Anticipating the Next Step in the Management of ALK-Positive NSCLC
Authors: Cheryl Ho
Journal: Journal of Thoracic Oncology (2018)

There have been multiple advances in the management of anaplastic lymphoma kinase (ALK)-positive NSCLC over the past few years. Crizotinib has been the established first-line therapy since 2011; however, data from the ALEX trial have now shifted practice to include alectinib in the frontline setting.1Solomon B.J. Mok T. Kim D.W. et al.First-line crizotinib versus chemotherapy in ALK-positive lung cancer.N Engl J Med. 2014; 371: 2167-2177Crossref PubMed Scopus (2460) Google Scholar, 2Peters S. Camidge D.R. Shaw A.T. et al.Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer.N Engl J Med. 2017; 377: 829-838Crossref PubMed Scopus (1486) Google Scholar Second-generation (ceritinib, alectinib, and brigatinib) and third-generation (lorlatinib and entrectinib) agents have demonstrated success in treating patients with resistance mutations and are evolving the treatment paradigm. With progression-free survival (PFS) of more than 2 years and overall survival exceeding 4 years, this is a great success story for lung cancer. Beyond targeted therapies, there have also been notable advances in immunotherapy with programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors in NSCLC. With established roles in first- and second-line management as single agents, further exploration of combinations with other immunotherapy agents, chemotherapy, and targeted therapy is ongoing. Early signals suggest that combinations with chemotherapy may significantly improve response rates and PFS, as seen in the phase II study of pembrolizumab plus carboplatin/pemetrexed in Keynote 021.3Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 17:1497–1508.Google Scholar The appetite for further exploration is evidenced by the multitude of combination trials available. In this issue of the Journal of Thoracic Oncology, Spigel et al. investigated the combination of ALK inhibitors and immunotherapy.4Spigel D.R. Reynolds C. Waterhouse D. et al.Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of ALK translocation-positive advanced non-small cell lung cancer (CheckMate 370).J Thoracic Oncol. 2018; 13: 682-688Abstract Full Text Full Text PDF Scopus (160) Google Scholar They present the results of a phase I/II study of nivolumab plus crizotinib in first-line treatment of ALK translocation–positive advanced NSCLC. In this study, 13 patients with good performance status received nivolumab, 240-mg flat dose every 2 weeks, with crizotinib, 250 mg twice daily. Grade 3 or higher hepatotoxicity developed in five of the 13 patients; none of these patients had hepatic metastases. Two patients on study died: the first had pneumonitis, rhabdomyolysis, and grade 3 or higher increases in alanine transaminase (ALT) and aspartate transaminase levels, and the second had grade 4 acute liver failure with disease progression. The timing of the hepatotoxicity was variable, with all instances appearing within 60 days of treatment initiation. The response rate of the 13 evaluable patients was 38%. On the basis of toxicity, the trial was closed early and a decision was made to not pursue further investigation. Was there a good rationale for considering this particular combination? Preclinical data suggest that there is an association with ALK and PD-L1 expression. Cell lines (H2228 and H3122) that are forced to express the echinoderm microtubule associated protein like 4–ALK fusion protein demonstrate an upregulation of PD-L1 level.5Ota K. Azuma K. Kawahara A. et al.Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer.Clin Cancer Res. 2015; 21: 4014-4021Crossref PubMed Scopus (360) Google Scholar The upregulation could reflect the tumor cells’ effort to promote immune resistance. In archival specimens, PD-L1 expression was noted in ALK-positive NSCLC. These data all suggest that perhaps there could be a role for combination ALK inhibitors and PD-1/PD-L1 antibodies to improve outcomes. ALK fusion NSCLC may be positive for the PD-L1 biomarker, but is it predictive? In a retrospective examination of PD-L1 status in treatment-naive ALK-positive specimens, the positivity rate ranged from 26% to 63% depending on the biomarker cutoff. 