Younger Women Less Likely to Respond to Immunotherapy

This paper is really at the edge of my ability to interpret immunology data, but I am a fascinated and eager student all the same. The authors looked at the immunologic landscape of tumor samples across age and sex, reporting not just on the presence of somatic driver mutations but how visible those mutations are to the immune system.

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IMpassion131: What happened?

On Thursday, Roche announced that IMpassion131, their phase III evaluating the combination of atezo plus paclitaxel, failed to hits its primary PFS endpoint in previously untreated patients with PD-L1+ metastatic triple-negative breast cancer (TNBC). But wait, you ask. Didn’t they already get approved in that indication? Isn’t it the standard of care? And on Wednesday, the answer was yes; today, it’s more like, Kind of. Because the approval specified nab-paclitaxel (Abraxane). IMpassion131 tested solvent-bound paclitaxel, better known as Taxol. This result is a reminder that these drugs aren’t necessarily interchangeable.

Atezo + Abraxane was granted an accelerated approval in PD-L1+ TNBC, and I would say up front that I don’t think this result creates any risk with the FDA, though label expansion may turn out to be an issue. But there’s a lot about this update that’s intriguing, particularly as it relates to Abraxane and the implications for the next and newest study in the TNBC series, IMpassion132. For patients with TNBC, the news changes the narrative from atezo as a break-from-the-pack wonder drug to its role in a combo and the importance of the chemo backbone.

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Update: I want to scream

It would be nice to scream.

The verdict on my voice? Based a perfunctory scope, there’s nothing they can do for me. My vocal cords remain partially paralyzed and won’t open sufficiently, but it can’t be fixed, and why try? I have metastatic cancer. I should worry about that. The shortness of breath? If it gets worse, and I can’t breathe, I should go to the emergency room.

Well, no shit.

I complained about the coughing, the shortness of breath, the fact that my heart rate suddenly jumped from 70 at a brisk walk to a resting 90. He told me other patients have it worse. I’m not other patients. I’m a 35-year-old embarrassed to see casual friends or meet new people, subtly being dropped from external calls at work, struggling on a flight of stairs and overcome with dread when the phone rings.

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I moved, but the DS-8201 stays

That drug. This is the volatile adolescent relationship I never had. I’ve been dose reduced and dose delayed multiple times; I have no idea how much drug I’ve actually had. My new center started me over at Cycle 1, so now I’ve really lost track. But the thing still works! Even my brain is stable. The side effects are brutal, and I think not discussed openly because the drug works so well and is so new, but the nausea and fatigue are unbelievable. I’ve never thrown up from a drug before this. I’ve got a carefully curated four-drug combo designed to control the nausea, and it’s shocking to me that it really takes that much, and honestly I’m a little surprised that after a decade, I haven’t adapted to regular doses of poison.

Two milestones passed since I last wrote. June 6 was ten years from my original diagnosis. I was living in Switzerland. The doctor who diagnosed me was honestly the only Swiss I met who was kind to me, and more importantly, she got me diagnosed. I was lying on a table after a breast ultrasound while the radiologist fought with her in German on the phone, right in front of me, about whether to perform a biopsy. I was 25, right? It was impossible. He was pissed but hung up the phone and did the goddamn biopsy. A week later, sitting across from my doctor in her office, I remember what she said, so gently. “You will require more treatment.” Okay. She told me it was cancer. When I didn’t burst into tears, she said, with some surprise, “You were expecting this?” Yes. I’d known, I’d always known. She called my boyfriend for me to tell him, to bring him in and talk to him. I couldn’t do it. I’ve never been able to tell anyone; I have my husband do it, always. July 8 was the anniversary of my surgery. I remember that morning vividly. It was the first time I’d seen the thermometer that you just hold to your forehead. I thought it was so cool. My boyfriend, now husband, and aunt were with me. We watched Lady Gaga perform on the Today show on the TV in the corner of the room. She looked so amazing that I got a platinum blond wig like hers and wore it around NYC when my hair fell out. The last thing I said to my husband as they were wheeling me away was, “I wish this weren’t happening.” I woke up and didn’t feel that different.

I forgot the anniversaries of both of these days, though they’d been fading in and out of my memory for a few weeks. They were so long ago, and it’s all so different now.

We moved to Palo Alto in June, and despite working in finance and living in Berkeley over a decade ago, somehow I’d never been here before we pulled up to the front door of our rented house. I cannot believe such a paradise exists. I can see the sun every day. (A marvel after Boston, Indiana, Sweden and Switzerland.) I bought a bike, an adorable little mint green e-bike, that I love and am using to go back and forth between my house and the hospital. If you see me on the road, please don’t hit me. My brain’s been irradiated, and I don’t quite trust my balance. I’m hoping this won’t end with an OS event.

So here I am, in a standoff with my bone marrow and soaking up the sun, ten years out from a diagnosis of metastatic IBC and two weeks from my 36th birthday. I am SO OLD.

News from ASCO Abstract Day

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.

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Tucatinib Receives FDA Approval

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:

NEJM 2020

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.

Immunomedics’ P3 Halted for Efficacy

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.