Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents

INTRODUCTION — Adverse drug reactions (ADRs) due to antineoplastic agents are a common form of iatrogenic injury, and the lungs are a frequent target [1-3]. While some antineoplastic agent-induced ADRs are potentially preventable (particularly those that are related to cumulative dosing), many are idiosyncratic and unpredictable.

Increasingly, cancer treatment is selected based on an individual tumor's molecular features, a practice termed molecularly targeted therapy. Examples include use of the monoclonal antibody trastuzumab for breast cancers that overexpress human epidermal growth factor 2 (HER2); imatinib, a tyrosine kinase inhibitor (TKI), for gastrointestinal stromal tumors (GISTs) with mutations in the KIT receptor tyrosine kinase, as well as chronic myelogenous leukemia (where the target is the Bcr-Abl fusion protein); and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies such as cetuximab for metastatic colorectal tumors lacking mutations in the KRAS oncogene. Many of these agents are associated with lung toxicity.

This topic review will provide an overview of the incidence and specific patterns of lung toxicity seen with molecularly targeted agents used for cancer therapy. A general discussion of the clinical presentation, pathogenesis, diagnosis, differential diagnosis, and treatment of pulmonary toxicity associated with the use of antineoplastic agents is covered separately, as is lung toxicity associated with conventional cytotoxic chemotherapy agents. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment" and "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents".)

SMALL MOLECULE KINASE INHIBITORS

Anti-EGFR agents — Gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, and mobocertinib are all orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase. They are primarily used in the treatment of advanced non-small cell lung cancer (NSCLC).

Approximately 1 percent of patients treated with gefitinib or erlotinib and 3 to 4 percent of patients treated with osimertinib or mobocertinib develop lung toxicity, usually within the first two to three months of therapy [4-7]. The risk is higher in patients with preexisting lung disease and in smokers [8,9].

Approximately one-third of patients who develop interstitial lung disease (ILD) while being treated with gefitinib die of this complication [4]. The mortality rate in patients who develop ILD while receiving erlotinib is not well characterized but is likely similar to gefitinib, based on available information. Mortality rates among patients who experienced ILD/pneumonitis when receiving osimertinib or mobocertinib appear slightly lower (15 and 27 percent, respectively), although the data are limited [6,7].

The mechanism underlying pulmonary toxicity with these agents is unclear. EGFR is expressed on type II pneumocytes and involved in alveolar wall repair. EGFR tyrosine kinase inhibitors (TKIs), by interrupting alveolar repair mechanisms, may potentiate the effect of lung injury due to other causes, including sepsis, radiation therapy, prior lung injury, and other medications [8-12]. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Pathogenesis'.)

Treatment is largely supportive, with immediate drug discontinuation, administration of supplemental oxygen, empiric antibiotics, and mechanical ventilation as clinically indicated. Systemic glucocorticoids are usually recommended, although the evidence to support their use is largely anecdotal, and fatalities still occur despite empiric treatment with high-dose glucocorticoids.

Gefitinib — Gefitinib-related ILD is uncommon overall. For unclear reasons, the incidence varies geographically; incidence rates are higher in Asian (2 to 6 percent) as compared with White populations (0.2 to 0.3 percent) [4,8,9,13-16], and lower in African Americans [17]. Lung toxicity is fatal in 31 to 45 percent of cases [8,13,18].

Risk factors for gefitinib-associated ILD include older age, poor performance status, smoking, a recent diagnosis of NSCLC, preexisting chronic ILD with extensive infiltrates on CT, and concurrent cardiac disease [8]. A prior history of fibrotic lung disease or concurrent chest irradiation may also be aggravating factors [8,9,13,19-22].

In a postmarketing analysis of 408 cases of ILD from gefitinib for NSCLC, the most common presentation was acute dyspnea with or without cough or low-grade fever [13]. Symptoms often became severe within a short time, and hospitalization was required. The median time to onset of symptoms was 24 to 31 days in Japanese and 42 days in American patients. One-third of cases were fatal.

There are four predominant patterns on CT scan: nonspecific ground glass opacities (n = 29), multifocal areas of airspace consolidation (n = 7), patchy ground-glass infiltrates with septal thickening (n = 3), and extensive ground-glass infiltrates or airspace consolidation with traction bronchiectasis (n = 20) [14]. Patients can also have nonspecific radiographic findings. The mortality was especially high (75 percent) among patients with extensive ground-glass infiltrates or airspace consolidation, a finding that is thought to reflect diffuse alveolar damage [14].

Among the cases that have been subject to biopsy, the most common histologic patterns are diffuse alveolar damage, interstitial inflammation with and without fibrosis, and organizing pneumonia; alveolar hemorrhage has also been described [15,18,19,21].

Treatment is largely supportive, with immediate and permanent discontinuation of the drug. In addition, some suggest that the early use of glucocorticoid therapy is beneficial [23]; however, the efficacy of glucocorticoid treatment has only been examined in retrospective series [19,21]. In the larger report detailing 70 cases of gefitinib-related ILD, glucocorticoids were administered to 66; additional antibiotic treatment did not increase the proportion of patients whose ILD improved (18 and 61 percent of those treated with and without antibiotics, respectively) [19].

Successful use of erlotinib in a patient who developed gefitinib-related ILD is reported [24,25].

Erlotinib — Limited information is available regarding erlotinib-induced lung toxicity. ILD, which is sometimes fatal, was initially reported in approximately 0.8 percent of patients receiving erlotinib [26-29]. A large post-marketing Japanese surveillance study (POLARSTAR) of 9907 patients reported an ILD rate of approximately 4 percent (grade 3 and above in 3 percent), with a 30 percent fatality rate [30]. In placebo-controlled randomized trials of erlotinib in advanced NSCLC, rates of cough, dyspnea, and ILD have been similar in the erlotinib and control groups [28,31]. However, ILD may have been underdiagnosed for several reasons. ILD requires diagnostic testing, which may not have been undertaken in patients who developed respiratory symptoms during antineoplastic therapy, possibly because they were assumed to be due to advanced NSCLC. Furthermore, it can be difficult to distinguish progressive cancer, particularly of the lepidic adenocarcinoma variant (previously called bronchoalveolar carcinoma) subtype, from drug-induced ILD. (See "Pathology of lung malignancies".)

Whether the concurrent use of cytotoxic chemotherapy and erlotinib increases the risk of ILD is also unknown [32-34].

The clinical presentation is typically acute with dyspnea, sometimes associated with cough or low-grade fever, which often becomes severe within a short time and requires hospitalization [35]. The median time to occurrence of ILD in this report was 47 days (range five days to more than nine months). As with gefitinib, preexisting pulmonary fibrosis may be a risk factor [32].

Fatalities are reported, although the true mortality rate among patients who develop ILD while receiving erlotinib is unclear [33,35,36]. In one report, one of four patients who developed lung toxicity during erlotinib monotherapy for NSCLC died [37].

Treatment is largely supportive with discontinuation of erlotinib. Glucocorticoid therapy may lead to clinical improvement [38], but fatalities still occur [32,33,36].

Afatinib — Afatinib is a highly selective irreversible inhibitor of the ErbB family, including ErbB1 (EGFR), ErbB2 (human epidermal growth factor 2 [HER2]), and ErbB4. Afatinib, 40 mg daily, was administered to patients with NSCLC in two randomized trials, and the following ILD rates were reported [39,40]:

●In Lung LUX 3, among 230 patients treated with afatinib, there were three cases of potential ILD (1 percent), and of the four deaths on treatment, two were from respiratory decompensation [39].