6Gainor J.F. Shaw A.T. Sequist L.V. et al.EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis.Clin Cancer Res. 2016; 2: 4585-4593Crossref Scopus (825) Google Scholar Correlation with responses was not seen; none of the patients responded to PD-1/PD-L1 therapy. Prospective data in ALK-translocated NSCLC with PD-1/PD-L1 inhibitors is limited, as the three studies that allowed accrual (Checkmate 057, Keynote 010, and POPLAR) had only a handful of patients who received immunotherapy (n = 19). It is well recognized that PD-L1 status is an imperfect biomarker in NSCLC. Beyond the heterogeneity in testing depending on the platform and the different cutoffs for trials, in practice discordance between PD-L1 status and response is not that uncommon. In this subpopulation of patients with NSCLC, clinical studies suggest that PD-L1 status may not be relevant for predicting benefit. Tumor mutational burden (TMB) as a predictive marker for PD-1/PD-L1 therapy in ALK-positive patients may provide better insight. The presence of multiple mutations may increase the immunogenicity of a tumor, thereby providing targets for T cells. Assessment of TMB, as determined by the number of somatic, coding, base substitution, and indel alterations per megabase of genome, proved to be low in ALK fusion NSCLC.7Spigel D.R. Schrock A.B. Fabrizio D. et al.Total mutation burden (TMB) in lung cancer (LC) and relationship with response to PD-1/PD-L1 targeted therapies.J Clin Oncol. 2016; 34 ([abstract]): 9017Crossref Google Scholar In Checkmate 026, a comparison of first-line nivolumab versus platinum-doublet chemotherapy in PD-L1–positive patients, an exploratory analysis examined TMB, defined as total number of somatic missense mutations present in a baseline tumor sample with use of whole exome sequencing. Patients with low and medium burden had inferior outcomes with first-line nivolumab versus with platinum doublet.8Carbone D.P. Reck M. Paz-Ares L. et al.First-line nivolumab in stage IV or recurrent non-small-cell lung cancer.N Engl J Med. 2017; 376: 2415-2426Crossref PubMed Scopus (1736) Google Scholar Further evaluation of the prevalence of high TMB in patients with driver mutations such as ALK fusions is required to understand how immunotherapy fits into the treatment strategy. Although it is clear that ALK fusion is a predictor of response to ALK inhibitors and it is likely that PD-L1 status in this subset is not predictive of response to PD-1–directed therapy, how to apply this knowledge to the combination is unknown. Preclinical work demonstrates that whereas echinoderm microtubule associated protein like 4–ALK cell lines may have increased PD-L1 expression, this expression is down-regulated when they are exposed to ALK inhibitors. In these cell lines cocultured with T cells, the combination of an ALK inhibitor with an anti–PD-1 antibody did not produce a synergistic effect.9Hong S. Chen N. Fang W. et al.Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients.Oncoimmunology. 2015; 5: e1094598Crossref PubMed Scopus (99) Google Scholar There may be a dynamic component to the immunogenicity of tumor cells related to therapeutic strategies for cancer management. Our understanding of the immune environment does not account for the responsiveness to treatments applied in real time, which may be critical for consideration of dual therapies. Resistance mechanisms to ALK inhibitors may provide insight into the best approaches to treatment. When we examine mechanisms of acquired resistance, they fall into two main categories: on-target and off-target alterations. On-target genetic modifications include the development of secondary mutations that to date have been addressed with next-generation ALK inhibitors.10Gainor 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 (765) Google Scholar Off-target mechanisms include upregulation of other pathways, including mesenchymal-epithelial transition, ROS1, and EGFR among others. Given the multiplicity of signaling pathways, combination targeted therapy is being explored to address resistance to the second- and third-generation ALK inhibitors. Combinations with immunotherapy may be one route to overcoming innate or acquired ALK resistance; however, the current trial unfortunately was not able to provide any insight into this particular question. We also learned from this trial that our understanding of toxicity and interactions of therapeutic agents is limited. The rate and severity of hepatotoxicity was out of keeping with the experience with ALK inhibition and immunotherapy independently. Although increases in aspartate transaminase and ALT levels are common with crizotinib, the severe hepatotoxicity rate is less than 10%. Crizotinib undergoes hepatic metabolism, with the major enzymes being cytochrome P450 family 3 subfamily A member 4 and cytochrome P450 family 3 subfamily A member 5, and it is hypothesized that severe liver injury may be due to accumulation of a toxic intermediate. Drug-induced liver injury is associated with the higher levels of eosinophils and CD20-positive and CD4-positive lymphocytes.11Zen Y. Yeh M.M. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury.Mod Pathol. 