- What is the translocation of the EML4-ALK gene?
- First-line therapy for lung cancer with the EML4-ALK gene translocation
- Stages of development of crizotinib
- What is done when crizotinib no longer works
- Ceritinib – Second-line therapy
- The stages of the development of ceritinib
What is the translocation of the EML4-ALK gene?
The EML4-ALK gene is the result of a chromosomal rearrangement, in which, due to random events, a part of the EML4 gene (the N-terminal portion) detaches and joins the portion of the ALK gene, containing the kinase domain. The result is the formation of a new gene that can give rise to the development of a lung adenocarcinoma.
The translocation of the ALK gene (Anaplastic Lymphoma Kinase) affects only 3-5% of patients diagnosed with pulmonary adenocarcinoma. It is a malignant tumor that mainly affects people between 45 and 50 years of age. Unlike other types of lung cancer, positive-ALK tumors are generally found in non-smokers.
To find out if in a specific case the lung tumor is ALK positive, we need to look for the presence of the ALK gene rearrangement on the biopsy performed at the time of diagnosis.
Therapeutic approach in lung cancer with EML4-ALK gene translocation- First-line therapy
Crizotinib and Alectinib make up the two therapeutic options available in Italy is the standard for first-line treatment of patients with translocation of the EML4-ALK gene.
Stages of development of crizotinib
The translocation of the EML4-ALK gene was first identified in 2007, isolating it from the DNA of a 62-year-old patient diagnosed with lung adenocarcinoma. Only 4 years later, in November 2011, based on the results of a Phase I study, crizotinib received approval from the US FDA, for the treatment of patients with lung adenocarcinoma positive for the ALK translocation. The Phase I study, PROFILE 1001, had indeed shown that crizotinib determines an objective response (tumor size reduction) in 60% of patients and a median progression-free survival of almost 10 months. These results are extraordinary if we consider that the enrolled patients had already been subjected to multiple lines of anticancer therapies and, therefore, had few therapeutic options.
In July 2012, based on the results of the phase III PROFILE 1007 study, the European Medicines Agency, EMA, also authorized the marketing of crizotinib for patients with non-small cell lung cancer and an EML4-ALK translocation, in disease progression following a first chemotherapy line. The study compared the efficacy of crizotinib with that of second-line chemotherapy (docetaxel or pemetrexed) in 347 patients previously undergoing first-line therapy with a platinum-based doublet. The results demonstrate that crizotinib triples the percentage of objective responses and doubles progression-free survival compared to standard chemotherapy. Based on these results, AIFA regulated the use of crizotinib in Italy in March 2015.
The results of the PROFILE 1014 study, designed to demonstrate the advantage of crizotinib compared to platinum-based first-line therapy, allowed the extension of crizotinib use as first-line in November 2015 by EMA and in March 2017 by AIFA. Up to then, crizotinib could only be prescribed after the failure of a first chemotherapy line which was represented by platinum-based drugs (Cisplatin or Carboplatin), in association with pemetrexed. The PROFILE 1014 study demonstrated that even in first line, crizotinib was able to double the percentage of objective responses and significantly increase progression-free survival.
In March 2017, AIFA extended the indication of crizotinib use to first-line treatment in patients with non-small cell lung cancer with a translocation of the EML4-ALK gene.
To learn more about the side effects of crizotinib, go to the side effects page.
Stages of development of alectinib
Alectinib is a second-generation ALK inhibitor that was initially developed to overcome the resistance mechanisms that occur with crizotinib and to improve blood-brain-barrier penetration, achieving better control over brain lesions. ALK positive patients indeed have a higher risk of developing cerebral metastases; 30% of cases have them at time of diagnosis and 60% of patients undergoing crizotinib therapy. Crizotinib unfortunately does not reach ideal concentrations at the level of the brain, thus leading to ineffective control over lesions found there.
The first evidence supporting alectinib’s effectiveness derives from the results of the phase I study AF-001JP in Japan, which included 70 ALK positive patients who were not previously treated with crizotinib. Alectinib achieved an objective response of 93.5%, and an 83% progression-free-survival at 12 months. A parallel phase I/II study AF-002JG was conducted in the U.S. and included 47 ALK positive patients (though they were previously treated crizotinib and developed disease progression). The objective response rate for the latter study was 55%. Of the enrolled patients, 21 had brain metastases, of which 6 achieved a complete brain response, 5 achieved partial brain response and 8 achieved stable disease.
These results along with two phase II studies, NP28673 and NP 28761, which were conducted in ALK positive patients progressing after crizotinib therapy ultimately led to the design of the phase III ALEX study. ALEX compared the effectiveness of crizotinib with alectinib in 303 patients who were not previously treated. Alectinib achieved a 53% reduction in risk of progression or death when compared to crizotinib; a disease-free progression of about 26 months was observed with Alectinib compared to crizotinib’s 10 months.
Based on these extraordinary results, Alectinib was approved in Italy on July 31st, 2018 for ALK positive patients who did not undergo previous treatments, thus becoming a new therapeutic option for these patients.