●In Lung LUX 6, one of 242 patients receiving afatinib developed grade 4 ILD but recovered following treatment with antibiotics and glucocorticoids [39,40].

Osimertinib — Across clinical trials, ILD/pneumonitis has occurred in approximately 2 to 3 percent of patients treated with osimertinib [6,41]; approximately 15 percent of cases (one in six) have been fatal [6].

The United States Prescribing Information for osimertinib recommends withholding the drug for any patient who presents with worsening of respiratory symptoms (eg, dyspnea, cough, fever), which may indicate ILD, and that the drug be permanently discontinued if ILD is confirmed [42]. In a dose-escalation trial of 253 patients with EGFR, there were six cases of potential pneumonitis-like events; all six cases resolved or were resolving following drug discontinuation [41].

The risk of ILD/pneumonitis may be higher when osimertinib is administered after an immune checkpoint inhibitor:

●In a retrospective study of 26 patients who received different types of EGFR TKIs administered before or after an anti-programmed cell death 1 (PD-1) antibody (eg, nivolumab, pembrolizumab), three out of seven patients treated with osimertinib after an anti-PD-1 agent developed ILD (42.8 percent), whereas treatment with a first- or second-generation agent after treatment with an anti-PD-1 agent, or with osimertinib before an anti-PD-1 antibody did not increase the risk for ILD [43]. Patients who developed ILD were treated with systemic glucocorticoids after discontinuation of EGFR TKI treatment and had resolution of their ILD.

●Another retrospective review of 126 patients with EGFR mutant NSCLC who were treated with an anti-PD-(L)1 agent and an anti-EGFR TKI, irrespective of drug or sequence of administration, also showed an increase in severe immune-related adverse events (irAEs) in 15 percent (6 of 41) of patients treated with an anti-PD-(L)1 agent followed by osimertinib, with four of the six patients experiencing pneumonitis [44]. IrAEs occurred at a median onset of 20 days after osimertinib initiation. Interestingly, severe irAEs were more common in patients who began osimertinib within three months of receiving an anti-PD-(L)1 agent compared with those who last received an anti-PD-(L)1 agent >3 to 12 months and >12 months prior to starting osimertinib. (See "Toxicities associated with immune checkpoint inhibitors".)

Lapatinib — In contrast to gefitinib, erlotinib, and osimertinib, lung toxicity appears to be very rare with lapatinib, a dual inhibitor of EGFR-I and HER2 (EGFR-2). There is only one case report of interstitial pneumonitis developing in a patient treated with lapatinib and capecitabine [45].

Dacomitinib — Dacomitinib is an irreversible inhibitor of the kinase activity of EGFR/HER1, HER2, and HER4; it is approved for first-line treatment of NSCLC with specific EGFR mutations. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)

Overall, potentially fatal ILD/pneumonitis was reported in 0.5 percent of the 394 patients treated with dacomitinib; 0.3 percent of cases were fatal [46]. In one trial, ILD led to discontinuation of the drug in 1.8 percent [47]. The United States Prescribing Information for dacomitinib recommends withholding the drug in patients with worsening respiratory symptoms that may indicate ILD, and permanent discontinuation if ILD is confirmed [42].

Bcr-Abl tyrosine kinase inhibitors

Imatinib — Imatinib, an orally active inhibitor of Bcr-Abl, KIT, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, is an effective treatment for gastrointestinal stromal tumors (GISTs) and Philadelphia-chromosome-positive chronic myelogenous leukemia (Ph+CML).

Most of the lung complications reported during imatinib therapy are related to fluid retention, a common side effect [48-50]. However, peripheral and periorbital edema are far more frequent manifestations of fluid retention than are pleural or pericardial effusions and pulmonary edema.

Rare cases of acute pneumonia with and without eosinophilic infiltrates [51-53], and subacute interstitial pneumonitis [54,55] are reported with imatinib treatment. Lung toxicity has been reported with doses as low as 100 mg per day [53].

The largest series consists of 27 cases of imatinib-induced ILD reported to Novartis in Japan [56]. The median time to development of ILD was 49 days (range 10 to 282). The most common clinical presentation was the subacute development of low-grade fever, dry cough, and progressive dyspnea on exertion, with or without hypoxia [51,57,58]. Preexisting lung disease was present in 11 of 27 patients (41 percent) in the Japanese series [56].

In general, radiographic studies show bilateral diffuse or patchy ground glass opacities, consolidation, and/or fine nodular opacities [56]. Findings on bronchoalveolar lavage (BAL) include lymphocytes, foamy macrophages, and/or eosinophilia [55,56,58]. Bronchial biopsies may show pulmonary alveolar proteinosis, interstitial inflammation and fibrosis, alveolitis, or organization [53,56,58]. Peripheral eosinophilia may be present [56].

Although the syndrome may resolve with drug discontinuation alone [53,58], most cases require glucocorticoid therapy for resolution [51,54,57,59,60]. Only one fatality has been reported [61].

Rechallenge — The decision to restart imatinib in a patient who has had pulmonary toxicity must be made on a case-by-case basis and should be based on the severity of the reaction and the availability of alternative therapies. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

Rechallenge does not always prompt a recurrence of lung injury [56,62]. In the Japanese series described above, imatinib was readministered to 11 patients after ILD improved; four had a recurrence of lung toxicity [56]. However, in general, rechallenge is not recommended, unless other therapeutic options are not available.

Dasatinib — Second generation Bcr-Abl TKIs such as dasatinib inhibit Bcr-Abl, KIT, and PDGFR, as well as other signaling pathways including Src kinases; they are used only for the treatment of Ph+CML.

Of the Bcr-Abl TKIs, dasatinib has been associated with the highest frequency of pulmonary side effects. During treatment with dasatinib, pleural, pulmonary vascular, and lung parenchymal abnormalities can develop separately or simultaneously.

Pleural effusion — Pleural effusions are more commonly seen in patients treated with dasatinib than with imatinib and may be bilateral or unilateral. Between 10 and 35 percent of patients treated with dasatinib in clinical trials developed pleural effusions, most often exudative and lymphocyte predominant [63-68]. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Other toxicity'.)

In one report of 172 older adult patients treated with dasatinib for Ph+CML, pleural effusions occurred in 30 percent, were recurrent in 15 percent, and required treatment discontinuation in 6 percent [65]. The mean time to onset of the pleural effusion was 11 months (range 3.6 to 18.6 months). Only the presence of concomitant pulmonary disease and higher initial daily dose (140 versus 100 mg) were significant risk factors. When the patients on the lower dose of dasatinib were analyzed separately, underlying pulmonary disease was no longer identified as a risk factor.

In the DASISION trial, pleural effusions occurred in significantly more patients treated with dasatinib as compared with imatinib (28 versus 0.8 percent) [68]. The incidence of pleural effusion was higher in patients age 65 or older (15 of 25, 60 percent) compared with those younger than 65 (38 of 233, 25 percent). Pleural effusion was managed with dose interruption (62 percent), dose reduction (41 percent), diuretics (47 percent), glucocorticoids (32 percent), and/or therapeutic thoracentesis (12 percent). Only 15 patients (6 percent) had to discontinue treatment, and no deaths were attributable to pleural effusions.

