Tag: ADC

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.

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.