Puma’s announcement on Monday that they hit one of their two primary endpoints in NALA is one of the more opaque press releases I’ve seen in a while, reporting a statistically significant PFS benefit for neratinib + capecitabine versus lapatinib + capecitabine, an OS benefit that did not reach significance and a statistically significant benefit in a secondary endpoint of “time to intervention for symptomatic central nervous system disease.” The latter endpoint is the one I most want to be meaningful because CNS was always the most compelling use case for this drug, and wouldn’t it be great if neratinib actually helped someone? Even when you squint, though, there’s not much to be encouraged by in these results, and this is a company press release. 

NALA is a phase III randomized study concocted on the whim of becoming third-line SOC in HER2+ metastatic breast (after THP and T-DM1), despite the fact that DS-8201a and, more relevantly for CNS mets, tucatinib have made considerably stronger moves to claim that spot. (DS-8201a is going after second-line, and we know nothing about the drug’s activity in CNS disease; tucatinib has focused on CNS.) There is nothing in Monday’s press release to suggest that neratinib has a credible claim to the third-line spot; a PFS edge over lapatinib + cape is nothing to write home about, and most patients in the 3L setting would likely prefer a trial or a more compelling Herceptin cocktail (more on the absence of Herceptin below), over neratinib + cape. This is not going to be the standard third line for visceral disease. That means we’re left with a CNS opportunity, which is a sad slice of the HER2+ market opportunity and, importantly, not all that different from what’s available now via guidelines. Since all we’ve seen from NALA so far are delays attributed to a slow rate of mortality events, with no info about the patient mix, there’s not much to build confidence in the validity of this benefit. It would be nice to know how many patients are in the CNS analysis, especially since the time to CNS intervention measure is just a secondary endpoint. There might not be anything here, and until we have tucatinib, Tykerb is just so much easier. Plus, in regular clinical use, you get Tykerb with Herceptin. 

The NALA comparator is infuriating, because it’s not real-world standard of care; no one drops Herceptin, and this is one of the reasons I love the Cascadian study; HER2CLIMB’s experimental arm gets tucatinib + Herceptin + cape. The triplet makes sense, has positive signal from a published phase Ib study and aligns with practice in that everyone gets Herceptin. (It’s like they had a market strategy or something, like they were planning to be the TKI of choice in HER2+ brain mets.) We have no evidence that neratinib will perform better than the true SOC, and with the toxicity, why guess? Why put that on the market in such a competitive environment? The evidence we do have trades QOL not for OS, but for imaging results, and it’s just not good enough. 

Actual data was promised sometime in 2019.