Combos, Results

The latest update on NKTR-214/Opdivo from Nektar and Bristol-Myers will keep the controversy burning over the ORR rate

Nektar Therapeutics $NKTR managed to slide 1 out of its 38 evaluable stage 4 melanoma patients into the win column with its closely-watched 3-month update on Opdivo/NKTR-214’s objective response rate. That managed to nudge up the ORR from 50% — a figure that routed Nektar’s stock at ASCO — to 53%, which isn’t likely to convince any of the critics that the biotech and its partners at Bristol-Myers Squibb have come up with the kind of combo that can change the standard of care in the field.

But if you expect anyone directly involved in this study to step back from the enthusiastic projections that were made on the first optimistic data points, you’d be flat wrong.

Adi Diab

While the crucial ORR barely budged, Adi Diab from MD Anderson pointed straight to a higher complete response rate, at 24% — “which is not seen with another combination.” He’s also offering a thumbs up to a 76% disease control rate — up from 71% at ASCO — as evidence that they’re on to something special.

Several analysts — including some in the EvercoreISI team — had been looking for something in the 60%-plus range for the ORR to win back the enthusiasm that has drained away for NKTR-214, a drug that a needy Bristol-Myers Squibb paid $1.85 billion upfront to partner on earlier in the year. The drug is designed to bind to the CD122 receptor on the surface of CD-8 and CD-4 positive immune cells to whip up an attack on various cancers.

And Diab says they can see exactly that response in patients with positive biomarker results for the tumor microenvironment.

As it stands, the researchers have a drug that appears to have clearly waned in the more mature 7.2-month median followup time for PIVOT-02, dropping from 64% at the first cut of the data at SITC last year. And just days ago Bristol-Myers outlined impressive 4-year overall survival results from CheckMate-067: 53% for Opdivo plus Yervoy combo, 46% for Opdivo alone, and 30% for Yervoy alone.

Diab, though, believes that with better experience using the drug, and better education for physicians and patients, the response rate can climb back up to 60%-plus. As for Yervoy, he adds, the CTLA-4 has a well known tox profile that leads to a high rate of adverse events that often prevent patients from completing treatment.

“We should not do comparisons with other trials, it’s not kosher,” Diab tells me at one point in our conversation. “But of course we’re going to do it.”

There’s been some intense controversy over their chances with this IL-2 drug, which uses pegylation tech to eliminate the drawbacks of the original therapy – Proleukin — that made it too toxic to use at full measure, in turn limiting its efficacy.

One likely takedown of the Nektar defense should come soon from Aaron Wedlund, the ex-Kerrisdale analyst who wrote a lengthy diatribe on NKTR-214, which he considers will make IL-2 the next IDO, another drug class once widely hailed as the next big thing in cancer drug combos now badly tarnished following a catastrophic Phase III combo failure with Keytruda.

Bristol-Myers enthusiastically bought into the next-gen IL-2 drug approach as it’s been unsuccessfully defending its PD-1/L1 crown against a hard-charging Merck, which has pushed Keytruda and chemo combos into the forefront of the lung cancer market. IL-2, they said, would be the next logical step to PD-1 and CTLA-4, with Yervoy.

Anything that puts this drug back in the Proleukin category, with more IL-2 successors in the pipeline, won’t be welcome by the developers.

It’s important to keep in mind that a bunch of short investors had fun — and made money — pulling Nektar’s stock down from some stunning highs that it had enjoyed. Raising doubts is good for spurring corrections, and Nektar’s stock has tumbled badly. The jury will remain out, though, until the Phase III progression-free survival data comes due around the spring of 2020.

Until then, and maybe even after, this debate will continue to rage.


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