Brain Mets at One Year

The one thing I said I would never do is whole brain radiation. Never, ever. That was the line. I was too scared of cognitive decline, that I wouldn’t be able to write, talk, walk or remember, and there is so much good stuff to remember.

I was diagnosed after going to the ER with a seizure that could be more gently characterized as episodes of visual changes. At intake, it was about 9 p.m. I insisted to the nurses and everyone who came by that I almost certainly had brain mets, but I still had to wait until after 3 a.m. for retinal detachment to be ruled out before they would put me on the list for an MRI. The ER was mobbed, and I spent the night on a stretcher in a hallway, using my coat as a blanket. I had an MRI the next morning, and while I was on the scanner I missed a call from my boss. Good remote employee that I am, this caused my heart to pound more than the impending test results. I kept muting and unmuting myself so he wouldn’t hear the sounds of the ER around me. This was actually the most surreal part of the day. The brain mets were known, as far as I was concerned; I didn’t know how I was going to explain them.

After the scan, they moved me out of a hallway and into an exam room, and some poor innocent ER resident came in and pulled my MRI up on a computer. I could see a handful of lesions, pretty big ones, but I couldn’t get a good look because the guy was clearly accustomed to looking at X-rays of fractures and lungs and not to scrolling through slices. So I didn’t see any of the other slices, but it seemed like the size of at least one of the lesions was pushing what could be managed with SRS, which as a treatment modality of course seemed comparably benign, and I’d have no objection to using it. I didn’t have a death wish with the brain mets, just an aversion to WBR.

They topped me up with Ativan and a massive dose of steroids and instructed me to go to my clinic, go straight there, right now, and I agreed. We stopped at the house so I could take a shower and put on makeup and change into nice clothes because I wasn’t facing The Institute looking like I’d just suffered a few hours of intermittent seizure activity then spent the night in a hallway before being told I had multiple brain mets.

The main thing I learned from that first meeting was that it was a lot more than three lesions. It was probably closer to a dozen. Hopefully that ER guy has since learned to scroll. When we were alone again, I told my husband that if they wouldn’t do SRS there, and we couldn’t find another institution to do it, and I couldn’t get tucatinib, that would be it. I was calling it.

I was ready for all of this, because I’d been having symptoms. The main one being confusion with bright lights at night; I couldn’t seem to see dimension when there were headlights and streetlamps competing for attention.

Why didn’t I say anything? Because it felt like only brain mets could, ahem, bring me down. I wasn’t having it.

Months earlier, I had bought ELO tickets for me and my father. My dad shaped my deep love for oldies and classic rock from when I was an infant, and I remember listening to Face the Music on his turntable when I was 8 or 9. He saw them live a couple of times in the 70s, but anyone who knows the band knows that Jeff Lynne’s not a never-ending tour guy, and I didn’t think I’d get a chance to see him in my lifetime. I was happy to take more or bigger mets in exchange for that night. What was I going to do, get a scan and start treatment and jeopardize the concert? I waited 10 years for the brain mets, but I’d been waiting for Jeff Lynne all my life.

It was so worth it. It was one of the best nights of my life. I think my dad feels the same. Of course I never told him that I was waiting out brain mets so we could have that time together.

This is going somewhere, as much as any of my anecdotes go anywhere. When I met my radiation oncologist, he told me WBR was my best option. Number of lesions aside, the size of the lesions alone was likely to cause so much fibrosis that I may suffer more symptoms than I was having already, and it would make follow-up challenging. All I asked about was the risk of cognitive decline. His answers were good, all of them. He had stories about patients who had better outcomes than I imagined to be possible. I started to consider WBR. He seemed worried that I wasn’t processing the rest of it, like the fact I had a little army of brain mets capsizing some essential brain function. You’ll lose your hair, he warned. He showed me the Paul Brown papers on hippocampal-sparing WBR in combination with memantine. WBR became the reasonable option.

It raised a question I’d never asked before in course of my treatment, because I was always so sure I would do well: what if I didn’t deteriorate?

I didn’t. A year out, and it’s like nothing happened. I compromised everywhere here, from when I reported the brain mets symptoms to the treatment itself. Maybe it cost me, and it could cost me more later (I’ve likely exhausted most options for further brain radiation). But I did what I wanted, and my brain and mobility and independence are intact. It reassures me whenever I think about it that I’m capable of staying true to myself when it counts.

This is not the kind of blog I usually write. Drugs and science are really the only things I want to talk about. But I wanted to tell this story so that other patients know good outcomes are possible. Think about where we were with HER2+ brain mets when I started, when even without the brain mets, I felt like I was on a precipice, always pushing up against the limits of treatment. There was no space for risk. Waiting to see if Tykerb and Xeloda would be effective was one of the only times I ever felt like a patient. I didn’t know then how many rules I’d have to break to stay myself, to get what I needed.

Now it’s 2020, and I can’t even count the lines of therapy I’ve had. I just started DS-8201. We’ll check in on the HER2+ pipeline in a future entry.

