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

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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.