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ALK rearrangment

Dr West

New FDA Approval for Zykadia (ceritinib) for ALK-Positive NSCLC: Why I Think It’s a Poor Choice for Initial Treatment

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The FDA just approved a new therapy for the approximately 4% of patients with NSCLC who have the molecular marker known as an ALK rearrangement. The agent Zykadia (ceritinib), a “second generation” ALK inhibitor that is more effective than Xalkori (crizotinib) in lab models of ALK-positive NSCLC, and the new approval was for Zykadia as first line treatment for ALK-positive lung cancer, a setting where we have historically favored Xalkori since it was approved in 2011. . Despite the FDA approval for ceritinib, I don’t believe it should be favored as a first line therapy for ALK-positive patients. Why would I not favor it?

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Dr West

Heat Shock Protein Inhibitor IPI-504: Particularly Active for Patients with an ALK Rearrangement?

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I’ve written in the past about a class of proteins known as heat shock protein inhibitors as a targeted anticancer therapy, and there are a few that have been in clinical trials, including IPI-504 from Infinity Pharmaceuticals and STA-9090 from Synta Pharmaceuticals, with others also in development. The only trial that has actually been the subject of a completed clinical trial in NSCLC is IPI-504. Dr. Lecia Sequist from Massachusetts General Hospital led this multicenter trial (10 participating sites, including Moffitt Cancer Center: Dr. Gray is one of the study authors) of IPI-504 administered at 400 mg/m2 IV on days 1, 4, 8, and 11 every 21 days to 76 patients who had previously received an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). In fact, these patients had generally received many prior treatments, with a median of 4 prior lines of therapy among the participants, with nearly all having already received an EGFR inhibitor. In addition, 45% of patients were never-smokers and 63% were women, so this is not a typical cross-section of the NSCLC population.

Nearly all patients were tested for the presence of an EGFR mutation, but they were eligible whether they had evidence of an EGFR mutation or were EGFR wild type (no mutation). One hypothesis of the investigators leading the trial was that IPI-504 could be an active agent in patients with an EGFR mutation, based on some preclinical lab-based research.

But the results didn’t turn out quite as the investigators had anticipated. The response rate (RR) in the entire trial population was 7% (5/76 patients), with a breakdown of 10% (4/40) for the patients with EGFR wild type, and 4% (1 of 28) with an EGFR mutation. While these results were below the threshold RR of 20% the investigators were hoping to see, they also did testing for an ALK rearrangement and KRAS mutation, along with a battery of other molecular markers when tissue was available. They found that while there was no clear association of better or worse outcomes in patients with a KRAS mutation, but they found the intriguing result that two of the three patients they identified with an ALK rearrangement had significant tumor shrinkage consistent with our definition of an objective response. Here are the “waterfall plots” of response vs. progression, with bars on the right extending down from the horizontal line reflecting tumor shrinkage (and longer downward bars corresponding to more shrinkage), while the upward bars on the left correspond to tumor progression (with the length upward corresponding to more growth):

sequist-ipi-504-rr-waterfall-by-mutation-status (click on image to enlarge)

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