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.

EXEL’s trash, Kadmon’s treasure? 10+ years with tesevatinib

Three years ago, I learned of KD-019, an EGFR-inhibiting wonder TKI for which there just happened be a study enrolling, right at the mid-tier academic institution/portal to hell in which I was currently sitting. I nodded along appreciatively to phrases like better than Tykerb! while thinking, Kadmon. Kadmon. Oh, right, the one where the CEO just got out of prison.

Continue reading “EXEL’s trash, Kadmon’s treasure? 10+ years with tesevatinib”

Puma Post-APHINITY

Puma presented at Cowen today, and I listened to the webcast hoping for a reaction to APHINITY, but alas, they kept Q&A to the breakout session. The tone of the presentation did seem a little grim, but between the crushing of adjuvant dreams and half the slides being devoted to unmanageable diarrhea, I guess it was always going to play grim. Continue reading “Puma Post-APHINITY”

Looking ahead with Cascadian Therapeutics

@Buyersstrike generously gave me the opportunity to trash neratinib on his site yesterday, and I thought I’d follow up with a post on a novel, oral, HER2-targeted drug I actually do like: ONT-380.

ONT-380 has been in development for a while, first at Array and then Oncothyreon Cascadian Therapeutics. It’s unique among HER2-targeted small molecules because it does not inhibit HER1 (EGFR), which lends it a more favorable AE profile – it’s the EGFR targeting that is associated with most of the skin rash and GI toxicities we see in this category.

Significantly, ONT-380 is being evaluated for the treatment of CNS mets. In breast, brain mets patients are the ones that actually die – you can live forever with metastatic breast cancer, but brain mets are generally a dealbreaker. (The flip side of the excellent survival stats in breast is why you only see PFS, and never OS, data in breast – with OS as a primary outcome, you’d never get a study analyzed, because you’d wait years collecting mortality events.) If you’re HER2+ positive, and your brain lesions are too multiple or too big for Gamma Knife and you don’t want whole brain radiation (n.b., you do not want whole brain radiation), you’re basically left with lapatinib. We need ONT-380.

There’s not a lot of public data, but there’s signal that the drug works. These results from the Ib trial combining ONT-380 with T-DM1 (Kadcyla) found that in heavily pre-treated MBC patients with and without measurable CNS disease, there was an overall response rate of 47% and a respectable median PFS of 6.5 months. Both of these measures are exceptional for brain cases. This is phase I data summarized in an ASCO abstract, so we don’t have a lot of details on the patient population or their responses, but there were even a couple of complete response (CR) cases in the measurable CNS mix.

The treatment of brain mets is a massive unmet clinical need, but it’s a tough strategy to pursue, because these studies are hard to enroll. The ideal patient would be someone asymptomatic who has never been treated for CNS mets, and in a clinical setting where screening MRI for brain is not standard of care, that profile is not common. Even if you found a perfect patient, you’d have to get them to a site that’s actually enrolling. (I am a strong advocate for de-centralizing clinical trials, but that is an uphill battle and a post for another day.) There are other enrollment challenges for their ongoing Phase II study as well; patients are randomized to receive Herceptin and capecitabine (Xeloda) +/- ONT-380, and prior treatment with capecitabine in the metastatic setting is an exclusion criterion; however, capecitabine is often given with lapatinib, which is permitted in this study as long as it was used >12 months prior to enrollment. A lot of HER2+ metastatic patients have had the Herceptin/Xeloda/Tykerb combo (it was my first-line metastatic treatment), because it’s just about the easiest cancer treatment you can do, and I don’t know how many patients receive Tykerb with just Herceptin or with Herceptin and another cytotoxic agent. At any rate, I doubt eligible ONT-380 patients are just falling into investigators’ laps. And while I have the same complaints about our slow, unwieldy, archaic regulatory body as anyone else, in this case, the FDA does seem to get it: they gave ONT-380 Fast Track status in June.

But there’s something I like about Cascadian that has nothing to do with science (give me some credit; we haven’t even seen PII yet). It’s this, via a screen cap from their website.

ont380-4

Do you see it? How about this?

ont380-3

For contrast, check out what I pulled from the Ixempra site (ixapebilone from BMS; a microtubule-binding agent, similar to a taxane).

ixempra-2

WTF is that? Who is that supposed to be?

These are marketing images, but they reflect a tension in the MBC treatment philosophy: are you going for a hike with your dog? Or are you just hanging on to see your grandchild born or whatever nonsense that lipstick mirror crap is supposed to signify? Cascadian is positioning itself as forward-thinking on multiple dimensions. They’re gambling on brain mets patients, who, despite a poor prognosis, are not staring in the mirror, trying to summon the will to hang on another day. Their patients are on a hike. You’re not dead; life still has meaning (this is part of why terrible side effect profiles on useless drugs are so offensive!). This company has balls. And they understand that patients Google, and good for Cascadian that these are the images they want patients to see.

Now bring on the PII results.