I put this here for JUNIPER’s reference and as the latest on what a KOL thinks of upcoming Endo/Ovarian treatment options. One thing I notice is the difference in progression free survival for the Karyopharm patients in the “all-comers” version of the trial (mPFS=5.7 months) versus the specific “wild-type p53” type (mPFS=13.7 months). The idea we’ve had around all-comers helping to understand the sortilin/efficacy relationship versus clouding up the efficacy signals in the 1a seems true in this trial. Also, seems “patient vignettes” do have some limited value if it’s strong response (Prelude had one durable Complete Response). Maybe we’ll have a “vignette” or two to mull over.
Key Takeaways:
We spoke to Dr. Marcela del Carmen to discuss emerging therapies in endometrial and ovarian cancer and our 3 main takes are: 1) Our primary focus was around the Phase 3 topline data in endometrial cancer from Karyopharm — KOL was very positive on the Phase 3 SIENDO data from Karyopharm and potential approval of selinexor (XPO1 inhibitor). Our KOL expects broad use of selinexor in at least the p53 wild-type population in the frontline maintenance setting. Our KOL was very positive on patient vignette from Adaptimmune’s Phase 1 SURPASS data for ADP-A2M4CD8 (MAGE-A4) in ovarian cancer – highlighting that the T cell therapy showed both an encouraging safety profile as well as fast responses; and 3) our KOL was highly encouraged by the patient vignette from Prelude’s PRMT5 inhibitor data showing a durable complete response.
KARYOPHARM SPECIFIC SOMMENTS: KOL very positive on SIENDO Phase 3 data, expects broad applicability: Our KOL was very positive on Karyopharm’s recent Phase 3 SIENDO data of Selinexor in endometrial cancer and believes the drug could have broad applicability in the maintenance setting given high unmet medical need (~85% relapse rate with no available maintenance therapies). Importantly, our KOL believes the drug could be used very broadly for patients with wild-type p53 where data showed a mPFS of 13.7 months vs. 3.7 months (HR: 0.38; p=0.0006). She believes up to 95% of her patients would be offered this drug in the maintenance setting (5% of patients may be too advanced/frail to benefit) and also noted that identifying p53 status was unlikely to be a barrier given that most patients are screened following diagnosis. Finally, she also expects PFS benefits to translate into OS benefits, and overall, believes the drug is likely to get approved given the lack of available therapies in the maintenance setting and positive topline data. Furthermore, our KOL was positive on the all-comers setting as well given the unmet medical need, even though the margin of benefit was less (mPFS of 5.7 months in all-comers). For p53 mutant population, it would depend on the balance of safety, seeing the hazard ratio and degree of p-value. Furthermore, our KOL was positive on the potential uptake in the maintenance setting in endometrial cancer, with strong parallels to the maintenance setting in ovarian cancer with PARP inhibitors.
· Initial Phase 3 SIENDO data and Phase 2 SIGN data bode well for a favorable safety profile: Our KOL was positive on the safety profile of Selinexor given 1) a ~10% discontinuation rate seen in SIENDO, and 2) favorable safety profile seen in Phase 2 SIGN trial with the caveat of a smaller “n”. From the Phase 2 SIGN data, she highlighted the limited rate of Grade 4 adverse events as well as Grade 3 adverse events at under 25% (including for thrombocytopenia), which she considers very manageable. Furthermore, the safety looked very good in comparison to the analogous maintenance setting with PARP inhibitors in ovarian cancer.
· What to watch for in upcoming full dataset from the Phase 3 SIENDO study in 1H22 data: Our KOL will be watching for sustained PFS benefits and hazard ratios with statistically significant p-values in the p53 mutant patients. She also points to monitoring the rate of thrombocytopenia closely – and is looking to see it remain below 25%.
ADAPTIMMUNE SPECIFIC COMMENTS:
Our KOL was encouraged by the patient vignette and responses seen in the Phase 1 SURPASS trial for ADP-A2M4CD8 (MAGE-A4) in ovarian cancer – highlighting that she considers even achieving stable disease as highly clinically meaningful in this difficult-to-treat population.
§ Our KOL was highly encouraged by the 1 CR ongoing at 6 months and the fast time to response at 8 weeks, as well as the favorable safety profile with minimal Grade 3+ CRS events (3/22 in all comers)
PRELUDE SPECIFIC COMMENTS: Although small n numbers, we focused on the patient vignette – our KOL was impressed by the long-lasting CR achieved in a heavily pre-treated patient with the patient remaining on therapy following 18 months of treatment – particularly given that these patients are only expected to live 4-6 months. She also pointed to the fast time to response with tumor reduction observed after only 7 weeks of treatment.
§ Additionally, our KOL noted that with the low bar in the HRD+ ovarian cancer setting, even achieving SD is clinically meaningful.