Keynote 811 plus#

And the OS was pretty outstanding with the minimal follow-up that we've had. So it was reassuring to see the PFS curve in this study was more typical of what you would look at with chemo, with a gradual decline in PFS. We were pleased to see that, and I think the most important thing was, in comparison to all other chemo-free approaches to date in this disease, typically they are with checkpoint inhibitors as monotherapy or, say, in combination with CTLA-4, we typically see a rapid drop in PFS and OS.ДЄnd particularly in unselected patients by biomarker, but even in PD-L1, say, one or higher, we were seeing that drop in KEYNOTE-059 Cohort 3, the first-line study with monotherapy pembro, or in the monotherapy KEYNOTE-062 study, where we were seeing this dramatic drop. So it rivals even MSI-high and anti-checkpoint inhibitor really. So we presented a response rate in those 40 patients that were enrolled here of 53% and a disease control rate of around 75% in that first-line setting, which I think is the highest response rate noted in this disease without chemotherapy, ever. So the benchmark response rate that was targeted to be considered adequate was the one we actually saw in the second-line setting, was around between 50-60%, and that would be better, per se, than the ToGA-referenced response rate, and potentially similar to what we actually call HER2-positive now after excluding those low-level HER2 patients, IHC0 and 1+, the quarter of patients in ToGA study that probably dragged the response rate a little bit lower than what we would typically expect. Catenacci: The design of this study, of course, was before we saw data from the more recent KEYNOTE-811, which was presented at the previous meeting at ASCO. Smyth: What were the results that you presented at ESMO?Дr. So we've presented the first part at ESMO this year.Дr.

It was a two-part design, where the first part was 40 patients to be enrolled, with a primary endpoint of response rate, at which point an assessment would be made whether or not the response rate was adequate enough and disease control rate adequate enough to proceed to the second part. But when looking at patients who were actually HER2-amplified in the blood at the time of enrolling and IHC 3+ pre-first-line and PD-L1-positive, the response rate was between 50-60%, albeit that was a subgroup analysis in smaller numbers.Д«ased on that and the logic and rationale that we would expect these to work in higher biomarker cohorts, that was the rationale of moving this to the first-line setting, and with a chemo-free approach, which is appealing if you could super-select patients so to speak by biomarker and get a response rate that was reasonable and a disease control rate that was reasonable, and potentially spare patients that either can't get chemotherapy or prefer not to if they had a choice.

The rationale there was based on the second-line study, was that although in all-comers, the response rate post-progression on first-line chemo with trastuzumab was around 18% and remember these were patients that were not re-checked to see if they were HER2-positive starting second line, and their PD-L1 scores could be any, and they were also based on pre-first-line therapy, it was around 18% in all-comers. The design of the study was selected by high expression of HER2, so it had to be IHC 3+, so IHC 2+ FISH+ were not eligible, and PD-L1 by combined positivity scoring or CPS of 1 or higher to be eligible, in addition to routine standard eligibility criteria.

Keynote 811 plus#

The MAHOGANY study, the Cohort A, the arm that we presented is basically an extension of the previous study that we did second line, which is a chemo-free, anti-HER2 antibody and anti-PD-1 antibody, originally was margetuximab and pembrolizumab in that second-line study, and in this study was margetuximab plus retifanlimab, an anti-PD-1 inhibitor.

Could you describe for us the design of the trial, please?Дr. Smyth: Dan, you're the lead author on a paper discussing margetuximab in HER2-positive gastric cancer, the MAHOGANY trial. Lizzy Smyth, from Cambridge, UK, and I'm here with Dan Catenacci from the University of Chicago to discuss updates from ESMO 21.