Abstract
Anaplastic lymphoma kinase (ALK) rearrangements were first implicated as driving mutations in non-small cell lung cancer in 2007. Since then, a number of novel, small-molecule inhibitors directed against the ALK receptor have demonstrated superiority over standard chemotherapies in the treatment of ALK rearrangement-positive lung cancer. Of considerable importance when considering such therapies is the ability of each to overcome mutations conferring acquired resistance, as well as penetrate the central nervous system (CNS), the most common site of metastasis and traditionally the most difficult to breach. Herein is a review of the efficacy, indications, and degree of CNS penetration for the ALK-targeting agents crizotinib, ceretinib, alectinib, brigatinib, and lorlatinib, as well as a summary of ongoing clinical trials comparing these drugs.
Lung cancer represents the leading cause of cancer-related mortality in the USA and worldwide (1, 2). About 80-85% of all lung cancer cases are classified as non-small cell lung cancer (NSCLC), a group of disparate diseases that are relatively insensitive to standard chemotherapeutic agents (2, 3). Historically, therapeutic approaches have, out of necessity, consisted of some variant of platinum-based double-agent treatment, associated with median survival times of less than 1 year following diagnosis (2, 4). However, with advances in molecular studies, a number of new subtypes of NSCLC have been identified and stratified by oncogenic driver, rather than histology alone. This, in turn, has led to the rapid development of novel and highly effective therapies against these various subtypes. One such variant, anaplastic lymphoma kinase (ALK) rearrangement-positive lung cancer, has experienced a particularly rapid evolution in treatment approach and outcome since 2011.
Biology
The ALK gene encodes a tyrosine kinase receptor from the insulin receptor superfamily on the p-arm of chromosome 2 (2, 5, 6). In normal development, it is involved in the formation of neurons during embryogenesis before becoming thereafter dormant (6). ALK involvement was first implicated in lung cancer tumorigenesis in 2007 (4, 7). ALK rearrangement-positive lung cancer primarily arises from translocation of the ALK gene and creation of subsequent fusion products. The most common of these is echinoderm microtubule-associated protein-like 4 (EML4)–ALK, although a number of other fusion products have been described. Such types of cancer may also less frequently arise from gene amplification or random mutations leading to the activation of the ALK gene itself (2, 8).
Regardless, these transformations represent between 3 and 7% of all NSCLC and result in constitutively active ALK signaling. A number of studies have demonstrated that ALK rearrangement-positive carcinomas rely upon this continued ALK signaling for growth and survival, and so throttling of the oncogenic driver itself has proven an attractive point of attack for directed therapy (9, 10).
ALK rearrangement-positive lung cancer has been reported in light-to never-smokers, younger patients (40- to 50-year-olds), and those with adenocarcinoma histology (11-14). Diagnosis is most typically made clinically via the Food and Drug Administration (FDA)-approved Vysis ALK Break-Apart FISH Probe Kit or with the VENTATA anti-ALK (D5F3) immunohistochemical assay, although confirmatory polymerase chain reaction has also been used (11, 15, 16). Since 2013, a number of national and international organizations have recommended routine ALK testing of all patients with NSCLC.
Central nervous system (CNS) disease. In considering ALK rearrangement-positive lung cancer, it is important to remember that in all NSCLC, metastasis to the CNS presents therapeutic challenge. CNS disease is the leading site of cancer progression and standard chemotherapy agents have poor CNS penetration due to the blood–brain barrier (BBB) and efflux drug pumps (16). Retrospective analysis indicates that between 20-30% of all ALK rearrangement-positive NSCLC have CNS metastases at the time of diagnosis (compared to 10-20% in NSCLC overall). This number increases to between 45 and 75% in patients those with ALK inhibitor, indicating that CNS disease represents a leading cause of mortality in ALK rearrangement-positive lung cancer (4).
ALK-Directed Therapy
A: Crizotinib. Crizotinib (Xalkori, PF-02341066) is a small-molecule inhibitor of the tyrosine kinases ALK, ROS1, and mesenchymal-epithelial transition factor (MET) and was the first direct ALK inhibitor tested in humans with ALK rearrangement-positive lung cancer. In 2010, the phase I study PROFILE 1001 looked at crizotinib as a second-line treatment in patients previously treated with platinum-based chemotherapy (17). Compared to a 10% response rate and 2.5 months median progression-free survival (PFS) in patients with ALK rearrangement-positive cancer treated with second-line chemotherapy, the crizotinib-treated arm demonstrated a significantly better overall response rate of 57% and a median PFS of 9.7 months. Shortly after this study, the FDA granted accelerated approval of crizotinib as a second-line therapy in the treatment of ALK rearrangement-positive lung cancer (18).
