Tuesday, February 14, 2017

"Get Your Affairs in Order?" Not So Fast


It wasn’t that long ago that a diagnosis of stage 4 Non-Small Cell Lung Cancer (NSCLC) was death sentence. Patients often heard “I’m sorry, there’s nothing more we can do” or “it’s time to get your affairs in order.” Unfortunately, too often that communication still happens today. However, with the advent and increasing availability of molecular testing, we are able to identify biomarkers that can lead to available targeted treatments. My friend Linnea Olson is one shining example of how far we’ve come in lung cancer treatment, and gives me hope for good outcomes if patients get their tumors tested. It’s also why I am such a passionate advocate cancer research and precision medicine.
                                             Linnea (on right) and Dr. Alice Shaw
In 2006, Linnea heard the words ‘there is nothing else we can do.” Never one to turn away from the truth she wanted to know more, she wanted to know how much time remained. The answer was three to five months. And so she began to let go of her life—and to help her family do the same – and started saying her goodbyes. But then at her next oncology appointment something totally unexpected happened. A recent biopsy had been submitted for genetic testing and had come back positive for a newly identified mutation in NSCLC called an ALK translocation. A phase I clinical trial for an experimental agent targeting ALK mutations had begun recruiting at Massachusetts General Hospital (MGH).
In 2008, she became the fourth person in the world with NSCLC to take crizotinib (Xalkori). Seven weeks later, her scans revealed remarkable improvement. She was lucky to be at the right place, at the right time, and with the right oncologist, Dr. Alice Shaw at MGH. Since then she has been a participant in three phase I clinical trials. Of course, she still has lung cancer. But now almost 11 years later she is still inspiring me and other lung cancer research advocates who believe that molecular testing is key to matching specific mutations to targeted treatments.
Since the original discovery of the ALK rearrangement in NSCLC in 2007, small molecule tyrosine kinase inhibitors of ALK have transformed the course of treatment for those patients with ALK-rearranged (ALK-positive) NSCLC. Crizotinib was the first targeted therapy developed for patients with advanced ALK-positive NSCLC and has proven to be superior compared with first line chemotherapy in many global trials. However, patients invariably relapse on crizotinib, often within the first year of treatment, and research has been ongoing, trying to change this.
To address the growing issue of crizotinib resistance, multiple next-generation ALK inhibitors have been developed. The first of these new drugs—ceritinib (Zykadia)—showed significant clinical activity in a global phase I study leading to its approval in the United States, Europe, and elsewhere. Alectinib (Alecensa) now joins ceritinib as another next-generation ALK inhibitor approved in the United States for patients with advanced ALK-positive NSCLC previously treated with crizotinib. These approvals raise several important questions regarding the management of patients with advanced ALK-positive NSCLC. First, in a patient who has relapsed on crizotinib, which next-generation ALK inhibitor should be prescribed? This question does not have a simple answer, since the pattern of relapse can differ from patient to patient. More head-to-head clinical trials comparing next-generation ALK inhibitors need to be performed, but based on the available single-arm studies of alectinib and ceritinib in crizotinib-resistant disease, the systemic efficacy of these drugs may be roughly comparable. Ultimately, the choice of next-generation ALK inhibitor will need to be individualized for each patient.
The second question that needs to be addressed is whether next-generation ALK inhibitors like alectinib should be used in the first-line setting in place of crizotinib. At present, the standard approach—sequential therapy with crizotinib followed by a next-generation ALK inhibitor—is associated with a combined median progression-free survival of 18 to 20 months. Whether first-line use of a next-generation ALK inhibitor can lead to a comparable outcome is not yet known. However, limited data with several of the next-generation ALK inhibitors suggest that this could be the case. The final question concerns resistance to alectinib as new mutations continue to be identified. This will be an ongoing battle and I believe with continued support of cancer research, we will see new treatments matched to the new targets. Considering where we were prior to 2006, there is much hope for patients that are tested and ALK-positive is identified. And like my friend Linnea, patients won’t here “get your affairs in order.”

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