Altering the dasatinib regimen from 70 mg twice daily to 100 mg daily reduces the risk of pleural effusion, without affecting antitumor efficacy [69]. Optimal treatment of dasatinib-related pleural effusions, when they occur, is not known. In case series, treatment has included systemic glucocorticoids, diuretics, thoracentesis, and dasatinib interruption or discontinuation [63,65,70,71]. Rarely, pleurodesis has been used [71]. Combinations of the above therapies have also been employed.

Pulmonary arterial hypertension — Case reports describe reversible pulmonary arterial hypertension (PAH) in patients treated with dasatinib for Ph+CML [68,72-76]. Data from the French Pharmacovigilance Agency suggest that the incidence of PAH among patients treated with dasatinib is low (0.45 percent), although this is likely an underestimate due to incomplete case finding [76]. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

In the DASISION trial, echocardiography was suggestive of PAH in 14 (5 percent) of dasatinib-treated patients, nine of whom had pleural effusions. Only one patient underwent a heart catheterization, which did not confirm the diagnosis of PAH [68].

Patients with PAH typically present with exertional dyspnea, fatigue, tachypnea, and peripheral edema, developing after 8 to 48 months of dasatinib therapy [72-76]. Reported pulmonary artery pressures (PAP) by right heart catheterization are 53 to 66 mmHg (systolic) [72-75] and 25 to 50 mmHg (mean) [74,76]. Although a few patients have experienced full clinical and hemodynamic recovery, the majority have not recovered completely after follow-up that ranges from 3 to 36 months (median 9 months) [72-76]. In one case series, an endothelin receptor antagonist was administered to two patients and a calcium channel blocker to a third [76]; it is unclear whether subsequent improvement was related to these therapies, dasatinib discontinuation, or both.

PAH has also been reported with ponatinib but not the other Bcr-Abl TKIs [76,77]. (See 'Ponatinib' below.)

Pneumonitis — Lung parenchymal changes are rarely described among patients who develop respiratory symptoms while receiving dasatinib [78,79]. In a series of 40 patients with CML, nine (23 percent) developed lung abnormalities from 29 to 500 days after starting dasatinib [78]. Three had parenchymal changes (ground glass or alveolar opacities and septal thickening) without pleural effusion, five had both pleural and parenchymal disease, and one had bilateral pleural effusions alone. In five patients, BAL fluid analysis showed lymphocytosis or neutrophilia. Bronchial biopsy was only undertaken in one patient and was nondiagnostic.

Dasatinib treatment was held in eight patients, while one received glucocorticoid therapy with no dasatinib interruption. Dasatinib-associated lung abnormalities resolved completely in seven patients and partially resolved in two. Among the seven patients with radiographic parenchymal changes, six had complete resolution within three months of dasatinib interruption (n = 5) or the addition of glucocorticoid therapy (n = 1); one had persistent septal thickening. There were no fatalities.

Rechallenge — Patients who develop dasatinib-induced PAH should not be rechallenged with the drug. Safe treatment with another second-generation TKI, nilotinib, has been described in eight patients with dasatinib-associated PAH [72,73,75,76]. An additional patient with severe PAH at presentation experienced progressive respiratory failure after stopping dasatinib but while taking nilotinib, although it was unclear whether nilotinib was contributory [76].

Imatinib treatment in patients who develop dasatinib-induced PAH has not been reported, although imatinib treatment preceding dasatinib-associated PAH has been described. In one report, one patient received two years of imatinib followed by two and a half years of dasatinib prior to development of PAH, which was presumably secondary to dasatinib and not imatinib [72]. It is hypothesized that PAH may represent an "off-target" side effect of dasatinib related to its interaction with over 40 kinases, many of which are not affected by the more selective nilotinib and imatinib [72,80].

The decision to restart dasatinib in a patient who has had pulmonary toxicity other than PAH must be made on a case-by-case basis and should be based on the severity of the reaction and the availability of alternative therapies. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

One option is to restart the drug at a lower dose. In the series described above, only one of four patients who had reintroduction of dasatinib at a lower dose following resolution of radiographic changes had recurrence of respiratory symptoms, manifest as bilateral pleural effusions, without a parenchymal component [78].

Nilotinib — Nilotinib targets Bcr-Abl, KIT, and PDGFR, but not Src kinases. Pleural effusion and other pulmonary toxicities are rare with nilotinib. In one trial, pleural effusion was noted in <1 percent of patients treated with nilotinib for Ph+CML [81,82].

Bosutinib — Bosutinib is a second-generation agent that targets Bcr-Abl and Src pathways, but not KIT or PDGFR. Like nilotinib and dasatinib, it is approved only for Ph+CML in adult patients. The main pulmonary toxicity is pleural effusion, which in one study of 118 patients, occurred in nine (8 percent), seven of whom had a history of developing pleural effusions on prior Bcr-Abl TKIs such as dasatinib [83].

Ponatinib — Ponatinib is a multitargeted TKI that specifically targets the T315I resistance mutation of the Bcr-Abl protein that is found in approximately 15 percent of patients with CML. PAH has been rarely reported in patients receiving ponatinib. In a case report, PAH developed after six months of treatment with ponatinib for CML, and marked improvement in PAP followed drug cessation and the addition of sildenafil and ambrisentan [77]. The case was complicated in that the patient had taken dasatinib (associated with PAH in numerous reports) for two years earlier in the course of her CML but did not develop evidence of PAH until six months after dasatinib was discontinued. (See 'Dasatinib' above.)

ALK inhibitors — Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are orally active inhibitors of the anaplastic lymphoma kinase (ALK); all are approved for treatment of advanced or metastatic non-small cell lung cancer if the tumor contains a characteristic EML4-ALK fusion oncogene. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)

All drugs in this class have been associated with development of ILD/pneumonitis:

●In clinical trials, crizotinib was associated with ILD in 50 of 1719 patients (3 percent) and with severe, life-threatening, or fatal pneumonitis in 26 (1.5 percent), which generally developed within three months of treatment initiation [84]. Crizotinib also inhibits mesenchymal-epithelial transition (MET), the tyrosine kinase receptor for hepatocyte growth factor, and this may also contribute to pulmonary toxicity. (See 'MET inhibitors' below.)

●In an analysis of 255 patients treated with ceritinib, pneumonitis was reported in 4 percent, and it was severe (grade 3 or 4) in 3 percent; one patient died [85]. In a phase I study of 130 patients treated at doses ranging from 50 to 750 mg daily, there were four cases of ILD that were possibly related to ceritinib therapy; all resolved with the discontinuation of the drug and symptomatic treatment [86].

●In clinical trials, severe (grade 3) ILD occurred in 1 (0.4 percent) of 253 patients exposed to alectinib [87].

●Severe or life-threatening pulmonary adverse reactions consistent with ILD/pneumonitis have occurred in <2 percent of patients treated with lorlatinib in clinical trials [88,89].

●In clinical trials, ILD/pneumonitis occurred in 4 to 9 percent of patients treated with brigatinib; grade 3 or 4 reactions occurred in 3.7 percent [90,91]. This acute pulmonary toxicity is somewhat different than that occurring with the other ALK inhibitors. It comes on rapidly (in the first one to nine days of treatment, median two days [90]), and after withholding brigatinib until pneumonitis clears, approximately one-half are able to resume therapy [90]. The United States Prescribing Information for brigatinib recommends starting with a low dose of brigatinib (eg, 90 mg once daily) and up-titrating the dose after seven days, if tolerated, to decrease the incidence of ILD [42]. If treatment with brigatinib is interrupted for ≥14 days, treatment should be resumed and up-titrated to the previously tolerated dose.

