More data are not always a good thing. Just ask Mersana, which sank 29% yesterday on the latest update on its lead antibody-drug conjugate, XMT-1536, in ovarian cancer.
The data look worse than those shared at last year’s Esmo meeting, which concerned an earlier cut from the same study. Specifically, yesterday’s update revealed a shrinking overall response rate, more adverse events including a treatment-related death, and unimpressive durability.
The sellside, which has pencilled in 2026 sales of $362m according to EvaluatePharma consensus, leapt to Mersana’s defence. Leerink said the data still supported accelerated approval of XMT-1536, which now has the generic name upifitamab rilsodotin.
This might be true given the late-line setting in which XMT-1536 is being tested – the phase I trial in question includes patients who failed up to four previous therapies, some of whom are platinum resistant. The current standard of care for this population is single-agent chemotherapy, and the prognosis is not good, with response rates of 4-12%, median progression-free survival of three to four months, and median overall survival of less than one year.
But Mersana’s chances of getting a broad label took a hit yesterday. Upri targets NaPi2b and, while overall response rates just about held steady in higher NaPi2b expressers, they dropped off markedly in lower expressers.
|Getting worse all the time: the evolution of upifitamab rilsodotin's phase 1 trial|
|Asco 2020||Esmo 2020||Jan 2021 update|
|Cut-off date||May 1, 2020||Aug 18, 2020||Dec 3, 2020|
|ORR in all-comers||35% (7/20)||34% (10/29)||28% (13/47)|
|ORR in NaPi2b-high patients||29% (4/14)||35% (7/20)||32% (10/31)|
|ORR in NaPi2b-low patients||25% (1/4)||29% (2/7)||15% (2/13)|
|Source: company presentations.|
Mersana looks like it is still hedging its bets: although the primary endpoint of its pivotal trial, Uplift, is ORR in the NaPi2b-high population, the study will enrol all-comers and assess ORR in all subjects as a secondary endpoint.
However, another complication is the fact that the company has yet to nail down the cut-off for NaPi2b-high/low patients.
The next question around upri concerns durability. Yesterday Mersana said that, in 10 patients with higher NaPi2b expression, median duration of response was around five months. The company noted at Esmo that anything over four months would be a good result.
However, the data look unimpressive versus the 5.5-month duration of response seen with Roche’s now-abandoned NaPi2b-targeted ADC, RG7599 (lifastuzumab vedotin).
Stifel analysts insisted that the durability of upri was in line with, or perhaps even better than, that of lifastuzumab vedotin given the more heavily pre-treated population in the upri study. Data in more patients are probably needed before a definitive call can be made, but the signs are not promising.
Finally, upri’s safety profile has deteriorated since Esmo – most worryingly, there was a death from pneumonitis that was deemed drug related. Mersana has put extra monitoring in place, which it hopes will prevent more severe cases.
Stifel analysts believe that pneumonitis is an on-target effect, and noted that off-target adverse events commonly seen with ADCs, such as neuropathy and neutropenia, were not observed with upri. As neuropathy was a dose-limiting factor for lifastuzumab vedotin, upri might still have an edge here. But Mersana has more to worry about than it did a few months ago.