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.  

Checking in on Breast ADCs

With Mersana struggling to dig its way out of the pain of a clinical hold, it seemed like a good time to check in on the many antibody-drug conjugates (ADCs) in development in metastatic breast cancer. T-DM1 made it look so easy.

Sponsor Target Payload Status
T-DM1 Genentech HER2 DM1 (maytansinoid) Approved
Sacituzumab govitecan (IMMU-132) Immunomedics TROP2* SN-38 (irinotecan metabolite) Phase 3
Trastuzumab deruxtecan (DS-8201a) Daiichi Sankyo HER2 Exatecan derivative Phase 3
SYD985 Synthon HER2 Duocarmycin Phase 3
XMT-1522 Mersana HER2 AF-HPA (auristatin) Phase 1b
Ladiratuzumab vedotin (SGN-LIV1A) Seattle Genetics LIV-1* MMAE (auristatin) Phase 1
ARX788 Ambrx HER2 MMAF (auristatin) Phase 1
Glembatumumab vedotin Celldex GPNMB MMAE (auristatin) Discontinued at P2b (METRIC)

Development-stage drugs bookended with T-DM1 and Celldex, since they’re referenced in this blog; asterisk if Sponsor claims you don’t need confirmed expression of the marker to benefit from the drug.

Mersana was put under a partial clinical hold in July when a patient died on-study. The hold was lifted two months later with some protocol changes – “increased monitoring”, more limitations on hepatic function for future subjects and a new dosing schedule, with the drug being administered every four weeks instead of every three. The ClinicalTrials.gov status is still active, not recruiting, and they haven’t updated the enrollment criteria or dosing schedule yet. So, as the stock will attest, we’ve heard nothing good about XMT-1522 so far, only bad, but I’m not totally horrified by the safety signal this early. Mostly because this is a heterogenous population in something of a baby basket trial. They’re enrolling the traditional HER2+ MBC cohort, which is, generally, a pretty healthy bunch – but they’ve also got HER2-low MBC, HER2+ gastric and HER2 mutated or overexpressed NSCLC cohorts. The mix as of June was 18 breast patients (HER2 status unspecified), 3 gastric patients (again, no HER2 detail) and 1 HER2-amplified gallbladder patient. There’s some unpredictability there, and likely variation in clinical status.

Would I enroll? No way. The drug is too weird. I don’t want a “novel HER2 antibody”. Mersana says their antibody attaches to a different HER2 epitope than Herceptin and Perjeta; that’s about all we know about it. They’ve also developed a novel binding technique and aren’t using a traditional linker. Too many variables, guys. If you want patients to enroll in a phase 1, at least make them feel like they’re getting some Herceptin. Daiichi and Synthon have an antibody that is virtually identical to trastuzumab, and that strikes me as exactly right; leave the uncertainty to the linker. For what it’s worth, trastuzumab is believed to contribute to the efficacy of T-DM1 – not just due to efficient binding, but by exerting some immune-mediating effects. I’ll take it. Why get creative? We don’t need a more perfect antibody. The benefit is in the payload.

Synthon has been so quiet about their trastuzumab-duocarmycin (alkylating agent) ADC that I was surprised to find that it opened a P3 a year ago in HER2+ MBC, adorably called TULIP. They’re from the Netherlands. They had an ASCO abstract. Preliminary ORR of 33%, and no one died. Their eyes got a little runny. Cool. Sounds good.

Daiichi has been so busy with DS-8201a lately that they probably deserve a separate post (spoiler: am pumped for this drug), and we’ll skip over Ambrx, which no one knows anything about. That brings us to the ADCs that target, well, something. Maybe cancer.

Seattle Genetics is developing what used to be called SGN-LIV1a, which purportedly targets LIV-1. What’s intriguing about this is the evolution of the study design on their P1, which has been open since the Year of Our Lord 2013. It’s progressed from a dose escalation in 50 subjects where positive LIV-1 expression on a new biopsy was required for enrollment to a 300-subject, multi-cohort free-for-all where a new biopsy is required for enrollment. The new biopsy thing kills me; where do sponsors get the audacity to require this? Despite making it a condition of enrollment, they don’t have to pay for it, as it can easily be billed as routine care. More importantly, it’s risky for many patients. Especially considering the risk/reward on P1s: if I can die from unexplored toxicity, you don’t get an invasive fresh biopsy. At any rate, SeaGen has now changed course to say that LIV-1 is expressed almost universally in metastatic breast cancer and reported some early results (25% ORR in a TNBC cohort of 60 subjects). I’m not sure the early responses will stand given Celldex, which also had an MMAE payload; whether the LIV-1 target is viable or not, these patients will have progressed on at least one tubulin binder and likely a couple. Let’s keep expectations low on this one, though they did beat IMMU on opening a first-line TNBC ADC + checkpoint inhibitor study (SGN-LIV1a + pembro) and got into the MORPHEUS study, so they’re definitely part of the conversation.