With the exception of brigatinib, permanent discontinuation of ALK inhibitors is advised in the event of treatment-related ILD/pneumonitis of any grade.

Trametinib — Trametinib is an orally active inhibitor of the mitogen-activated protein kinase enzymes MEK1 and MEK2; it is approved for treatment of metastatic melanoma containing a specific BRAF mutation. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)

In clinical trials of patients treated with trametinib, ILD or pneumonitis occurred in approximately 2 percent after a median of 160 days [92,93]. The United States Prescribing Information for trametinib recommends withholding trametinib in patients with new-onset cough, dyspnea, hypoxemia, pleural effusion, or chest radiographic opacities pending clinical evaluation and permanent discontinuation for treatment-related ILD or pneumonitis [42]. Information on reversibility is not available.

BRAF inhibitors

Vemurafenib — Vemurafenib is an orally active BRAF inhibitor (V600E) that is approved for the treatment of advanced melanoma and Erdheim-Chester disease. (See "Erdheim-Chester disease", section on 'BRAF inhibition' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)

Cases of ILD have been reported, including two cases of sarcoidosis-like granulomatous reaction. Drug discontinuation led to favorable outcomes in these rare reports [94,95].

Encorafenib plus binimetinib — Encorafenib is an orally active BRAF inhibitor (V600E or V600K) approved for use in combination with binimetinib, an orally active MEK inhibitor, for patients with unresectable or metastatic melanoma with a BRAF mutation. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Encorafenib plus binimetinib'.)

In clinical trials, two patients (0.3 percent) treated with encorafenib and binimetinib developed ILD, including pneumonitis [96]. The  recommends assessing any new or progressive pulmonary symptoms for possible ILD and withholding treatment, dose reducing, or permanently discontinuing based on the severity of the reaction [42].

Additionally, 6 percent of patients developed a venous thromboembolism while receiving encorafenib and binimetinib, with 3.1 percent of those patients having a pulmonary embolism. The United States Prescribing Information recommends withholding the medication, reducing the dose, or permanently discontinuing the medication based on the severity of the reaction [42].

Idelalisib, duvelisib, and alpelisib

●Idelalisib – Idelalisib is an oral inhibitor of phosphoinositide 3-kinase (PI3K) delta; it is approved for treatment of relapsed chronic lymphocytic leukemia, follicular lymphoma, and small lymphocytic lymphoma. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Idelalisib'.)

Fatal and serious pneumonitis has occurred in patients treated with idelalisib [97]. In two phase II trials of idelalisib monotherapy for patients with refractory follicular lymphoma, pneumonia (including infectious and noninfectious causes) of any severity occurred in 11 to 19 percent and was severe (grade 3 or worse) in 7 to 17 percent of cases [98,99].

Patients who present with new cough, dyspnea, hypoxia, interstitial opacities, or a ≥5 percent decline in pulse oxygen saturation during therapy should have the drug interrupted and be evaluated for pneumonitis [97]. Patients with pneumonitis thought related to idelalisib have been treated with drug discontinuation and administration of glucocorticoids.

●Duvelisib – Duvelisib is an oral dual inhibitor of PI3K delta and gamma that is approved for treatment of chronic lymphocytic leukemia. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

Serious, sometimes fatal pneumonitis without an apparent infectious cause has been reported in 5 percent of patients treated with duvelisib [100]. The median time to onset was four months. The United States Prescribing Information for duvelisib recommends providing prophylaxis for PJP pneumonia during treatment with duvelisib [42]. The drug should be withheld in any patient with new or progressive pulmonary signs or symptoms (eg, cough, dyspnea, new radiographic opacities, or a decline by >5 percent in oxygen saturation), pending an evaluation for etiology. Treatment with systemic glucocorticoids is recommended for moderate (grade 2 (table 1)) noninfectious pneumonitis, with a resumption of therapy allowed with a dose reduction after resolution, while more severe cases warrant treatment discontinuation.

●Alpelisib – Alpelisib is an orally active inhibitor of PI3K alpha that is approved in combination with endocrine therapy in hormone receptor-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer. According to the , severe pneumonitis, including ILD, has been reported in patients treated with alpelisib [42]. In clinical trials, 1.8 percent of 284 patients treated with alpelisib experienced pneumonitis [96,101]. In patients with new or worsening respiratory symptoms or who are suspected of having pneumonitis, the United States Prescribing Information recommends stopping treatment immediately to evaluate the patient [42]. In those with confirmed pneumonitis, treatment should be discontinued [96,101].

PDGFR-alpha inhibitors — Avapritinib is a platelet-derived growth factor receptor alpha (PDGFRa)-directed TKI that is approved for patients with unresectable or metastatic GIST with a PDGFR-alpha exon 18 (D842V) mutation. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Avapritinib for PDGFRA D842V mutant tumors'.)

In the phase 1 NAVIGATOR trial, dyspnea occurred in 17 percent of patients and pleural effusions occurred in 12 percent of patients treated with avapritinib (2 percent grade 3 or worse). According to the United States Prescribing Information, avapritinib should be held for any grade 3 or 4 toxicity, including pulmonary toxicity, until resolution to grade 2 or less. Avapritinib can be resumed at the same or reduced dose per clinical judgment [42].

FLT3 inhibitors

●Midostaurin – Midostaurin is an orally active inhibitor of the fms-related tyrosine kinase (FLT3) gene and is approved for use in patients with acute myeloid leukemia (AML) and the FLT3 mutation. In the phase 3 clinical trial, 28 patients (8 percent) who received midostaurin plus chemotherapy experienced grade 3 to 5 pneumonitis or radiographic pulmonary opacities [102].

The United States Prescribing Information reports that there have been cases of both ILD and pneumonitis, some fatal, and recommends discontinuing midostaurin in patients who experience signs or symptoms of ILD or pneumonitis without an infectious cause [42].

●Gilteritinib – Gilteritinib is a second orally active inhibitor of FLT3 and is approved for use in patients with AML and the FLT3 mutation. The United States Prescribing Information notes dyspnea in 35 percent of patients and cough in 28 percent of patients treated with gilteritinib [42]. Twelve percent of patients experienced grade 3 or higher dyspnea. There are recommendations for treatment interruption and dose reductions for grade 3 or higher toxicities. (See "Differentiation syndrome associated with treatment of acute leukemia".)

MET inhibitors — Mesenchymal-epithelial transition (MET) is a tyrosine kinase receptor for hepatocyte growth factor. Two specific inhibitors of MET, capmatinib and tepotinib, are approved in the United States for treatment of advanced NSCLC with specific MET mutations that lead to MET exon 14 skipping. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'MET abnormalities'.)

●Capmatinib – Interstitial lung disease (ILD)/pneumonitis occurred in 4.5 percent of patients treated with capmatinib in the GEOMETRY mono-1 trial [103,104], with 1.8 percent of patients experiencing grade 3 toxicity, and one death. The median time to onset was 1.4 months. Other pulmonary toxicities commonly occurred in patients treated with capmatinib in the GEOMETRY mono-1 trial [103,104]. Grade 3 pleural effusions occurred in 4 percent of patients treated with capmatinib. Additionally, 24 percent of patients experienced dyspnea, with 7 percent of patients experiencing Grade 3 or 4 dyspnea.

