The past couple of years have seen a surge in the number of immuno-oncology combination trials, though the tidal wave of research has yet to yield conclusive clinical benefits. This could change in 2018, with numerous studies of novel targets including Lag3, CD122 and Icos due to read out (see tables below).
The most eagerly awaited is IDO inhibition, with Incyte due to unveil results from the hugely important Echo-301 study. Hopes are high that combination strategies can be found to add to the strong benefits seen with PD-(L)1 blockade, but caution is warranted. Progress will be slow, and next year could see ambiguous or incremental steps rather than huge leaps onward.
Incyte hopes for the latter, of course, and a lot is riding on succesful readout of the first rigorous phase III data in this space. Echo-301 tests a combination of epacadostat with Merck & Co’s Keytruda in first-line melanoma, a tumour type that has already been transformed by the arrival of the anti-PD-1 antibodies.
The sellside has built huge expectations around the asset – consensus has epacadostat becoming a blockbuster by 2021, according to EvaluatePharma – and Incyte has a market value to match: $21bn.
These figures reflect success in more than melanoma; studies are ongoing in lung, bladder and kidney cancers among others, under various collaborations with owners of anti-PD(L)1 antibodies. A hit in melanoma, which is highly immunogenic, is crucial if wider benefits are to be inferred. Failure in this setting would not only cause Incyte to crash, but could also dent optimism in other I-O combinations.
|Keeping an eye on I-O: checkpoint targets trials to watch out for in 2018|
|Target||Project||Company||Study, indication, combo||Trial ID|
|IDO||Epacadostat||Incyte||Echo-301: melanoma; + Keytruda||NCT02752074|
|Lag3||Relatlimab (BMS-986016)||Bristol-Myers Squibb||Checkmate-142: Colorectal cancer, + Opdivo||NCT02060188|
|CD122 (IL-2Rβ)||NKTR-214||Nektar Therapeutics||Pivot02: + Keytruda. Propel: + Opdivo, + Tecentriq||NCT02983045; NCT03138889|
|…and going down|
|Ox40||PF-04518600||Pfizer/Merck KGaA||Javelin Medley: + Bavencio||NCT02554812|
|CSF-1R||Cabiralizumab||Bristol-Myers Squibb/Five Prime||+ Opdivo||NCT02526017|
|CSF-1R||PD-0360324||Pfizer/Merck KGaA||Javelin Medley: + Bavencio||NCT02554812|
Another key I-O target is Lag3, where Bristol’s relatlimab already showed efficacy at the recent SITC meeting in Lag3-positive patients who had progressed on anti-PD-(L)1 therapy. Several early trials might yield additional data, but most keenly awaited will be Bristol’s Checkmate-142 colorectal cancer combo with Opdivo.
Meanwhile, Nektar made waves at SITC when it showed that its CD122 agonist NKTR-214 combined with Opdivo prompted responses in PD-L1-negative subjects, raising hopes that it could turn “cold” tumours “hot”. Still, there were just 36 patients here, and further updates from two NKTR-214 studies will be keenly awaited in 2018 (SITC – Nektar’s plan to make cold tumours blossom, November 14, 2017).
An especially important trial to watch, according to Evercore ISI’s Jon Miller, is Pfizer/Merck KGaA’s Javelin Medley, which looks at combining Ox40, 4-1BB and CSF-1R targeting with Bavencio, as well as a triple combo comprising the Ox40 and 4-1BB agents plus Bavencio.
Still, Mr Miller admits that Ox40 has fallen out of favour as a next-generation candidate – Roche went so far as abandoning its asset RG7888.
A similar assessment could be made of CSF-1R, after Five Prime’s cabiralizumab abstract at SITC disappointed investors, raising perhaps unfounded questions over toxicity, and doubts over incremental efficacy over Opdivo (“Surprise” SITC late-breaker breaks Five Prime, November 8, 2017).
What and where?
No doubt more information will emerge next year about pharmacology. Some I-O combo approaches, like PD-(L)1 and CTLA4, largely aim to release two brakes on the immune system. Others, like those involving 4-1BB, concern a general immune system activation, while others still are more subtle. Many, of course, have yet to be fully understood.
Innate Pharma’s failure with lirilumab, the sole Kir-targeting asset, seems to have been explained by novel understanding that hitting this NK checkpoint is complicated by the fact that a negative feedback loop of sorts subsequently prevents those NK cells from maturing (The market writes off lirilumab, November 23, 2017).
It is highly likely that other novel mechanisms will unravel when tested in larger studies, or that encouraging monotherapy data fails to translate into a viable combination strategy.
Other checkpoints are involved in cell infiltration, rather than merely activation/inactivation. For instance, Icos ligand blockade – important for the recently floated Jounce – might be involved in T regulatory cell depletion, while Lag3 plays a complex role in activation of antigen-presenting cells, and CSF-1R is thought to inhibit activation and signalling in another cell type – the tumour-associated macrophage.
Mr Miller says he is also looking forward to data on generally immunostimulating targets like Sting, IL-2, IL-12 and TLRs. The tables in this analysis represent only a tiny slice of the clinical effort, and data will emerge from many other studies.
Still, concern has already been growing that expectations are too high given how slow progress has been in this field, and the disappointments with Ox40, CSF-1R and Kir bear out some of these worries. Investors have thus been served several reminders that the questions of what to combine and where are not easily answered.
Sean Bohen, chief medical officer at Astrazeneca, cautioned recently that it would take time to answer these questions empirically through clinical trials.
“There is sometimes a bit of exuberance that we’ve cured cancer – I’ve seen it through multiple mechanisms in my career, and the latest is certainly I-O,” Mr Bohen said at a press conference in October. “What is remarkable – and I don’t think there’s any irrationality in the exuberance around this – is that some subsets of patients seem to have a really durable benefit.”
Identifying who these patients are, and whether the group can be expanded by using combinations, represent formidable challenges.
|Keeping an eye on I-O: other combo trials to watch out for in 2018|
|Project and target||Company||Study, indication, combo||Trial ID|
|MBG453||Novartis||+ PDR001 (PD-1)||NCT02608268|
|TSR-022||Tesaro||Amber: + TSR-042 (PD-1)||NCT02817633|
|JTX-2011||Celgene/Jounce||Iconic: + Opdivo||NCT02904226|
|GWN323||Novartis||+ PDR001 (PD-1)||NCT02740270|
|CMP-001||Checkmate Pharmaceuticals||Melanoma, + Keytruda||NCT02680184|
|IMO-2125||Idera Pharmaceuticals||Melanoma, + Yervoy||NCT02644967|
|Utomilumab||Pfizer/Merck KGaA||Javelin Medley: + Bavencio||NCT02554812|
|Urelumab||Bristol-Myers Squibb||Includes B-cell NHL, GBM; + Opdivo||NCT02253992; NCT02658981|
EP Vantage’s immuno-oncology combination report can be downloaded here.