Lorlatinib in the treatment of anaplastic lymphoma kinase-positive non-small-cell lung cancer

Rearrangements of the anaplastic lymphoma kinase (ALK) gene, which encodes for the ALK receptor tyrosine kinase, are detected in ∼5% of patients with non-small-cell lung cancer (NSCLC) with adenocarcinoma histology.1Barlesi F. Mazieres J. Merlio J.P. et al.Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).Lancet. 2016; 387: 1415-1426Abstract Full Text Full Text PDF PubMed Scopus (623) Google Scholar Crizotinib was the first ALK tyrosine kinase inhibitor (TKI) approved for metastatic, ALK-positive NSCLC and was superior to platinum-based therapy in the first-line setting. However, crizotinib resistance develops due to secondary mutations in the ALK tyrosine kinase domain, ALK amplification, or activation of bypass pathways.2Lin J.J. Riely G.J. Shaw A.T. Targeting ALK: precision medicine takes on drug resistance.Cancer Discov. 2017; 7: 137-155Crossref PubMed Scopus (280) Google Scholar Crizotinib also has relatively poor central nervous system (CNS) penetration, leading to frequent CNS disease progression.3Camidge D.R. Pao W. Sequist L.V. Acquired resistance to TKIs in solid tumours: learning from lung cancer.Nat Rev Clin Oncol. 2014; 11: 473-481Crossref PubMed Scopus (610) Google Scholar Next-generation ALK TKIs, such as ceritinib, alectinib, and brigatinib, were developed with increased activity against ALK resistance mutations and superior CNS penetration. Phase III clinical trials of the next-generation ALK TKIs demonstrated a superior progression-free survival (PFS) and CNS activity compared with standard therapies, which led to their adoption as first-line therapy. First-line next-generation ALK TKIs have significantly improved the outcomes of patients with ALK-positive NSCLC, but the new clinical challenge is developing therapies for patients with disease progression after next generation ALK TKI's. Lorlatinib is a novel ALK TKI with broad activity against ALK resistance mutations, including the G1202R resistance mutation, which is more common at the time of disease progression with next-generation ALK TKIs.4Gainor J.F. Dardaei L. Yoda S. et al.Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer.Cancer Discov. 2016; 6: 1118-1133Crossref PubMed Scopus (673) Google Scholar It also has demonstrated high CNS penetration due to reduced efflux by P-glycoprotein compared with other ALK TKIs.5Zou H.Y. Friboulet L. Kodack D.P. et al.PF-06463922, an ALK/ROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical models.Cancer Cell. 2015; 28: 70-81Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar Preclinical data provided a strong rationale to investigate lorlatinib after next-generation ALK TKIs. The study published in this issue of Annals of Oncology by Felip and colleagues6Felip E. Shaw A.T. Bearz A. et al.Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs.Ann Oncol. 2021; 32: 620-630Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar reports the updated results of the second-line trial of lorlatinib, where patients were assigned to specific cohorts based on prior therapy. The primary efficacy assessments were extra-CNS and CNS objective response rates (ORR). In expansion cohort 3B, patients had received one prior second-generation ALK TKI, which is a common clinical scenario. The ORR, the median duration of response (DoR), and median PFS were 42.9% [95% confidence interval (CI): 24.5% to 62.8%], 6.2 months (95% CI: 4.2-35.3), and 5.5 months (95% CI: 2.9-8.2), respectively. The intracranial ORR and DoR in the subset of patients with CNS evaluable disease (n = 9) was 66.7% (95% CI: 29.9% to 92.5%) and 20.7 months (95% CI: 4.1-37.1), respectively. When the efficacy is assessed based on last prior ALK TKI before lorlatinib, the ORR response rate with previous alectinib, brigatinib, and ceritinib were 40.5% (95% CI: 24.8% to 57.9%), 40% (95% CI: 5.3% to 85.3%), and 55.6% (95% CI: 38.1% to 72.1%), respectively. While this is a post-hoc, exploratory analysis, it suggests that the specific next generation ALK TKI used prior to lorlatinib does not influence the activity of lorlatinib. Thus, the updated analysis confirms the second-line activity and CNS activity of lorlatinib. With all the caveats of cross-trial comparisons, the activity observed with lorlatinib is similar to brigatinib and superior to ceritinib in a similar setting.7Hida T. Seto T. Horinouchi H. et al.Phase II study of ceritinib in alectinib-pretreated patients with anaplastic lymphoma kinase-rearranged metastatic non-small-cell lung cancer in Japan: ASCEND-9.Cancer Sci. 2018; 109: 2863-2872Crossref PubMed Scopus (40) Google Scholar, 8Stinchcombe T.E. Doebele R.C. Wang X. et al.Preliminary clinical and molecular analysis results from a single-arm phase 2 trial of brigatinib in patients with disease progression after next-generation ALK tyrosine kinase inhibitors in advanced ALK+ NSCLC.J Thorac Oncol. 2021; 16: 156-161Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 9Nishio M. Yoshida T. Kumagai T. et al.Brigatinib in Japanese patients with ALK-positive NSCLC previously treated with alectinib and other tyrosine kinase inhibitors: outcomes of the phase 2 J-ALTA trial.J Thorac Oncol. 2021; 16: 452-463Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar However, the sobering aspect of these studies is that a minority of patients experience a response to therapy, with a smaller subset experiencing durable benefit. This is probably due to variation in the coverage of ALK-dependent resistance mechanisms by the ALK TKIs studied and that as many as half of patients may have an ALK-independent mechanism of resistance.4Gainor J.F. Dardaei L. Yoda S. et al.Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer.Cancer Discov. 