A case report shows that drug resistance in ALK-positive non–small cell lung cancer is a dynamic process. In this patient, an acquired mutation conferring resistance to the highly selective investigational ALK inhibitor lorlatinib unexpectedly restored responsiveness to crizotinib, an older and less potent drug.
Drug resistance in ALK-positive non–small cell lung cancer (NSCLC), a known problem, can have unexpected twists. Researchers from Massachusetts General Hospital in Boston recently reported the case of a patient with advanced ALK-positive NSCLC, whose eventual relapse on the investigational ALK inhibitor lorlatinib (Pfizer) paradoxically restored her responsiveness to crizotinib (Xalkori; Pfizer) (N Engl J Med 2016;374:54–61).
The patient's treatment regimen began with crizotinib, followed by ceritinib (Zykadia; Novartis) and then lorlatinib. “When she stopped responding to crizotinib, we profiled her tumor and found an ALK mutation, C1156Y, which causes resistance by increasing ALK's kinase activity,” says Alice Shaw, MD, PhD, a thoracic oncologist and the study's first author. “She didn't respond to ceritinib, but upon switching to lorlatinib, her response was quickly apparent.”
Lorlatinib, which Shaw describes as “the newest next-generation ALK inhibitor, designed to overcome all known crizotinib-resistant mutations,” reduced the patient's tumor burden by 41% in just 5 weeks. Unfortunately, she relapsed again after 9 months, with worsening liver metastases and impending liver failure.
“There didn't seem to be any options left, but we decided to do another biopsy,” Shaw says. This time, the researchers found an additional ALK mutation, L1198F, on the same allele as C1156Y. Cell-line studies indicated that L1198F promoted resistance to lorlatinib and other next-generation ALK inhibitors, but unexpectedly restored sensitivity to crizotinib. Treatment with crizotinib was therefore restarted, “although we generally move toward more potent, selective ALK inhibitors, and almost never look back,” Shaw notes. The patient's recovery was swift; she regained liver function within weeks, and her second response to crizotinib lasted nearly 6 months.
Through biochemical and crystallography analyses, the researchers determined that L1198F interferes with lorlatinib's binding to ALK, but increases crizotinib's affinity for its target. “We think the enhanced binding due to L1198F negates the increased kinase activity from C1156Y, thereby resensitizing tumor cells to crizotinib,” Shaw explains.
“It's interesting that this subset of NSCLC retains ALK dependency; the tumor keeps modulating the oncogenic driver as we pressure it with different drugs,” says Christine Lovly, MD, PhD, an assistant professor at Vanderbilt Ingram Cancer Center in Nashville, TN. “This study highlights the importance of monitoring tumor heterogeneity and evolution throughout therapy.”
“Obtaining repeat biopsies from patients who relapse on targeted therapies, for molecular profiling, is key,” Shaw adds. “This isn't standard practice, although I'm seeing more of it. Once blood tests assessing cell-free tumor DNA are validated and become mainstream, we'll have a more efficient, less invasive way to pinpoint resistance mutations in ALK-positive NSCLC.”
Shaw and Lovly also advocate combining ALK inhibitors, which have so far been used as sequential monotherapy, to better keep resistance at bay. “Rational combinations would be particularly useful in the frontline setting, because that's our first and best chance of achieving the most meaningful response,” Lovly says.
Lorlatinib is still in early-phase studies, but “as we continue to study resistance that emerges, we may see L1198F appear more often,” Shaw says. Meanwhile, she's struck that this mutation alters the very leucine residue lorlatinib's designers at Pfizer exploited to enhance the drug's selectivity for ALK over other kinases.
“It's intriguing, from a chemistry standpoint—how we may be able to anticipate mutations based on a drug's design, and in doing so, perhaps find ways to overcome them,” she says. –Alissa Poh
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- ©2016 American Association for Cancer Research.