Crizotinib as the first-generation ALK inhibitor has shown significant activity in ALK-mutated non-small cell lung cancer (NSCLC). Second- and third-generation ALK inhibitors are entering clinical applications for ALK+ NSCLC. In addition, a third-generation ALK inhibitor, lorlatinib (PF-06463922), was reported to resensitize NSCLC to crizotinib. This review provided a summary of clinical development of alectinib, ceritinib, brigatinib (AP26113), and lorlatinib.

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Second- and third-generation ALK inhibitors for non-small cell lung cancer

Since the approval of the first molecularly targeted tyrosine kinase inhibitor (TKI), imatinib, in 2001, TKIs have heralded a new era in the treatment of many cancers. Among their innumerable adverse effects, interstitial lung disease (ILD) is one of the most serious, presenting most frequently with dyspnea, cough, fever, and hypoxemia, and often treated with steroids. Of the 28 currently approved TKIs, 16 (57 %) are reported to induce ILD with varying frequency and/or severity. The interval from drug administration to onset of ILD varies between patients and between TKIs, with no predictable time course. Its incidence is variously reported to be approximately 1.6–4.3 % in Japanese populations and 0.3–1.0 % in non-Japanese populations. The mortality rate is in the range of 20–50 %. Available evidence (primarily following the use of erlotinib and gefitinib in Japan because of the unique susceptibility of that population) has identified a number of susceptibility and prognostic risk factors (male sex, a history of smoking, and pre-existing pulmonary fibrosis being the main ones). Although the precise mechanism is not understood, collective evidence suggests that immune factors may be involved. If TKI-induced ILD is confirmed by thorough evaluation of the patient and exclusion of other causes, management is supportive, and includes discontinuation of the culprit TKI and administration of steroids. Discontinuing the culprit TKI presents a clinical dilemma because the diagnosis of TKI-induced ILD in a patient with pre-existing pulmonary fibrosis can be challenging, the patient may have TKI-responsive cancer with no suitable alternative, and switching to an alternative agent, even if available, carries the risk of the patient experiencing other toxic effects. Preliminary evidence suggests that therapy with the culprit TKI may be continued under steroid cover and/or at a reduced dose. However, this approach requires careful individualized risk–benefit analysis and further clinical experience.

Tyrosine Kinase Inhibitor-Induced Interstitial Lung Disease: Clinical Features, Diagnostic Challenges, and Therapeutic Dilemmas

Interstitial Lung Disease Associated With Crizotinib in Patients With Advanced Non-Small Cell Lung Cancer: Independent Review of Four PROFILE Trials.

The incidence of ALK inhibitor-related pneumonitis in advanced non-small-cell lung cancer patients: A systematic review and meta-analysis

Background Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor approved by the US Food and Drug Administration to treat crizotinib-refractory non-small cell lung cancer. We performed this meta-analysis to synthesize the results of different clinical trials to evaluate the efficacy and safety of alectinib. Methods A search of 3 databases, including PubMed, Web of Science, and the Cochrane Library, was performed from the inception of each database through September 5, 2017. We have pooled the overall response rate (ORR), disease control rate, progression-free survival, and intracranial ORR to evaluate the efficacy of alectinib. Discontinuation rate, rate of dose reduction or interruption due to adverse events as well as the incidence of several adverse events were aggregated to evaluate its safety. Results A total of 8 studies with 626 patients have been included in our study. The pooled efficacy parameters are as follows: ORR 70% (95% CI: 57% to 82%), disease control rate 88% (95% CI: 82% to 94%), progression-free survival 9.36 months (95% CI: 7.38% to 11.34%), and intracranial ORR 52% (95% CI: 45% to 59%). ALK inhibitor-naive patients tend to have better responses than crizotinib-pretreated patients. The aggregate discontinuation rate is 7% (95% CI: 4% to 10%), and the pooled rate of dose reduction or interruption is 33% (95% CI: 24% to 42%). The incidences of most adverse events were relatively low, while the incidences of 2 frequently reported adverse events, myalgia (18%) and anemia (25%), were even higher than with the first-generation ALK inhibitor crizotinib. Conclusion Generally, alectinib is a drug with preferable efficacy and tolerable adverse effects, and it is suitable for the treatment of intracranial metastases.

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The efficacy and safety of alectinib in the treatment of ALK+ NSCLC: a systematic review and meta-analysis

Crizotinib, an orally active multi-targeted small-molecule anaplastic lymphoma kinase (ALK) inhibitor, is an effective treatment modality for advanced ALK-positive non-small-cell lung cancer (NSCLC). Most drug-related adverse events are mild to moderate; however, some patients may develop acute interstitial lung disease (ILD) which is sometimes fatal. We present a case of crizotinib-associated ILD in a 47-year-old woman treated with crizotinib for metastatic adenocarcinoma of the lung. The patient presented with acute breathlessness and hypoxaemia in the second month of crizotinib therapy; radiological and histopathological work-up was suggestive of acute interstitial pneumonia. The patient improved clinically with corticosteroid therapy and was successfully re-challenged with crizotinib. In conclusion, while treating NSCLC patients with crizotinib, it is important to promptly investigate and treat any new-onset respiratory symptoms, as the latter could represent an adverse effect related to therapy. Prompt discontinuation of the offending drug and initiation of corticosteroid therapy may prevent adverse outcomes.

N. Anil Kumar

Papers

Acute interstitial lung disease in a patient with anaplastic lymphoma kinase-positive non-small-cell lung cancer after crizotinib therapy