In P3 this time. So are we done here? This outcome would be much more satisfying if it weren’t so freaking obvious.Continue reading “Entinostat Fails. Again.”
We’ve been waiting for this all year, right, this bright spot in a sea of dread? Nothing perks me up like the latest in metastatic breast cancer research.
My abstract highlights – including new results on DS-8201, tucatinib, the accursed entinostat and a novel Pfizer ADC plus my predictions for late-breaking abstract results – after the break.Continue reading “News from ASCO Abstract Day”
Little tucatinib is all grown up! The TKI that started out at Array long, long ago has now been FDA approved in combination with Herceptin and Xeloda for the treatment of 2L+ HER2+ metastatic breast cancer. Additional international approvals could be imminent, as the submission was part of a concurrent review program between the FDA and worldwide regulatory authorities. This is fantastic news for everyone but the Kadcyla sales force, though Genentech will get a slice of the pie via some incremental Xeloda sales.
The approval was supported by data from the HER2CLIMB trial, which enrolled 612 subjects and randomized them 2:1 to tucatinib or placebo plus Herceptin and Xeloda. Subjects with brain mets at baseline comprised 47.5% of the study population. This is their story:
Among subjects with measurable disease at baseline, the confirmed objective response 40.6% in the tucatinib group and 22.8% in the placebo group. But look at those numbers! The brain mets patients didn’t do much worse than patients with visceral mets. Cascadian went in boldly by enrolling brain mets patients, and the gamble paid off. They have brain mets featured prominently in their labeling, and they’re an example for all the companies that have excluded brain mets patients from their trials for fear of muting response rates. But patients in the real world, in HER2+ breast cancer, have brain mets. I have brain mets. I’ve looked at a lot of eligibility criteria, and while we’ve seen brain mets exclusions gradually relax over the past decade, most trials that allow them still caution that they must be stable.
Cheers to you, Cascadian/SeaGen.
After a slow-enrolling trial, a failed acquisition, an FDA Complete Response Letter, years of unspecified manufacturing issues and about eleven different management teams, Immunomedics finally had some good news last week: their phase 3 ASCENT trial was halted for efficacy. Wait, not just efficacy, compelling efficacy. (That’s a new one for me.) And since Immunomedics’ leadership roles are rented, not owned, there was naturally a concurrent announcement that they’ve appointed a new CEO.
The 529 subjects enrolled in ASCENT were randomized 1:1 to receive either sacituzumab (a TROP-2-directed ADC with an irinotecan metabolite payload) or standard of care chemo. Patients had to have had at least two prior lines of therapy in the metastatic setting, including a taxane, so the single-agent chemo options allowed by the trial are not particularly exciting and set sacituzumab up well on the efficacy endpoints: eribulin, capecitabine, gemcitabine, or vinorelbine. The primary endpoint is PFS, with secondary endpoints including OS and duration of response.
I do think sacituzumab will be approved under its current accelerated designation, which means the full analyses will have to be delivered at some point. A full approval could still be a year out, but I don’t think that’s the only reason behind what I expect to be a lack of fanfare come PDUFA day in June. This drug just isn’t going to be a blockbuster. It addresses a small market (TNBC patients number about 10-15% of the breast cancer population), and this “targeted” therapy brings with it some heinous toxicities that remind us it’s closer to a chemo reformulation than a Kadcyla, which I know has lost its luster but really felt like a game-changer circa 2010. And while a Kadcyla comparison isn’t apples-to-apples, as it’s HER2+ targeted and addresses a larger, likely healthier market, we’ll reference it here because, practically, there aren’t that many other ADCs kicking around to reference.
One of the benefits of ADCs is you take a supremely toxic payload and, by targeting it to a protein, minimize the adverse events and make the drug tolerable. Kadcyla did this with maytansine, which is a tubulin binder with side effects too severe to be clinically useful. Link it to Herceptin, and poof! Problem solved.
Even with the TROP-2 “targeting”, which I’ve always found suspect given the high reported AE rates (TROP-2 is thought to be expressed in many solid tumors but only minimally in normal tissue – so is the issue the antibody or the linker?), sacituzumab is a difficult drug to tolerate. In the phase 1/2 study, 41% of subjects experienced adverse events of grade 3 or higher, with 39% experiencing grade 3 or higher neutropenia. It did knock diarrhea, which is the biggest issue with irinotecan, down to 59% overall and 13% grade 3 or higher, which is … better. On the less deadly side, about half of patients lost their hair. Targeted, you say? EMILIA, Kadcyla’s P3, demonstrated a serious adverse event rate of 18%. That’s what an ADC can do. That’s how you improve quality, not just quantity, of life. Anyone can go on, and likely stay on, Kadcyla with a minimum of surveillance and intervention, though, in general, HER2+ patients are easier to manage and are more likely to be healthier at baseline. That’s what TNBC needs and what immunotherapy is trying to deliver, however modest the results have been so far. There are a lot of drugs out there, so when do we get quality and not just “options”?
In fairness, sacituzumab rates as an option. Immunomedics has been parading the early efficacy data around for so long that I nearly have it memorized: it’s about a 30% response rate and 6 months of PFS, right? That kind of response rate is good in TNBC; I’d expect standard of care to be 15-20%, worse as you move further away from first-line treatment, and PFS to be closer to 4 months. As for how that predicts the outcome of the study and the FDA decision, the AEs will be worse in the treatment group, but it’s going to get approved. The question is what kind of market is waiting for it. We haven’t seen much excitement from anyone not on Immunomedics’ payroll, but we know that at least as of 2017, Seattle Genetics was … less than enthused with their antics. I’m with Seattle. TNBC is a truly underserved population that needs better, but this drug has real limits.
This is exciting: ASCO is funding a registry on how cancer patients are managed during the Covid-19 pandemic, seeking to capture 12-month outcomes on patients included in the all-comers cohort (the study is agnostic on tumor types, whether the patient is cancer-free or metastatic, and treatment modality). The full list of objectives and outcomes is available here, but they’re capturing everything from baseline status to treatment modifications to symptom severity to cancer and virus outcomes in Covid-confirmed patients. The meaty CRF is here. I love it.
Of course, everyone is using a registry for everything now, and there’s a potential competitor in place from the “Covid-19 and Cancer Consortium”. While ASCO put most of their protocol information online, the Consortium’s page highlights their participating institutions, and … it’s a good mix of sites, representing both Big Cancer and smaller community networks (I’m really curious to see a breakout of patient management by center size and geography in the analyses). On their website, ASCO differentiates their registry by noting that it’s more holistically focused on patient outcomes rather than Covid-specific treatment outcomes, so it would be great if centers could participate in both … but no one wants to fill out CRFs twice, even when they’re not strained by a pandemic. It would be a shame to miss out on the data ASCO is looking to capture. This is not the time for RCTs, and I’m happy to see that Covid-19 patients are being treated the way I think (advanced) cancer patients should be treated all the time: dole out chloroquine, remdesivir, losartan, cell therapies, whatever you’ve got. We know there’s no data. We don’t know what works. So let’s watch and learn.
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!
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.
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.
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.
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.