Tucatinib Meets Primary Endpoint in HER2CLIMB

Joining DS-8201 as a likely FDA approval in early 2020 is tucatinib, a HER2-targeted small molecule TKI that I’ve been fangirling for years. If this keeps up, I’m going to be able to treat my cancer with actual new medicine and not just mental fortitude.

Not to malign the Herceptin-plus-X paradigm that’s bridged me all this time, but it’s been a while since the T-DM1 and Perjeta launches of 2013. In metastatic cancer years, it’s a real long while.

Onto the successes of HER2CLIMB, Cascadian Therapeutics’ (now Seattle Genetics’) phase III trial comparing tucatinib + Herceptin + Xeloda to placebo + Herceptin + Xeloda. The trial enrolled 612 subjects and was randomized 2:1, and subjects had been previously treated with Herceptin, Perjeta and T-DM1. The press release notes that 47% of subjects had brain mets at the time of enrollment. A classic placebo-controlled RCT in a tough crowd? Yes, please. What’s not to like about these guys?

We don’t know a lot yet, with actual numbers to be presented at San Antonio. But to pull the highlights from the press release:

  • Tucatinib + H/Xeloda combo met its primary PFS endpoint, with a 46% reduction in risk of PD or death compared to placebo + H/Xeloda
  • Among secondary endpoints, OS was superior for the tucatinib arm versus placebo + H/Xeloda, with a 34% reduction in risk of death
  • For patients with brain mets at baseline, tucatinib + H/Xeloda offered a 52 percent reduction in the risk of PD or death compared to placebo + H/Xeloda

Not a bad teaser, right? Congrats, Cascadian.

DS-8201 has a PDUFA Date

Yes! The date is F1Q:20, so I might be getting a prolonged OS for Christmas!


Daiichi announced today that they’ve been granted FDA Priority Review for their highly worthy DS-8201, which looked promising out of the gate and recently demonstrated a 59.5% response rate in HER2+ metastatic breast cancer patients who had previously been treated with T-DM1. Those results, from a 118-subject Phase 1, were published in June. The study also reported some total insanity, like a 20.7-month duration of response (DOR) and a 22.1-month PFS. It’s not comparable given the phases, designs and number of subjects enrolled in this phase 1 versus EMILIA, but T-DM1 had a phase III PFS of around 9-10 months, so DS-8201 is likely to displace that agent as the second-line treatment of choice in this setting (first-line being taxane + Herceptin + Perjeta).

The data above are old news, but the press release says the submission package also includes pivotal phase 2 DESTINY-Breast01 data, which “validated” the phase 1 results and which no one has seen yet, though they note that it will be presented at San Antonio. DESTINY 1 looks at a similar population (T-DM1 pre-treated MBC), but its 230 subjects were randomized to varying dose levels. Primary endpoint is ORR, so it would be shocking if this result isn’t pretty compelling, considering what we’ve seen so far. 

Like T-DM1, DS-8201 is an ADC where Herceptin is conjugated to a chemo agent; in DS-8201’s case, it’s a TOP-I inhibitor, similar to irinotecan.

Where did we leave off?

Was it the brain mets? We’ll start with the brain mets.

There were a bunch of them. A dozen? A couple were giant. I had whole brain radiation, which I always swore I wouldn’t do out of fear of cognitive decline. Six months out, I can still tie my shoes and spell my name, so I guess it’s turning out fine. 


When the WBR was over, I did what any reasonable person with no access to tucatinib and looking to avoid the Maintenance Nerlynx would do: I hopped on a plane to Germany. (Before you judge me for my rash leap to dangerous, unproven treatments administered in rogue foreign clinics, rake Pubmed for some rigorous efficacy data on FDA-approved brain mets interventions. I’ll wait.) 

One of the reasons I was excited to come back to the blog was so I could tell this story. My German doctor almost made me cry the day I met him, in the most unexpected way.

He was walking me through treatment options in his office, some EMA-licensed, some not, many occupying a regulatory gray area for which we don’t really have a U.S. analogue. The rules around the manufacture and administration of these treatments seemed a little vague, and my worry was that the treatments themselves would end up supply-constrained (what would be more frustrating than having one dose of a treatment and then never being able to secure a follow-up dose?), or that the clinic itself would be shuttered for some nonsense violation, and I’d lose access that way. Note that I wasn’t worried about safety, which is a fun consequence of the brain mets. What can hurt me now but being afraid?

My doctor assured me that it wouldn’t be a problem. He elaborated, and some of this (particularly the legal circumstances and terminology) may have been lost in translation, but the gist of it was this:

There was a court case in Germany where a physician was charged with murder for falsifying lab results and other medical records for a patient in need of an organ transplant, making the patient appear sicker than he was. For this reason, the patient was moved up the transplant list and received the transplant while other patients awaiting organs died. The falsified documentation was uncovered, and the physician was charged and found guilty. On appeal, a higher court reversed the judgment, deciding that the doctor was responsible for his patient, not every sick person in Germany.  This set a precedent that gave physicians a lot of latitude in patient care. He’d go on to add that it applied to unproven or unlicensed therapies if the doctor determined that the benefits outweighed the risks, which he made evident to me was a pretty low bar given the brain mets.    

All I heard, loud and clear, was My only obligation is to you.

I almost burst into tears. What is this blog other than the hope that a doctor would say those words to me? I love trashing scummy companies as much as anybody, but why would any of this bother me so much if I weren’t clinging to that ideal? In that office, suddenly, my guard was down and I relaxed; I would try anything, pay anything, keep any secret, now and later and long after I’m gone (let my husband deal with that one; tell them the nachtkrapp got me), because for once the transparency existed where it mattered and not where it didn’t.

U.S. healthcare is programmed so this scene would never happen, and I would argue that the cost of that is trust. The physician-patient relationship is not a partnership, and it won’t be as long as we continue to cloak the reality that your doctor doesn’t always want what you want. This was not my first experience with ex-U.S. care, and I’m conflicted about those experiences; in the EU I received in many respects higher-quality, more pragmatic care than I could dream of in the U.S., but there was also some great frustration that an American adult who grew up in the candy store of U.S. healthcare can probably never reconcile. But that conversation, in that German clinic, was the clearest validation I’ve seen that the ideal is possible. It can be done. This is how you empower a patient.