Immunomedics continues to be irritating. They are relentless in their promotion of their TNBC unicorn that has an SN-38 payload that’s – what is it? – four billion times as potent as irinotecan? Does that mean the patients will survive four billion times as long? IMMU has years of follow-up on these subjects by now, but we’ve only been fed the same tiny nibbles of data over and over; as a reminder, it was a 30% response rate on a cohort of MGH dream patients. This won’t hold up in phase 3, but IMMU got FDA to accept their BLA on Glitter Unicorn-umab on P1/2 data, with a PDUFA date set for January. It’s hard to call whether they’ll get approved or be forced to wait for the P3, but if they do get approved, here’s hoping they go away for a while. With weak data, IMMU should be pretty well trapped in the third-line setting, and we can let more interesting agents (and study designs) sort out earlier lines of TNBC treatment.

With all this activity and so many viable drug candidates, I’m wondering if investors aren’t being more forgiving of Mersana in part because we don’t really need them. We have some near-term approvals coming that will significantly increase the number of ADCs on the market, but the big change since T-DM1 in 2013 is that we’re now fully committed to combination therapy. Targeted drugs with manageable toxicity profiles are making creative cocktails possible, and the results are a lot more compelling than what we’re seeing in the box-checking monotherapy trials that get these agents approved. For instance, T-DM1 performs well on its own, but we’ve already been teased with a 60% response rate when you pair the drug with neratinib. It’s never been easy to enroll a phase 1, but when the sky’s the limit on combos where there’s already some comfort and clinical experience, the competition for patients and investigators is going to intensify.

ASCO Issues Grudging Nod of Approval for Complementary Cancer Therapies

Related image

When I started seeing headlines that ASCO had “endorsed” certain complementary therapies for breast cancer, I was intrigued. It’s estimated that around half of patients use complementary therapies in their cancer treatment, though I suspect the actual number is higher. We’ll never know for sure because it’s mostly done in secret, as saying the word “curcumin” in an oncologist’s office usually escalates to a mix of deep concern and condescension; you may hear yourself say “vitamin”, but it comes out as “sacrificing sheep to the onc-goddess.” Is this witchcraft coming into the light? I clicked.

“Music therapy.” “Relaxation.” “Yoga.” ASCO concurs that these interventions, as evaluated by the Society for Integrative Oncology and published in their 2017 guidelines, are “safe” for ameliorating side effects in patients undergoing breast cancer treatment. This is no ordinary “safe”, either. While I appreciate the effort to stratify the various complementary modalities based on evidence, which should clarify the vitamin/animal sacrifice distinction, the SIO screened for interventions based on the existence of a confirmatory RCT. These results were then held to an outrageous standard; an “A” rating (i.e, one voodoo doll out of five) meant that there was a “high certainty that the net benefit is substantial”. I don’t think my Tykerb meets that standard.  Continue reading “ASCO Issues Grudging Nod of Approval for Complementary Cancer Therapies”

It’s not just Baselga

One of the most intriguing parts of the ProPublica/New York Times piece on Jose Baselga’s persistent, ahem, irregularities in disclosing industry relationships was the section where he reviewed a list of his own publications and provided the reporters with a color-coded document explaining why he did or did not disclose certain relationships. This document also included a selection of the publications whose disclosures he plans to correct, which represented a fraction of the total (and I don’t think it’s lost on anyone that the further we scroll down the list, the fewer publications we see coded as properly disclosed, with no additional qualification). 

I don’t need to affirm that scientific work needs to include proper disclosures, and I can’t imagine anyone who has had any contact with Big Cancer was surprised by this article. It’s probably unfair to say that it could have been anyone, but effectively, it could have been anyone, and if you’re writing this piece, Baselga is absolutely where you start. He is as flagrantly corporate as they come, and his baffled response to the accusations (“Asked if he planned to correct his disclosures, Baselga asked reporters what they would recommend.” He said that, seriously?) seems to suggest that he really didn’t see this coming. I can believe it, especially when you factor in the extent to which MSKCC has institutionalized its industry relationships.    

