Tucatinib Receives FDA Approval

Little tucatinib is all grown up! The TKI that started out at Array long, long ago has now been FDA approved in combination with Herceptin and Xeloda for the treatment of 2L+ HER2+ metastatic breast cancer. Additional international approvals could be imminent, as the submission was part of a concurrent review program between the FDA and worldwide regulatory authorities. This is fantastic news for everyone but the Kadcyla sales force, though Genentech will get a slice of the pie via some incremental Xeloda sales.

The approval was supported by data from the HER2CLIMB trial, which enrolled 612 subjects and randomized them 2:1 to tucatinib or placebo plus Herceptin and Xeloda. Subjects with brain mets at baseline comprised 47.5% of the study population. This is their story:

Among subjects with measurable disease at baseline, the confirmed objective response 40.6% in the tucatinib group and 22.8% in the placebo group. But look at those numbers! The brain mets patients didn’t do much worse than patients with visceral mets. Cascadian went in boldly by enrolling brain mets patients, and the gamble paid off. They have brain mets featured prominently in their labeling, and they’re an example for all the companies that have excluded brain mets patients from their trials for fear of muting response rates. But patients in the real world, in HER2+ breast cancer, have brain mets. I have brain mets. I’ve looked at a lot of eligibility criteria, and while we’ve seen brain mets exclusions gradually relax over the past decade, most trials that allow them still caution that they must be stable.

Cheers to you, Cascadian/SeaGen.

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.

Cancer and Covid-19: Patient Registries Open

This is exciting: ASCO is funding a registry on how cancer patients are managed during the Covid-19 pandemic, seeking to capture 12-month outcomes on patients included in the all-comers cohort (the study is agnostic on tumor types, whether the patient is cancer-free or metastatic, and treatment modality). The full list of objectives and outcomes is available here, but they’re capturing everything from baseline status to treatment modifications to symptom severity to cancer and virus outcomes in Covid-confirmed patients. The meaty CRF is here. I love it.

Of course, everyone is using a registry for everything now, and there’s a potential competitor in place from the “Covid-19 and Cancer Consortium”. While ASCO put most of their protocol information online, the Consortium’s page highlights their participating institutions, and … it’s a good mix of sites, representing both Big Cancer and smaller community networks (I’m really curious to see a breakout of patient management by center size and geography in the analyses). On their website, ASCO differentiates their registry by noting that it’s more holistically focused on patient outcomes rather than Covid-specific treatment outcomes, so it would be great if centers could participate in both … but no one wants to fill out CRFs twice, even when they’re not strained by a pandemic. It would be a shame to miss out on the data ASCO is looking to capture. This is not the time for RCTs, and I’m happy to see that Covid-19 patients are being treated the way I think (advanced) cancer patients should be treated all the time: dole out chloroquine, remdesivir, losartan, cell therapies, whatever you’ve got. We know there’s no data. We don’t know what works. So let’s watch and learn.