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Lots to discuss here. First, a disappointment for patients - TP53 mutant MDS/AML remains a major unmet need, with short HMA response and poor HCT outcomes. Once again underscores need for RCTs and how we can be misled by single arm P2 combination data./1 https://www.globenewswire.com/news-release/2020/12/28/2150874/0/en/Aprea-Therapeutics-Announces-Results-of-Primary-Endpoint-from-Phase-3-Trial-of-Eprenetapopt-in-TP53-Mutant-Myelodysplastic-Syndromes-MDS.html
I was puzzled by the high response rate being reported, because in my own patients (it was open label) there seemed to be no difference from HMA. They were either not responding or responding briefly and relapsing... I thought maybe I was doing something wrong. /2
Some patients who got randomized to HMA alone were frustrated because of hype for APR-246 & dropped out or went on other trials. It will be interesting once we see full dataset to see how that may have influenced results. Efforts were made to include them in ITT analysis./3
The CR rate was higher w/ combination (33 vs 22%) but p=0.13 and CR was primary endpoint rather than OS; trial may have been underpowered even for CR at n=154. CR can be meaningful in MDS/AML but what really matters most to patients is OS & PRO (living longer & living better.)/4
The markets were not happy with $APRE - down nearly 80% once result announced. The drug is being tried in other TP53 mutant settings./5
With @andrewbrunner I was doing an analysis before leaving academia on what result in a P2 HMA combination in MDS truly is unexpected. This is an important question in MDS because we’ve been burned so many times before by P2 results- with HDACi + HMA, Lenalidomde + HMA, etc./6
And then when it came to a P3 like S1117 that @MikkaelSekeres led and other RCTs, the combinations were no better than HMA monotherapy. One wonders what this means for things like magrolimab + HMA which also showed promising P2 combination data but no randomized data yet. /7
Finally, as always when commenting on a trial, my COI: I was an investigator on Aprea P2 and P3 trials and did 1 advisory mtg for them a couple years ago. And, less tangibly. have friends both among fellow investigators and company leaders. Really disappointed by result. /8End