This is not to defend Baselga or to minimize the failures to disclose, which can be attributed to laziness or stupidity or deliberately obscuring financial relationships, which are likely all at least occasionally true, depending on the publication in question. None of those reasons are good, and all tie to character. But there’s nothing about this that’s personal to him; the issues of conflict and bias exist for everyone, and the only thing that Baselga and his Word doc personally remind us of is the belief that disclosure is optional or the relationships themselves a matter of interpretation. Business drives patient care in these big-center settings, and that’s not going to change. So how can our conflict reporting rise to reality?

If you start clicking around on ASCO abstracts this year (no particular reason it’s ASCO, just an easy way to spot-check for these issues) you can see the huge variability in what authors report. Some don’t seem to think the travel category applies to them. Some have so much detail that there are little narratives – “we’re working on a patent for [whatever]”. There’s similar inconsistency in whether institutional funding gets reported. There’s also an “other relationship” category that pops up sometimes, which … I have no idea what that means. And of course you get the Baselga version, which was basically blank. Yup, no red flags there. He clearly did all that taselesib work for free. 

The point is that it’s entirely left up to author discretion. There are no checks. It doesn’t matter that they got paid; these people didn’t take vows of poverty when they became physicians, and they do the work (I’m sure all that enthusiasm for taselisib did not come easy), so pay them. But they must be required to report it, cleanly and consistently, and not in a half-assed but-it’s-the-rule way, which does not work. We know they don’t care. The phrase you hear over and over at the start of slide presentations at conferences is, “I have no relevant disclosures.” I’m glad you think that. That wasn’t the question. Then there are the blanket “No disclosures” people, which no one believes (who paid for the work? Who paid for your flight?), and there doesn’t seem to be a mechanism to challenge that.

In a perfect world, the submission pages for journals and conferences would link to your OpenPayments profile. Would that be impossible to implement? It’s impractical for society and editorial staff to check every single entry on every single author, but could OpenPayments fulfill its commitment to transparency and make it possible to port data out? Proper disclosure has any number of forces working against it, but it would help if it were easy and automated. I get that the nature of the physician filling out his own form is that it’s an opportunity to differentiate between a $200k consulting relationship and some biotech that bought him a $9 sandwich two years ago, but until there’s a better way – that sandwich is on the record, for the good of science and his own integrity. 

This is a systemic issue, and Baselga is having an example made of him. He deserves it. But it’s not about him, and hopefully this is a public shaming that moves Baselga and his peers away from the idea that compliance is optional, trivial, a matter of preference rather than a professional obligation.         

Handicapping IMpassion130

A couple of weeks ago, Genentech announced that interim data were forthcoming (ESMO? SABCS seems a long way off) from IMpassion130, their P3, 900-subject, 1:1 randomized atezo + Abraxane v. placebo + Abraxane study in first-line, triple-negative metastatic breast cancer. To tide us over, they offered up a teaser: the study met its co-primary PFS endpoint in the intent-to-treat and PD-L1+ populations, and the company reported a positive trend in OS in the PD-L1+ population. The language was not subtle. In addition to touting 130 as the “first positive Phase III immunotherapy study in triple negative breast cancer,” Genentech said they were going to “submit to authorities globally with the aim of bringing this combination to people with triple negative breast cancer as soon as possible.”

What kind of data might be backing this up? Merck were slow to combine pembro and chemotherapy, so we don’t have a lot of context for what successful immunotherapy looks like in metastatic TNBC. But let’s mine abstract libraries past for details anyway. Continue reading “Handicapping IMpassion130”

Disclosure Loophole: “Partnering” with Patient Groups

Physicians disclose their industry payments to one another, in meeting slides and at the very ends of papers, and that’s about as much transparency as exists in clinical trial operations. Many patients don’t know their doctor is often paid by the head for enrolling study subjects. While I think that doctors should disclose their financial relationships to patients, I also think the same standard should apply to any entity with patient contact.  

Odonate Therapeutics is the latest company with rights to the oral taxane tesetaxel; the Daiichi drug was previously licensed to Genta, which of course went bankrupt in 2012. There are two publications on Pubmed showing the drug’s lack of efficacy in humans, specifically a phase I/II non-small cell study that reported a response rate of 5.6% and an all-solid-tumors study that reported a best overall response of stable disease in 82% of subjects when the drug was combined with capecitabine. Those papers were published in 2008 and 2011, respectively, and, combined with a graveyard of studies of unknown ClinicalTrials.gov status in melanoma, bladder cancer and gastric cancer, you’d think tesetaxel was finished.

