As the dust settled on yesterday’s post-market Asco abstract drop Jounce Therapeutics emerged as a clear loser. Early numbers from a study of its lead asset, JTX-2011, hint that the Icos mechanism might have even less combinatorial mileage than IDO showed weeks ago.
That said, at least two other combo approaches to be profiled at Asco next month still have legs, the abstracts suggest. Armo’s IL-10 project is yielding stellar data, showing why Lilly was so keen to buy this group for $1.6bn; and Nektar, the subject of a Bristol-Myers Squibb tie-up worth $1.85bn up front, is just about treading water with its IL-2-focused strategy (see table below).
Though the failure of Incyte’s IDO/PD-1 combination study Echo-301 sent shockwaves through biotech, the idea of pairing immuno-oncology with other mechanisms remains a major focus. This is backed up by the Lilly/Armo and Bristol/Nektar deals, and Jounce itself is partnered with Celgene.
Not so Iconic
However, Celgene might be casting a nervous eye over the Asco abstract, which concerns the phase I/II Iconic study of JTX-2011 with or without Opdivo in various cancer types.
Initial remission rates look woefully low: just 8% for JTX-2011 monotherapy, and 9% for the Opdivo combo. This comprises three partial responses in gastric cancer (one being with monotherapy) and one with the combination in triple-negative breast cancer. Jounce was off 30% this morning.
Incyte’s possible problem was that inhibiting IDO as well as PD-(L)1 simply removed two immune system brakes with no added stimulation, and the group failed to show an additive combinatorial benefit. JTX-2011, however, agonises the co-stimulatory molecule Icos, and its lack of activity suggests fundamental problems, as an Icos-stimulated cell would be expected to be PD-L1-positive.
In contrast, Armo’s pegilodecakin/AM0010, a pegylated form of IL-10, is riding high. In a trial in combination with Opdivo or Keytruda the remission rate was 41% among 26 NSCLC subjects. What should be of far greater interest, however, are data in 12 patients expressing PD-L1 at <1%, who are at present not candidates for Keytruda monotherapy or Opdivo.
Here, Armo has reported an overall response rate of 33%, a finding that might back this combo approach. Update on a separate second-line pancreatic cancer cohort, where pegilodecakin monotherapy has already been disclosed as yielding 16% overall remission, will be keenly awaited to handicap upcoming readout of a pivotal trial in this tough setting. Median overall survival here is 10.2 months, versus five to six months historically, Armo claims.
However good this might be Armo’s market valuation will solely reflect the Lilly buyout to which it has already agreed. Not so Nektar, which might have Bristol’s massive endorsement to its credit, but which of course continues to operate independently. Given the size of the bet expectations are huge for NKTR-214, an agonist of CD122, the IL-2 receptor’s β chain.
Nektar’s Asco update of a phase I/II Opdivo combo trial in various cancers at least shows efficacy from additional patients broadly in line with that reported at last year’s SITC meeting – the data that prompted the Bristol deal (SITC – Nektar’s plan to make cold tumours blossom, November 14, 2017).
Overall remission in all-comers is 53%, versus 50% at SITC, while in the all-important PD-L1-negative cohort it amounts to 52% (up from 43%). Nektar today fell 10%, likely reflecting the massive expectations.
Investors interested in combos will also take interest in Dynavax’s shift from hepatitis B to immuno-oncology. Its TLR 9 agonist SD-101 plus Keytruda has yielded overall remission of 60% in 25 anti-PD-1-naive melanoma subjects; Keytruda’s label cites remission rates of 34% in first-line melanoma, and 25% in Yervoy-refractory patients.
Meanwhile, though Merck KGaA’s fusion protein M7824 is not in combo trials it mechanistically targets two distinct pathways – PD-L1 and TGF-β. An Asco update showing a 38% overall response rate in HPV-associated cancers appears to beat historic 15-20% rates with anti-PD-(L)1 drugs.
This asset in particular should continue to generate interest as Merck has declared it to be its most important pipeline hope – with a standing above even Bavencio.
|Selected Asco 2018 abstracts on combined immuno-oncology approaches|
|Project||Company||Detail||Trial ID||Asco abstract|
|JTX-2011 +/- Opdivo||Jounce/Celgene||ORR in gastric cancer and TNBC||NCT02904226||3000|
|AM0010 +/- Opdivo/Keytruda||Armo (Lilly)||ORR in NSCLC and pancreatic cancer||NCT02009449||9018|
|NKTR-214 + Opdivo||Nektar/BMS||ORR in various cancers||NCT02983045||3006|
|SD-101 + Keytruda||Dynavax||ORR in anti-PD-1-naive melanoma||NCT02521870||9513|
|M7824||Merck KGaA||ORR in HPV-associated cancers||NCT02517398||3007|