Since that initial trial, crizotinib has continued to prove its merit over standard chemotherapeutic regimens. In PROFILE 1007, a phase III trial comparing second-line therapies in patients who had failed at least one previous platinum-based therapy, median PFS in the crizotinib arm was 7.7 months compared to 3.0 months in the second-line chemotherapy arm (either pemetrexed or docetaxel). Likewise, the overall response rate (ORR) in crizotinib-treated patients was significantly better at 65% compared to 20% (19).
In another phase III study (PROFILE 1014) comparing crizotinib to pemetrexed plus platinum chemotherapy in the treatment of naïve ALK rearrangement-positive lung cancer, the drug's superiority over first-line regimens was established. Median PFS in the crizotinib arm was measured as 10.9 months compared to 7.0 months in the chemotherapy arm. Similarly, the ORR to crizotinib was 74% compared to 45% for patients treated with pemetrexed plus platinum therapies (20). As a result of this study, crizotinib was approved as first-line agent by the FDA in 2013 (18, 21).
Typically dosed at 250 mg twice daily, crizotinib is a relatively well-tolerated medication. In all of the crizotinib trials, quality of life measurements (cough, dyspnea, chest pain, fatigue, physical conditioning, etc.) were significantly better in the crizotinib-treated arms. The side-effect profile largely centers around grade 1 to 2 gastrointestinal manifestations, although grade 3 and 4 events have been reported in the form of elevated transaminase levels (Table I).
Acquired crizotinib resistance. Despite the initial successes demonstrated with crizotinib, time has shown that a majority of patients treated thus, will develop resistance to the drug and experience relapse within approximately 12 months (19, 22). Resistance to crizotinib can be separated into ALK-dominant and ALK-independent processes. In the former, either new gain-of-function mutations or amplification of the ALK gene serve to maintain constitutive ALK signaling even in the face of ongoing crizotinib therapy (17). Several such mutations have been described, the most common of which include the so-called gate-keeper mutation L1106M. These several mutations represent approximately one-third of resistant cases (18, 22). The latter, on the other hand, does not exactly represent insensitivity to crizotinib, but rather reactivation of bypass signaling pathways such as epidermal growth factor receptor (EGFR) or c-KIT which in large part obviate the tumor's dependence upon ALK activation for continued growth (20, 22). Clinically, it is clear that PFS with crizotinib therapy rarely extends beyond a year.
It should also be noted that crizotinib has a minimal impact on controlling metastatic CNS disease. Crizotinib is a known substrate of P-glycoprotein, a key efflux pump in the BBB (22). One study demonstrated extremely low concentrations of crizotinib in cerebrospinal fluid (23), indicating that the BBB may prevent it reaching therapeutic levels in lesions of the CNS. Interestingly, there is also one report indicating that isolated radiotherapy of CNS lesions in patients whose disease progresses on crizotinib led to favorable outcomes following resumption of crizotinib therapy, highlighting a potential method by which the efficacy of the agent may be prolonged (24).
B: Ceritinib. Ceritinib (Zykadia, LDK378), a second-generation small-molecule ATP-competitive tyrosine kinase inhibitor of the ALK receptor, is structurally different from and approximately 20-times more potent than crizotinib (25). Ceritinib has demonstrated promise in both crizotinib-treated and crizotinib-naive ALK positive lung cancer (26). For instance, a 2014 multicenter single-arm open-label clinical trial enrolled 163 patients with ALK rearrangement-positive NSCLC that progressed despite crizotinib therapy. The results demonstrated an ORR of 54.6% with ceritinib as a second agent with a median PFS of 7.4 months (25) on top of the initial PFS achieved with crizotinib. This study ultimately garnered fast-track FDA approval of ceritinib as a second-line treatment.
In another phase I trial, ORR to ceritinib was 58%, with minimal difference seen between crizotinib-treated and crizotinib-naïve cases (56 and 62%, respectively). With a median PFS of 10.7 months in the crizotinib-naïve arm, there was evidence of near-equivalent efficacy between the two drugs as first-line agents. In 2017, a randomized open-label phase III trial (ASCEND 4) compared ceritinib to standard platinum-based chemotherapies. When compared to chemotherapy alone, ceritinib led to an actual doubling of median PFS (16.6 vs. 8.1 months) (27). The results of ASCEND 4 led to FDA approval of ceritinib as a first-line therapy in ALK rearrangement-positive lung cancer in May of the same year (28). In summary, ceritinib demonstrated not only improved PFS when used after crizotinib failure but also showed comparable efficacy as a first-line treatment.