All patients should be monitored for new of worsening pulmonary symptoms, and the drug should be interrupted in patients with suspected ILD/pneumonitis and permanently discontinued if no other potential cause is discovered.

●Tepotinib – ILD/pneumonitis occurred in 2.2 percent of patients treated with tepotinib; one case was fatal [105]. All patients should be monitored for new of worsening pulmonary symptoms, and the drug should be interrupted in patients with suspected ILD/pneumonitis and permanently discontinued if no other potential cause is discovered.

RET inhibitors — Rearrangements between the rearranged during transfection (RET) gene and various fusion partners are identified in 1 to 2 percent of NSCLC, and they can be targeted by specific RET inhibitors. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'RET rearrangements'.)

One such drug, pralsetinib, an oral kinase inhibitor which is approved in the United States for treatment of metastatic RET fusion-positive NSCLC, has been associated with severe, life-threatening, and potentially fatal ILD/pneumonitis. Across clinical trials, pneumonitis has occurred in approximately 10 percent of treated patients, including 2.7 percent with grade 3-4, and 0.5 percent with grade 5 (fatal) reactions [106]. The United States Prescribing Information provides a recommendation to withhold the drug for any grade 1 or 2 ILD/pneumonitis until resolution, and to permanently discontinue the drug for recurrent ILD/pneumonitis or any grade 3 or 4 toxicity [42].

Interestingly, pneumonitis was less frequent (≤2 percent) with a second oral RET inhibitor, selpercatinib [107].

TRK/ROS1 inhibitors — The neurotrophic tyrosine receptor kinase (NTRK) genes, NTRK1, NTRK2, and NTRK3, encode transmembrane tropomyosin-related tyrosine kinases (TRKs) [108,109]. Fusions involving one of the RK genes were among the first gene translocations described in cancer. TRK fusion-positive tumors are uncommon overall but found in a wide variety of malignancies. Specific TRK inhibitors are available, and approved for advanced tumors of any histology harboring TRK fusions. (See "TRK fusion-positive cancers and TRK inhibitor therapy".)

Entrectinib is also an inhibitor of c-ROS oncogene 1 (ROS1), and is approved for ROS1-rearranged NSCLC. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'ROS1 rearrangements'.)

Pulmonary complications are frequent, although usually mild, with these drugs:

●Entrectinib – In a pooled analysis of four trials of patients with TRK fusion-positive or ROS1-rearranged NSCLC tumors receiving entrectinib, dyspnea occurred in 31 percent of patients, pleural effusion occurred in 10 percent of patients, and respiratory failure occurred in 2 percent of patients [110].

●Larotrectinib – In a combined analysis of three phase I/II trials in patients with TRK fusion-positive tumors receiving larotrectinib, dyspnea occurred in 18 percent of patients and cough occurred in 26 percent of patients; these adverse effects were primarily grade 1 or 2 in nature [111,112].

AGENTS TARGETING VEGF — The development of a blood supply is a necessary prerequisite for tumor growth. The dominant factor controlling angiogenesis is vascular endothelial growth factor (VEGF). Inhibition of VEGF by a variety of methods produces a marked antitumor response. (See "Overview of angiogenesis inhibitors".)

Three different approaches have clinical activity in blocking the VEGF pathway: the use of small molecule tyrosine kinase inhibitors (TKIs; eg, sunitinib, sorafenib, pazopanib) to block the intracellular domain of the VEGF receptor; monoclonal antibodies, such as bevacizumab, that bind to circulating VEGF and prevent its activating the VEGF receptor (VEGFR); and aflibercept, a fusion molecule consisting of portions of the binding domains of several VEGFRs attached to the Fc portion of human IgG1 that binds to and inhibits VEGF binding to all classes of VEGFR as well as placenta growth factor (PlGF) binding to VEGFR1.

Bevacizumab — There are several complications associated with the use of bevacizumab, three of which have the potential to affect the lungs: hemorrhage, tracheoesophageal (TE) fistula and thromboembolic disease. Although bevacizumab clearly increases the risk for arterial thrombosis, whether it also increases the risk of venous thromboembolic disease is uncertain. These topics are covered in detail elsewhere. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Pulmonary hemorrhage and cavitation' and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Tracheoesophageal fistula' and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Arterial and venous thromboembolism'.)

Whether the presence of tumor cavitation (which is more common with squamous cell cancers) implies a higher risk of hemorrhage is unclear.

Sunitinib and sorafenib — Tumor cavitation and bleeding complications have been observed rarely with the use of sunitinib and sorafenib for non-small cell lung cancer (NSCLC). However, pulmonary hemorrhage has not been described in patients receiving either drug for other malignancies, and neither agent is approved for treatment of lung cancer. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

Dyspnea and cough have been reported with sunitinib. In a review of the drug approval report for treatment of gastrointestinal stromal tumors (GISTs) or advanced renal cell cancer, severe (grade 3 or 4) dyspnea was seen in 19 percent of patients and cough, in 13 percent [113]. There are no reports of sunitinib-induced pneumonitis. However, postmarketing experience has revealed cases of pulmonary embolism, some fatal [114]. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'VEGFR tyrosine kinase inhibitors'.)

Rare cases of pulmonary toxicity with dyspnea, cough, and fever have been reported in patients receiving sorafenib. In a postmarketing surveillance study of patients receiving sorafenib for advanced renal cell carcinoma or unresectable hepatocellular carcinoma, pulmonary toxicity was very uncommon (0.44 percent) [115]. However, among those affected, diffuse pulmonary opacities were noted on chest imaging in approximately 50 percent, and the case fatality rate was 41 percent (25 of 62). Thus, for suspected pulmonary toxicity in patients receiving sorafenib, early cessation of the drug is the most prudent approach.

Pazopanib — Pazopanib is a multitargeted TKI directed against the VEGF receptors 1, 2 and 3, platelet-derived growth factor receptors, and KIT that is approved for treatment of renal cell carcinoma and soft tissue sarcoma. Pneumothorax has been reported in patients treated with pazopanib:

●In the phase III PALETTE study evaluating the efficacy of pazopanib for the treatment of locally advanced or metastatic nonliposarcoma soft tissue sarcoma, 8 of 246 treated patients developed pneumothorax (3 percent) [116].

●In a single-center series, 6 of 43 (14 percent) patients treated with pazopanib developed pneumothorax [117]. All had pleural or subpleural lung metastases, which suggests that the mechanism was due to tumor necrosis leading to alveolar-pleural fistula.

Caution is advised before considering treatment with pazopanib in patients with soft tissue sarcoma with lung metastases [116,117].

OTHER MONOCLONAL ANTIBODIES

Agents targeting the EGFR

●Cetuximab and panitumumab – Cetuximab (Erbitux) and panitumumab (Vectibix) are monoclonal antibodies that directly target the epidermal growth factor receptor (EGFR); they are both used for treatment of advanced colorectal cancer, and cetuximab is also beneficial for head and neck cancer.

Severe acute infusion reactions, which may include bronchospasm, have been described in 2.5 to over 20 percent of patients treated with cetuximab, depending on the geographic area. Infusion reactions are much less frequent with panitumumab (4 percent overall, 1 percent severe). This subject is discussed in detail elsewhere. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Panitumumab' and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Cetuximab'.)

