ASCO-GI – ALX resurrects evorpacept
The company reveals fresh biopsy status as a primary endpoint, and declares Aspen-06 a win.
The company reveals fresh biopsy status as a primary endpoint, and declares Aspen-06 a win.
The latest update to the perambulating Aspen-06 study of ALX Oncology's CD47 inhibitor evorpacept has thrown into stark relief the importance of determining whether a gastric cancer patient truly is HER2-positive at study entry.
What will surprise, however, is the company's revelation that measurement of response rates in a subgroup of patients in whom fresh HER2 biopsies were available constituted an Aspen-06 primary endpoint. This claim, made on Thursday, wasn't apparent in ALX's previous disclosures about Aspen-06, and doesn't appear in the study's clinicaltrials.gov entry.
ALX told ApexOnco that this subgroup constituted "a primary endpoint since the start of the study, [and] is reflected in the study protocol as filed with the FDA in 2022". The issue was that earlier there were insufficient numbers of patients with fresh biopsies to report on.
Hero to zero
It was already clear that the lack of fresh HER2 biopsies might have caused Aspen-06 to turn from a positive to a negative trial, and in any case the trial was known to be a bust on ORR in the all-comers population.
It recruited late-line gastric cancer patients who had progressed on HER2 therapy and were positive for HER2 expression, testing evorpacept plus Herceptin, Cyramza and paclitaxel, versus Herceptin/Cyramza/paclitaxel alone. The primary ORR endpoint related to a comparison against the triplet control group, as well as versus a cross-trial ORR of 30% in Lilly's Rainbow study of Cyramza plus paclitaxel.
When first toplined in October 2023 an interim readout was hailed as one of the first successes for a CD47 inhibitor, with ORRs of 52% for the active quad versus 22% for triplet control. At that time ALX spoke only about a primary endpoint in all-comers, as still stated in Aspen-06's clinicaltrials.gov entry.
However, by the time more than twice as many patients were enrolled ORR waned to 40% in the active arm and rose to 27% for control, and the trial turned into a bust, missing a 0.025 p value threshold for statistical significance. It was then that ALX pointed out a decrease in the proportion of patients with a “fresh” biopsy – defined as a biopsy after prior anti-HER2 treatment.
The issue is important because a patient who is HER2-positive before their first HER2-directed treatment might lose this antigen on progression, before entering Aspen-06; according to an archival biopsy they would still be deemed HER2-positive, however. ctDNA analysis in Aspen-06 suggests that a third of patients with archival samples were not, in fact, HER2-positive.
Last July that ALX mentioned that ORR was measured in two prespecified Aspen-06 populations – all-comers and fresh HER2 biopsy patients, while noting "two primary objectives": final ORR analyses versus internal and versus historical control.
Doubling down
Now it's going further. On a Thursday investor call ahead of data presentation at the ASCO Gastrointestinal Cancers symposium ALX's recently appointed chief medical officer, Alan Sandler, stated: "Response rates in the fresh biopsy population was a primary endpoint."
It was here that ALX now claims a win, with ORRs of 59% versus 23% for the control triplet. However, ALX provided no p values, didn't reveal a threshold for statistical significance, and indeed didn't even say whether statistical significance had been hit.
Evorpacept's evolution in Aspen-06
| Date | Cutoff | Patients | ORR in active quad | ORR in triplet control | Description of primary endpoint |
|---|---|---|---|---|---|
| 3 Oct 2023 | 29 Aug 2023 | 54 | 52% | 22% | 50% ORR improvement vs historic; 10% delta between both arms |
| 31 Jul 2024 | 24 May 2024 | 127 | 40% | 27% | 50% ORR improvement vs historic 30%; >10% delta between quad and triplet Two prespecified HER2+ve populations: all-comers and subset with “fresh” HER2 biopsy |
| Fresh biopsy subgroup | 48 | 55% | 23% | ||
| 23 Jan 2025 | 2 Dec 2024 | 127 | 41% | 27% | ORR in all-comers vs triplet; ORR in all-comers vs historic; ORR in fresh HER2 biopsy subgroup vs triplet; ORR in fresh HER2 biopsy subgroup vs historic |
| Fresh biopsy subgroup | 48 | 59% | 23% | ||
Source: ALX presentations.
A further issue is safety, with Aspen-06 showing a 9% rate of treatment-emergent deaths. However, there was only one treatment-related death (oesophageal perforation) among the 63 patients in the active cohort, and ALX called the evorpacept quad "generally well tolerated".
The company is now floating the possibility of an accelerated approval, and said it would reveal a regulatory plan at an R&D day next month. It earlier said it would discuss survival data with the FDA, and has now presented PFS curves; however, while these seemed numerically positive, there was heavy censoring and wide confidence intervals owing to small patient numbers.
A key revelation was the push for a pivotal trial that's truly driven by the HER2 biomarker. ALX is likely to argue against use of archival biopsies, but mandating a fresh biopsy would add an extra burden; thus ALX might try to rely on ctDNA analysis, but the problem is that this type of "liquid" biopsy is notoriously unreliable.
ALX stock fell as much as 20% on Thursday, before closing down 9%.
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