Cancer in the Time of Coronavirus

I’m a cancer-riddled germophobe with one neutrophil, so I’ve been preparing for this for the past ten years. Purell? Stocked. Lysol wipes? Come to my house, and I will hook you up. Masks, ranging from simple surgical masks to the slightly fancier Respokare models? In stock. I’ve also worked from home since 2008, which is its own quarantine. But now you’re all like me!

Coping with Quarantine

Work from home setups are personal. I like a desk and to pretend I’m in a real office. I draw the line at work clothes and dress for the gym. I have a friend who lounges on the couch with My 600-Pound Life playing in the background, muted as needed. Most of us probably listen to CNBC with the laptop on the kitchen table, only to be lured away when you smell someone in the house cooking some food.

Go outside. I get some fresh air a couple of times a day, even if it’s just a lap around the block. This is one of the joys of working from home; taking your phone and going outside, and not having to feel guilty. Plus most of us feel like we have somewhere to walk from our front doors, while the neighborhood around my old office at 59th and Park was not exactly amenable to a peaceful lunchtime stroll.

When I do have to go into the office or travel for a meeting, I try on all my work clothes in a panic to make sure I haven’t gotten too fat for them. Remember this for when this is all over and we return en masse to the office: athleisure offers a lot of stretch.

Infection

I don’t know how people imagine getting sick, how specific it is. The virus still seems to be seen as something other; every time someone clears their throat it’s quickly accompanied by, “Don’t worry, it’s not that.” On a flight a few weeks ago the idiot in the seat in front of me thought it was hilarious to tell both of his seatmates as they boarded that he “hasn’t been to China in weeks, heh heh.” I jammed my Smartwater into the seatback pocket nice and hard.

It does seem suspect to me that the early stages of COVID-19 would feel like, you know, just a cold. Little bit of a scratchy throat, cough cough, whatever. A few years ago, I had some totally treatable bacterial pneumonia and the back pain was ungodly. I thought I had shattered a disc and had some simultaneous upper respiratory drama. I’m thinking this virus is going to hurt, even in mild cases. You need it anyway for fever reduction, so make sure you have Tylenol.

I’m afraid of what will happen to me if I get sick, when I get sick (since the estimates are that about 50% of the U.S. population will ultimately be infected). I’m immunocompromised, but I’m a woman in my 30s. I have lung mets, but my lung function is perfect, and my blood O2 is 100%. I should have a mild to moderate case, treatable at home. There are people so much sicker than me that should statistically push me out of the bad side of the curve. But what if the curve does not unfurl in my favor, and how much more careful can I be? I take all the immune supplements in the world, so what else is left? Drink more water?

These calculations are familiar to patients who have cancer. The question is always, even secretly, What are the odds? What are my odds? There are recurrence rates, response rates, adverse event rates, measures of duration of response. There are no perfect prediction models, but you’re always running the numbers, adjusting and re-adjusting for a bad scan, a good scan, bad data, new drugs. You eyeball everyone in the waiting room, most of whom are early-stage patients, looking for someone like you (or close enough, since most people assume I’m there with my mom) and judging where they fall on the curve. How do I lock in my spot?

There’s more, each scenario bending into a progressively darker turn. Will I be able to keep my appointment for a chest CT, or do they need the scanner? Do I want to be in imaging with these coughing patients? My treatment could be delayed. What if they’re reserving saline for the sickest hospital patients and can’t mix drug? What if there are drug shortages? Nursing shortages? What if they stop treatment as a containment mechanism, to keep patients out of the hospital, or cut back schedules so patients aren’t so crowded together in the waiting rooms and in the infusion rooms? I need my drug every three weeks, don’t have the luxury of a delay. (Who does?) What if they only treat early-stage patients, the curable ones?

Would I get a ventilator? Do I deserve one?

In the Hospital

I’ve been lucky in that I haven’t been hospitalized a lot. But it’s been enough that I can say that if you end up in the hospital, these will be the worst days of your life. An open-ended hospitalization for something like an infection is nothing like spending a night or two in the hospital after surgery. The sickness itself becomes almost secondary, because time has no meaning. Nothing has meaning. You sleep and stare at your iPad. You wake up for blood draws. That’s the only reason you wake up. Blood draws and imaging. The first time I was in the hospital, I understood why pets help old people live longer. All I thought about was my dog. Not just that I missed her company, but the structure and value she gave to my time. Suddenly I didn’t have to wake up to feed her. I didn’t have to walk her. I didn’t have to take her for her shots. It didn’t matter if I got out of bed. I thought about killing myself. I’ve only ever had that feeling in the hospital, and it came back on subsequent visits. The last time I was in, I had a reason to get up and walk around the floor, an actual direction: there was a bulletin board at the end of the hall that had pictures of dogs. I used to go and stare at it, and all I could think about was going home to take care of my little girl.

