SITC 2018 – No honey for Nektar

Despite a $1.85bn up-front payment from Bristol-Myers Squibb in February, investors in Nektar Therapeutics have had a nervous few months. Almost a third of the group’s value has leaked away this year, partly as the markets turned sour but also because of growing doubts over its lead cytokine asset, NKTR-214.

Unfortunately, the long-awaited NKTR-214 update at the SITC meeting, the abstract of which has just been unveiled, will offer them little solace. With 38 subjects now in the first-line melanoma Opdivo combination cohort the remission rate is still 50% – the same as at the group’s disappointing Asco update, and no better than historical data for Opdivo plus Yervoy.

Those Asco results had raised the first doubts over NKTR-214, a CD122-biased IL-2 agonist that carries with it much of the hopes for cytokine therapeutics. In 28 patients the Asco dataset revealed a 50% remission rate, well below the 85% seen in stage 1 of Pivot-02 (Asco 2018 – Loxo receives accolades but Nektar’s sweetness fades, June 3, 2018).

At SITC the abstract shows that the first-line melanoma cohort now includes another 10 subjects, taking the total evaluable to 38. Yet Nektar is able to report only a further five remissions, meaning that overall the response rate remains at 50%.

One caveat is that this is still a July 2018 data cut, and the actual presentation should offer more mature data. This is due to be given at SITC’s “Cytokines Reinvented” session at 6:07pm Eastern time on Friday; Nektar is also planning an analyst webcast on Saturday afternoon.

However, what has just been revealed in the abstract will make for nervous reading. Perhaps most alarmingly, mechanistically NKTR-214 is doing what it should, but this does not seem to be translating into stand-out efficacy. 

Researchers report “clear activation of the IL-2 pathway”, rising lymphocyte numbers and patients converting from PD-L1-negative to positive. Yet the actual responses, though durable, remain at an unimpressive number. Opdivo’s US label cites a 50% remission rate from the drug’s first-line melanoma trial, Checkmate-067, where it was given in combination with Yervoy.

Caution

While some analysts had played up the possibility of subjects in stable disease at the Asco data cut going into remission later, others expressed extreme caution going into SITC.

Evercore ISI recently said the lack of existing monotherapy data for NKTR-214 was a key red flag, especially in light of Roche’s Esmo success with an IL-2 variant, RG7461, which yielded responses when given as monotherapy to melanoma subjects who had failed checkpoint blockade.

“We see merit to the IL-2 agonism strategy, but believe Nektar hasn’t optimised the dose/exposure of NKTR-214 before ploughing ahead at full speed,” Evercore wrote two days ago. They said the Pivot-02 cohort would need to show a response of “well north of 60% to have any confidence that the combination of NKTR-214 and Opdivo is differentiated from monotherapy checkpoint inhibitors”.

Yet to be revealed at SITC is the number of remissions among PD-L1-negative subjects. This is important for cytokine therapy to retain its promise as a means of turning “cold” tumours immunogenic and thus broadening the response rate to checkpoint blockade.

It is of course still possible for Nektar to seize triumph from the jaws of defeat on Friday, though this would require a miraculous turnaround in patients responding after July. As it stands, NKTR-214 looks to be in danger of becoming another asset whose combinatorial promise fails to match expectations.