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.

The Puma Panel

I didn’t think neratinib was getting through. As much as I want more flexibility in prescribing and a more moderate drug approval pathway, why does it have to be neratinib?

Despite very modest clinical benefit, a lot of toxicity and a broad label, this morning’s FDA panel voted 12-4 in favor of more options for cancer patients. The panelists did seem to take patient selection seriously, though it’s unclear how that will pan out when Puma is loose in the market. What I’m curious about is whether patients will demand it, whether the patient representatives Puma paid to speak – the what-if-Mommy-dies, I-want-to-do-everything-to-fight-this types – are representative of the overall population. Continue reading “The Puma Panel”

Puma Post-APHINITY

Puma presented at Cowen today, and I listened to the webcast hoping for a reaction to APHINITY, but alas, they kept Q&A to the breakout session. The tone of the presentation did seem a little grim, but between the crushing of adjuvant dreams and half the slides being devoted to unmanageable diarrhea, I guess it was always going to play grim. Continue reading “Puma Post-APHINITY”

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.

Galena and the vaccine that won’t die

Galena continues to hobble along with NeuVax, resisting defeat even though their peptide vaccine targeting HER2-positive breast cancer has failed in patients who have HER2-positive breast cancer as well as in patients who have breast cancer that is, ahem, HER2-lite (this is not a thing). With each failed study, Galena becomes less ambitious: the company announced the presentation of a study-update abstract at San Antonio where the study in question features neither real cancer nor real endpoints.

Continue reading “Galena and the vaccine that won’t die”

New strategies for SEs, but same old neratinib

Neratinib is basically useless and has unmanageable side effects. Puma can publicly acknowledge only one of these problems, so here we are, with the company testing various diarrhea prophylaxis strategies to support an argument that a 2% increase in five-year disease-free survival among early-stage HER2+ breast cancer patients is somehow worth all this misery. Continue reading “New strategies for SEs, but same old neratinib”