Odonate sat on the drug for four years before going public in 2017 and announcing plans to conduct a 600-subject phase III trial in hormone-positive metastatic breast, CONTESSA. For ASCO this year, they helpfully stripped out their target CONTESSA population from data reported at ASCO 2012. That trial, which Genta sponsored, was called TOB203. The latest poster seems to exist entirely to promote CONTESSA, given that the only difference between them is that the 2018 poster is purple and the 2012 poster is blue. (Linked to the full-size posters because the pics are coming out small; and yeah, I’m sure that response rate in their previously-untreated, cherry-picked subgroup is going to hold in a phase III RCT.)



But ASCO isn’t Odonate’s only creative effort at marketing their trial. Because is it really over until you’ve preyed on the patients themselves? The first press release on the new Odonate website is dated October of 2017, where the company announced their financial support for the Susan G. Komen foundation. In case you were wondering, $1.5 million at Komen buys you a purple banner proclaiming you a “partner” at the bottom of the screencap for your emotionally-manipulative video.

This video is featured prominently at www.CONTESSAstudy.com, and given that Komen has previously licensed their pink ribbon to a bucket of fried chicken, this is not the most egregious offense. It gets worse. And no, I don’t think this is all on Odonate.

On June 1, this headline popped up at BreastCancer.org’s metastatic breast cancer forums, which are the most popular breast cancer forums online. There are over 20,000 posts, and this one is right at the top.

Per the site moderators:


Why, yes, that is an exclamation point. There are 650+ trials recruiting or about to open in metastatic breast cancer listed on ClinicalTrials.gov, and funnily enough, this is the only one that gets an exclamation point on the cancer boards. And what exactly are we so excited about?


Oh hell no. I replied to the post stating basically exactly that. I mean, this entire blog pretty much exists because oncologists are corrupt, but let’s just baseline here: if you talked up a trial like this to a patient, you’d lose your license. This is beyond irresponsible. It is effectively an endorsement of a clinical trial. (I found one other trial announcement on the board, for the NCI-funded E2112, and you can compare the treatment when you don’t pay up.) And check out the URL in the post: “Featured” Trial. It’s featured. Because they gave us money, but we’re not going to disclose that anywhere. CONTESSA is, at present, the only trial listed on the page linked in the post. BreastCancer.org are under no professional obligation to accurately represent the drug, and the obvious defense is that they don’t have the expertise to evaluate the available data, but isn’t that the point? You can’t buy that kind of promotion at a doctor’s office. You can only get it here.

And an exclamation point is certainly in order when discussing an investigational drug. That f*cking exclamation point. 

Let me emphasize: I can’t fault Odonate for their “partnerships”. I kind of respect the imagination. They have one sad product that has been plagued by failed trials, a past clinical hold and several changes of ownership; since they have made the baffling choice to keep this thing alive (…why?), they’ve got no choice but to enroll a trial. So while tesetaxel may be doomed and reflect an embarrassing misunderstanding of the direction of oncology, the idea to fund patient groups in exchange for trial promotion may be the best idea anyone at Odonate has ever had. Not that it’s a high bar, but patients are scarce, this drug has disappointed, any onc has better business prospects and if a patient’s peers and advocates endorse it, well, that might be the only chance it has to enroll. I believe it’s absolutely morally wrong to waste patients on shit drugs, but the onus is on the entity that accepts the cash to behave ethically. You can always decline the money. Easy e-mail – We act in the best interests of the patients we represent.

But that e-mail didn’t go out, and the check cleared, so there you go. These people are bound to nothing; not honor, not patient outcomes, and they preach to metastatic patients with OS on the line. We demand our beauty bloggers disclose when they receive a free lipstick to review, but the moderators on cancer forums, who have the power to keep a post at the top of the very first page and influence decisions that are literally life and death, are not held to any standard?

This story has been kicking around for a month, because I wanted to give BreastCancer.org a chance to make it right. And to their credit, they made an effort. They changed the title of their trials page from “Featured Clinical Trials” to “Sponsored Clinical Trials.” (That f*cking exclamation point is still in the header of the forum post.) Whether my comment triggered it or not, and I hope I’m not the only person who objected, I’m happy about the change. I commented on the thread again to applaud them for their transparency, making sure to reference the old language, lest anyone who visits the page in the future forget that there was a time when BreastCancer.org thought they would get away with using “featured” as code for “paid advertising”. Give patients some credit. I suspect most of us understand that industry relationships are an essential part of drug development and don’t care – as long as people are honest about it. I don’t believe drug companies are out to get us, and my distrust is generally with the physician-middlemen who pretend (to patients, not their peers) industry doesn’t exist and doesn’t influence care. Of course it does. Let’s admit it and go forward, in service of true openness and collaboration.