Background
Alectinib is one of the key drugs for treating patients with ALK-positive non-small cell lung cancer (NSCLC), because it is effective and is well tolerated [
1]. Interstitial lung disease (ILD) is an important adverse effect associated with alectinib treatment as well as with all tyrosine kinase inhibitors (TKI) [
2]. Generally, when ILD occurs, TKI therapy should be terminated, although treatment with certain molecular targeting inhibitors such as those specific for mammalian target of rapamycin (mTOR) can be continued [
3]. It is unclear whether the physician should continue alectinib when ILD is diagnosed. Here we report two patients with alectinib-induced ILD who were able to continue alectinib therapy.
Discussion and conclusions
Alectinib is a key drug for treating patients with
EML4-ALK-positive NSCLC. In particular, alectinib is highly effective and well tolerated [
1], although some patients may experience severe acute ILD [
4]. In the ALEX trial and the J-ALEX trial, the incidence of alectinib-induced ILD was reported 1% and 8%, respectively [
5,
6]. Physicians generally must discontinue alectinib in such cases, although we believe that certain patients can continue therapy.
In general, drug-induced ILD is suspected when the following criteria are met:(1) history of exposure to the suspected drug, (2) report of suspected previous drug-induced ILD, (3) exclusion of other causes, (4) improvement after discontinuation of a suspected drug, and (5) recurrence of symptoms on rechallenge [
7]. Patient 1 did not meet criteria 5 and patient 2 did not meet criteria 4 and 5.; however, there was no evidence of infection and other etiologies of ILD. Furthermore,
Ikeda et al. reported a patient with alectinib-induced ILD who had GGO and no clinical symptoms, similar to our patients [
8]. We conclude therefore that our patients had alectinib-induced ILD.
Generally, drug-induced ILD is characterized by lymphocyte-predominant BALF, while bacterial pneumonia may be associated with neutrophil-predominant BALF.
Ait-Tahar et al. reported higher immune responses of B and cytotoxic T cells in ALK-positive patients with anaplastic large cell lymphoma than in ALK-negative patients [
9]. It is suggested that having ALK fusion gene may lead to higher immune response. Analysis of the BALF of Patient 1 revealed lymphocyte-predominant disease, which might reflect “ALK fusion gene-related drug hypersensitivity”. This “hypersensivity” may lead to the risk of ILD. Otherwise the BALF of Patient 2 was neutrophil-predominant, which may be influenced by the low recovery rate from BALF. Additionally, since there was no evidence of other etiology of the GGO, the absence of lymphocyte-predominant BALF did not exclude drug-induced ILD.
We continued alectinib despite the suspicion of ILD, because patient1 did not have any symptoms, patient 2 had only very sligh cough.
Créquit P et al. reported that six of 29 patients with ILD who were treated with crizotinib, the first available ALK inhibitor for treating NSCLC, had few clinical symptoms [
10]. Moreover, they reported that patients with crizotinib-induced ILD had longer median progression-free survival compared with those without crizotinib-ILD (19.9 vs 6.2 months,
p = 0.04). Therefore, these findings suggest that a patient with ALK inhibitor-induced ILD may exhibit a higher response compared with those without ALK inhibitor-induced ILD. To our knowledge, this is the first report that patients with ILD Grade 2 or less were able to continue alectinib therapy.
Alectinib may induce severe ILD. For example, CT detected bilateral GGO in a patient with progressive dyspnea [
4]. According to
Créquit P et al., a patient with crizotinib-induced ILD died from acute respiratory distress syndrome on day 28 after the initiation of crizotinib therapy, and this patient previously experienced reversible erlotinib-induced ILD [
10]. Therefore, if physicians want to continue alectinib treatment for a patient with alectinib-ILD Grade2 or less, the very careful observation is needed.
There are some limitations to the present study. First, we retrospectively studied two patients who were treated at a single center, and more patients must be studied, or a multicenter prospective study will be required. Second, the recovery rate of BALF was insufficient, so BALF analysis may not have reflected the effect of alectinib for the lungs accurately. Third, it is not clear if our patients responded longer to therapy compared with those without alectinib-induced ILD.
We conclude that certain patients with alectinib-induced ILD Grade2 or less may continue alectinib therapy if they are closely managed, because they may therefore achieve a prolonged response to therapy that leads to longer survival.