SITC – the morning after the night before

Nextcure’s Society for Immunotherapy of Cancer presentation gave investors little reason for cheer, but there's better news for Pieris, Celyad and Nektar.

Nextcure found out this morning that SITC gives and it takes away. The group’s stock had surged 249% when the abstract of its presentation at this immunotherapy conference was unveiled, but the full data presented on Saturday failed to enthuse, and today reason resumed its seat: Nextcure crashed 53%.

There was better news at the meeting for Nektar, Pieris and Celyad, but for investors the Nextcure debacle should serve as a cautionary tale. The desperation for single-agent activity in PD-L1-refractory cancer is considerable, but Nextcure has now managed to wipe out almost all the gains it had made a week ago.

That enthusiasm was prompted when a second partial remission to Nextcure’s NC-318, an anti-Siglec-15 MAb, was seen in a lung cancer cohort, while an earlier partial response deepened and became complete. The group’s trial is in treatment-refractory solid tumours, and the markets were keen for additional signs of activity to emerge at the full SITC presentation.

Instead, what became apparent is how many patients NC-318 did not work in. The trial has now given the MAb to 13 NSCLC, seven melanoma, seven ovarian, four breast and three colorectal cancer subjects – without any additional efficacy being reported beyond the two already known responses.

And things got worse: the complete response had come from the lowest, 8mg, NC-318 dose, raising questions over why much higher doses appear to be relatively inactive. And Nextcure failed to back its argument for the MAb’s efficacy with any Siglec-15 biomarker data, promising only that Siglec-15 expression would be evaluated retrospectively in phase II dose expansion.

Swimmers plot for Nextcure's NC-318. Source: Dr Anthony Tolcher & SITC.

Pieris, on the other hand, did not disappoint, and delivered on a promise to show first-in-human responses for PRS-343, its Her2/4-1BB bispecific. Five of 18 evaluable Her2-positive subjects got the highest, 8mg/kg every two weeks dose, and two of these responded; no remissions were seen at lower doses.

However, while Pieris stressed that efficacy was linked to biomarker evidence of 4-1BB agonism, it is too early to say whether PRS-343 can turn “cold” tumours “hot”. One of the responders had failed treatment with Keytruda and Opdivo, but was PD-L1-positive; no biomarker data on the second were provided. Pieris opened up a cautious 2% this morning.

Swimmers plot for Pieris's PRS-343. Source: Dr Sarina Piha-Paul & SITC.

Meanwhile, Celyad’s protracted spell without any meaningful data ended at SITC, with the company making a case for allogeneic cell therapy. The AlloShrink trial of CYAD-101 has yielded two partial responses in 12 relapsed colorectal cancer patients treated so far – a respectable indication of early efficacy in this cancer.

Equally important, for an allogeneic cell therapy, is the fact that no graft-versus-host disease has been seen, and this will be monitored closely as the CYAD-101 dose is escalated; data from all 15 subjects to be recruited are expected in the first quarter of next year.

Like Celyad’s autologous lead, CYAD-01, CYAD-101 targets NKG2D ligands. Behind CYAD-101 lies a “TCR inhibitory molecule” concept to silence endogenous T-cell receptors – the cause of GVHD – though in fact this might not be Celyad’s brightest allogeneic hope: earlier-stage Celyad assets use short hairpin RNA technology to knock out the T-cell receptor.

And the last of this quartet of SITC-relevant stocks, Nektar, was up 6% this morning, though the update on its troubled Pivot-02 study was basically a rehash of data already seen at Asco. The main difference was that one previously PD-L1-negative subject in this first-line melanoma trial of bempegaldesleukin plus Opdivo was now classified as PD-L1-positive.

The company argued that the remissions it had already seen were deepening, and indeed across Pivot-02 nine complete responses had started as partial remissions. Since Opdivo plus Yervoy is already approved in this setting, on the back of similar ORR data in the Checkmate-069 study, Nektar’s best bet at present seems to be to play up bempegaldesleukin’s relatively cleaner safety.

Deepening response? Pivot-02 in 1st-line melanoma (NCT02983045)
Presentation Data cut Subjects Objective response rate CR rate ORR in PD-L1-neg
SITC 2017 Nov 2, 2017 11 7 (64%) 2 (18%) 3/5 (60%)
Asco 2018 May 29, 2018 28 14 (50%) 3 (11%) 5/11 (45%)
SITC 2018 Oct 1, 2018 38 20 (53%) 9 (24%) 6/14 (43%)
Asco 2019 Mar 29, 2019 38 20 (53%) 13 (34%) 6/14 (43%)
SITC 2019 Sep 25, 2019 38 20 (53%) 13 (34%) 5/13 (39%)
Source: Company presentations & meeting abstracts.

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