The fact that ceritinib demonstrates effects on crizotinib-resistant disease may be attributed to both its increased potency, as well as its action against certain acquired resistance mutations. By using cell lines derived from biopsies of crizotinib-resistant tumors, ceritinib was found to actively inhibit growth of at least four common resistance-associated mutations (L1196M, G1269A, S1206Y, and I1171T). However, a number of other mutations were found to confer resistance to ceritinib itself (namely G1202R and F1174C), indicating probable causes of disease progression despite ceritinib treatment (25).
Ceritinib is typically dosed at 750 mg daily and the side-effects consist primarily of gastrointestinal disturbances (Table I). Whereas little to no grade 3 to 4 diarrhea has been reported in crizotinib use, it does occur in approximately 7% of ceritinib-treated patients. There is also a significantly higher rate of grade 3 or 4 nausea (8). Finally, like crizotinib, ceritinib can lead to significant elevation of transaminases in some patients. All of the above symptoms appear to be reversible upon withdrawal of the drug (26).
C: Alectinib. Alectinib (Alcensa, CH5424602), a second-generation ALK-specific tyrosine kinase inhibitor that also demonstrates rearranged during transfection (RET) proto-oncogene activity, was recently shown to be a major actor in treating ALK rearrangement-positive lung cancer. While initial phase II studies demonstrated consistent benefit in the use of alectinib in crizotinib-refractory disease (29, 30), its true promise lies in its potential as a first-line therapy. In the phase III trial J-ALEX, Japanese patients with ALK inhibitor-naïve ALK rearrangement-positive cancer were given either alectinib or crizotinib as first-line therapy. At the end of the study (approximately 2 years), median PFS for the crizotinib-treated arm was 10.2 months, whereas median PFS had not yet been reached in patients treated with alectinib (31). Of note, some patients had been previously treated with standard chemotherapies, and at 300 mg twice daily, the dose of alectinib in this trial was lower than in most subsequent studies.
The result of J-ALEX was mirrored in its global cousin ALEX, an international randomized open label study comparing alectinib to crizotinib in previously untreated advanced ALK rearrangement-positive NSCLC. In this study, median PFS in the alectinib-treated arm was 25.7 months compared to 10.4 months for the crizotinib-treated patients. In addition, alectinib was associated with a 53% lower risk of progressive disease or death over the study time (16). While alectinib was dosed at the more typical 600 mg twice daily in this study, its superiority to crizotinib was demonstrated in both cases. As a result, alectinib received FDA approved for first-line treatment of ALK rearrangement-positive lung cancer in November of 2017 (32).
As for ceritinib, at least one retrospective study indicated that alectinib offers superior treatment (33). While direct comparisons between the ASCEND and ALEX trials cannot be drawn, general PFS trends between the various studies would seem to corroborate this. Future studies are required to more directly compare the two therapies.
CNS activity. While it is true that alectinib retains activity against common crizotinib-resistance mutations such as ALK L1196M (25) and that, like ceritinib, it is a more potent inhibitor of the ALK receptor, its true advantage likely lies in the management of CNS disease. Unlike the other ALK inhibitors, alectinib does not appear to be a substrate of P-glycoprotein, one of the major efflux pumps located in the BBB (34). As a result, it likely has relatively higher activity in the CNS than other ALK inhibitors, something indirectly demonstrated by survival trends. In the ALEX trial, only 12% of patients in the alectinib-treated group developed CNS progression compared to 45% in the crizotinib-treated group. Furthermore, because CNS involvement was assessed in each patient prior to enrollment, it was possible to measure response to previously diagnosed CNS disease. In the alectinib-treated arm, 59% of such patients demonstrated a CNS response duration of greater than 12 months, while only 36% showed the same on crizotinib therapy (16).
Unfortunately, as with crizotinib and ceritinib, eventual resistance to alectinib is seemingly inevitable. The most common mutations identified include I1171N (unique to alectinib) as well as G1202R (which is shared with ceritinib) (35).
Standard alectinib therapy is 600 mg orally twice daily. Side-effects (Table I) chiefly include anemia (20%), myalgia (16%), diarrhea (45%), and vomiting (38%), however, rates of adverse events leading to dose reduction/discontinuation appear to be lower than for therapy with crizotinib (16).
D: Brigatinib. Brigatinib (AP26113), another second-generation ALK inhibitor, differs from the others in its enhanced activity against tumors with a wide array of resistance-associated mutations (36). Twelve times more potent than crizotinib, preclinical study demonstrated a superior inhibitory profile for 17 separate secondary ALK mutations including G1202R, one of the major causes of failure in both ceritinib and alectinib therapy (37). It is too early to discern what bearing such studies will have in actual practice, though initial trials appear to indicate favorable results.