Of course, all this changes in the ICU and under sedation. My experiences have been easy; I could get up and brush my teeth. I could have visitors and send e-mails. Let’s skip over alternate, severe scenarios, like the ones involving a ventilator. No one needs to think about it. And most of us, myself included, have the reassurance of knowing it’s unlikely. The numbers are clear on that, even when there’s still so much uncertainty.

Recovery

We have so much to fix, and we’re just getting started. ‘Til then, stay home, and since we’re on a human affection diet for the foreseeable future, give your dog all the kisses and snuggles. He can’t give you COVID.

 

 

 

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.

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.

Puma Releases NALA Results

 

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. 

Puma Hobbling Along a Year After Neratinib’s Launch

The Nerlynx needs your help. On their 3Q earnings call, Puma Biotech presented brutal sequential sales for neratinib, tanking the stock, hopes & dreams, etc. 


In millions.

That’s a 3.5% increase from 2Q18 to 3Q18. 

This is not the story for, say, Perjeta, which was initially launched in the small market of first-line HER2+ metastatic breast. A year out from its introduction, in an equivalent period as referenced above, sales increased 34.5% over the previous quarter. Six years later, after having picked up approvals in the adjuvant and neoadjuvant settings, Roche reported Perjeta sales of CHF 2.0 billion ($2.0 billion) for the first nine months of 2018, which is a 24% increase year-over-year. Kadcyla, another HER2+ drug which is still only approved for use in metastatic patients, grew 30.8% between its fourth and fifth quarters on the market and has booked CHF 728.0 ($743.3 million) in sales so far this year, an 8% increase over the prior-year period. Deviating from HER2 for a minute, Ibrance was launched in first-line, HR+ breast and was growing 36.2% a year from launch, only to report nearly $3 billion in sales in the first nine months of 2018, even as U.S. sales are being impacted by increased competition.

This is just an illustration of the growth trajectory that can be expected with a new breast cancer drug managed correctly. Puma’s performance is not normal. They continue to promise that Europe will deliver revenues, but there was one tidbit in the earnings call transcript that I missed before: their proposed label in the EU market is ER+, HER2+ patients, while in the U.S. it’s all HER2+ patients (about 20-25% of the 260k new U.S. breast cancer diagnoses each year). I checked the APHINITY demographics and was surprised to find the ER+/HER2+ cohort was as big as it was – about 64% of patients in that study (compared to 57% in Puma’s own EXTENET) – but they’re still losing a big chunk of the market. Whether the drug will get any traction in the conservative EU market is a different issue, but when Americans are skeptical, what does that tell you?  

Still no news on NALA in the metastatic setting, aside from reiterating that it’s going to be 4Q this year or the first half of next year. No urgency, it seems, though at this rate Kadcyla could be approved in the neoadjuvant setting before we even see NALA, further eating away at the utility of neratinib. For an anecdotal example of what Puma’s extended adjuvant delusion is costing them, my own doctor had a HER2+ metastatic patient with decent systemic control and progressive brain mets. Whatever I think of Puma management, we have one drug in breast cancer that passes the blood-brain barrier. Tucatinib is coming, but at the moment, if you’ve failed Tykerb, neratinib is the only marketed option. My doctor was worried insurance wouldn’t pay for it because of the early-stage label. I said of course they would. It’s in the guidelines.

She had no idea what I was talking about. I pulled up the press release about neratinib being added to the HER2+ CNS guidelines on my phone. I only knew about this because I stalk the company. An actual doctor who needs the drug available had no clue. This is how Puma thinks things should be done. Insurance apparently said yes to the neratinib request on the first go, and the patient is on it now, so you’re welcome, guys. 

The unmanageable diarrhea came up on the earnings call, as it always does, and the keyword remains compliance. Puma assured investors that the specialty pharmacies are sufficiently hounding patients to refill, that they’re offering vouchers for loperamide, and that they’re working to get budesonide and colestipol prophylaxis added to the label (so many drugs for these patients!). What is the rationale? The patient is waffling on refilling their prescription, because, you know, there’s nothing wrong with them, and it’s the free Imodium that persuades her? Like the free hat when you sign up for the low-rent gym in the shopping center parking lot? I can’t think of another management team so out of touch with their own market. How many Puma staff and affiliates are charged with pressuring healthy patients to take unnecessary meds versus reaching the prescribers and patients who could actually benefit from neratinib – and have every motivation to take the drug as prescribed, with the hope of refilling all the way through improved OS?