In contrast to the anti-EGFR small molecule tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, pulmonary parenchymal toxicity appears to be uncommon with cetuximab [118-120]. In a series of 2006 patients with advanced colorectal cancer, cetuximab-related lung injury occurred in 24 (1.2 percent) and was severe in only 15 [120]. Fourteen patients received pulse glucocorticoid therapy, and ten patients died of drug-induced lung injury, eight of whom had received glucocorticoids. The incidence of cetuximab-induced lung injury appeared greater in patients who were older, had prior interstitial disease, or had early onset of lung injury (within 90 days of initiating treatment).

Initial reports suggested that pulmonary toxicity is rare with panitumumab; pulmonary fibrosis developed in 2 of 1467 patients enrolled in clinical trials (<1 percent) [121]. However, an increased number of cases of fatal interstitial lung disease and pulmonary fibrosis have been reported to the US Food and Drug Administration (FDA) during postmarketing surveillance, prompting a warning about this issue in December 2011. Panitumumab is typically discontinued if interstitial lung disease develops, as pulmonary disease associated with panitumumab has been fatal in some patients. (See 'Anti-EGFR agents' above.)

●Amivantamab – Amivantamab, a bispecific antibody directed against EGFR and the MET receptor, is approved for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'EGFR exon 20 insertion mutations'.)

In a safety population of 129 patients treated with the drug, interstitial lung disease (ILD)/pneumonitis developed in 3.3 percent, with 0.7 percent experiencing grade 3 ILD/pneumonitis [122]. The United States Prescribing Information recommends that patients be monitored for new or worsening symptoms that may indicate ILD/pneumonitis (eg, cough, dyspnea, fever) [42]. The drug should be withheld if ILD/drug-related pneumonitis is suspected and permanently discontinued if no other potential causes are identified.

Rituximab — Rituximab is a B cell depleting anti-CD20 monoclonal antibody that contains both mouse and human components. Although it has been primarily used for the treatment of CD20-positive non-Hodgkin lymphoma, indications in rheumatology and solid organ transplant have increased the number of patients exposed to this agent.

One of the most predictable side effects of rituximab is an infusion reaction that occurs within the initial 30 to 120 minutes of the first exposure in over 50 percent of patients. The most common symptoms and signs are headache, fever, chills, sweats, skin rash, dyspnea, mild hypotension, nausea, rhinitis, urticaria, pruritus, asthenia, and a sensation of tongue and throat swelling (angioedema); bronchospasm is present in fewer than 10 percent of cases. Infusion reactions are markedly less common with subsequent infusions. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab'.)

Pulmonary parenchymal toxicity is uncommonly reported [123-125]. The incidence in patients receiving rituximab for lymphoma has been addressed in the following reports:

●In a series of 107 patients, nine (8 percent) developed interstitial pneumonia (ILD) while receiving rituximab-containing chemotherapy for non-Hodgkin lymphoma [124]. The median number of cycles of rituximab prior to presentation was two. Clinical symptoms included high fever, with or without dyspnea or non-productive cough. Treatment consisted of high-dose glucocorticoids with a slow taper and empiric antibiotics against atypical pathogens. Eight patients responded to glucocorticoids, while one died of secondary infection. Rechallenge resulted in recurrence of interstitial pneumonitis in two of four patients and is generally not recommended.

●In a randomized trial, ILD was reported in a higher percentage of patients treated with rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine plus prednisone) as compared with CHOP alone (14 versus 0 percent) [125]. However, some of these cases represented opportunistic infection with Pneumocystis jirovecii or a fungal infection.

Discontinuation of the drug and prompt initiation of glucocorticoids typically leads to resolution of pulmonary manifestations; however, fatalities are reported. In a systematic review of the published literature, nine of 31 patients with rituximab-associated lung injury died (29 percent) [126].

Particularly if glucocorticoid therapy is being considered for patients with rituximab-associated ILD, it is mandatory to exclude an infectious etiology with appropriate cultures, often including BAL. Empiric antimicrobial therapy directed at likely pathogens is often indicated while diagnostic procedures and cultures are performed. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

Tafasitamab — Tafasitamab is a CD19-directed cytolytic antibody that is approved, in combination with lenalidomide, for treatment of relapsed or refractory diffuse large B-cell lymphoma in patients not eligible for transplant. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Tafasitamab'.)

In a trial of combined therapy, cough was frequent but typically mild (26 percent, grade 3 or 4 in 1.2 percent) as was dyspnea (12 percent all-grade, 1.2 percent severe) [127]. Respiratory tract infections, bronchitis, and pneumonia developed during treatment in 24, 16, and 10 percent, respectively, but were severe in less than 5 percent. Notably, some of this treatment-related toxicity could be attributed to the lenalidomide, which is also associated with pneumonitis in about 15 percent of cases. (See "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents", section on 'Lenalidomide'.)

Trastuzumab — Trastuzumab (Herceptin) is a humanized monoclonal antibody that binds to a specific epitope of the human epidermal growth factor 2 (HER2) protein on the breast cancer cell surface. Between 20 and 40 percent of women have an infusion reaction during the first treatment with trastuzumab; symptoms may include dyspnea, fever, chills, nausea, headache, and abdominal pain. Most reactions are mild; only approximately 0.3 percent of patients have serious infusion reactions with features of anaphylaxis (bronchospasm, hypotension, angioedema). (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Trastuzumab and other HER2-targeted therapies'.)

Isolated cases of acute respiratory distress syndrome (ARDS), subacute interstitial pneumonia, and organizing pneumonia have been reported in patients receiving trastuzumab (incidence less than 1 percent) [128-132]. Although infrequent, pulmonary toxicity due to trastuzumab may be life-threatening [130-132]. Discontinuation of trastuzumab is advised in any patient who develops pneumonia or ARDS during treatment. Improvement following treatment with glucocorticoids has been reported; however, the role of glucocorticoid therapy in trastuzumab-induced pulmonary toxicity has not been formally studied [128,129,131,133].

Trastuzumab should be used with caution in patients with preexisting lung disease or with widespread metastatic disease to the lungs [132].

Ado-trastuzumab emtansine — Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that incorporates trastuzumab with the cytotoxic microtubule inhibitor DM1. It is approved for advanced breast cancer in patients previously exposed to trastuzumab and taxanes. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

Acute pneumonitis (including severe, life-threatening cases) is rarely reported with T-DM1. In clinical trials, the incidence has been low overall (0.5 to 4.0 percent) [134,135]. Signs, symptoms, and clinical findings included dyspnea, cough, fatigue and pulmonary opacities. Patients with preexisting dyspnea because of advanced malignancy or other comorbidity may be at increased risk. Information is not available on reversibility with or without glucocorticoids. Treatment with T-DM1 should be discontinued in any patient who develops pulmonary toxicity [136].

Fam-trastuzumab deruxtecan — Fam-trastuzumab deruxtecan is a second antibody-drug conjugate, in which trastuzumab is linked to a cytotoxic topoisomerase 1 inhibitor. It is approved for advanced breast cancer in patients previously exposed to trastuzumab and taxanes. It is also used, off-label, for HER2-overexpressing metastatic colorectal cancer. (See "Systemic treatment for HER2-positive metastatic breast cancer" and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, HER2 overexpressors'.)

