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ALK-targeted therapeutics represent ‘profound revolution’ in personalized cancer therapy
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Patrick C. Ma, MD, MS
Albert Einstein once said: “Learn from yesterday, live for today, hope for tomorrow. The important thing is not to stop questioning.”
That is the essence of research.
Alice T. Shaw, MD, PhD, and Jeffrey A. Engelman, MD, PhD, both of Massachusetts General Hospital Cancer Center, wrote an excellent review article recently published in the Journal of Clinical Oncology, titled “ALK in Lung Cancer: Past, Present, and Future” (Shaw AT. J Clin Oncol. 2013;31:1105-1111).
Taking a look at the drug development timeline of anaplastic lymphoma kinase oncogenic fusion (ALK-positive)–targeted therapeutics from this perspective illustrates the profound revolution we are undergoing in personalized targeted cancer therapy.
Yesterday
Although ALK was first identified in lymphoma as oncogenic fusion as NPM-ALK in the past, the novel ALK gene rearrangement — most commonly as EML4-ALK — was discovered in non–small cell lung cancer only as recently as 2007 (Soda M. Nature. 2007;448:561-566). Remarkably, 4 short years later, the first ALK-targeting small molecule inhibitor, crizotinib (Xalkori, Pfizer), received FDA approval based on impressive clinical activity and benefit seen in phase 1 and 2 studies.
As if it is not dramatic enough, crizotinib was originally intended to be developed as a MET kinase inhibitor, which in turn found its home-run triumph in its approval as an ALK inhibitor. In NSCLC, our understanding of the ALK-positive tumor biology and its effective clinical inhibition is particularly meaningful. This is because ALK-positive NSCLC, which constitutes about 5% of all advanced disease, is predominantly found in young patients with no or light smoking history.
However, acquired drug resistance remains the rule despite initial response to crizotinib. Thus, it is imperative that we develop better ALK targeting inhibitors and other alternative strategies to overcome drug resistance, which can be the result of diverse molecular mechanism. Fortunately, there seems to be a good portion of resistant tumor progression that is still driven by ALK-dominant mechanisms — eg, ALK kinase domain resistant mutations, ALK gene copy number gain and CNS resistant progression due to insufficient drug penetrance (Camidge DR. Nat Rev Clin Oncol. 2012;9:268-277).
Today
In mid-March, the FDA granted breakthrough therapy designation to the investigational compound LDK378 (Novartis), a highly selective ALK inhibitor, for the treatment of patients with ALK-positive metastatic NSCLC. The decision came about 1½ years after the FDA granted full approval of crizotinib.
The timeline and pace of drug development of the first- and now second-generation ALK inhibitors are phenomenal. The results of a phase 1 study of LDK378 in 88 patients with ALK-positive advanced cancers that progressed through crizotinib — either due to resistance or intolerance — showed a stunning 88% response rate.
Thus, it is only fitting that FDA granted the newly established “breakthrough therapy” designation to LDK378.
Although it does not guarantee the eventual FDA approval of the drug, it does signify the intention of the regulatory agency to expedite development and review of the drug, as the program is designed to help ensure therapeutically important drugs available at an earlier time. This is absolutely great news to ALK-positive patients, as well as everyone who cares about and for them.
Two phase 2 studies of LDK378 have been initiated, and phase 3 studies are anticipated later this year. Novartis plans its first regulatory filing by early 2014.
Tomorrow
We now have the second therapeutic that can treat ALK-positive NSCLC. It is still in clinical trial studies, but hopefully soon it will be another FDA-approved standard treatment option.
Although it is good to have more treatment options, we must not stop questioning.
Would LDK378 be a better upfront therapeutic than crizotinib, or should it be reserved as a secondary strategy to inhibit acquired crizotinib-resistant/intolerant, ALK-positive NSCLC?
Would other novel therapeutics that are in clinical trial development to overcome crizotinib resistance — such as HSP90 inhibitors or the other second-generation ALK inhibitor CH5424802 — measure up to LDK378?
Last but not least, we must ask: Why can’t we have a cure? Is it too much to ask? Do we have to worry about LDK378 resistance, which seems inevitable?
However, one thing is sure: We now have more reasons to be hopeful for tomorrow. Although we can fully and justifiably celebrate the progresses made in the past and the present, it is truly just the beginning for all of us to start working for the future.
For more information:
Patrick C. Ma, MD, MS, is director of aerodigestive oncology translational research at Cleveland Clinic’s Taussig Cancer Institute. He can be reached at Cleveland Clinic Main Campus, Mail Code R40, 9500 Euclid Ave., Cleveland, OH 44195.
Disclosure: Ma reports no relevant financial disclosures.