INSIDE THE BLACK BOX is an occasional column providing insight into the U.S. Food and Drug Administration (FDA) and its policies and procedures. In this installment, FDA oncologists Sean Khozin, MD, MPH, and Dikran Kazandjian, MD, discuss anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC) and the recent approval of ceritinib. Drs. Khozin and Kazandjian are Clinical Reviewers in the Division of Oncology Products 2, Office of Hematology and Oncology Products, Center for Drug Evaluation and Research.
On April 29, 2014, the FDA granted accelerated approval to ceritinib (Zykadia) capsules for the treatment of patients with ALK-positive metastatic NSCLC who have shown disease progression on or are intolerant to crizotinib (Xalkori).
Ceritinib Background
What is ceritinib and how does it fit into the new paradigm of personalized cancer therapy?
Dr. Khozin: The treatment of lung cancer has traditionally been based on histology. In recent years, however, the discovery of driver mutations has created a new paradigm where treatment is tailored, or personalized, to the specific mutations that are thought to be oncogenic and responsible for the initiation and maintenance of cancer.
Potentially targetable driver mutations have been discovered in over half of all NSCLCs. ALK gene rearrangements represent one example and are found in about 5% of NSCLC cases. This oncogenic event leads to an ALK gene fusion product with a constitutively active tyrosine kinase domain. Ceritinib is an ALK kinase inhibitor that inhibits the proliferation of ALK-dependent cancer cells.
Role of ALK in Lung Cancer
Tell us about the discovery of ALK in lung cancer and why it is so important.
Dr. Kazandjian: Interestingly, ALK genetic alterations were first discovered in 1994, when ALK fusion translocation events were identified in non-Hodgkin lymphoma. Morris and colleagues showed that a translocation event involving chromosomes 2 and 5 created a fusion protein juxtaposing the tyrosine kinase part of ALK to nucleophosmin (NPM-ALK fusion). Given that the ALK protein is not normally expressed outside of neural development, the expression of the chimeric ALK protein was determined to be an oncogenic driver and implicated in the dysregulation of cell proliferation and apoptosis in anaplastic large cell lymphoma.
The ALK story becomes even more interesting if we fast-forward to 2007, when Soda and colleagues first showed that an ALK alteration—in this case a small chromosomal inversion event—resulted in the expression of a fusion protein with the ability to cause skin tumors in mice. The researchers determined that this chimeric tyrosine kinase fusion protein incorporated a 5ʹ region of the breakpoint partner echinoderm microtubule-associated protein-like 4 (EML4) gene and the 3ʹ intracellular cellular kinase domain of the ALK gene. Furthermore, they found that 5 of 75 archived samples from patients with NSCLC had this aberration.
Fortuitously, crizotinib had been identified as a lead compound in 2005 and was already in early-phase trials in lung cancer as a c-MET inhibitor. Subsequently, it was found to also inhibit ALK, which quickly led to two patients with ALK-positive NSCLC being enrolled in an ongoing trial. After these two patients were found to have responses in early 2008, an ALK-positive NSCLC cohort was added and additional responses were observed. As a result, in mid-2009, a single-arm phase II trial and a randomized phase III trial were initiated, and a previously existent fluorescence in situ hybridization (FISH) assay to detect ALK inversion/translocation events was further refined and validated for use in these trials.
Crizotinib received accelerated approval in 2011. Regular approval was granted in 2013 after confirmatory trials showed objective response rates between 50% to 65% and progression-free survival rates of about 7 months. This was deemed to be highly clinically meaningful since traditional chemotherapy delivers response rates of only about 10% and progression-free survival rates of about 3 months.
Treatment Limitations
In the ALK-positive subset of NSCLC, it appears that the oncogenic driver target is clear and that crizotinib clearly inhibits this pathway; why are patients not being cured?
Dr. Kazandjian: As mentioned previously, crizotinib shows impressive antitumor activity in the ALK-positive subset of NSCLC compared to standard chemotherapy and can be considered a tailored medicine. However, with further understanding of the biology of NSCLC, it has become clear that it is a very heterogeneous disease. Early in the development of NSCLC, there may be clones with different genetic alterations, and resistance can occur when clones that are inherently resistant become the majority of the tumor bulk. This phenomenon may occur in both EGFR-positive and ALK-positive NSCLC.
Reported mechanisms of resistance for ALK-positive NSCLC include ALK mutations, ALK copy number gains, and oncogenic driver mutations in other genes. Very similar to the “gatekeeper mutations” of T315I in BCR-ABL and T790M in EGFR, the L1196M substitution mutation has been shown to confer resistance to crizotinib in about a third of patents. Other mutations are coming to light, and most of these secondary mutations occur in the kinase domain regions of ALK and affect drug-to-ALK binding. ALK gene copy number gains lead to more chimeric ALK protein than crizotinib can inhibit.
Mutations in other known proto-oncogenes and oncogenic pathway aberrations have been shown to drive ALK-positive tumors after crizotinib resistance. Interestingly, one such mutation is the well-described EGFR exon 21 L858R mutation, which is the major driver in the EGFR subtype of NSCLC. Other EGFR mutations along with mutations in other oncogenes, including KRAS, have been described.
