Treatment of c-MET Antibody-Drug Conjugate Asymptomatic Pneumonitis with a Novel Steroid Regimen in Non–Small Cell Lung Cancer: A Case Report

Antibody-drug conjugates (ADCs) are a novel class of anticancer medicines that combine the precision of monoclonal antibodies (MAbs) with the power of cytotoxic agents. The MAb targets a cancer cell or cellular component of a tumor microenvironment and the cytotoxic agent (or “payload”), attached via an organic spacer, then applies its antitumor activity leading to cell death. The mechanism of action of ADCs is thought to typically produce many advantages over conventional agents, including fewer off-target effects and less systemic toxicity.^[1]

A molecular target of interest in ADC development has been the receptor tyrosine-kinase c-MET. Overexpression of c-MET and constitutive activation of its signaling pathway have been implicated in various tumor types, including non–small cell lung cancer (NSCLC).^[2] Phase I studies of c-MET ADCs as monotherapy or in combination with other agents for various solid tumors have demonstrated promising results.^[3–5]

Notably, several trials of ADCs have reported lung toxicities. A meta-analysis of 39 ADC solid tumor studies found a total incidence of 5.86% (95% CI, 3.54–8.66%) and 10.58% (95% CI, 4.34–18.81%) for all-grade pneumonitis in ADC monotherapy and combination therapy, respectively. Trials thus far have implicated c-MET ADCs in development of interstitial lung disease (ILD)/pneumonitis, with incidence varying from 0 to 10.5%.^[3–6] NSCLC carries the highest incidence of pneumonitis of all solid tumors analyzed, with a 22.18% (95% CI, 2.14–52.61%) incidence.^[7] The treatment of stage IV NSCLC is palliative, focused on limiting disease progression and enhancing quality of life, thus limiting the adverse effects of promising new therapies like ADCs is a priority.

Herein we report the case of a patient with stage IV NSCLC who was able to continue ADC therapy on a novel steroid regimen despite development of ADC-induced pneumonitis after initiation of telisotuzumab vedotin (Teliso V), a c-MET ADC using antimicrotubule pharmacophore monomethyl auristatin E (MMAE) via cleavable linker, in combination with the epidermal growth factor receptor (EGFR) inhibitor osimertinib. The patient consented to the publication of his case.

A 70-year-old man with a history of coronary artery disease presented to his primary care provider with a year of progressive chronic cough, intermittent hemoptysis, night sweats, and unintentional weight loss in December of 2021. A chest radiograph revealed a 9.3-cm rounded, pleural-based mass in the posterior and medial right lower lobe suspicious for malignancy. Subsequent computed tomography (CT) of the chest measured the mass as 8.2 × 6.6 × 7.4 cm with a 2-cm subcarinal lymph node and 1.4-cm right hilar lymph node. Positron emission tomography (PET) CT with a local oncologist demonstrated additional F-18 fluorodeoxyglucose (FDG)-avid diffuse osseous and adrenal lesions. Pathology from ultrasound-guided biopsy of the lung mass confirmed the diagnosis of stage IV lung adenocarcinoma. Molecular analysis revealed ATR, EGFR L858R, FBXW7, NOTCH1, and TP53 somatic mutations on solid tumor biopsy. Programmed death ligand 1 (PD-L1) Tumoral Proportion Score was 70% (see Fig. 1 for the complete timeline of the patient’s clinical course).

In March 2022, the patient enrolled in the NORTHSTAR study (ClinicalTrials.gov Identifier: NCT03410043) and began single-agent osimertinib 80 mg daily. Imaging in May 2022 on the trial drug demonstrated treatment response, with decrease in the size of the primary tumor, shrinking nodal and adrenal metastases, and healing skeletal metastases. Repeat CT scan in August 2022 revealed further decrease in the primary tumor but a new left adrenal nodule. Subsequent PET CT detected areas of increasing sclerosis and metabolic activity in the lumbar spine. Biopsies of lumbar spine and the left adrenal nodule confirmed metastases. Liquid biopsy and fluorescence in situ hybridization demonstrated a new MET amplification. The patient underwent palliative radiotherapy (XRT) to L1–L4 starting in September 2022 with 3000 cGY delivered in 10 fractions.

Following completion of XRT in October 2022, the patient enrolled in a clinical trial of Teliso V administered as 1.6 mg/kg intravenously every 2 weeks, plus osimertinib 80 mg daily (ClinicalTrials.gov Identifier: NCT02099058). By December of 2022 (the end of cycle 2), imaging showed improvement in the left adrenal metastasis. However, diffuse, acute/subacute bilateral consolidative opacities developed, thought to represent asymptomatic pneumonitis. Treatment was held and a 28-day 0.5-mg/kg prednisone taper was initiated (40 mg for days 1–7, 30 mg for days 8–14, 20 mg for days 15–21, 10 mg for days 22–28). This steroid regimen was based on clinical guidelines for ADC-induced asymptomatic pneumonitis from trastuzumab deruxtecan (T-DXd).^[8] The pneumonitis cleared and the patient resumed osimertinib 80 mg daily and Teliso V now dosed at 1.3 mg/kg (a 19% dose-reduction) every 2 weeks.

