SITC 2018 – The search for immuno-oncology combos continues

Once hotly tipped approaches from Aduro, Tesaro and Merck & Co might yet hold promise, but disappointing early data cuts have burst the bubble of investor expectations.

What level of efficacy needs to be seen in an immuno-oncology combination trial for investors not to run for the hills? At the SITC meeting several companies found out that, despite their assurances, the market had lost patience with many approaches of which much had earlier been expected.

One of these was Aduro, making this the second time this group got hit in the space of a month: during the Esmo meeting it had lost a third of its value after disappointing early data with Merck & Co’s Sting agonist MK-1454. Aduro is developing its own Sting agonist, ADU-S100 – the subject of a $225m deal with Novartis, and of an eagerly awaited presentation at SITC.

Hopes were not high when the abstract of this paper, unveiled last week, did not mention efficacy, only detailing patient discontinuations and ADU-S100’s safety profile.

Apparently good news therefore greeted investors on Friday, when updated results from an August data cut of a phase I monotherapy solid tumour trial detailed two partial remissions among 40 evaluable subjects; crucially, one of these had failed prior anti-PD-1 therapy, suggesting that the Sting agonist was adding a benefit.

But, rather than helping reverse the Esmo fall, the data made matters worse, and Aduro lost another 14%. A separate study, combining ADU-S100 with Novartis’s anti-PD-1 project spartalizumab, is ongoing.

Hints of activity?

It is clear that mere hints of efficacy are not enough, even in patients who have failed checkpoint blockade; after all, some of these might respond when merely retreated with an anti-PD-(L)1 MAb, if in the intervening period their tumour has become immunogenic, for instance.

Even worse off was Tesaro, whose stock crashed 19% on Friday in response to a trial of that company’s anti-Tim-3 MAb TSR-022 in combination with the anti-PD-1 TSR-042, specifically in anti-PD-1-refractory patients. Investors, nervous about prospects for Tesaro’s marketed Parp inhibitor Zejula, were keen for signs that the group’s pipeline might pick up the slack.

Like Aduro, Tesaro’s SITC abstract had revealed nothing about efficacy in the study in question, called Amber. That was kept back for the SITC oral presentation, which on Friday described an overall response of 9% among 11 patients given TSR-022 at 100mg, and 15% in the 20 dosed at 300mg.

True, this suggests a dose response, though the numbers are tiny. But much more relevant is that this level of efficacy is woefully inadequate as companies search for the secret sauce to boost the efficacy of monotherapy checkpoint blockade. A vitally important point is that all three 300mg responders were PD-L1 positive, so it is impossible to say that Tim-3 blockade was adding anything.

Analysts had earlier cited a response rate of 10-15% as being the benchmark in checkpoint-relapsed patients, so theoretically TSR-022 plus TSR-042 falls within that. But in reality some studies suggest that salvage chemotherapy after PD-(L)1 inhibition is considerably more efficacious.

In a savage summing up Evercore ISI analysts opined that a higher, 900mg, TSR-022 dose might improve activity, but that overall Tesaro’s “me-fifteen immuno-oncology pipeline” was uninspiring.

Selected SITC presentations
Project Company Mechanism Setting Efficacy
ADU-S100 Aduro/Novartis Sting agonist Monotherapy 5% ORR (n=40)
TSR-022 Tesaro Anti-Tim-3 TSR-042 combo 13% ORR (n=31)
MK-7684 Merck & Co Anti-Tigit Monotherapy 3% ORR (n=34)
MK-7684 Merck & Co Anti-Tigit Keytruda combo 19% ORR (n=43)
MK-4280 Merck & Co Anti-Lag-3 Monotherapy 6% ORR (n=18)
MK-4280 Merck & Co Anti-Lag-3 Keytruda combo 27% ORR (n=15)
Source: SITC.

Other previously heavily hyped novel immuno-oncology approaches that are now firmly on the “await more data” pile include Tigit and Lag-3. On these, Merck & Co revealed data at SITC that again suggested activity but failed to raise the roof, basically making it impossible for investors to decide whether the company was seeing anything it would not have done with checkpoint blockade alone.

Perhaps this illustrates a fundamental problem about the amount of investor attention that has fallen on the SITC meeting over the past few years. The conference is clearly in the market’s immuno-oncology sweetspot, but it is fundamentally a forum for scientists to discuss extremely early results.

Novel approaches such as complex fusion proteins from Cue Biopharma (CUE-101) and Alpine Immune Sciences, to list just two, or even the way Celyad is counteracting T cell fratricide in producing its lead CAR-T asset by including a PI3K inhibitor in manufacturing, should be of great interest to academics. But they do little more than indicating a possible way forward.

The slightly more advanced datasets could still change over time, and to read too much into them at this point could be mistake. Perhaps SITC has become a victim of its own success, but unfortunately this has now accelerated a deflation of the biotech bubble.

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