In the prospective phase I/II trial ALTA, brigatinib was examined in patients with crizotinib-resistant cancer and demonstrated an ORR of 54%. While this is roughly equivalent to similar studies looking at ceritinib and alectinib (50-56%), median PFS of 12.9 months (and 15.6 months by the independent review board) was in fact significantly better with brigatinib when compared to 5.7-6.0 months for ceritinib and 8.1-8.9 months for alectinib (25, 29, 35). This increase in PFS may correspond to expanded coverage of developed ALK resistance, although this cannot yet be conclusively determined. Importantly, the ORR of 67% and the median PFS of 15.6 months in patients with measurable brain metastases were even higher, indicating that like alectinib, brigatinib may have superior CNS activity (37). It received accelerated FDA approval in 2017 for ALK rearrangement-positive lung cancer which demonstrates progression or intolerance to crizotinib (38).
Regarding first-line application, the ongoing ALTA-1L trial opened in April of 2016 and is a phase III study comparing brigatinib to crizotinib in ALK inhibitor-naïve ALK rearrangement-positive NSCLC (39).
There are currently two doses being used by ongoing studies: 90 mg and 180 mg with a 7-day lead-in of 90 mg. As with the other ALK inhibitors, gastrointestinal side-effects including nausea, vomiting, and diarrhea are common (Table I). Unlike the others, however, is the rapid development of severe pulmonary toxicity upon initiation of the agent (pneumonia, interstitial lung disease, and pneumonitis). With a 3.7% rate of fatal events (largely pulmonary in etiology), it is currently recommended that patients be monitored for new or worsening pulmonary symptoms for the first week of treatment (38).
E: Lorlatinib. Lorlatinib (PF-06463922) is a third-generation ALK inhibitor with wide activity against many known resistance-associated mutations, including G1202R (40, 41). Tailored to penetrate the CNS, animal studies have demonstrated approximately 30% CNS availability with superior efficacy in CNS lesions compared to alectinib (40). In humans, a recent study demonstrated potential use in both treatment-naïve and previously treated ALK rearrangement-positive cancer. A 2017 phase II trial showed an ORR of 90% in treatment-naïve patients, 69% in crizotinib-treated patients, 33% in those treated with a non-crizotinib ALK inhibitor, and 39% in those treated with two or three previous ALK inhibitors (42). Based on this study, lorlatinib was granted FDA breakthrough approval in 2017. The phase III trial CROWN comparing lorlatinib to crizotinib as first-line therapy is ongoing (43). Thus far, the drug appears generally well tolerated, with only a 3% rate of discontinuation due to drug-related adverse events and no associated deaths, however, it remains to be seen if this trend holds true in larger study populations.
Prospective Inhibitors and Treatments
While the current data for ALK rearrangement-positive lung cancer have changed, there are more studies ongoing. Another ALK inhibitor X-396 (ensartinib) is being compared to crizotinib in metastatic ALK rearrangement-positive lung cancer that has received no more than one chemotherapy and no prior ALK inhibitors (44). In addition, phase III comparison front-line studies between brigatinib and crizotinib (45), alectinib and crizotinib (46), and lorlatinib and crizotinib (47) are underway. In a second-line phase III, alectinib is being compared to standard chemotherapy (pemetrexed or docetaxel) for patients with ALK rearrangement-positive NSCLC that have previously received platinum chemotherapy and crizotinib (48). In addition, adjuvant crizotinib is being studied after surgery for patients with stage IB-IIIA NSCLC (49). Finally, many interesting questions are being asked in phase II studies including second-line treatment after alectinib (50), combining ALK inhibitors with stereotactic radiation (51), with bevacizumab (52), and with programmed death ligand 1 inhibition (53). All the above questions will assist in further improving outcomes for these patients.
Conclusion
Efficacy of treatment for ALK rearrangement-positive lung cancer has advanced considerably in the past decade. After the introduction of crizotinib, newer generations of ALK-directed treatments are proving superior as first-line therapies and important in treating diseases resistant to the first-generation drug. This improved efficacy is due to both activity against resistance-associated mutations, as well as CNS penetration and activity. With several of these agents receiving either accelerated or regular FDA approval within the past year, it will be important to follow survival trends in the general population and to continue to compare both first-and second-line agents against one another.
Footnotes
This article is freely accessible online.
- Received June 17, 2018.
- Revision received July 18, 2018.
- Accepted July 26, 2018.
- Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved