Another twist in Cardiff’s onvansertib plan

Trading below cash and with just $89m in the bank Cardiff Oncology will need to go to investors for more money soon, so its recent playing up of onvansertib data is understandable. However, on closer reading the results appear sketchy, both in colorectal cancer, onvansertib’s lead setting, and in the pancreatic cancer dataset updated last night.

Perhaps the biggest problem with the pancreatic data is the limited patient numbers involved, yet Cardiff is already trumpeting the start of a first-line study. This is not dissimilar to its colorectal plan, which has seen a phase 3 front-line trial designed and apparently set to begin, with the aim of yielding interim data in mid-2024.

At least the pancreatic trial, combining onvansertib with standard of care, won’t cost Cardiff anything to run. The company said yesterday that this would be an investor-initiated effort, but how much backing is there for running such a study? 

Onvansertib’s phase 2 trial in second-line pancreatic ductal adenocarcinoma has evolved slowly, last year yielding one partial response among five subjects. Later three more patients were added with no new remissions – not great for what isn’t even a monotherapy trial; onvansertib is being tested here in combination with nanoliposomal irinotecan, leucovorin and 5-FU.

Yesterday Cardiff said there were now 21 evaluable patients; yet still there is just one confirmed remission, though the group said another three patients with apparently partial responses were awaiting confirmatory scan. Caveat emptor.

Unconvincing?

If that’s unconvincing then Cardiff’s colorectal cancer data should give further pause. The company last year moved to enter phase 3 here, specifically in first-line RAS-mutant disease, and later scrapped the second-line phase 2 Onsemble trial, presumably for lack of efficacy.

The backing for testing onvansertib in first-line colorectal cancer appears limited, coming from a phase 1/2 study in the second-line setting, where an Avastin/chemo triplet combo has been tested in KRAS-mutant disease. Here Cardiff has started claiming a 73% remission rate, three times higher than “historical controls”.

So where’s the catch? The 73% claim actually comes from a study whose data have been deteriorating, having in 2020 stood at a 36% confirmed ORR (45% including unconfirmed responses), but which now, considering all 66 evaluable patients, show an ORR of only 27%. 

Cardiff has is instead started zeroing in on 15 patients who had not received first-line Avastin, saying 11 responded. Since the onvansertib combo includes Avastin, it might be supposed that at least some activity derives from the Roche drug in patients not previously exposed to it. The data exclude two non-responders who were later reclassified as Avastin-exposed.

Onvansertib in KRAS-mutant colorectal cancer: evolving data from a phase 1/2 dose finding study

Note: *two non-responding patients initially categorised as Avastin-naive were later reclassified as Avastin-exposed. Source: company statements.

Lastly the company is saying nothing about Onsemble, the phase 2 second-line colorectal study it scrapped last month. According to clinicaltrials.gov this had run for six months and enrolled 23 subjects, so presumably these will have yielded some data.

Perhaps the second-line colorectal setting is irrelevant, since Cardiff isn’t taking onvansertib forward here, though whether there is enough to back its first-line enthusiasm is a separate question. Yesterday Cardiff said phase 3 would comprise the CRDF-004 exploratory and CRDF-005 registrational trials.

CRDF-004 is expected to yield interim data in mid-2024. Whether it’s possible for a first-line phase 3 study that hasn’t yet started dosing to provide meaningful results within eight months or so – and Cardiff’s current cash runs out in 2025 – is another question for investors.

Onvansertib is a PLK-1 inhibitor, a class that has yet to shine clinically. OncologyPipeline reveals a few other clinical assets, the most established of which, Notable Labs’ volasertib, was invented at Boehringer Ingelheim but was later divested. That should be another reason for caution.

PLK-1 inhibitors in clinical development

Note: *TTK/PLK-1 inhibitor; the rest are PLK-1 inhibitors. Source: OncologyPipeline.