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Between 2007 and 2011, a collaboration among clinical oncologists, pathologists, and industry scientists led to the identification of a new molecularly defined subset of non-small cell lung cancer, followed by the finding that crizotinib, then under development as a MET inhibitor, was an inhibitor of anaplastic lymphoma kinase.
Alice T. Shaw, MD, PhD
Between 2007 and 2011, a collaboration among clinical oncologists, pathologists, and industry scientists led to the identification of a new molecularly defined subset of non-small cell lung cancer (NSCLC), followed by the finding that crizotinib, then under development as a MET inhibitor, was an inhibitor of anaplastic lymphoma kinase (ALK). Clinical testing rapidly established the efficacy of crizotinib in patients with ALK-rearranged NSCLC, and FDA approval of crizotinib (Xalkori) followed for this indication in August 2011.1
That less than five years had elapsed between discovery of a newly defined subtype of NSCLC and the development, testing, and FDA approval of an effective targeted therapy (along with a diagnostic test) may serve as a model for successful next-generation development of targeted therapies, according to Alice T. Shaw, MD, PhD, from Harvard Medical School and Massachusetts General Hospital, in Boston. Shaw traced events that mark this example of contemporary bench-to-bedside science at the 11th International Congress on Targeted Therapies in Cancer that Physicians’ Education Resource, LLC (PER®) hosted in Washington, DC, in August.
ALK rearrangements were first discovered in anaplastic large cell lymphoma about 20 years ago, and “rediscovered” in 2007 by Hiroyuki Mano, MD, PhD, and colleagues from Japan. Mano led a research team that found a fusion gene with portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and ALK in a small subset of Japanese patients with NSCLC.2 The EML4-ALK fusion activates ALK, which is normally not expressed in the lung.
Mano’s research also found that, not only was the EML4-ALK fusion gene a potent oncogenic driver in nude mice models, but blocking the kinase activity of EML4-ALK “completely abrogated” the oncogenic activity.2 Gene translocations that activate tyrosine kinases may represent excellent drug targets for many cancers, especially with NSCLC, according to Shaw.
ALK rearrangements occur in 3% to 7% of patients with NSCLC who share a few key characteristics. Specifically, ALK rearrangements are enriched in patients who are never- or light smokers and tend to be found in patients who are 10 to 15 years younger than the average patient with NSCLC. They occur primarily in the adenocarcinoma type of NSCLC.3,4
When the expansion phase of the phase I clinical study of crizotinib commenced—at approximately the same time as the ALK-rearranged NSCLC subtype was identified—early results showed that the majority of patients had responded.5,6 In the phase II follow-up, single-arm study in patients with advanced ALK-positive lung cancer, the drug produced a similarly high response rate of about 60%. In both studies, median progression-free survival (PFS) was about 8 to 10 months. Crizotinib approval was based on the response rate seen in these trials.1
The role of crizotinib in the treatment of ALK-positive lung cancer was confirmed by a head-to-head comparison of crizotinib to standard chemotherapy in patients with advanced ALK-positive lung cancer.7 In this phase III trial, all patients were ALK-positive by the standard fluorescence in situ hybridization (FISH) assay, and all had failed first-line platinum-based chemotherapy. The primary endpoint was PFS. Secondary endpoints were response rate, overall survival, safety, and patient-reported outcomes.7
Patients were randomized 1:1 to receive either crizotinib or a standard second-line agent, such as pemetrexed or docetaxel. No crossover was designed. However, once patients progressed on the chemotherapy arm, they came off study and received crizotinib in a separate ongoing phase II study, according to Shaw.7
The study met its primary endpoint of PFS. Median PFS with crizotinib was nearly 8 months (7.7 months) versus 3 months with standard chemotherapy with a hazard ratio [HR] of 0.49 and a highly statistically significant P value.7 At over 60%, the response rate with crizotinib was consistent with data that had previously been seen in the phase I and II studies. Reponses with chemotherapy were low, at about 20%.7
Especially encouraging in this phase III trial were responses to a patient-reported outcomes instrument.7 “Patients who received crizotinib experienced significantly improved disease-related symptoms and also reported improved quality of life relative to baseline, compared to those patients who had received chemotherapy,” Shaw said.
That study is currently being followed by another randomized study of crizotinib versus first-line platinum plus pemetrexed.8 Additional data on crizotinib in the first-line setting may be available within the next year.
These highly positive data with crizotinib in ALK-positive NSCLC have led to a surge of interest in targeting ALK in other forms of cancer in which ALK is rearranged. (ALK rearrangements have been reported in such cancer types as inflammatory myofibroblastic tumors, anaplastic large cell lymphoma, and sporadically in breast cancer and colorectal cancer.)
Meanwhile, several next-generation ALK inhibitors are currently in clinical trials:
In addition to ALK, chromosomal rearrangements involving ROS1 and RET have been identified as targetable oncogenes in NSCLC.
ROS1 was first discovered in the context of glioblastoma multiforme, the most common and most aggressive malignant primary brain tumor in humans.12 ROS1 is also a target of crizotinib, with a proportion of kinase domains that are similar to ALK at the amino acid level.13
Although less common than ALK rearrangements (they occur in about 1% of patients with NSCLC who are treated within Shaw and colleagues’ practices), ROS1 rearrangements share the demographic profile with patients with ALK-positive NSCLC: most commonly younger than average, never- or light smokers, with adenocarcinoma histology.13
The efficacy of crizotinib against NSCLC with ROS1 genetic alterations has been demonstrated. In the same phase I trial in which ALK-positive patients were tested, an expansion cohort for patients with ROS1 was included. The overall response rate was in the 50% to 60% range.5
RETas Shaw said, they are reported to occur in only about 1% to 2% of patients with NSCLC.14 In vitro data have determined that RET fusions were oncogenic drivers, and that cancer cells harboring RET fusions would be sensitive to RET inhibition.15
In a first clinical validation of RET rearrangement as another target in NSCLC, a group in New York examined whether the multitargeted kinase inhibitor cabozantinib would have activity in patients with RET fusions.16 Of three patients, two had “very nice” responses, Shaw said. The third patient had stable disease. Importantly, she said, the responses had endured for longer than six months (at the time of publication of the data).16
Ponatinib is a potent RET inhibitor. This targeted agent is currently under investigation in patients with RET-positive lung cancer who have relapsed on cabozantinib, and patients who are tyrosine kinase inhibitor-naïve.17
Today, it is evident, Shaw said, that chromosomal rearrangements leading to oncogenic kinase activation are clearly an emerging and important paradigm in epithelial cancers. Cancers harboring tyrosine kinase fusions drive the initiation and progression of malignancy, and this leads to a state of oncogene addiction, which is the basis for patient responses to kinase inhibitors.
“To date, several tyrosine kinase inhibitors have been shown to be very active in these patients, and, in the case of ALK-positive lung cancer, have become the standard of care.”
Going forward, Shaw said, multiplex analyses that are becoming available should include screening for fusion kinases such as ALK, ROS1, and RET. In addition to informing treatment decision making, this strategy, according to Shaw, will “…facilitate the discovery of new targets for our patients.”