Update: the morning after I posted, investigators presented SANDPIPER data in an MBC session. In response to modest benefit and AE concerns, Roche announced that they would not be pursuing an FDA submission.
Spoiler alert: check out this table presented today at ASCO.
I enrolled in a study combining taselisib with HER2-targeted therapy (T-DM1 or HP, with prior therapy on either option allowed) in metastatic breast cancer. Worth noting: PI3K mutations were not required for enrollment, in line with Genentech’s overall all-comers strategy (e.g., non-targeted atezo). My experience was not apples-to-apples with the MATCH patients, who were enrolled solely on the basis of a PI3K mutation, regardless of tumor origin. But I think it’s analagous, given that I only enrolled because of my PI3K mutation. In 2012 I had a Caris test, which was then much more exciting than it is now; so exciting that I wasn’t even mad that they depleted a five-centimeter block of tumor doing a panel of about a dozen genes plus chemosensitivity testing. We’ve come a long way in six years. Among the results was a PI3K mutation. The wonderful Dr. Cristofanilli, whose enthusiasm for targeted therapies and novel diagnostics is truly inspiring (whether he’s entirely right about their clinical relevance, it’s contagious), told me five years ago to try Afinitor in combination with Herceptin and vinorelbine. Afinitor targets mTOR, which shares a pathway with PI3K and is approved for use in hormone-positive breast cancer, in combination with Aromasin, among other indications. He recommended it over a T-DM1 trial, because he predicted, accurately, that in the near future it would be no problem to get T-DM1, though at the time it seemed like the drug would never make it to market; payer uncertainty with the off-label Afinitor was another issue (BOLERO-3 was published a couple of years later, and I imagine this would make reimbursement less of a wildcard, assuming the prescriber was willing to push for it). While I was touched that after one appointment, he would’ve gone to bat with my insurer, I went with the T-DM1 trial. There were so many next-gen PI3K inhibitors in development, and I had my eye on BKM120.
I waited. And waited. Development was apparently discontinued sometime late last year. If you look at Novartis’ 2017 annual report, BKM120 is suddenly absent from the pipeline. This was not entirely surprising, to the extent that I didn’t even see it reported anywhere, given the AEs; PI3K inhibitors are known to cause neuro issues, and the poor ER+ study subjects with their indolent cancers were up and trying to kill themselves on trial. There were also efficacy concerns. BYL719 still has a heartbeat, but I haven’t heard much about it. They’re trying it with letrozole in HR+ breast, and it seems fine.
Anyway, this story is about taselisib. I enrolled, and I lasted one week. The nausea was terrible, terrible, ondansetron every eight hours terrible, which I usually avoid because I’m so scared that if I take it, I’ll build up some kind of anti-emetic tolerance and this drug that is considered magic and the best choice we have against nausea will no longer work for me. My usual strategy against nausea is to eat candied ginger (it’s stocked with all the nuts in Whole Foods) and to lie absolutely still, which is reasonably effective. Plus my skin progressed, after a few years of relative stability, and I panicked. It just went crazy.
ME: I feel like I did something mutagenic. That maybe the PI3K was there, but it wasn’t driving anything, and now I’ve woken it up.
DOCTOR: Yeah, that’s legitimate.
He’s the best because he tells me the truth.
Like 100% of the MATCHed patients referenced above, I was not a responder. There seems be some suspicion of the drug among physicians; my husband came home recently and said someone asked him, re: taselisib, “Does that thing even work?”
Well. We’ve associated the efficacy of drugs targeting the mTOR pathway with hormone-positive breast because that population is pretty overwhelmingly PI3K-mutated (it may be as high as 50%). But if you look at MATCH, the mutation doesn’t really explain it. For me personally, this also isn’t the first time I’ve targeted the mTOR pathway; I’ve taken metformin since diagnosis, and if that has any anti-cancer activity, it’s along this pathway, and I definitely haven’t associated it with rapid PD.
I haven’t written about my taselisib experience because I really don’t know what to make of it; it’s disappointing, and I don’t want this blog to be a series of lame anecdotes, because oncology is a thrill to me in ways that are separate from my own case. While I want to be honest about what happens to me, it’s a lens and not the thing itself. So when I see that I join the 0% of MATCH patients who were PI3K mutated and yet taselisib non-responders, there is some relief that I’m not going to be the one to be a black mark on this drug (I did ask my doctor if I would be on the record as non-evaluable, because I progressed halfway through the first cycle, or as a PD, and I don’t actually know what happened), but I also want us to believe in genomics until something better comes along. Maybe PI3K is just not an ALK, or, in ASCO 2018 terms, a RET. It’s not like chemo works so great. We can do better than that, right?