"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.”
