SITC – Nektar’s plan to make cold tumours blossom

Nektar Therapeutics had laid the groundwork for its key wholly owned asset, NKTR-214, at Asco, and early results from the first study of this project in combination with Opdivo have made the group one of the winners of the SITC conference.

True, the data were early, and came from a relatively small pool of subjects, but they were enough to send Nektar’s stock up 14% yesterday, after an initial 26% surge. Perhaps the most interesting aspect is NKTR-214’s efficacy in PD-L1-negative tumours, causing hope that the compound can turn “cold” tumours “hot”.

This, of course, is seen as vital to broadening the potential of immunotherapy in cancer. Highly impressive and durable efficacy has been seen in some patients, but this tends to correlate with how hot, or immunogenic, a tumour is; as such, many of today’s combinations attempt to get tumours to express the PD-L1 target on their surface, thereby making them immunogenic.

PD-L1-negative response

Nektar’s SITC data, from 36 subjects with various, mostly first-line, cancers in the dose-escalation stage of the Pivot-02 study, appear to show precisely this. The NKTR-214 plus Opdivo combo yielded a 50% overall response rate, but what really sent the pulses racing was the remission rate in 21 patients with PD-L1-negative tumours: 43%.

Roth analysts did not hold back with their praise, yesterday writing that NKTR-214 could now “become the backbone of PD-1 and PD-L1 immuno-oncology combos”.

The company is thinking ahead: as well as the Opdivo combo, under a clinical collaboration with Bristol-Myers Squibb, it has trials under way in various cancers, adding NKTR-214 on top of Roche’s Tecentriq or Merck & Co’s Keytruda.

In Pivot-02 Nektar defined PD-L1 negativity as 1% or lower expression of this antigen. The tumours studied were first-line melanoma, first and second-line renal cell carcinoma, and NSCLC patients who had not already received immunotherapy.

NKTR-214’s safety profile also impressed: grade 3 or 4 treatment-related adverse events were seen in 10.5% of patients, and in just one of 25 on the planned phase II dose of 0.006mg/kg plus 360mg Opdivo every three weeks. As for negative surprises, there was just one, partial, remission in seven second-line renal cell carcinoma subjects.

Mechanistic backing

NKTR-214’s ability to induce immunogenicity, if true, seems to be backed by its mechanism of action; the protein is an agonist of CD-122, also known as the IL-2 receptor’s beta chain, an antigen expressed on effector T cells and natural killer cells, whose activation stimulates their proliferation.

At Asco Nektar presented early findings from a monotherapy trial showing that NKTR-214 prompted PD-L1 expression on cytotoxic T cells, and strongly increased numbers of these cells infiltrating the tumour while depleting immunosuppressive T regulatory cells.

There is an interesting parallel between NKTR-214 and NKTR-358, an asset Nektar licensed to Lilly earlier this year for $150m up front (Lilly hopes to bloom through Nektar attraction, July 24, 2017). The latter also acts on IL-2, but in the opposite direction, aiming to stimulate T regulatory cells, with possible use in autoimmune conditions.

It is possible that the market can see a commercial deal around the corner for NKTR-214, though in its broad combination programme Nektar seems to be hedging its bets pretty well. The company, once an inhaled drug delivery player, now clearly sees oncology as a major focus, and it might just want to hold on to NKTR-214 for now.

Selected combo studies of NKTR-214
Study Combined with Cancer type(s) Trial ID
Pivot-02 Opdivo Melanoma, RCC, NSCLC NCT02983045
Propel Tecentriq Bladder, NSCLC NCT03138889
Propel Keytruda Melanoma, NSCLC, bladder NCT03138889
Reveal  NKTR-262 (small molecule TLR agonist) Various Yet to begin

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobPlieth on Twitter

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