With the beginning of cycle 5 in February 2023, the patient began experiencing grade 1 (G1) dyspnea with imaging findings of ground-glass opacities in the lower lobes, clinically consistent with recurrence of pneumonitis. The primary lung tumor and skeletal metastases remained stable while the adrenal metastasis demonstrated near-resolution. The patient was initiated on a 6-day 24-mg methylprednisolone taper (24 mg on day 1 with 4-mg daily dose-reduction) and treatment was continued. His shortness of breath resolved by March 2023; however, the dyspnea returned along with dry cough and chest discomfort by the end of the month. Pulmonary function tests (PFTs) revealed mild restrictive lung disease and mild reduction in diffusion capacity (61%). The patient’s pulmonary team decided to initiate him on 10 mg prednisone daily because the lowest dosing of the 28-day prednisone taper in December 2022 was 10 mg, and the patient reported best quality of life while on that dose.

The patient remained asymptomatic with normal PFTs and stable imaging findings until August 2023 when he began experiencing congestion, coughing, fatigue, and dyspnea on exertion. Imaging at the end of September 2023 demonstrated new ground-glass opacities in the lung periphery and stable primary tumor. Repeat PFTs showed worsening diffusion capacity (59%). The patient’s pulmonary team cleared him for further therapy and continuance of maintenance prednisone, as it was unclear if symptoms were from recurrence of drug-induced pneumonitis or a viral illness. Apart from two self-reported negative COVID tests, no further workup to differentiate viral etiology versus pneumonitis was pursued.

In early October 2023, the patient reported persistent respiratory symptoms and was started on an empiric course of Augmentin for community-acquired pneumonia. His symptoms did not significantly improve and repeat PFTs at the end of the month showed a further decrease in diffusion capacity (48%). The patient’s osimertinib and Teliso V were held. Separately, the maintenance prednisone was tapered from 10 mg to 5 mg (7.5 mg for 1 week, then reduced to a new maintenance dose of 5 mg) for concern of steroid-induced myopathy, as the patient had subjectively reported leg weakness. These symptoms were later attributed to adverse effects from Teliso V and/or osimtertinib following an electromyography/nerve conduction study that demonstrated chronic axonal neuropathy and a lumbar puncture with normal findings, both conducted in February 2024.

Imaging in November 2023 demonstrated further worsening of infiltrates. A bronchoalveolar lavage was negative for overt infection, only notable for a mild increase in neutrophils and eosinophils on cytology. The patient completed another 28-day 0.5-mg/kg prednisone taper on the same schedule as that in December 2022, with no maintenance steroid dosing after completing the taper. In early December 2023, he reported an improvement in symptoms and diffusion capacity improved (69%). Imaging showed improvement in ground-glass opacities, but there was an increase in size of both the primary tumor and adrenal metastasis. The patient resumed osimertinib 80 mg daily and Teliso V, now reduced to 1.0 mg/kg every 2 weeks (a 38% dose-reduction from the original dose), 6 weeks after pausing treatment.

The patient’s coughing and shortness of breath quickly returned following resumption of the trial drugs. Imaging in January 2024 revealed progression in the lung opacities with stable tumors (see Fig. 2). Diffusion capacity again decreased (51%) and the pneumonitis was re-classified as grade 2 (G2). The clinical trial team elected to discontinue Teliso V after 16 cycles, as it was believed to be the offending agent. The patient then began another 28-day 0.5-mg/kg prednisone taper on the same schedule previously described. By February 2024, the patient reported moderate improvement in symptoms with some residual cough, and CT imaging showed marginal improvement in the lung opacities. In addition, the patient’s adrenal metastasis increased in size and was now found to have intracranial metastases.

In March 2024, the patient underwent stereotactic radiosurgery for the brain metastases. A repeat liquid biopsy was positive for EGFR L858R but did not identify any targetable mechanisms of resistance to osimertinib. The patient was not a candidate for additional ADC clinical trials given his prior pneumonitis and instead started on combination osimertinib and pemetrexed therapy at last follow-up in April 2024.

We present a patient with metastatic NSCLC who developed ADC-induced pneumonitis after initiating combined c-MET ADC/EGFR inhibitor therapy despite clinical benefit. The patient required eventual cessation of ADC therapy but was able to remain on treatment for 15 months with multiple rounds of dose-reductions and a novel steroid regimen.

