As the dust settles on a weekend’s worth of presentations at Asco, Loxo Oncology has emerged as a clear winner. But Nektar Therapeutics has been punished for data that stoked fears about a weakening response with its candidate, NKTR-214, as investor jitters around PD-1 combos grow.
Loxo’s targeted candidate for Ret mutation cancers showed strengthening responses in lung, thyroid and pancreatic cancer to justify expansion of its phase I trial. For Nektar, updated data on its IL-2 modulator NKTR-214 in melanoma and renal cell carcinoma have tempered some of the hype around cytokine modulation and raised questions about why Bristol-Myers Squibb was willing to write a cheque for $1.85bn just to in-license the project.
Targeting a niche
Updated results from an ongoing study of Loxo’s Ret-targeted kinase inhibitor, Loxo-292, were very warmly received by attendees at the conference, having improved substantially from the last cut of the data.
Response rates in both non-small cell lung cancer and medullary thyroid cancer (MTC) – both important tumour types for the Ret-mutated subset – showed notable improvements, to 77% and 45% respectively, from 65% and 14% respectively previously. Loxo has seen no relapses among patients who have responded to treatment, an encouraging signal.
Investors will be watching data from Loxo's closest rival, Blueprint Medicines, for a similar signs. But for now, the latest results spell more bad news for Blueprint, whose BLU-667 is left with some serious catching up to do. Of course, that company's data could also improve and neither trial is close to being over, but if first-mover advantage is going to be an important factor in this tiny cancer subtype, then Loxo looks to be gaining the upper hand.
|Targeting Ret – selected responses so far|
|NSCLC ORR||MTC ORR||Trial details|
|Loxo-292||77%||45%||NCT03157128 (seeking 180 patients)|
|BLU-667||50%||40%||NCT03037385 (seeking 115 patients)|
|Notes: ORR = overall response rate, NSCLC = non-small cell lung cancer, MTC = medullary thyroid cancer. Source: Asco, AACR abstracts.|
Meanwhile, Nektar had a less positive response to updated results with NKTR-214 that were described by some as confusing.
The main issue was an apparent waning of response in the second stage of the open-label phase I/II Pivot trial of NKTR-214 plus Bristol’s Opdivo in various cancers. In its defence, Nektar said that patients have not been receiving the drug for long.
But with the company pushing quickly into pivotal trials, alarm bells rang among investors still reeling from the failure of another much-hyped immuno-oncology combo, PD-1 plus IDO.
Nektar’s NKTR-214 is one of the leading candidates in the cytokine inhibition space, and is thought to work well with PD-1 inhibition due to its ability to turn non-immunogenic tumours into ones that will respond to an immunotherapy.
The Pivot trial was designed to enable quick advancement into phase III, and Nektar said it met that threshold.
But others were not so convinced. In stage one of the Pivot trial, the combination achieved an objective response in stage IV never-treated metastatic disease in 11 of 13 melanoma patients, seven of 11 renal cell carcinoma patients and six of 10 urothelial carcinoma patients.
At Asco Nektar presented data from stage two of the trial from melanoma and RCC patients, which added 15 patients to each of these cohorts. The second stage saw three additional responses in melanoma and five in RCC, meaning objective response rates in these cohorts fell to 50% and 46% respectively.
At present, the results are in-line with Opdivo’s combination with Yervoy – NKTR-214 might represent a more benign combo agent than Yervoy, which has concerns around toxicity. However, if response rates fall further in Pivot there will be questions about whether NKTR-214 adds anything to Opdivo monotherapy.
The case of Nektar provides a cautionary tale about overhyping assets while clinical data are scant. Loxo might be celebrating its Asco win – but even this should be tempered with the knowledge that Loxo-292 has also been tested in very few patients and has yet to be subjected to a placebo-controlled trial. The big tests for both agents are yet to come.
This story has been updated to reflect investor sentiment around the Nektar data.