One thing I'm thinking about as I work through, have you looked at the potential impact of Enhertu (T-DXd) on the FLAMINGO-01 trial dynamics? The DESTINY-Breast05 data showed a pretty meaningful reduction in recurrence risk vs. T-DM1 in the adjuvant setting, and I believe the FDA decision on that indication is expected around Q3 2026.
My question is basically this: if Enhertu becomes the new standard of care for high-risk HER2+ patients during the enrollment and event-accrual window of FLAMINGO-01, could that lower the baseline recurrence rate in the placebo arm enough to make it harder to reach the 14-event threshold for the interim analysis? It seems like it could both extend the timeline and potentially complicate the statistical powering of the trial.
I'm still early in thinking this through so I may be missing something — would love to hear your perspective on whether this changes the risk calculus at all, or if GP2's positioning as a post-treatment maintenance vaccine makes it largely complementary regardless of what happens upstream. Thanks again for the work.
Sorry for the delay, and caveat this all by again saying I’m a generlist here. Great question, and one I've been working through as well. The short answer I have is that GP2 sits downstream of whatever adjuvant ADC the patient receives. FLAMINGO-01 enrolls patients after they've finished all trastuzumab-based therapy, so if Enhertu replaces T-DM1 as the standard, GP2 simply follows Enhertu instead. They're sequential, not competitive, and mechanistically they do very different things: Enhertu delivers a cytotoxic payload to kill tumor cells, while GP2 trains the immune system to maintain long-term surveillance against HER2-expressing cells. In that sense, better upstream debulking may actually make the vaccine's job easier.
That said, your concern about the trial dynamics is legitimate. If Enhertu compresses the placebo arm's recurrence rate, it could slow event accumulation toward the 14-event interim threshold and stretch the timeline. GLSI appears aware of this and has flagged plans to increase study size and accelerate enrollment to accumulate patient-years faster. Whether they can execute that on a $7M/year burn rate is a fair question. But the core thesis, whether GP2's Phase IIb signal replicates at scale, doesn't change based on what ADC patients received before entering the trial. It's the pace of getting the answer that shifts, not the answer itself. In addition, the EU markets have charged ahead with the GP2 trial despite Enhertu receiving approvals there - makes me thing they see value in still having both as treatment options.
Hi! Great write-up, really appreciate.
One thing I'm thinking about as I work through, have you looked at the potential impact of Enhertu (T-DXd) on the FLAMINGO-01 trial dynamics? The DESTINY-Breast05 data showed a pretty meaningful reduction in recurrence risk vs. T-DM1 in the adjuvant setting, and I believe the FDA decision on that indication is expected around Q3 2026.
My question is basically this: if Enhertu becomes the new standard of care for high-risk HER2+ patients during the enrollment and event-accrual window of FLAMINGO-01, could that lower the baseline recurrence rate in the placebo arm enough to make it harder to reach the 14-event threshold for the interim analysis? It seems like it could both extend the timeline and potentially complicate the statistical powering of the trial.
I'm still early in thinking this through so I may be missing something — would love to hear your perspective on whether this changes the risk calculus at all, or if GP2's positioning as a post-treatment maintenance vaccine makes it largely complementary regardless of what happens upstream. Thanks again for the work.
Sorry for the delay, and caveat this all by again saying I’m a generlist here. Great question, and one I've been working through as well. The short answer I have is that GP2 sits downstream of whatever adjuvant ADC the patient receives. FLAMINGO-01 enrolls patients after they've finished all trastuzumab-based therapy, so if Enhertu replaces T-DM1 as the standard, GP2 simply follows Enhertu instead. They're sequential, not competitive, and mechanistically they do very different things: Enhertu delivers a cytotoxic payload to kill tumor cells, while GP2 trains the immune system to maintain long-term surveillance against HER2-expressing cells. In that sense, better upstream debulking may actually make the vaccine's job easier.
That said, your concern about the trial dynamics is legitimate. If Enhertu compresses the placebo arm's recurrence rate, it could slow event accumulation toward the 14-event interim threshold and stretch the timeline. GLSI appears aware of this and has flagged plans to increase study size and accelerate enrollment to accumulate patient-years faster. Whether they can execute that on a $7M/year burn rate is a fair question. But the core thesis, whether GP2's Phase IIb signal replicates at scale, doesn't change based on what ADC patients received before entering the trial. It's the pace of getting the answer that shifts, not the answer itself. In addition, the EU markets have charged ahead with the GP2 trial despite Enhertu receiving approvals there - makes me thing they see value in still having both as treatment options.