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. 

APHINITY!

It worked!

Which is all we know right now, with actual numbers to come later in 2017 (ASCO?), but this morning Roche announced that APHINITY met its primary endpoint of significant improvement in disease-free survival in patients treated with Herceptin, Perjeta and docetaxel in the adjuvant setting.

I can’t wait to see the numbers, but it almost doesn’t matter: Herceptin going off-patent is no longer an issue, and Roche has secured its ownership of the HER2+ patient from date of diagnosis until, well, forever. I’ll be interested to see if Perjeta becomes a co-backbone of HER2+ treatment alongside Herceptin, in the sense that you never really stop Herceptin, regardless of how many times the patient progresses on it; we tend not to even do a lot of biopsies to confirm that HER2 status hasn’t reversed, despite the fact that a flip from HER+ to HER2- does happen in the recurrent and metastatic settings. It’s too soon to consider whether Perjeta will still be the first-line HER2 treatment of choice in recurrent or metastatic disease if the patient has been previously treated with Perjeta, but assessing durability of benefit through multiple courses of treatment is one of the many possible next steps for this agent.

Nivo disappoints, but it didn’t have to be this way

In August, when BMS announced that nivolumab failed to meet its primary endpoint in Checkmate 026, I brushed it off. The flaw was obvious: Checkmate 026 randomized treatment-naive advanced non-small cell lung cancer (NSCLC) subjects with PD-L1 of 1+% to nivo monotherapy or chemo. The competing Merck pembrolizumab study targeted the same previously untreated advanced NSCLC patient population, with the significant difference that Merck’s patients were enrolled based on 50+% PD-L1 expression (note: the studies used different diagnostics/PD-L1 thresholds).

So BMS over-reached. They went head-to-head with Merck for the broader label (not requiring positive PD-L1 expression for treatment, which dramatically increases the patient population), and hubris makes fools of us all. Like a lot of people, I figured the results would improve on subgroup analyses.

As you’ve seen by now, the results did not improve, and Checkmate 026 appears unsalvageable.

Continue reading “Nivo disappoints, but it didn’t have to be this way”

Oh, Canada. “Limits to Personalized Cancer Care” in the NEJM

The NEJM, despite its habit of publishing every precision medicine milestone in the past 15 years (including the Herceptin and Zelboraf papers cited in the first paragraph of this editorial), elected to give voice to the naysayers: per an opinion from physicians at the Princess Margaret Cancer Centre, treating cancer based on genomic profiling is unproven, expensive, toxic, and requires further investigation in controlled trials before we should consider it as a treatment strategy. No shock that this came out of Canada, that hotbed of medical innovation.

Continue reading “Oh, Canada. “Limits to Personalized Cancer Care” in the NEJM”

You can enroll in a clinical trial, but that doesn’t mean you should

One of the the core accusations of this blog is that cancer patients are pushed toward clinical trials in spite of alternatives with demonstrated safety and efficacy, which takes advantage of two patient biases: new (if unproven) means better and your physician has your best interests at heart.

Physicians are paid to participate in clinical trials. Let’s get that out of the way. There is nothing objective about recommending trials to patients; you only need to notice how often a physician points a patient toward a trial outside his or her practice to deduce that trial suggestions are not without bias.

Continue reading “You can enroll in a clinical trial, but that doesn’t mean you should”

Looking ahead with Cascadian Therapeutics

@Buyersstrike generously gave me the opportunity to trash neratinib on his site yesterday, and I thought I’d follow up with a post on a novel, oral, HER2-targeted drug I actually do like: ONT-380.

ONT-380 has been in development for a while, first at Array and then Oncothyreon Cascadian Therapeutics. It’s unique among HER2-targeted small molecules because it does not inhibit HER1 (EGFR), which lends it a more favorable AE profile – it’s the EGFR targeting that is associated with most of the skin rash and GI toxicities we see in this category.

Significantly, ONT-380 is being evaluated for the treatment of CNS mets. In breast, brain mets patients are the ones that actually die – you can live forever with metastatic breast cancer, but brain mets are generally a dealbreaker. (The flip side of the excellent survival stats in breast is why you only see PFS, and never OS, data in breast – with OS as a primary outcome, you’d never get a study analyzed, because you’d wait years collecting mortality events.) If you’re HER2+ positive, and your brain lesions are too multiple or too big for Gamma Knife and you don’t want whole brain radiation (n.b., you do not want whole brain radiation), you’re basically left with lapatinib. We need ONT-380.

There’s not a lot of public data, but there’s signal that the drug works. These results from the Ib trial combining ONT-380 with T-DM1 (Kadcyla) found that in heavily pre-treated MBC patients with and without measurable CNS disease, there was an overall response rate of 47% and a respectable median PFS of 6.5 months. Both of these measures are exceptional for brain cases. This is phase I data summarized in an ASCO abstract, so we don’t have a lot of details on the patient population or their responses, but there were even a couple of complete response (CR) cases in the measurable CNS mix.

The treatment of brain mets is a massive unmet clinical need, but it’s a tough strategy to pursue, because these studies are hard to enroll. The ideal patient would be someone asymptomatic who has never been treated for CNS mets, and in a clinical setting where screening MRI for brain is not standard of care, that profile is not common. Even if you found a perfect patient, you’d have to get them to a site that’s actually enrolling. (I am a strong advocate for de-centralizing clinical trials, but that is an uphill battle and a post for another day.) There are other enrollment challenges for their ongoing Phase II study as well; patients are randomized to receive Herceptin and capecitabine (Xeloda) +/- ONT-380, and prior treatment with capecitabine in the metastatic setting is an exclusion criterion; however, capecitabine is often given with lapatinib, which is permitted in this study as long as it was used >12 months prior to enrollment. A lot of HER2+ metastatic patients have had the Herceptin/Xeloda/Tykerb combo (it was my first-line metastatic treatment), because it’s just about the easiest cancer treatment you can do, and I don’t know how many patients receive Tykerb with just Herceptin or with Herceptin and another cytotoxic agent. At any rate, I doubt eligible ONT-380 patients are just falling into investigators’ laps. And while I have the same complaints about our slow, unwieldy, archaic regulatory body as anyone else, in this case, the FDA does seem to get it: they gave ONT-380 Fast Track status in June.

But there’s something I like about Cascadian that has nothing to do with science (give me some credit; we haven’t even seen PII yet). It’s this, via a screen cap from their website.

ont380-4

Do you see it? How about this?

ont380-3

For contrast, check out what I pulled from the Ixempra site (ixapebilone from BMS; a microtubule-binding agent, similar to a taxane).

ixempra-2

WTF is that? Who is that supposed to be?

These are marketing images, but they reflect a tension in the MBC treatment philosophy: are you going for a hike with your dog? Or are you just hanging on to see your grandchild born or whatever nonsense that lipstick mirror crap is supposed to signify? Cascadian is positioning itself as forward-thinking on multiple dimensions. They’re gambling on brain mets patients, who, despite a poor prognosis, are not staring in the mirror, trying to summon the will to hang on another day. Their patients are on a hike. You’re not dead; life still has meaning (this is part of why terrible side effect profiles on useless drugs are so offensive!). This company has balls. And they understand that patients Google, and good for Cascadian that these are the images they want patients to see.

Now bring on the PII results.