Pulmonary Toxicities of Targeted Therapy

Introduction

Prior to the 1990s, cytotoxic chemotherapy was used uniformly for all malignancies. This resulted in heterogeneous responses even within a specific tumor type. As insight was gained about the role of driver mutations (key alterations in the oncogenic addiction pathways of malignant cells), the concept of targeted therapies was born. By inhibiting driver pathways for carcinogenesis, these targeted agents were successful in managing cancers that did not have robust responses to cytotoxic chemotherapy. Imatinib, a tyrosine kinase inhibitor targeting the BCR-ABL1 fusion gene seen in chronic myeloid leukemia, and trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, were among the earliest targeted agents discovered. The success of these agents heralded an era of targeted therapies that are now being used in a broad spectrum of solid tumors and hematologic malignancies. With genomic sequencing being used more frequently than in the past, newer therapeutic targets are being discovered. With these discoveries come targeted drug development that will lead to many more targeted therapies in the coming years.

There are some limitations to molecular-targeted therapies. In malignancies that develop in the presence of carcinogen or environmental exposures, often multiple coexisting mutations are observed. In such malignancies, targeting a single pathway either leads to a complete lack of response or development of early resistance by a variety of escape pathways. Some examples of such cancers are non–small-cell lung cancer (NSCLC) related to smoking or melanoma as a result of exposure to ultraviolet (UV) radiation. Even in malignancies that are dependent on a driver mutation for oncogenesis, tumor cells eventually develop resistance to targeted agents via alternate pathways.

In the current era, molecular-targeted therapies play an important role in the treatment of multiple tumor types. Preclinical work has shown that these agents demonstrate clinical efficacy when combined with other therapeutic modalities such as immunotherapy. Ongoing clinical trials are exploring the utility of combining these molecular-targeted therapies with immunotherapies; therefore it is quite likely that the clinical application of targeted agents will continue to rise in the foreseeable future.

As targeted therapies are being widely used, it is imperative that prescribing clinicians are aware of the potential for toxicity and monitor patients closely while on therapy. In this chapter, we will discuss pulmonary toxicities of targeted therapies. Similar to other drugs, lung toxicity with targeted therapy may be idiosyncratic, or may be more predictable when related to cumulative dosing of the drug. By having a low-degree of suspicion in patients on therapy with drugs that have the potential for pulmonary toxicity and early intervention, morbidity and mortality can be significantly reduced. In the next section, we describe the various targeted therapies listed by class and their specific pulmonary toxicities including the pathogenesis, risk factors, and clinical manifestations.

Agents and Mechanism of Action

Specific EGFR–Targeting Agents

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  Gefitinib: The incidence of gefitinib-associated ILD has been reported to be slightly different in postmarketing experience in the United States (0.3%) versus Asian populations (2%). Patients usually present with dyspnea, with or without cough, and low-grade fever, with a median onset of symptoms between 24 and 42 days. Endo et al. performed a multi-institutional analysis of the various radiographic manifestations of ILD and classified them into four major patterns: (1) nonspecific ground-glass opacities, (2) multifocal airspace consolidations, (3) patchy ground-glass opacities with septal thickening, and (4) extensive ground-glass opacities or consolidations with traction bronchiectasis ( Fig. 14.1 ). The majority of the patients had areas of ground-glass opacities, or a pattern of extensive parenchymal involvement (fourth pattern), which reflects diffuse alveolar damage. The fourth pattern was associated with the highest mortality. The histological findings on pathology include interstitial pneumonitis or fibrosis and other less common findings such as diffuse alveolar damage, organizing pneumonia, hypersensitivity, or eosinophilic pneumonitis.

  

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  Erlotinib: The overall incidence of ILD with erlotinib is approximately 1.1% ( Fig. 14.2 ). In an analysis of 9907 Japanese patients treated with erlotinib in the phase IV POLARSTAR surveillance study, the reported incidence was 3.4% to 5.1%. Risk factors for ILD include preexisting pulmonary fibrosis or lung disease, radiation, and use of other drugs with potential for pulmonary toxicity, such as gemcitabine. Clinical presentation and imaging findings are similar to gefitinib-induced lung disease.

  

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  Afatinib: Afatinib is an irreversible ErbB family TKI. Three out of 230 patients in the LUX-Lung 3 trial developed ILD. One out of 242 patients in the LUX-Lung 6 trial had fatal ILD secondary to afatinib.

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  Osimertinib: The overall incidence of pneumonitis has been reported to be around 3.5%. Osimertinib is an irreversible EGFR-TKI that selectively inhibits EGFR sensitizing mutations, as well as the resistance mutation, T790M, but has lesser activity against wild-type EGFR, which could be a potential explanation for the lower grade 3 and 4 adverse events noted in comparison with erlotinib or gefitinib. The clinical manifestations appear to be similar to other EGFR TKIs. A unique pulmonary manifestation of osimertinib, which has been described in literature, is transient asymptomatic pulmonary opacities that occur at a median time of 8.7 weeks (range 1.6–43 weeks) into therapy and last for a median duration of 6 weeks (range 1–11 weeks). Patients with these asymptomatic transient opacities may be continued on therapy with close monitoring.

