealed EGFR ex­20ins mutation in the pleural fluid. Con­sequently, our patient was started on amivantamab – the only agent targeting EGFR ex20ins in NSCLC available in Hong Kong.⁵

Amivantamab is an EGFR-MET bispecific antibody approved as monotherapy for advanced NSCLC with EGFR ex20ins following failure of platinum-based therapy. Its approval was based on results from the open-label, phase I CHRYSALIS trial.^2,5

The CHRYSALIS trial evaluated ami­vantamab in 114 patients with locally advanced or metastatic EGFR ex20ins–positive NSCLC that had progressed on or after platinum‑based chemotherapy. At baseline, 99 percent of patients had ECOG PS of 0 or 1.² Preliminary results at a median follow-up of 9.7 months showed that amivantamab was associ­ated with an overall response rate (ORR) of 36 percent by investigator assessment and 40 percent by blinded independent central review in the efficacy population (n=81). Median progression-free surviv­al (PFS) was 8.3 months, and median overall survival (OS) was 22.8 months.⁵

In a longer-term follow-up of CHRYSALIS (median, 19.2 months; n=114), 42 percent of patients remained alive. Median PFS was 6.9 months, and median OS was 23.0 months.⁶ These results demonstrated amivantamab’s robust efficacy and durable responses in patients with EGFR ex20ins–positive NSCLC previously treated with platinum-based chemotherapy.^5,6

Treatment benefit with amivantam­ab was evident in patients with sta­ble disease (SD) and those with ≥PR. A response-based analysis of the CHRYSALIS study showed that among patients whose disease did not progress at 12 weeks of treatment, the risk of death was reduced by 67 percent for those with SD (hazard ratio [HR], 0.33; 95 percent confidence interval [CI], 0.14–0.77; p=0.011) and by 79 percent for those with ≥PR (HR, 0.21; 95 percent CI, 0.08–0.54; p=0.001) as best re­sponse, vs those with progressive disease. These findings highlighted the value of disease control with ami­vantamab, irrespective of the depth of response.⁷ (Figure 2)