NSCLC that is positive for ALK, a receptor tyrosine kinase (RTK), typifies a phenomenon termed â€œoncogene addiction,â€ in which tumor cells depend on a single causative pathway or protein for their growth and survival.
Non-small cell lung cancer (NSCLC) that is positive for anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase (RTK), typifies a phenomenon termed “oncogene addiction,” in which tumor cells depend on a single causative pathway or protein for their growth and survival. In such cases, inhibiting the oncogene in question is frequently well tolerated by healthy tissue while devastating for survival of malignant cells.1
The discovery that activating rearrangements of theALKgene is the addictive mutation in a subset of NSCLC cases, and the subsequent development of inhibitors of the ALK protein, have offered the possibility of an unprecedented combination of safety and efficacy for this patient population.
Alice T. Shaw, MD, PhD, on Crizotinib Resistance in ALK-Positive Lung Cancer
Shaw is an attending physician at Massachusetts General Hospital.
ALKhas an enzymatic domain that shares significant sequence identity with the proto-oncogene, c-ros oncogene 1 (ROS1). Rearrangements and fusions of theALKlocus are present in a subset of several different cancers, including anaplastic large cell lymphoma and inflammatory myofibroblastic tumor. In addition, the fusion geneEML4-ALKcan be found in 3% to 6% cases of NSCLC.2 The prognosis of patients with ALK-positive NSCLC relative to other genotypes is uncertain, with reports of both improved and worsened survival relative to ALK-negative NSCLC. As many as 50% of patients with activated ALK have been estimated to develop central nervous system (CNS) metastases; however, it has not been determined whether there is an increased risk compared with other cases of NSCLC.3
Because normal ALK activity is predicted to be largely restricted to nervous system development, with little-to-no expression in adult human tissue, the specific inhibition of ALK with a small molecule is expected to effectively target cancerous cells and spare healthy ones.4One agent, crizotinib, is approved for use in patients with ALK-positive NSCLC, and several other agents are under investigation. The differentiating features of ALK-directed approaches, as well as the most recently available clinical data, are summarized here.
Crizotinib (Xalkori®; Pfizer) is a first-in-class ALK inhibitor that is approved for use in ALK-positive NSCLC in the United States and as a second-line therapy in Europe. It is an oral selective inhibitor of RTKs, including ALK, MET, and ROS1,5which acts as an ATP-competitive inhibitor of enzymatic activity of the target kinases.6
A recently completed phase III study (PROFILE 1007) demonstrated the efficacy of crizotinib versus chemotherapy in patients with locally advanced or metastatic ALK-positive NSCLC previously treated with platinum-based chemotherapy.7Participants received either crizotinib at a dosage of 250 mg twice daily, or intravenous chemotherapy every 3 weeks. Crizotinib increased median progression-free survival (PFS) over chemotherapy (7.7 months vs 3.0 months), a difference that was highly significant (P < .001). The objective response rate also increased from 20% with chemotherapy to 65% with crizotinib (P < .001). No evidence for increased overall survival (OS) was found in an interim analysis. Furthermore, patient-reported outcomes revealed crizotinib was associated with greater reductions in lung cancer symptoms and greater improvements in global quality of life than chemotherapy. Another phase III trial (PROFILE 1014; NCT01154140) is evaluating the efficacy of crizotinib relative to standard chemotherapy as a first-line treatment in ALK-positive NSCLC.
According to Jeffrey M. Rothenstein, MD, with the University of Toronto, in Ontario, Canada, ALK inhibitors are well tolerated, but common adverse events (AEs) include visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels. “Proactive monitoring, treatment, and education concerning those adverse events will help to optimize patient outcomes with these drugs,” he added.