2018; Crossref Scopus (160) Google Scholar With nivolumab, hepatitis was reported in less than 10% of patients, with grade 3 or higher occurring 2% of patients. The mechanism of injury is immune mediated, with predominantly lobular hepatitis with milder portal inflammation and infiltration of CD3-positive and CD8-positive lymphocytes into the hepatic tissues.11Zen Y. Yeh M.M. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury.Mod Pathol. 2018; Crossref Scopus (160) Google Scholar The alternate mechanisms of hepatic injury may explain why the severity is so notable but do not account for the high incidence seen in this trial. Because of the nature of nivolumab, no pharmacokinetic interactions with ALK inhibitors were anticipated, and consequently, it would have been difficult to predict the events that occurred, highlighting the importance of careful monitoring of any and all combination trials. Other ALK inhibitor and immunotherapy trials are ongoing, including trials of combinations of crizotinib with ipilumumab and crizotinib plus pembrolizumab. Preliminary results of the combination of ceritinb with nivolumab have been presented.12Felip E. De Braud F.G. Maur M. et al.Ceritinib plus nivolumab (NIVO) in patients (pts) with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer (NSCLC).J Clin Oncol. 2017; 35 ([abstract]): 2502Google Scholar Pretreated and treatment-naive patients received nivolumab, 3 mg/kg intravenously every 2 weeks, and ceritinib with a low-fat meal at 300 mg/d and 450 mg/d. Two dose-limiting toxicities were noted at the 300-mg/d level; both were grade 3 or higher increases in ALT levels. At the 450-mg/d dose level, five dose-limiting toxicities were reported; two were hepatic related. Grade 3 or higher increases in ALT level were seen in 25% of patients. The response rate and median PFS were 68.8% and 16.6 months, respectively, in ALK inhibitor–naive patients compared with 35% and 4.6 months, respectively, in pretreated patients. The severity of the hepatotoxicity was lower than in the study by Spigel et al.,4Spigel D.R. Reynolds C. Waterhouse D. et al.Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of ALK translocation-positive advanced non-small cell lung cancer (CheckMate 370).J Thoracic Oncol. 2018; 13: 682-688Abstract Full Text Full Text PDF Scopus (160) Google Scholar and longer follow-up allowed confirmation of the activity of treatment. The difference in toxicity may be related to the dosing of the ALK inhibitor; in the crizotinib trial a full dose was used in combination regimen, whereas ceritinib therapy was started at a lower level, with the usual daily dose being 750 mg. The ceritinib study has been modified to incorporate a 150-mg/d dose level to help establish a recommended phase II dose. Despite the diverse mechanisms and metabolism of ALK inhibitors and immunotherapy, caution in combining agents and starting at doses less than the single-agent effective dose may be more prudent. The trial presented by Spigel et al.4Spigel D.R. Reynolds C. Waterhouse D. et al.Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of ALK translocation-positive advanced non-small cell lung cancer (CheckMate 370).J Thoracic Oncol. 2018; 13: 682-688Abstract Full Text Full Text PDF Scopus (160) Google Scholar combined ALK inhibition with immunotherapy as the potential next step in the management of ALK-positive NSCLC. The goal of combined ALK inhibition and immunotherapy in the frontline setting is to produce durable responses and delay resistance. Unfortunately, the combination was hampered by significant hepatotoxicity, and the ability to assess efficacy was limited. The addition of immunotherapy to ALK inhibition demonstrates some clear safety signals; what remains to be seen is whether there is a reward in terms of efficacy. The cautionary note of this study should be heeded in future iterations of these combinations, and the reporting of the other combination trials will help guide the future in ALK-positive disease. Phase 1/2 Study of the Safety and Tolerability of Nivolumab Plus Crizotinib for the First-Line Treatment of Anaplastic Lymphoma Kinase Translocation — Positive Advanced Non–Small Cell Lung Cancer (CheckMate 370)Journal of Thoracic OncologyVol. 13Issue 5PreviewCrizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is a first-line treatment for ALK translocation–positive advanced non–small cell lung cancer (NSCLC); however, patients eventually progress. Immunotherapies, including the programmed death-1 inhibitor nivolumab, have resulted in durable responses and long-term overall survival in patients with NSCLC. We hypothesized that combining targeted therapy with immunotherapy could result in more patients with responses and/or more durable responses. Full-Text PDF Open Archive