Esmo 2020 – can Alkermes succeed where Nektar failed?

Early signs suggest that Alkermes might have found a therapeutic window with its IL-2-targeting agent, ALKS 4230.

Disappointing results with Nektar Therapeutics’ bempegaldesleukin made targeting IL-2 look like a dead end. But Alkermes reckons it has managed to design a molecule that gets around the toxicity that has limited the use of older agents.

Data presented at the Esmo meeting suggest that the group might be on to something: a particularly promising sign came in the form of two partial responses to ALKS 4230 monotherapy in melanoma. The agent was less convincing in renal cancer, and the small number of patients trialled so far means caution is still warranted.

More efficacy, less tox?

Stimulating IL-2 activates the immune system, so has long been pursued as a cancer target; indeed, Novartis’s recombinant IL-2 Proleukin has been approved since 1998, albeit with strenuous safety warnings.

Toxicity arises because IL-2 stimulation causes a surge in other cytokines and vascular leak syndrome, Dr Ulka Vaishampayan of the University of Michigan, who presented the ALKS 4230 data at Esmo, explained.

“The majority of that toxicity comes from binding to the IL-2 alpha receptor,” she told Evaluate Vantage. ALKS 4230, a novel fusion protein, preferentially binds to the intermediate affinity IL-2 receptor and avoids the alpha receptor, so could bypass these issues, Alkermes believes.

Source: Company presentation

This selectivity could also give ALKS 4230 an efficacy advantage, Dr Vaishampayan added, because hitting the intermediate affinity receptor means it does not activate immunosuppressive T regulatory cells.

However, one known side effect of the older IL-2s is severe hypotension – and there was a case of grade 3 hypotension with ALKS 4230 monotherapy reported at Esmo. Dr Vaishampayan does not believe this is a cause for concern, because it “was fairly transient and very quickly resolved with intravenous fluids”. This will no doubt be closely watched as more data with ALKS 4230 emerge.

Apart from this the project’s tolerability looked good, with the most common adverse events being transient fevers and chills.

IL-2 Artistry

Dr Vaishampayan believes that the data featured at Esmo provide “proof of principle that [ALKS 4230] monotherapy does have efficacy”.

The monotherapy results come from 15 patients treated with intravenous ALKS 4230 in part B of the phase I/II Artistry-1 trial. Of six melanoma patients, there was one partial response at a cut-off date of July 24, Esmo heard. Since then, there has been another partial response, which has yet to be confirmed, Alkermes reported.

Both responders had received prior checkpoint inhibitors and had mucosal melanomas, an aggressive disease subtype, making them particularly tough to treat.

Source: Company presentation

It was not all good news, however: there were no responses in nine renal cancer patients receiving ALKS 4230 monotherapy.

Dr Vaishampayan admitted: “I don’t know what to make of it yet. Maybe in kidney cancer, which already has significant sensitivity to checkpoint inhibitors, we might not see activity unless we use a combination therapy.”

Keytruda combo

As luck would have it, Alkermes is also testing ALKS 4230 alongside Merck & Co’s PD-1 blocker Keytruda in various cancers, and here data were also available at Esmo, from part C of Artistry-1.

As always with combos the results are hard to interpret, but Alkermes reported one complete and two partial responses in a cohort of 13 ovarian cancer patients at the August 7 cut-off.

The responders were heavily pre-treated and platinum-resistant, another difficult-to-treat population, Dr Vaishampayan noted.

There were also partial responses to the combo in one triple-negative breast cancer patient, one pancreatic cancer patient, and two oesophageal cancer patients; one of the oesophageal PRs  remains unconfirmed.

Source: Company presentation

The next big event for ALKS 4230 will be data with a subcutaneous version from the Artistry-2 study, due this year. It is also expanding the monotherapy cohort of Artistry-1 by 20 patients.

In showing monotherapy activity, ALKS 4230 has got one up on Nektar’s bempegaldesleukin, which was trialled primarily in combination with Bristol Myers Squibb’s Opdivo in the hope that it might turn “cold” tumours “hot”. Results from the Pivot-02 trial were ultimately disappointing.

Bristol has not given up on bempegaldesleukin, which it licensed from Nektar for $1.85bn in February 2018, adding two registrational Opdivo combo studies to bempegaldesleukin’s existing three trials earlier this year.

Meanwhile, monotherapy with Roche’s RG7461, an anti-FAP/IL-2 fusion protein, has spurred responses in melanoma, as reported at Esmo 2018, but the company “has gone fairly quiet on this molecule since”, noted Evercore ISI’s Umer Raffat.

For now, it is advantage Alkermes – but more data will be needed before declaring ALKS 4230 a winner.

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