Anaplastic Lymphoma Kinase (ALK) Inhibitors

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  The identification of the role ALK rearrangements in 2% to 7% of patients with NSCLC in 2007 led to the development of ALK inhibitors to target the EML4-ALK fusion oncogene. The ALK inhibitors that have been used in clinical practice since 2011 include crizotinib (a multitargeted small molecule TKI) and second-generation agents including ceritinib, alectinib, and brigatinib. Although crizotinib was the first targeted agent to be approved, in the global ALEX study, alectinib demonstrated superior efficacy in terms of progression-free survival and central nervous system (CNS) progression and had lower toxicity in comparison to crizotinib. Although the overall incidence of pneumonitis with ALK inhibitors is low, many of these can be severe and life threatening. Among patients treated with the earlier ALK inhibitors crizotinib and ceritinib, 1% to 4% develop pneumonitis. Alectinib has been associated with a lower incidence of pneumonitis (0.4%). Brigatinib has a higher incidence of pulmonary toxicity, with 3.7% of patients in the 90 mg group and 9.1% of patients in the 180 mg after a 90-mg lead-in group reported in the ALTA trial. Pneumonitis developed in 6.4% of patients within 9 days of initiation of brigatinib-therapy, with a median onset of 2 days. Therefore patients who are initiated on brigatinib should be monitored very closely for respiratory symptoms in the first few weeks of therapy. ^,

BCR-ABL1 Tyrosine Kinase Inhibitors

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  Imatinib: Imatinib is a TKI that inhibits BCR-ABL, the constitutive abnormal gene product of the Philadelphia chromosome, in addition to other targets in such as platelet-derived growth factor (PDGFR), stem cell factor, and c-Kit. Imatinib has clinical activity in chronic myelogenous leukemia (CML), Philadelphia chromosome positive acute lymphoblastic leukemia (ALL), certain hypereosinophilic syndromes, and gastrointestinal stromal tumors (GISTs). A variety of pulmonary toxicities have been associated with the use of this drug including pleural effusions, interstitial pneumonitis, hypersensitivity pneumonitis, and eosinophilic pneumonia.

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    The most common pulmonary complication of imatinib is secondary to the associated fluid retention, which can lead to pleural effusions and pulmonary edema. In patients with CML, 1.3% of newly diagnosed patients and 2% to 6% of other CML patients on imatinib develop severe fluid retention. The incidence of severe fluid retention is higher in patients with GIST at 9% to 13.1%.

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    The median time to onset of interstitial pneumonitis was 49 days (range 10–282 days) in the largest case series of 27 patients with imatinib-induced ILD. Notably, there was no clear correlation between the dose or duration of therapy and development of pneumonitis. Among these patients, 41% had preexisting pulmonary disease, suggesting a predisposition in this patient population. Imaging findings in these patients revealed a hypersensitivity pattern (30%) ( Fig. 14.3A – C ), interstitial pneumonitis (26%), and cryptogenic organizing pneumonia (15%) ( Fig. 14.4 ), a peribronchovascular bundle pattern (15%), and a nodular pattern in 11% of patients. Transbronchial lung biopsies were performed in five patients which demonstrated varying degrees of inflammatory changes and fibrosis. Peripheral eosinophilia was noted in 5 of 27 patients.

    
    

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  Dasatinib: Dasatinib is a second-generation BCR-ABL TKI that binds to both active and inactive conformations of the ABL gene and is 325 times more potent than imatinib in inhibiting the growth of BCR/ABL cells in vitro. It is predominantly used in the treatment of CML. It has the highest incidence of reported pulmonary adverse events.

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    The most common pulmonary toxicity reported with dasatinib is the development of pleural effusions. The median time to onset of pleural effusions is 11 months (range3.6–18.6 months). In a 5-year analysis of patients from the DASISION trial comparing dasatinib to imatinib, the overall incidence of pleural effusions was 28% in the dasatinib group versus 0.8% in the imatinib group. Patients who were older than65 years had a higher incidence of pleural effusions. Some reports suggest that the rate of recurrent pleural effusions can be as high as 15%. Other risk factors that have been associated with the development of pleural effusions include prior pulmonary disease in patients treated with higher doses (140 mg).

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    Pulmonary hypertension has also been noted with dasatinib in an estimated 5% of treated patients, however, because all reported patients did not have confirmatory right heart catheterizations, the exact incidence is unknown. Based on data from the French Pulmonary Hypertension registry, pulmonary hypertension occurs after 8 to 48 months of exposure. Patients in this registry developed precapillary pulmonary hypertension. Evidence suggests that receptors of tyrosine kinases (RTKs) such as PDGFR, fibroblast growth factor 2, c-KIT, c-Src, and epidermal growth factor, play a role in the pathogenesis of pulmonary hypertension. As an example, the src tyrosine kinase pathway is essential for the activation of K ⁺ channels in the pulmonary smooth muscle cells, which results in muscle relaxation. TKIs that inhibit this pathway result in pulmonary vasoconstriction and vascular remodeling over time, resulting in pulmonary hypertension. Unlike imatinib and nilotinib, dasatinib is a potent inhibitor of RTKs that may be responsible for the higher incidence of pulmonary hypertension observed with the drug. Whereas in some patients pulmonary hypertension may be reversible, most patients do not recover completely despite discontinuation of the drug.

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    The other less common pulmonary toxicity of dasatinib is pneumonitis, which is usually reversible with interruption of therapy.

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  Bosutinib: Up to 8% of patients treated with bosutinib can develop pleural effusions. Additionally, a case report of worsening preexisting pulmonary hypertension while on bosutinib has been described.

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  Nilotinib: Pulmonary toxicity is rare and is seen in less than 1% of treated patients.

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  Ponatinib: For patients with CML who develop the T315I resistance mutation, ponatinib is the drug of choice. Pleural effusions can be seen in 1% of treated patients. Other pulmonary toxicities are rare. A case report of a patient who had been treated with dasatinib in the past and developed pulmonary hypertension while on treatment with ponatinib has been described.