Management of ADC-induced ILD/pneumonitis varies by drug. Recommendations for tisotumab vedotin and enfortumab vedotin are to pause treatment for G2 pneumonitis until improved/resolved. The most aggressive guidelines for management of ADC-ILD/pneumonitis are for T-DXd. These include immediate steroid initiation and permanent discontinuation of T-DXd for grade 2 or higher ILD/pneumonitis. For G1 ILD/pneumonitis, patients must temporarily halt T-DXd until fully resolved, with dose reduction if resolved in over 4 weeks. Steroids should be considered on a case-by-case basis.^[9] In our patient’s case, his pneumonitis was treated with steroids when radiologically evident despite being asymptomatic and was controlled on daily low-dose steroids for a 6-month period while on Teliso V with grade 0 pneumonitis. The definitive use of steroids both in asymptomatic pneumonitis and as a daily suppressant represent new management options for ADC-ILD/pneumonitis that warrant further investigation.

Other clues for management of ADC-induced ILD/pneumonitis may be derived from proposed pathogenesis. Relevant to Teliso V, these include premature release of cytotoxic agent due to linker instability, ADC bystander effect, and off-target receptor-mediated uptake of ADCs.^[10] The ADC bystander effect refers to the ability of membrane-permeable ADC payloads, cleaved from their linker, to diffuse from intracellular sites and move to neighboring cells in the tumor environment where it can exert its effect. However, this is thought to contribute to off-target toxicity as the payload may move to normal tissue as well. This could explain other adverse effects of ADCs, such as ocular toxicity, neuropathy, and bleeding. Specific to lung toxicity, Kumagai et al^[11] demonstrated increased uptake of T-DXd in the alveolar macrophages of monkeys. In addition to low expression of HER-2 in alveolar macrophages, they also express high levels of Fc gamma receptor, a receptor class that interacts with numerous antibodies. This may lead to nonspecific uptake of ADCs, resulting in ILD/pneumonitis.^[10]

Moreover, NSCLC appears to be associated with higher rates of ADC-ILD/pneumonitis than other solid tumors. NSCLC sees the highest rates of drug-induced pneumonitis in anticancer drugs with different mechanisms of action. It is likely that independent processes enhance the risk of ADC-ILD/pneumonitis in NSCLC.^[12,13] This may be due to underlying pulmonary pathology (e.g., chronic obstructive pulmonary disease, emphysema, radiation) increasing susceptibility to further damage or tumor burden leaving lungs prone to pulmonary toxicities from treatment.^[7]

The contribution of osimertinib to the development of ILD/pneumonitis is unclear. Osimertinib has been strongly linked to drug-induced pneumonitis in patients with NSCLC.^[14] Furthermore, higher rates of ILD/pneumonitis may occur with combination ADC therapy.^[7] However, before and after ADC use, the patient demonstrated tolerability of osimertinib, suggesting that whatever effect it may have contributed was less than that of ADC in the development of pneumonitis. There are limited data on osimertinib/ADC combination therapy, but a phase I-II study of osimertinib in combination with ADC trastuzumab-emtansine demonstrated G1 pneumonitis in only 2 of 27 patients,^[15] an incidence lower than that reported with osimertinib monotherapy.^[14] A study using Teliso V in combination with erlotinib (anti-EGFR) had no occurrences of ILD/pneumonitis.^[5] More studies of anti-EGFR/ADC combination therapy are needed to tease out drug-drug interactions.

There are three important limitations of this case report that prohibit extrapolating a causal relationship between the steroid regimen and improvement in pneumonitis. The first being that the patient was not maintained on a consistent regimen throughout management of his pneumonitis. Second, the patient had cessation of trial drugs during most pneumonitis flares, thus it is possible that discontinuation of Teliso V was enough to improve symptoms. Third, the patient may have had overlapping clinical findings from viral/bacterial pneumonias so the extent of pneumonitis may be overstated in the clinical record. A randomized clinical trial of patients with ADC-induced ILD/pneumonitis on varying steroid regimens would help to eliminate these confounding variables. A notable drawback of the management of pneumonitis in this case is that the patient required intensive monitoring and frequent dose adjustments to stay on the study drug, likely hampering his quality of life and contrary to the goals of palliative management for stage IV NSCLC.

Despite these limitations, this report showcases new approaches to steroid regimens in ADC-ILD/pneumonitis and suggests that its management should be individualized.

ADC-ILD/pneumonitis poses a significant challenge in this promising new class of anticancer therapy. This patient, who was able to continue combined c-MET ADC/osimertinib therapy on a novel steroid regimen despite developing progressive ADC-induced pneumonitis, highlights possible mechanisms for ADC-ILD/pneumonitis development and introduces new strategies for immunosuppression.