Two Cases of Amivantamab-Induced Pneumonitis in Patients With NSCLC: Case Report

Abstract

Although drug-induced interstitial lung disease has been reported with cancer-directed antibody-drug conjugates and EGFR tyrosine kinase inhibitors, it remains a rare event in patients treated with amivantamab. In this report, we present two cases of suspected amivantamab-related drug-induced interstitial lung disease in patients with canonical EGFR mutant NSCLC after progression on osimertinib.

Introduction

Amivantamab is a bispecific antibody against EGF and MET receptors approved for patients with NSCLC with EGFR exon 20 insertion mutations and seeking approval for the treatment of NSCLC with canonical EGFR mutations.¹

Common side effects of amivantamab are infusion-related reactions, neutropenia, paronychia, rash, anemia, hypoalbuminemia, constipation, and leukopenia.¹ As more targeted NSCLC therapies emerge, drug-induced interstitial lung disease (DI-ILD) has become an important toxicity to monitor. Although not reported as a common adverse effect with amivantamab, DI-ILD has been well-documented among EGFR tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs).² In this report, we present two cases of suspected amivantamab-related DI-ILD in patients with canonical EGFR mutant NSCLC after progression on osimertinib.

Case Presentations

Case 1

A 57-year-old male individual who had never smoked was diagnosed with stage IVB EGFR exon 19 deletion lung adenocarcinoma. At diagnosis, sites of malignancy included the right middle lung and right pleura. The patient wished to avoid chemotherapy if possible.

The patient started osimertinib, but after nine months he experienced a worsening right pleural effusion. Repeat Tempus xT testing of the right pleural fluid revealed EGFR exon 19 deletion (65%), TP53 C135F (57.3%), CCNE1 amplification, tumor mutational burden 3.2 mutations per megabase (thirty-fifth percentile), MET overexpression, CCNE1 overexpression, and ERBB3 overexpression. Subsequently, bevacizumab was added with continued osimertinib. After another four months, imaging revealed increased right pleural nodularity and an enlarging right pleural effusion. Given disease progression and preserved EGFR exon 19 deletion and MET overexpression, tepotinib was added with continued osimertinib. After one year, the patient experienced worsening right pleural metastases.

The patient remained averse to cytotoxic chemotherapy, and amivantamab was initiated with the continuation of osimertinib. He experienced a grade 2 infusion-related reaction with amivantamab initiation that did not recur with subsequent infusions. Palliative radiation was administered to the right flank one week after the first amivantamab dose. One day later, he presented to the hospital with acute hypoxic respiratory failure. Chest angiography revealed acute pulmonary emboli and extensive bilateral ground glass opacities (Fig. 1). Lovenox and EKOS catheters were used for pulmonary emboli, and broad management with empirical antibiotics, diuretics, and high-dose corticosteroids was initiated. The infectious workup was negative. After several days, no clinical improvement was observed. Suspicion was highest for both amivantamab-related DI-ILD and disease progression contributing to respiratory failure. Ultimately, the patient and family decided to withdraw life-sustaining treatment after 1.5 weeks in the intensive care unit, and the patient died shortly after.

Figure 1.

Patient 1 treatment timeline and progressive radiographic lung findings pre- and post-amivantamab therapy.

Case 2

A 50-year-old female individual who had never smoked was diagnosed with stage IVB EGFR exon 19 deletion lung adenocarcinoma. At diagnosis, sites of malignancy included a right suprahilar mass with mediastinal invasion, osseous metastases with soft tissue extension, and right adrenal gland metastasis.

Before molecular testing resulted, the patient was hospitalized for pulmonary infarction of the right upper lobe, right pleural effusion, and pathologic vertebral fracture. While hospitalized, circulating tumor DNA results revealed an EGFR exon 19 deletion. Osimertinib was started and she underwent palliative radiation of bone metastases.