Severe, life-threatening, and potentially fatal ILD, including pneumonitis, has been reported in a higher number of patients treated with this drug than with ado-trastuzumab emtansine. In a systematic review of 14 studies totaling 1193 patients receiving the drug for a variety of advanced solid malignancies, the overall incidence of all-grade ILD/pneumonitis was 11.4 percent, with the majority of cases (79 percent) being grade 1 or 2; however, grade 5 (fatal) toxicity occurred in 13 of the 122 cases (10.7 percent) [137].

The United States Prescribing Information for fam-trastuzumab deruxtecan emphasizes close monitoring for signs and symptoms of ILD, with prompt radiographic evaluation of respiratory complaints, early initiation of glucocorticoids, and permanent discontinuation of the drug for ≥grade 2 ILD/pneumonitis (table 1) [42].

OTHER ANTIBODY-DRUG CONJUGATES — Enfortumab vedotin is a nectin-4-directed antibody microtubule inhibitor drug conjugate that is approved for metastatic refractory urothelial cancer. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'Enfortumab vedotin'.)

Over several clinical trials, 3.1 percent of the 680 patients treated with the drug developed pneumonitis of any grade, and it was grade 3 or 4 in 0.7 percent; the median time to onset was 2.9 months [138]. The United States Prescribing Information for enfortumab vedotin recommends withholding the drug for persistent or recurrent grade 2 pneumonitis with subsequent dose reduction, and permanent discontinuation of the drug for grade 3 or 4 pneumonitis [42].

Tisotumab vedotin is a tissue factor-directed antibody and microtubule inhibitor drug conjugate approved for use for those with recurrent or metastatic cervical cancer with disease progression on, or after, chemotherapy. (See "Management of recurrent or metastatic cervical cancer", section on 'Second-line therapy'.)

Over several clinical trials, two patients (1.3 percent) developed pneumonitis, one of which was fatal [139]. The United States Prescribing Information for tisotumab vedotin recommends withholding the drug for persistent or recurrent grade 2 pneumonitis with subsequent dose reduction, and permanent discontinuation of the drug for grade 3 or 4 pneumonitis [42].

CHECKPOINT INHIBITORS — Checkpoint inhibitors are immunomodulatory antibodies that enhance the immune system. The primary targets are the programmed cell death 1 (PD-1) receptor (eg, pembrolizumab, nivolumab), programmed cell death ligand 1 (PD-L1; eg, atezolizumab), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; eg, ipilimumab). These agents have been approved for advanced melanoma and advanced non-small cell lung cancer, among other disease states. A spectrum of lung toxicities has been reported with these agents; the symptoms, grading of severity, recommended diagnostic workup, and management are discussed separately (table 2). (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Initial management of advanced non-small cell lung cancer lacking a driver mutation" and "Toxicities associated with immune checkpoint inhibitors", section on 'Pneumonitis'.)

CDK 4/6 INHIBITORS — The cyclin-dependent kinase (CDK) 4/6 inhibitors palbociclib, ribociclib, and abemaciclib are used in combination with endocrine therapy as a first-line therapy for advanced hormone receptor-positive, human epidermal growth factor 2 (HER2)-negative breast cancer.

Postmarketing surveillance has revealed a small risk of potentially severe lung inflammation in patients treated with these three drugs [140]. Specific risk factors have not been identified. The United States Prescribing Information for all three drugs recommends monitoring patients regularly for pulmonary signs or symptoms such as hypoxia, cough, dyspnea, or otherwise unexplained radiologic interstitial opacities, and that treatment be interrupted and possibly discontinued for new or worsening symptoms/signs [42]. Dose interruption or dose reduction is recommended in patients who develop persistent or recurrent grade 2 ILD/pneumonitis (table 1); the drugs should be discontinued in all patients with grade 3 or 4 ILD/pneumonitis.

PARP INHIBITORS — Pneumonitis is uncommonly described in patients treated with poly (ADP-ribose) polymerase (PARP) inhibitors, but can be fatal. The best data come from an analysis of 16 randomized trials of a variety of PARP inhibitors in a variety of malignancies; the incidence of pneumonitis across treatment arms was 0.79 percent (28 out of 3551 treated patients) [141]. In an accompanying analysis of 84 cases of pneumonitis in patients treated with PARP inhibitors and reported to the US Food and Drug Administration adverse event reporting system from 2004 to 2020, the median time to onset was 81 days, and 87 percent of the cases occurred within six months of treatment initiation, though the range was wide (1 to 588 days). Olaparib was associated with the most cases (n = 61), and rucaparib and talazoparib with the least cases (3 cases in total). The fatality rate among affected patients was 16 percent (13 out of 79 patients).

There are rare reports of venous thromboembolism, including fatal cases of pulmonary embolism with olaparib, mainly in patients with castration-resistant prostate cancer treated with the drug in combination with androgen deprivation therapy [142]. The United States Prescribing Information for olaparib recommends that clinicians monitor for signs and symptoms of venous thromboembolism and treat as medically indicated, which may include long-term anticoagulation [42].

RAPAMYCIN AND ANALOGS — Pneumonitis is a known side effect of inhibitors of mTOR (mechanistic [previously called mammalian] target of rapamycin). In a meta-analysis of trials in which temsirolimus and everolimus were used to treat solid malignancies (2233 patients), the incidence rates of high-grade and overall pulmonary toxicity were 3 and 12 percent, respectively [143,144]. The presentation varies from asymptomatic radiographic abnormalities to significant respiratory impairment; most cases resolve with drug discontinuation. (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Respiratory system'.)

Everolimus and temsirolimus are macrolide mTOR inhibitors that have antiproliferative properties; they are active in the treatment of advanced renal cell cancer and nonsecretory advanced neuroendocrine tumors. Although infrequent, potentially fatal interstitial lung disease (ILD) is reported in patients receiving these agents, as described in the following sections [145-148].

Temsirolimus — Temsirolimus has been associated with pneumonitis in 0.5 to 5 percent of patients with cancer who were enrolled in clinical studies; some had severe toxicity, including rare fatalities [147,149-152]. Symptoms and signs suspicious for pneumonitis include pleural effusion, hypoxia, cough, dyspnea, and malaise.

Low-grade pneumonitis may be more common than severe pneumonitis [153]. Radiographic findings consistent with drug-induced pneumonitis were detected in 36 percent of patients receiving temsirolimus for advanced neuroendocrine tumors and endometrial carcinoma in an independent review of serial radiographic studies performed for response assessment [154]. Radiographic findings included ground glass opacity or consolidation. One-half were asymptomatic. Drug treatment was continued in some cases without worsening of the pneumonitis.

However, others have shown a high rate of recurrent pneumonitis after rechallenge. In a phase II trial, four (2 percent) of 208 patients treated with temsirolimus developed ILD of varying severity, including grades 3 and 4 (table 1) [148]. Patients were managed with antibiotics and/or glucocorticoids and/or temsirolimus dose reduction or discontinuation. Of the four patients who were retreated after symptom resolution, two experienced recurrent pneumonitis.

Monitoring and management guidelines are not yet established for patients who develop radiographic changes while receiving temsirolimus, with or without symptoms indicative of ILD. A suggested approach has been proposed based on an analysis of experience in a phase III trial (table 3) [151]. However, only four patients in this trial developed pneumonitis of any severity while receiving temsirolimus, only one of which was severe.

In our view and that of others, clinical suspicion of symptomatic drug-induced lung toxicity generally justifies treatment discontinuation and consideration of an alternative agent [145,146]. There is no published experience with glucocorticoid therapy.

