“Surprise” SITC late-breaker breaks Five Prime

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The only thing stranger than Five Prime Therapeutics being laid low yesterday by a first-in-human study at SITC, a relatively obscure meeting, was the bizarre chain of events leading up to the debacle.

The stock crashed 41% on the first report of the anti-CSF-1R MAb cabiralizumab’s activity in combination with Opdivo in pancreatic cancer in an SITC late-breaker the group later insisted should not have been published until December. A defence of the data on a call today did not fully reassure the markets, Five Prime creeping up 15% this morning.

Today the company said the data as they appeared baldly in SITC’s abstract book presented an incomplete picture. And it insisted that SITC had earlier assured it that late-breaking abstracts would not be published until December 7, something that appears strange given that this would have been a month after the meeting ended.

“We were surprised to see the late-breakers published online [yesterday],” said the group’s chief executive, Rusty Williams, on today’s analyst call. “SITC grossly mismanaged the process. I’ve never seen anything like this.”

The SITC (Society for the Immunotherapy of Cancer) retorted with a tweet, stating that the December date referred to publication of the late-breakers in its scientific journal, adding: “They were included in the annual meeting poster book, as SITC always does.”

To add insult to injury, Five Prime yesterday attempted to issue an emergency statement and host a conference call, but was prevented from doing so when Globenewswire, its press release distributor, suffered an extended IT failure.

No other company that scored an SITC late-breaker appears to have complained of unexpectedly early abstract disclosure, and Iovance specifically pointed EP Vantage to SITC’s policy page, which states that late-breaker embargoes lift on November 7 (SITC preview – All eyes on Incyte and Infinity, October 26, 2017).

Toxic

Five Prime’s problem yesterday related to toxicity: grade 3-5 adverse events attributed specifically to cabiralizumab were seen in 43% of patients in its trial. As for efficacy, Leerink analysts said the trial provided the first evidence of cabiralizumab’s ability to sensitise patients to Opdivo.

However, the enthusiasm can be questioned. The overall remission rate among 31 evaluable pancreatic cancer patients was just 10%, all responses being partial. A recent small trial of Opdivo with Abraxane had yielded a 29% remission rate, though Five Prime pointed to the second-line approval of Onivyde plus chemo, based on overall remission of only 7.7%.

The group also tackled the toxicity issue, saying there were only three deaths, none of which was in the cabiralizumab monotherapy arm. In fact, all occurred in NSCLC subjects – the trial’s safety database comprises 205 patients with various tumours – and were due to respiratory problems.

On efficacy, the company argued that all three remissions were seen in pancreatic cancer that was microsatellite-stable, which typically does not respond to checkpoint blockade. Moreover, by central review there was another partial remission, taking the rate up to 13%.

Still, durability of cabiralizumab plus Opdivo in the abstract seems poor, with 87% of patients progressing by six months. And while it cannot be denied that advanced pancreatic cancer is extremely intractable the data could call into question cabiralizumab’s underlying mechanism.

The agent works on the theory that tumour-associated macrophages (TAMs), an immunosuppressive cell type, help damp down T-cell response. Cabiralizumab’s ability to bind CSF-1R could inhibit TAM activation and signalling, which if combined with an anti-PD-1 MAb could release two breaks on the immune system.

The SITC abstract says elevations in creatinine phosphokinase and aspartate transaminase were due to cabiralizumab’s ability to deplete macrophages, which would otherwise have metabolised these enzymes.

Five Prime has for some time been a proxy for the promise of immuno-oncology combinations, and yesterday’s stock reaction could be another sign that overblown expectations are fading.

Selected agents targeting CSF-1
Project Company Status Selected study Trial ID
Emactuzumab Roche Phase II Combo with Tecentriq in solid tumours NCT02323191
Cabiralizumab Five Prime/Bristol-Myers Squibb Phase II Combo with Opdivo in various cancers NCT02526017
MCS-110 Novartis Phase II Combo with PDR001 in advanced malignancies NCT02807844
AMG 820 Amgen Phase II Combo with Keytruda in solid tumours NCT02713529
IMC-CS4 Lilly Phase II Combo with Imfinzi or tremelimumab NCT02718911
SNDX-6352 Syndax Pharmaceuticals Phase I Dose escalation  in solid tumours NCT03238027
Source: EvaluatePharma.

Cabiralizumab and another Five Prime immuno-oncology project are partnered with Bristol-Myers Squibb. An earlier deal the biotech company had with Glaxosmithkline, covering its FGF ligand trap FP-1039, was canned last year.

The full cabiralizumab data will be presented at SITC on Saturday. While investors remain cautious, at least there is no indication that Bristol will follow Glaxo’s lead: the US big pharma group has apparently committed to starting a phase II cabiralizumab plus Opdivo study in pancreatic cancer shortly.

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