We’ve been waiting for this all year, right, this bright spot in a sea of dread? Nothing perks me up like the latest in metastatic breast cancer research.
My abstract highlights – including new results on DS-8201, tucatinib, the accursed entinostat and a novel Pfizer ADC plus my predictions for late-breaking abstract results – after the break.
Drugs that Deliver
DS-8201 has never let us down, and a subgroup analysis looked at biomarkers associated with improved overall response rate, duration of response and median PFS. Unsurprisingly, fewer prior lines of treatment, first- or second-line treatment with pertuzumab and normal kidney and liver function were associated with better outcomes. But there were some interesting results among the factors that didn’t influence efficacy outcomes, among them age, race, region, ECOG PS, best response to TDM-1, time since diagnosis and history of brain mets. (I love a democratic treatment option, one I’m not going into with a bias against me.) Interestingly, among the subjects who were PD at data cutoff, metastases presented most commonly in the liver, lung and lymph nodes; only 8% (of 48 subjects) had CNS progression.
Tucatinib didn’t give us much we didn’t already know and couldn’t have predicted, but does it hurt to revisit their HER2CLIMB results in these dark times? The study randomized subjects 2:1 to tucatinib plus Herceptin + Xeloda or placebo plus H + X. In the brain mets subgroup, median CNS PFS was 9.9 months in the tucatinib arm and 4.2 months in the placebo arm. Median OS was 18.1 months for tucatinib and 12.0 months for controls. And this is an interesting update: as background, one one of the neat things about this study was that they were willing to treat beyond PD. (Can I gaze any more adoringly at Cascadian?) Among patients who progressed in the CNS alone and who continued tucatinib after local treatment, the risk of second PD or death was reduced by 67%, and median PFS from randomization was 15.9 months for tucatinib versus 9.7 months for controls. These guys – they gambled big on this drug, and the data just keeps paying off.
There are updated results from the P3 SOPHIA trial of margetuximab, the Herceptin alternative where subjects were randomized 1:1 to chemo + margetuximab or chemo + placebo. I know – chemo, gross, what year is this, etc., but as we observed above, HER2+ patients just won’t die (though my doctor keeps assuring me that hospice is waiting in the hall whenever I’m ready). The major SOPHIA outcomes were reported at San Antonio last December, with a statistically significant improvement in PFS for marg + chemo (5.8 months) over Herceptin + chemo (4.9 months). ORR was 25.2% in the marg arm versus 13.7% in the Herceptin arm. OS was not statistically significant, though it “favored” marg, with both cohorts surviving ~20 months from randomization. The new data from ASCO broke out hazard ratios by chemo choice, and the lowest PFS hazard ratios were associated with eribulin and gemcitabine compared to Xeloda and vinorelbine zzzzzzzz. Not a thrill, but even with DS-8201 and tucatinib winning the spotlight with their respective unicorns, we still have room for a workhorse.
Okay, Thanks
I forgot this trial was happening, and if any data had been reported before now, I forgot that too: to recap, T-DM1 + pembro in HER2+, PD-L1 unselected patients with >1 line of therapy in the metastatic setting but no prior T-DM1. The 20 patients reported here were pretty clean in terms of prior treatment, and we still only saw an ORR of 20%. PFS was 9.6 months. This phase 1 is still enrolling at two sites and has been since 2017, reflecting an excellent use of time and resources (counting subjects as resources) to create the kind of low-impact data that should be obviated by clinical judgment. No one wants to treat off-label, but isn’t a phone call to the patient’s insurer to approve pembro plus anything a better use of everyone’s time?
New Stuff
Pfizer reported results from a dose-escalation P1 of PF-06804103, its novel ADC that combines a HER2-targeted antibody with the chemo agent auristatin. (Hyper-toxic microtubule binder auristatin is a #goals payload for many little biotechs; Mersana’s failed XMT-1522 was an auristatin.) The study enrolled 35 HER2+ breast or gastric subjects, and clinical activity was observed in the 25 enrolled at the highest dose levels. Preliminary ORR in that subgroup was 52.4%. From these results and the study page, we should be heading into dose expansion, which will enroll up to 124 subjects. This is intriguing, so hopefully we don’t have to wait too many more ASCOs for those results.
There was no better place to put a vitamin E analog sponsored by a company I’d never heard of than under “new stuff”, but yeah, it’s a vitamin E analog that’s being developed by a company called Veana Therapeutics. They’re calling it an “immunotherapy.” I’m going to start calling the zinc lozenges I take when I get the sniffles an immunotherapy now too. They’re enrolling a phase 1 where 24 innocents will receive alpha-TEA plus Herceptin. Their ClinicalTrials.gov listing is worth a click, mostly because it explains how Herceptin works to treat HER2+ breast cancer, but not so much their own drug. Off to a good start, aren’t we, guys?
I thought this was going to be a bigger year for TNBC. The only thing that caught my eye is AZ enrolling an 800-subject phase 3 capiversatib + paclitaxel versus pac monotherapy study for first-line treatment of metastatic TNBC. The phase 2 in an identical population, as reported in December, showed improved PFS and OS when capivasertib was added to chemo. I like these AKT inhibitors, and I don’t know why they seem to be under the radar. Roche has one too, also aiming for first-line metastatic TNBC. They’re combining their ipatasertib with atezo and Abraxane and presented some pretty good data last year.
People Who Suck
Oh look – when you add entinostat to atezo in TNBC patients, it does not improve outcomes and just adds toxicity. At some point, Syndax and its collaborators should be dragged before whatever the GCP equivalent of a war crimes tribunal is to answer for their refusal, in the face of all data and reason, to admit that entinostat does not work. Investors are supposed to be on the edges of their seats for efficacy results from E2112, the big NCI study in hormone-positive breast that already failed to demonstrate PFS benefit. The drug logged an earlier failure in TNBC. It failed in ovarian cancer. There was some baffling excitement around ENCORE 601 when limited melanoma data were reported, drawn from what was supposed to be a 200-subject trial in NSCLC and colorectal as well as melanoma, and when are we going to be able to stamp that one a fail? Where is the stake that will puncture this company’s demonic heart?
Still to Come
Late-breaking abstracts! We’ve got one in metastatic breast, and it may not be worthy of that exclamation point:
A randomized phase III trial of systemic therapy plus early local therapy versus systemic therapy alone in women with de novo stage IV breast cancer: A trial of the ECOG-ACRIN Research Group (E2108).
Do we really need a 400-subject RCT to tell us that aggressively lowering tumor burden will promote more durable responses? Fine, whatever; it’s kind of a subdued year (really?), but I’m still happy it’s on.
See you at Virtual ASCO! I’m planning for more pajamas, but no less drinking.
B4 U Consent 