High response rates are observed with crizotinib in patients with ALK-positive NSCLC, but acquired resistance and relapse are frequent. The mechanisms of this resistance can include mutation of the ALK kinase domain, reducing the ability of crizotinib to bind, as well as amplification of the ALK fusion gene. Resistance can also arise from so-called “bypass mutations,” which activate compensatory signaling pathways such as epidermal growth factor receptor (EGFR), KIT, or KRAS, eliminating the need for ALK signaling to support tumor growth.8,9
Alice T. Shaw, MD
“Acquired resistance in ALK-positive NSCLC appears to be a multifactorial process that may necessitate the use of treatment combinations,” noted Alice T. Shaw, MD, with the Massachusetts General Hospital Cancer Center, in Boston. “Identifying the mechanisms underlying resistance to ALK-positive NSCLC is an area of intense, ongoing investigation,” she added. “Such research may help in the development of new treatment strategies not only in ALK-positive NSCLC, but also in the treatment of other kinase-driven malignancies.”Two experimental drugs, LDK378 and alectinib, are being developed with the potential for addressing the problem of escape mutations in ALK. LDK378 is a highly selective and potent second-generation ALK inhibitor from Novartis Pharmaceuticals that has demonstrated activity against a preclinical tumor model carrying theALKC1156Y mutation, which is present in some patients with crizotinib resistance.10
Based on promising phase I results, LDK378 was granted “Breakthrough Therapy” status by the Food and Drug Administration (FDA) in March 2013. This new designation was created for drugs that exhibit significant improvement over existing treatments for life-threatening conditions, with the rationale of speeding these drugs through the development and review process. In addition to the benefits of the already-established Fast Track program, Breakthrough Therapy status offers more frequent contact with the FDA regarding trial design and data collection to ensure rapid progress through the regulatory system.11
Phase II clinical trials of LDK378 are being conducted in patients with advanced ALK-positive NSCLC who are crizotinib-naïve (NCT01685138) as well as in patients with crizotinib-resistant NSCLC (NCT01685060). Phase III trials comparing LDK378 with standard chemotherapy are also underway, both in patients previously treated with chemotherapy and crizotinib (NCT01828112) or in treatment-naïve patients (NCT01828099).The FDA has also granted Breakthrough Therapy status to alectinib (CH5424802; RO 5424802), an ALK inhibitor being developed by Chugai/Roche Pharmaceuticals. In an open-label, phase I/II study in an ALK inhibitor-naïve patient population in Japan, alectinib was found to result in no dose-limiting toxicity at the highest dose of 300 mg twice daily, which was subsequently used as the recommended phase II dose. A 93.5% objective response rate was achieved in the 46 patients enrolled in the phase II portion of the trial, including 41 partial responses and 2 complete responses.12Alectinib induced few severe AEs in this trial, with 12/46 (26%) grade 3 responses, including decreased neutrophil count and increased blood creatine phosphokinase. No grade 4 AEs or deaths were reported in this study.
Researchers led by Sai-Hong Ignatius Ou, MD, PhD, from the University of California, Irvine School of Medicine presented data at the European Cancer Congress 2013 on a separate phase I study of alectinib. In all, 45 participants were treated twice daily with a range of doses between 300 mg to 900 mg. Two dose-limiting toxicities occurred at the 900-mg dose, while none occurred at 600 mg, which was set as the phase II recommended dose (NCT01588028). Of note, of 20 patients with CNS lesions at the time of enrollment, 16 (80%) remained progression-free for more than 6 months of the study, possibly due to better CNS penetration by alectinib compared with crizotinib.13A direct comparison of alectinib and crizotinib in a phase III trial is being planned and an additional phase II trial in crizotinib-resistant patients is underway. (NCT01801111).AP26113 is another novel ALK inhibitor with activity against crizotinib-resistant ALK mutants being developed for clinical use by Ariad Pharmaceuticals. Updated results from an ongoing phase I/II study (NCT01449461) were presented at the 15th World Congress on Lung Cancer. The recommended phase II dose is 180 mg once daily. Fifteen of 24 patients with activated ALK have responded to AP26113, including 12/16 (75%) patients treated previously with crizotinib only. Similar to the alectinib results, 4 of 5 (80%) of patients with CNS lesions had evidence of improvement, including 1 patient who had become resistant to both crizotinib and LDK378. The most common severe AE (grade 3/4) was pneumonia (5%); however, most AEs were grade 1/2 and included fatigue (40%), nausea (36%), and diarrhea (33%).14Inhibitors of heat shock protein 90 (HSP90) are also being explored for use in patients with ALK-positive NSCLC. HSP90 functions as a chaperone protein and preclinical studies have shown that the EML4ALK fusion is a client of HSP90. Furthermore, these studies demonstrated a synergistic effect of HSP90-targeting drugs when combined with ALK inhibitors.15Several phase I/II clinical trials are underway, investigating various HSP90 inhibitors both as monotherapies and in combination with crizotinib (NCT01579994; NCT01712217) and LDK378 (NCT01772797).As new agents targeting ALK have entered clinical testing, new guidelines for ALK testing have also emerged. Last year the College of American Pathologists, the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology jointly issued a new guideline for molecular testing of NSCLC patients.16One of the primary recommendations is to test for ALK fusion events in all patients with advanced (stage IV) adenocarcinomas or with mixed lung cancers with an adenocarcinoma component. Because the potential benefits of targeted therapy are so promising, this testing should take place regardless of a patient’s smoking history, sex, race, or other risk factors. The guideline furthermore recommends testing for ALK fusion proteins using fluorescence in situ hybridization (FISH), although reverse transcriptase polymerase chain reaction (PCR) and immunohistochemistry have also been used.17
“These mutations, includingEML/ALK, are only the tip of the iceberg,” said Bilal Piperdi, MD, associate professor of Clinical Medicine, Department of Medicine (Oncology), Albert Einstein College of Medicine. According to Piperdi, advances in molecular testing would allow for clinicians to test for multiple mutations at a time, including some of the uncommon ones. “It will be a challenge for us as clinicians to see how these mutations interact and to identify some of the better targets to treat these cancers,” he added.Targeted therapy for ALK-positive NSCLC, of which crizotinib is now the only approved agent, is able to produce high response rates, while sparing patients some of the side effects of conventional chemotherapy. Development of resistance is a major limitation of crizotinib; but this is being addressed by the development of second-generation ALK inhibitors as well as treatments with alternate mechanisms of action, such as HSP90 inhibitors. With new dosing regimens and combinations currently in trials, the search for long-term disease control continues.