2018 started with a major test of the IDO mechanism, and as the year draws to a close investors want proof from a different immuno-oncology approach: cytokines. Those following Nektar’s cytokine agonist NKTR-214 will hope that it avoids the fate of Incyte’s epacadostat, the IDO inhibitor that flunked its key trial in April.
Nektar is due to present an update on first-line melanoma patients in the Pivot-02 study of NKTR-214 at the SITC meeting on November 9; like epacadostat this is being tested in combination with PD-1 blockade. Especially keen to avoid comparisons will be Bristol-Myers Squibb, which paid $1.85bn for NKTR-214 rights just two months before epacadostat blew up.
Of course there is no suggestion that the two mechanisms have much in common. IDO inhibition affects tryptophan metabolism, which is thought to have an indirect immunosuppressive effect; NKTR-214 is a CD122-biased IL-2 agonist aiming directly to stimulate proliferation of effector T cells.
Still, while checkpoint blockade has revolutionised cancer treatment, it is clear that combinations with other I-O agents have failed to live up to their billing. Perhaps this broad issue explains investor fears, which have resulted in Nektar stock falling 33% year to date.
And the Pivot-02 study has already disappointed once this year – at its update at Asco (Asco 2018 – Loxo receives accolades but Nektar’s sweetness fades, June 3, 2018). The trial, testing NKTR-214 plus Bristol’s Opdivo, actually comprises numerous tumour types, but it is melanoma – in particular the first-line cohort – that will be highlighted at SITC.
Key to watch here will be responses in PD-L1-negative subjects. PD-(L)1 blockade is known to work very well in some melanoma patients, so broadening activity to those who do not express this key biomarker is an important measure of the efficacy that a combinatorial approach brings.
|NPV as % of mkt cap||94%|
|Event||Data from the Pivot-02 study|
|Timing||5:05pm EST, Nov 9, 2018|
Unfortunately for Nektar and Bristol the signs are not great. After the combo posted an 85% remission rate in the first 13 melanoma patients, a 15-strong expansion cohort resulted in just three additional responses, reported at Asco, meaning that overall remission now stands at 50%.
It will therefore be vital for the SITC update to show improvement from this. A 50% response rate in first-line melanoma is precisely what the approved Opdivo plus Yervoy combo yielded in the Checkmate-067 study, and merely replicating this efficacy – albeit with a project less toxic than Yervoy – will cut little ice.
Mizuho analysts worked hard to limit the damage after the Asco update, highlighting the mechanistic differences between Incyte's failed epacadostat and NKTR-214, and suggesting that the former’s specific problem could be lack of a therapeutic window. “From a safety perspective NKTR-214 remains superior,” they wrote.
They also said some of the new melanoma patients treated with NKTR-214 had only had one scan at the last follow-up, and speculated that up to five subjects with stable disease could yet convert to remissions. Two additional responses would push the ORR to 57%, while all five would take this to 67% – still not overwhelmingly positive.
That’s not all
Still, however much potential there is here for NKTR-214 to disappoint at SITC, Nektar and Bristol can still argue that possibly the best is yet to come.
Pivot-02 includes numerous other tumour types that could be more interesting than melanoma, and the melanoma cohort additionally includes second and third-line patients who have failed PD-(L)1 blockade.
A key part of the rationale behind cytokine stimulation is that it can make “cold” tumours immunogenic and thus amenable to checkpoint blockade. It was a year ago that Nektar reported a 43% response rate in patients with various PD-L1-negative tumours, a finding that likely convinced Bristol to sign up.
As such, continued efficacy in the late-line cohort will be crucial to determining NKTR-214’s potential. Sharp-eyed watchers will have noted with interest the data with Roche’s RG7461, an IL-2 variant, presented at Esmo last month: four responses to RG7461 monotherapy in 43 melanoma patients who had failed checkpoint blockade.
Underwhelming data next week could make Bristol’s bet look foolish, but the company will argue that all is not yet lost.
|Study||Trial ID||SITC abstract|