Her metastatic disease was stable for one year, at which point imaging revealed recurrent cancer in the right upper lobe with adjacent mediastinal lymphadenopathy. Carboplatin and pemetrexed were initiated with continued osimertinib. Nevertheless, weeks later, she was hospitalized with post-obstructive lung empyema complicated by pulmonary emboli. Tempus xF circulating tumor DNA testing revealed EGFR exon 19 deletion (35.4%), MET copy gain, TP53 splice variant (6.5%), and EGFR copy gain. Because of the infectious complication from platinum doublet, the patient preferred to avoid further chemotherapy.

Tepotinib was initiated with continued osimertinib. Unfortunately, tepotinib was discontinued owing to intolerable gastrointestinal side effects after two months and disease progression occurred one month later. Capmatinib was initiated with continued osimertinib but was only tolerated for two weeks. Amivantamab was subsequently initiated with continued osimertinib.

The patient experienced a grade 1 infusion-related reaction with the initial dose which did not recur with subsequent infusions. She tolerated amivantamab therapy for one month. Nevertheless, she then presented with acute hypoxic respiratory failure. Imaging revealed diffuse bilateral ground-glass opacities and pericardial effusion (Fig. 2). High-dose intravenous methylprednisone, diuretics, and empirical antibiotics were initiated; nevertheless, her respiratory status continually declined. The patient ultimately transitioned to hospice and died after a three-week hospitalization.

Figure 2.

Patient 2 treatment timeline and progressive radiographic lung findings pre- and post-amivantamab therapy. AUC, area under the curve; CID1, cycle 1, day 1.

Discussion

The incidence of DI-ILD, pneumonitis with amivantamab therapy is rare: in the CHRYSALIS Phase I amivantamab monotherapy trial, ILD incidence was 4%.¹ In MARIPOSA, a phase 2 study of first-line amivantamab plus lazertinib, ILD incidence was 3.1%.¹ Among ADCs, a meta-analysis reported the incidence of ADC-related all-grade pneumonitis in patients with solid tumors to be 5.9%; nevertheless, the incidence reached 22.2% in patients with NSCLC, the highest among solid tumors. Pneumonitis was also reported as the most common cause of ADC treatment-related death.² Additional studies investigating EGFR TKI pulmonary toxicity have found an average DI-ILD incidence of 1% to 4%.³

These studies reveal a pattern of ILD/pneumonitis that may be associated with amivantamab on the basis of its structural and mechanistic similarities to these drug classes. Although we cannot definitively attribute these ILD cases to amivantamab alone because it was combined with osimertinib, the prolonged duration between osimertinib initiation and ILD onset (over 500 d for both patients), and the rapid onset of ILD after amivantamab initiation strongly suggests that amivantamab-induced ILD development. The MARIPOSA trial of first-line lazertinib plus amivantamab for NSCLC will play an important role in further elucidating ILD incidence.⁴

The pathophysiology of DI-ILD remains unclear; nevertheless, cytotoxic and immune-related mechanisms have been suggested.⁵ Unfortunately, whereas immune-mediated pneumonitis is typically steroid responsive, our cases of DI-ILD due to amivantamab did not clearly benefit from high-dose glucocorticoids. The prognosis of DI-ILD is poor owing to limited effective reversal agents, multiorgan failure, and concomitant progression of underlying disease.⁵

Conclusion

There is an urgent need to better understand DI-ILD related to EGFR TKIs, ADCs, and amivantamab, as the use of these targeted agents is anticipated to notably increase. Their frequent steroid-refractory nature prompts the need for investigational reversal therapies.

CRediT Authorship Contribution Statement

Alexander J. DeWeerd: Conceptualization, Writing - original draft, Writing - review & editing.

Elizabeth Sun: Writing - original draft; Writing - review & editing.

Wade T. Iams: Conceptualization, Supervision, Writing - review and editing.

Disclosures

Dr. Iams has served as a consultant for Genentech, Jazz Pharma, G1 Therapeutics, Mirati, Takeda, Janssen, Amgen, Bristol-Myers Squibb, OncLive, Clinical Care Options, Chardan, Outcomes Insights, Cello Health, and Curio Science. The remaining authors declare no conflict of interest.