Crizotinib Resistance
Since almost all ALK-positive NSCLCs will eventually stop responding to crizotinib therapy, how can resistance be overcome?
Dr. Kazandjian: One mechanism of acquired resistance to crizotinib may be the development of a second-site mutation that prevents binding of the drug to the ALK-kinase region. This type of resistance could potentially be overcome by newer-generation ALK inhibitors with different three-dimensional chemical structures that may have more favorable binding profiles to these mutated ALK proteins. Secondly, more potent newer-generation ALK inhibitors may help overcome the resistance caused by ALK copy number gains.
Finally, crizotinib resistance caused by activation of other oncogenic pathways by crosstalk or by mutations of other oncogenes poses a more difficult situation. In these resistance types, the biology needs to be further elucidated, and specifically, the pathways and key drivers need to be identified. Currently, a number of therapies targeting these other oncogene products (eg, EGFR, c-MET) are either in clinical trials or will be in the near future. The future will tell whether resistance caused by activation of other oncogenic pathways can be successfully overcome by target-directed therapies.
Other important questions about resistance are whether it can be prevented in the first place and the optimum timing of treatment with newer-generation ALK inhibitors. For example, should upfront therapy consist of newer-generation ALK inhibitors to prevent the emergence of the L1196M mutation, or should upfront therapy consist of crizotinib followed by newer-generation ALK inhibitors at disease progression?
Future trials will need to address these questions and determine how they ultimately affect survival of patients with ALK-positive NSCLC. One thing is clear: for certain subtypes of NSCLC, targeted therapies have revolutionized treatment options and outcomes for patients compared to a decade ago.
Ceritinib Data
Can you describe the data supporting ceritinib’s approval?
Dr. Khozin: The main support for ceritinib’s approval came from a multicenter single-arm trial in 163 patients with metastatic ALK-positive NSCLC who had disease progression on or who were intolerant to crizotinib. All patients received ceritinib orally at a dose of 750 mg once daily.
The primary endpoint of the trial was objective response rate according to RECIST v1.0, as evaluated by both investigator and a blinded independent central review committee. The trial results showed an objective response rate of 44% and a duration of response of 7.1 months based on review committee–determined tumor assessments. The analysis by investigator assessment showed similar results, with an objective response rate of 55% and duration of response of 7.4 months.
These results were considered to be clinically meaningful in a population of patients previously treated with crizotinib, and 91% had disease progression on prior crizotinib therapy. Ceritinib therefore appears to overcome resistance to ALK inhibition in about half of patients previously treated with crizotinib. The most common adverse reactions in the trial were gastrointestinal events such as diarrhea, nausea, vomiting, and elevated transaminases.
Breakthrough Therapy Designation
On March 6, 2013, FDA granted ceritinib Breakthrough Therapy designation based on preliminary evidence of clinical activity in patients with metastatic ALK-positive NSCLC previously treated with crizotinib. How did that affect the interactions with the sponsor and the review process?
Dr. Khozin: We made a concerted effort to mobilize FDA’s administrative and scientific resources to give the sponsor intensive guidance on their clinical development program, so adequate data for the safe and effective use of ceritinib in the appropriate NSCLC patient population could be generated in the most efficient manner. We carried the same commitment into the New Drug Application (NDA) review process, which enabled us to perform a thorough benefit-risk analysis and approve the drug 4 months ahead of the goal date for priority review.
Optimized Review Process
What challenges did FDA face in helping to expedite the development program and the review process for ceritinib?
Dr. Khozin: After ceritinib was granted Breakthrough Therapy designation, FDA took a proactive approach, which required flexibility on the part of FDA staff and the sponsor to facilitate rapid exchange of information via a host of formal meetings and information requests. This became even more important after NDA submission in order to sustain a tightly coordinated review process.
Special emphasis was placed on the manufacturing aspects of ceritinib’s drug development to avoid delays and to safeguard against potential deficits in the commercial manufacturing process. Issues surrounding the content and structure of the data for the NDA were also important to facilitate an expedited review. It is clear that the use of interoperable and platform-independent data standards in NDA submissions can create efficiencies in the review process beyond what is feasible with traditional methods of data capture and analysis.
Lessons Learned
How can the lessons learned from the experience with ALK inhibitors be applied to other drugs in development for NSCLC?
Dr. Khozin: The strategy of molecular enrichment has been the most important factor in the success of not only ALK inhibitors but also EGFR inhibitors in the treatment of patients with metastatic NSCLC. In both cases, patient selection based on the presence of specific genetic alterations allowed for a rational approach to drug development, which in the case of ceritinib, enabled an expedited pathway toward FDA approval.
Enrichment strategies backed by sound scientific evidence are, therefore, of paramount importance and may explain the lag in the development of some of the current investigational agents for advanced NSCLC where no predictive biomarkers have been established. The use of technologies such as next-generation sequencing on multiplexed samples and innovative trial designs such as the Lung Cancer Master Protocol, coupled with advances in data standardization and computing platforms, have paved the way for a new paradigm that can support an efficient path toward development of new drugs for patients with NSCLC. ■
Disclosure: Drs. Khozin and Kazandjian reported no potential conflicts of interest.
Inside the Black Box is Guest Edited by Richard Pazdur, MD, Director of the FDA’s Office of
Hematology and Oncology Products.