You can find more about the side effects of alectinib on its respective page.
Second line therapy- after crizotinib
When crizotinib loses its effectiveness as a first line therapy, there are two therapeutic options currently approved in Italy to be chosen from as second line. These are ceritinib or alectinib.
Stages of development of ceritinib
Ceritinib is a second-generation ALK inhibitor that is currently approved in Italy for second-line treatments for patients carrying the ALK gene translocation. It is used when the tumor is no longer sensitive to crizotinib.
In the phase I/II study ASCEND-1 (published in Lancet in March 2016), 255 patients were enrolled. 66% of these were previously treated with crizotinib, while 34% received ceritinib as their first ALK inhibitor treatment. Ceritinib was effective in both patient subgroups, achieving a 72% objective response rate and a median duration of 17 months in those who were not previously treated and achieving a 56% objective response rate with a median duration of 8.3 months in those who progressed under crizotinib. These results are impressive considering that for the latter subgroup, the probability of obtaining an objective response is less than 10%. Ceritinib was also associated with brain metastases control in 80% of cases.
In order to further confirm these results, the phase II study ASCEND-2 was designed and published 5 months later in the Journal of Clinical Oncology. 140 patients were enrolled in 51 centers across Europe, Asia and America between December 2012 and September 2013. All patients were previously treated with crizotinib and underwent disease progression. Furthermore, most patients had already received at least 3 lines of therapy. Despite the multiple lines of previous treatments, a reduction in lesion size was observed in 75% of cases, with a response duration of just under 10 months. Ceritinib’s effectiveness may be better appreciated considering that 70% of these patients also had brain metastases. Control of brain lesions was also confirmed in this study in 74% of cases.
Based on these promising results, the phase III study ASCEND 5 (published in Lancet in June 2017) was designed with the aim of demonstrating ceritinib’s superiority over standard chemotherapy in patients undergoing progression with crizotinib therapy.
Generally, in order for a new treatment to be approved as the new standard of care, it must be demonstrated that its effectiveness is superior to the one already in use. The standard chemotherapy at the time (June 2013) was docetaxel or pemetrexed. 326 patients enrolled in 99 centers in 20 countries were randomized between June 2013 and November 2015 to receive chemotherapy or ceritinib. Ceritinib prolonged progression-free-survival four times compared to chemotherapy (6.7 months vs 1.6), reduced risk of progression by about 60% and achieved a higher objective response rate (50% vs <10%).
These results paved the way for ceritinib’s approval in July 2017 by AIFA, allowing patients to have an alternative effective therapeutic option that can prolong survival.
To learn more about the side effects of ceritinib, please go to the page dedicated to Ceritinib.
Second-line therapy – after alectinib
In the case of disease progression after alectinib, there are no further treatments currently approved by the National Health Service in Italy. It is however possible to request access to two other ALK inhibitors that are not yet registered. These are lorlatinib, a third generation ALK inhibitor developed to overcome resistance mechanisms occurring with crizotinib, ceritinib and alectinib treatment and capable of crossing the blood-brain barrier and brigatinib, a second-generation ALK inhibitor, which can also be affective after treatment with ceritinib or alectinib.
Finally, starting a few months ago, patients in Italy progressing after ALK inhibitor therapy are able to request (on a personal basis) a combination therapy using chemotherapy (carboplatin and paclitaxel), an anti-vascular drug (bevacizumab) and a PD-L1 inhibitor (atezolizumab), as demonstrated by the Impower 150 study.
Brigatinib, a new therapeutic option
Brigatinib is a second-generation ALK inhibitor that has shown promising clinical benefit.
Its effectiveness was initially evaluated in a phase I/II study, in which 137 patients were enrolled including 79 ALK positive patients. The recommended dose for phase II was 180 mg. In patients progressing after crizotinib, brigatinib achieved an objective response of 62%, while for patients not previously treated, an objective response of 100% was recorded. Among the reported adverse events, pneumonia occurred in 7% of cases. Considering this high percentage of pneumonia occurrence, and to test the tolerability and efficacy of brigatinib’s two doses, the phase II ALTA study was designed. 222 patients progressing after crizotinib were enrolled in this study and randomized to receive either 90 mg once a day or a 90 mg dose for 7 days followed by 180 mg once a day. The objective response rate was 45% in the first group and 54% in the latter. Median progression-free-survival was 9.2 months under the 90 mg dose and 12.9 months under the 180 mg dose. Based on these results, the 90 mg dose for first 7 days of treatment was chosen and in the case of no side effects, the dose may be increased to 180 mg.
With the aim of testing brigatinib’s effectiveness in treatment-naïve patients, the phase III ALTA-1L study was designed. The study compared brigatinib with crizotinib in 275 patients and the results demonstrated brigatinib’s superiority in terms of progression free survival (not reached in the brigatinib arm and 9.8 months in the crizotinib arm). Brigatinib also demonstrated a higher percentage of response at the level of the brain (78% vs 29%).
