Category: Clinical Studies

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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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.

Continue reading “News from ASCO Abstract Day” →

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.

Cancer and Covid-19: Patient Registries Open

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.

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.

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. 

Syndax Misses Primary PFS Endpoint for Entinostat

Syndax announced on Thursday that they missed PFS in their P3 E2112 study comparing entinostat + exemestane (Aromasin) to placebo + exemestane in advanced HR+ breast cancer, which resulted in a top-notch corporate quote:

“While the PFS analysis did not show a statistically significant benefit, E2112 was primarily designed to determine whether the combination of entinostat and exemestane could improve OS based on the compelling OS results obtained in the Phase 2b ENCORE 301 trial …”

They didn’t even WANT to hit PFS, okay?

Never mind that there are two primary endpoints in E2112, meaning it’s an and/or situation and the study was not, in fact, primarily designed to assess OS. 

ENCORE 301, the basis on which Syndax received their Breakthrough Therapy designation, is reported here. That study (N=130, randomized 1:1 to entinostat + exemestane or placebo + exemestane) met its primary endpoint, with PFS of 4.3 months in the entinostat arm and 2.3 months in the control arm. OS was an exploratory endpoint, with entinostat associated with median OS of 28.1 months, compared to 19.8 months in the control arm. The enrollment criteria are similar between ENCORE 301 and E2112, except premenopausal patients and prior fulvestrant are both allowed in E2112, and E2112 appears to have a cohort with non-measurable disease. 

It would be unusual for the benefit of an anti-cancer therapy to be better reflected in OS than PFS; this might happen with PD-1/PD-L1s, but that may not be universally agreed, and it’s not likely to be the case for entinostat. Syndax are trying to recast entinostat as an immunotherapy with their checkpoint inhibitor collaborations (oh look, it’s a 10% response rate with pembro), but when I tried the drug a couple years ago, it was just an HDAC inhibitor. And it sucked. 

I was on entinostat for three cycles and got dose reduced after the first and again after the second, which remain my only dose reductions in eight years of nonstop treatment. I was off study for progression at the end of the third cycle, once I’d used up my two protocol-permitted dose reductions without improvement in my labs. Weird how that happened, right?  

Whatever: I was happy to be kicked off, because I have never felt more like dying in my life as on that drug. It was miserable. I felt sick and tired all the time, it wiped out my white cells, red cells and platelets, and my bones felt hollow. It sounds ridiculous, and this was never attributed to the study drug, but they were not like that before. They were totally normal bones before.

The feeling resolved after I went off study, but not before I broke my hand in a freak incident involving a leash that … brushed across my hand very fast. You would think this sort of thing would not cause a spectacular extremity fracture (the surgeon who wired it together later presented it at a conference!), and it could have been a coincidence, but I blame the entinostat.  

The lack of efficacy is the focus here (with a pointed reminder that not all drugs anointed Breakthroughs pan out), and a P3-grade PFS fail rightly overshadows toxicity and my unconfirmed Bird Bones anecdote. I just like the story, lest there be any suspicion that entinostat has “well-tolerated” going for it. In a true stretch of corporate credibility, we’re being forced to wait for E2112 to fail definitively, because Syndax were clear they would keep performing scheduled OS analyses until everyone was dead. Or, you know, they see an OS benefit. Whichever comes first. 

Alpelisib Summits Mt. PI3K

ESMO was a snooze, right? No new drugs out of nowhere, no hotly-anticipated studies knocking it out of the park (cough, IMpassion, cough). Which I guess frees us up to talk about alpelisib.

Novartis announced results from their SOLAR-1 study, which succeeded where buparlisib (also NVS) and taselisib (Roche) failed. In patients with PI3K-mutated, hormone-positive and HER2-negative advanced breast cancer, alpelisib plus fulvestrant achieved a PFS of 11 months, compared to 5.7 months for fulvestrant alone, and an ORR of 36% for alpelisib + fulvestrant, which compares to 16% in fulvestrant alone. These are hormone-positive patients, so we won’t have OS data for another few decades, but these are good numbers. It wasn’t Ibrance/letrozole, which blew out a wild PFS in the first-line setting (notably, the SOLAR-1 patients will have progressed on an AI as well as possibly a CDK 4/6 inhibitor), but it’s good, and the first real validation we’ve seen of PI3K targeting in breast.

This would have been a perfect announcement if not for the AEs. Hyperglycemia was reported for 64% of alpelisib patients (compared to 10% among controls); in 37%, hyperglycemia was grade 3/4. Grade 3 hyperglycemia is defined as blood sugar of 250-500 mg/dL; grade 4 is >500 mg/dL. Which sounds challenging, even in patients who theoretically have bigger problems. These are patients that are poised to live a really long time with a good quality of life. Is any onc out in the community, dealing with real patients, psyched about managing blood sugar of 400? The press release didn’t break out the rate of dose reductions, but what does that inevitability do to efficacy? 

To their credit, Novartis has been fairly relaxed about enrolling diabetics in its PI3K studies. SOLAR-1 excluded type 1, but allowed controlled type 2; BELLE-2 and BELLE-3, the buparlisib studies in HR+ MBC, didn’t appear to restrict based on diabetes or blood glucose, though other, investigator-led studies did. SANDPIPER, the P3 taselisib, excluded Type 1 or Type 2 diabetes requiring anti-hyperglycemic medications. Still, not everyone is going to be represented in the SOLAR-1 population, and there’s a reasonable likelihood that physicians will be prescribing for patients with high baseline blood glucose or less well-controlled diabetes. (And while there’s an argument that metformin and PI3K/AKT/mTOR inhibitors are synergistic, and that by adding metformin to one of these drugs you’d get both protection against a blood sugar crisis and enhanced anti-cancer efficacy, there’s at least some evidence with everolimus that it’s not so straightforward. Though these diabetic neuroendocrine patients who were on metformin when starting evero did better than their non-diabetic counterparts.)

Everolimus is an older, HR+ breast-approved mTOR inhibitor that popped up in a couple of ESMO abstracts (here and here) that aren’t really interesting enough to discuss on their own but that roughly echoed what we know from BOLERO-2, which is that evero doesn’t really care about PI3K positivity. This is notable since this drug for patients with targetable, frequently-mutated PI3K has been one of the prime examples of precision medicine in practice. It’s been offered to me a couple of times based on genomic sequencing (never in a large center, obvs), which I always declined because I was waiting for one of the next-gen PI3Ks. Taselisib turned out to be a disaster, despite the all the strategizing that preceded signing that consent. I think this is a good example of the kind of hold that sequencing has over patients; those mutations feel a lot like capital, and I put a huge amount of effort into deciding when and how to cash it in. Diabetes aside, if alpelisib works, and exclusively in PI3K-mutated patients (there is PI3K-wild-type cohort in SOLAR-1 being tracked for a secondary endpoint), it could help reverse what has felt like a big disappointment in personalized medicine.