Everolimus — Everolimus is an orally active mTOR inhibitor; clinical pneumonitis has been reported in 8 to 14 percent of patients receiving systemic treatment with everolimus; as with temsirolimus, there appears to be a higher incidence of low-grade than high-grade pneumonitis [152,153,155-160]. The following represents the range of findings:

●In a placebo-controlled randomized trial of everolimus for advanced renal cell carcinoma, clinical pneumonitis was suspected in 37 (14 percent) of the 274 patients who received everolimus [155]. Ten had severe (grade 3) pneumonitis (table 1), five of whom had radiologic evidence of pneumonitis before drug administration.

●In another phase III trial, pneumonitis of any grade was detected in 22 patients (8 percent) receiving everolimus for advanced renal cell cancer, and it was grade 3 severity (table 1) in eight [146].

●Similarly, in a randomized trial of octreotide with or without everolimus for treatment of advanced carcinoid in 429 patients, pneumonitis of any grade was detected in 18 patients who received combined therapy (8 percent) versus none in the control group; pneumonitis was serious (life-threatening, requiring hospitalization or intervention, causing disability or permanent damage) in three patients [161].

●In a retrospective review of 64 patients receiving everolimus for non-small cell lung cancer (NSCLC), 24 (38 percent) had newly occurring or worsening radiographic findings consistent with pneumonitis during therapy, and 21 developed ILD within three months of starting treatment [156]. In most of the patients, pneumonitis remained at the same or lower grade without discontinuation of therapy.

●Pneumonitis has also been reported following the placement of an everolimus-eluting coronary artery stent, but the frequency with which this occurs is unclear [162,163].

Baseline ILD appears to be a risk factor for everolimus-associated pneumonitis; in one series, it was present in 29 versus 8 percent of patients who did and did not develop pneumonitis during treatment, respectively [155]. Of the six cases that were graded as severe (grade 3 or 4, (table 1)), four had ILD at baseline; two were fatal.

The most common symptoms are dyspnea, cough, fatigue, and fever [155,156]. The most common radiographic features are focal areas of consolidation at the lung bases or ground glass opacities, but some patients manifest diffuse ground glass or consolidative opacities [155,156].

Findings on bronchoalveolar lavage (BAL) were described in a report of seven patients who developed interstitial lung disease while receiving everolimus for advanced renal cell cancer, four patients underwent BAL, all of whom had BAL lymphocytosis (43 to 82 percent) and two had an increased eosinophil count (10 and 14 percent) [159]. Transbronchial lung biopsies obtained from three patients revealed interstitial lymphocytic inflammation and mild septal thickening of alveolar walls; some alveoli had fibrinous exudates.

The clinical course of everolimus-related ILD has been described in two reports:

●In the placebo-controlled randomized trial of everolimus for advanced renal cell carcinoma, in which clinical pneumonitis was suspected in 37, glucocorticoid therapy was initiated in 16 [155]. Twenty of the 37 cases (54 percent) were reversible within the follow-up period. Of the 10 patients with grade 3 pneumonitis, six received glucocorticoids. One of the three patients who continued everolimus had resolution, one improved, and one died, thought due to disease progression rather than drug toxicity. Of the seven who discontinued treatment, all had complete resolution. The contribution of glucocorticoid treatment to recovery was unclear.

●In one of the retrospective series described above, of seven patients who developed ILD during treatment with everolimus, two cases had mild ILD, the drug was continued successfully, but in the four cases of grade 3 ILD, drug was discontinued and glucocorticoids instituted, with radiographic and symptomatic clearing within two months [159]. There were too few patients to determine the relative effects of drug interruption or glucocorticoid therapy on pneumonitis.

Monitoring and management guidelines have been suggested for patients who develop symptoms or radiographic changes while receiving everolimus based on the grade of pneumonitis (table 1) [155,160,164].

●Grade 1 pneumonitis – Observe the patient closely (eg, repeat chest radiograph/computed tomography [CT] scan every two cycles) while continuing everolimus therapy.

●Grade 2 pneumonitis – Reduce everolimus dose of 5 mg daily until improvement to grade 1 or less, and discontinue everolimus if improvement to grade 1 or less does not occur within three weeks. Glucocorticoids are administered only if cough is troublesome. Obtain chest CT scan and pulmonary function tests each cycle.

●Grade 3 pneumonitis – Prescribe systemic glucocorticoids after infection is excluded; after improvement, taper glucocorticoids as tolerated. Everolimus is interrupted until improvement of pneumonitis to grade 1 or less. Everolimus may be resumed in two weeks at a reduced dose of 5 mg daily if clinical benefit is evident. Monitor chest CT and pulmonary function tests each subsequent cycle.

●Grade 4 pneumonitis – Prescribe systemic glucocorticoids after infection is excluded; after improvement, taper glucocorticoids as tolerated. Permanently discontinue everolimus.

SOTORASIB — Sotorasib is an inhibitor of the RAS GTPase family, and is approved for treatment of advanced non-small cell lung cancer with a RAS G12C mutation. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Sotorasib'.)

Sotorasib can cause interstitial lung disease (ILD)/pneumonitis that can be fatal. In a report of 357 patients receiving the drug, ILD/pneumonitis occurred in 0.8 percent, all cases were grade 3 or 4 at onset, and one case was fatal [165]. The median time to first onset was two weeks (range 2 to 18 weeks). Notably, not all patients who develop cough or dyspnea (which occurred in approximately 20 percent of patients while on treatment) have ILD/pneumonitis.

The United States Prescribing Information recommends withholding sotorasib if ILD/drug-related pneumonitis is suspected and permanent discontinuation if no other potential causes are identified [42].

SUMMARY AND RECOMMENDATIONS

●Frequency of pulmonary toxicity – Although pulmonary toxicity associated with molecularly targeted therapy is relatively infrequent (especially interstitial lung disease [ILD]), the diagnosis should be entertained once careful investigations have excluded alternative explanations, including opportunistic infections, radiation-induced lung injury, or metastatic involvement of the lungs. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Differential diagnosis'.)

●Making the diagnosis – There are no clearly defined criteria for drug-induced lung disease. Because signs and symptoms are generally nonspecific, the diagnosis usually remains one of exclusion. A presumptive diagnosis can be made when pneumonitis develops shortly after the initiation of treatment, an alternative explanation for the respiratory compromise is lacking, and the pneumonitis resolves soon after withdrawal of the presumed agent and/or after glucocorticoid treatment.

●Management of patients with suspected pulmonary toxicity

•For patients who develop lung toxicity during treatment with a molecularly targeted agent, the decision to continue treatment, interrupt therapy, or switch to an alternative agent must be carefully considered based on the clinical circumstances, and the nature and severity of the pulmonary toxicity. In general, suspicion of significant lung toxicity justifies discontinuation of the drug, at least temporarily. Severe pulmonary toxicity (especially grade 4, (table 1)) that is felt to be likely attributed to the drug generally warrants permanent discontinuation.

•For patients who develop ILD, no specific treatment has proven effective besides discontinuation of the suspected offending agent. Glucocorticoids are frequently used, but their effectiveness is based only on anecdotal reports. Although the risk of opportunistic infection may be slightly increased, a short course of high-dose glucocorticoids is usually appropriate in rapidly progressive or severe disease. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James Jett, MD, who contributed to earlier versions of this topic review.