2016; 6: 1118-1133Crossref PubMed Scopus (673) Google Scholar The development of predictive markers to improve outcomes of patients with disease progression on next-generation ALK TKIs is a high priority in this field. The presence of ALK resistance mutations may indicate the NSCLC continues to depend on the ALK pathway, and further ALK-directed therapy may be effective. The absence of ALK resistance mutation may indicate that ALK independent mechanisms are responsible for resistance and further ALK-directed therapy may not be effective. In a retrospective study, patients with ALK resistance mutation detected on the cell-free DNA (cfDNA) and tumor biopsies were compared with patients without ALK mutation. Patients with an ALK resistance mutation detected experienced a higher response rate to lorlatinib who experienced a higher response rate to lorlatinib.10Shaw A.T. Solomon B.J. Besse B. et al.ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer.J Clin Oncol. 2019; 37: 1370-1379Crossref PubMed Scopus (179) Google Scholar In patients with ALK resistance mutation compared with patients without mutation detected on tumor biopsy, there was a significantly longer PFS, and in the subset of patients who underwent de novo tumor biopsy, the difference in PFS was more pronounced. The data on ALK mutation status are very intriguing but require additional validation in a larger number of patients and, ideally, prospectively. Importantly, the presence of ALK resistance mutation does not guarantee the absence of an ALK-independent resistance mechanism, and the clinical activity of the next ALK TKI may depend on the specific ALK mutation. There are practical barriers to implementation of routine tumor biopsy for testing of ALK mutation status, as many patients have only CNS disease progression, disease progression in sites not amendable to a biopsy, or may undergo biopsy and have insufficient tumor tissue for testing. Other patients may need to transition to the next line of therapy in a timely manner and may not be able to tolerate the inevitable delays associated with tumor biopsy and testing. Testing by cfDNA is a promising alternative and can assess for ALK resistance mutations in multiple metastatic sites. Testing with cfDNA may have lower sensitivity in patients with isolated CNS disease progression and may have greater sensitivity when detecting multiple mutations.11Dagogo-Jack I. Rooney M. Lin J.J. et al.Treatment with next-generation ALK inhibitors fuels plasma ALK mutation diversity.Clin Cancer Res. 2019; 25: 6662-6670Crossref PubMed Scopus (74) Google Scholar,12Aldea M. Hendriks L. Mezquita L. et al.Circulating tumor DNA analysis for patients with oncogene-addicted NSCLC with isolated central nervous system progression.J Thorac Oncol. 2020; 15: 383-391Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Most likely, a combination of cfDNA and tumor biopsies will be needed, and future studies of novel ALK TKIs should attempt to collect both. CNS disease progression has significant clinical implications, and demonstrating CNS activity is critical to the development of novel therapies in NSCLC. Felip et al. should be commended for the diligent assessment of the CNS activity in this trial. Magnetic resonance imaging of the brain was carried out every 6 weeks for the first 30 months, and then every 12 weeks, and responses were assessed by independent central radiology review. The analysis of first progression event being CNS or non-CNS, using a competing risk analysis in patients with and without brain metastases, demonstrates the activity of lorlatinib (Figure 2A and B in 6Felip E. Shaw A.T. Bearz A. et al.Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs.Ann Oncol. 2021; 32: 620-630Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). For patients with and without baseline CNS metastases, extra-CNS disease was the more common first site of disease progression. The high prevalence of brain metastases at baseline in this study demonstrates the clinical importance of assessing the CNS activity of novel ALK TKIs. The time of clinical trials assessing for CNS disease progression based on ‘local standard of care’ or based on the development of symptomatic brain metastases has passed. Secondary analyses assessing the outcomes of patients with and without baseline brain metastases and without a pre-specified imaging schedule are of limited clinical utility. Based on the results of the recent phase III trial of lorlatinib compared with crizotinib as first-line therapy in ALK-positive NSCLC, lorlatinib was approved by the American Food and Drug Administration (FDA) in March 2021 as first-line therapy in the near future.13Shaw A.T. Bauer T.M. de Marinis F. et al.First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer.N Engl J Med. 2020; 383: 2018-2029Crossref PubMed Scopus (192) Google Scholar,14FDALobrena (lorlatinib tablets). Supplement approval/fulfillment of postmarketing requirement.https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/210868Orig1s004ltr.pdfDate: 2021Google Scholar This raises questions about the relevance of second-line lorlatinib. Many clinicians will adopt first-line lorlatinib based on the efficacy results, especially the CNS efficacy. Other clinicians may continue to use one of the currently available ALK TKIs due to the unique adverse events of lorlatinib (e.g. hypercholesterolemia, hypertriglyceridemia, cognitive effects, and mood effects) or preserve lorlatinib as a second-line option. Most of us will decide based on the individual characteristics of the patient and their preferences. Second-line lorlatinib will continue to be an important treatment option for many patients, and most patients receive multiple lines of therapy in this disease. As the number of treatment options for ALK-positive NSCLC has increased, the pertinent clinical questions are the optimal sequence of therapies and the potential role for combination therapy in select patients. None declared.