Accelerated approvals of checkpoint-blocking antibodies have generated controversy when not confirmed in larger studies, but Merck & Co’s latest win should sweep away doubt, and then some. The Keynote-826 study of Keytruda plus chemo in cervical cancer has today been toplined positive for overall and progression-free survival, and spells a win on all fronts: in the front-line setting, with or without Avastin, and irrespective of patients’ PD-L1 status. Keytruda already carries a cervical cancer label, but this is for second-line use in tumours expressing PD-L1 at ≥1%, and on an accelerated basis. Thus Keynote-826 will not only confirm this conditional green light, but could also expand the Merck drug’s use to front-line all-comers who can tolerate chemotherapy. Full data, to be revealed at a scientific meeting or perhaps on Keytruda’s label if approval comes quickly, will show the extent of the survival benefit versus chemo alone, and determine whether Avastin needs to be included in the mix. True, cervical cancer will account for just a fraction of Keytruda’s $26.9bn of forecast 2026 revenues, according to Evaluate Pharma sellside consensus, but the win is important: no other checkpoint antibodies carry a cervical cancer label.

After the miss of one inhaled pan-Jak inhibitor in asthma last year, Theravance is now mourning the failure of another in Covid-19. The data come from a phase 2 study in 210 hospitalised patients with Covid-19-associated acute lung injury and impaired oxygenation. The 106 patients treated with TD-0903, also called nezulcitinib, for just under a month had a median 21 respiratory failure-free days during the treatment period – but so did those treated with placebo. With a p value of 0.61, the difference, such as it was, was not statistically significant. Neither did TD-0903 improve all-cause mortality (p=0.08) or hit any of other secondary endpoints. Theravance touted a post-hoc analysis of patients who had baseline C-reactive protein levels below 150mg/l, in whom there was a nominal improvement in mortality and time to recovery. The company said it would take the data to regulators, but much of the talk of future development of TD-0903 on today’s conference call was focused on non-Covid-19 indications, including acute lung injury caused by Sars, Mers, flu or parainfluenza. The sole Jak that is authorised in hospitalised Covid-19 patients remains Lilly's Olumiant – but this is oral, not inhaled. 

Lotilaner is already used to control fleas in animals. Tarsus Pharmaceuticals’ efforts to get it approved in humans took a step forward today with a pivotal trial win for TP-03, a lotilaner eyedrop for Demodex blepharitis. There are currently no therapies for this eye disorder, which is caused by a Demodex mite infestation in the eyelashes. Saturn-1 met its primary endpoint, with TP-03 significantly reducing collarettes, or “eyelash dandruff” – the waste products of these mites – versus placebo. Tarsus plans to file the project in the US next year pending data from a second pivotal study, Saturn-2. Still, questions remain. Tarsus said adverse events were all mild, but a 12% rate of burning/stinging might raise alarm bells. Another question is how big this market really is. Tarsus, which floated last October, reckons there could be as many as 25 million US patients, but this is based on a 1,000-patient study, called Titan. This found that 58% of patients visiting eyecare professionals had collarettes, and Tarsus has extrapolated this to the 45 million visits to eyecare professionals each year. The group, whose stock was up 15% in premarket trading, fell 10% this morning.

That Glaxosmithkline was prepared to part with $625m up front for Iteos’s phase 1 anti-Tigit MAb EOS-448 shows that the pharma giant considers this a "must own" immuno-oncology mechanism. The terms point to a highly competitive process, which also means that there must be other large developers shopping in this space. The big three I-O players already have assets in their pipelines, but there are plenty of others, like Astrazeneca and Pfizer, that would presumably be interested. That is great for news for those unencumbered projects, and it is no coincidence that Mereo shares opened up 15% today, a surge that soon settled down to a 5% rise. Still, while the Glaxo-Iteos deal sounds rich, it is worth remembering that the small biotech has agreed to pay 40% of the R&D costs associated with an “aggressive” pre-agreed global development plan; in return, Iteos will jointly commercialise EOS-448 in the US and get 50% of the profits from the region. A further $550m is available if certain clinical and regulatory hurdles are crossed, with another $900m attached to sales milestones. The tiny Belgian developer has long been a proponent of Tigit, and this deal certainly justifies its enthusiasm: Iteos shares surged 30% in early trade.

(This story has been updated to include the Junshi Tigit project.) 

Though formally this year’s Asco conference kicked off on Friday, all the session abstracts and presentations, including late-breakers, had already been made available either on its virtual platform or at special press briefings. So far Evaluate Vantage has covered the following stories from the meeting:

June 9:

Asco 2021 movers – PDS wins, but big pharma reigns

June 7:

The exon 20 army lines up behind Rybrevant

June 4:

Alpine hopes to banish the ghost of Tegenero

Merus’s slight improvement might not win over investors

Alkermes’s disappointment hones melanoma niche focus

June 3:

Bristol makes more progress in stomach cancer

Financial toxicity in the spotlight

Full Olympia results sweep away Parp doubts

Asco 2021 justifies Novartis’s radioligand Vision

Keytruda’s adjuvant kidney win is the real deal

May 21:

Abstract lift drives first stock moves

May 20:

Off-the-shelf cell therapy inches towards reality

Merus intrigues in pancreatic cancer

Guardant shoots for the moon

May 19:

Adaptimmune’s T-cell receptors see a route to market

Bristol’s Lag3 case for a replacement for Yervoy

Adjuvant lung cancer beckons for Tecentriq, but only in PD-L1 expressers

The notorious 2006 blow-up of a phase 1 trial of Tegenero’s CD28-agonist MAb TGN1412, in which volunteers suffered severe inflammatory reactions, has cast a long shadow. 15 years later Alpine Immune Sciences is hailing early data with ALPN-202 as evidence that CD28 can, after all, be hit safely. ALPN-202 is a protein inhibiting PD-L1 and CTLA-4, as well as co-stimulating CD28, its premise being that just removing the immune system brake is not enough, and T cells need an additional signal. Today’s Asco presentation of the Neon-1 trial concerns 23 on average fifth-line subjects with various cancers, and shows just one partial response, in ovarian/fallopian tube cancer, that relapsed 40 days later. The much better news is ALPN-202’s relative safety, with only one related grade 3 toxicity despite evidence of maximal CD28 co-stimulation at most doses. While Alpine claims this to be the first demonstration that clinical CD28 agonism can be safely achieved for cancer immunotherapy, many successful Car-T projects also use CD28 co-stimulation, so perhaps Alpine is simply repeating this trick with an antibody-like approach, and with endogenous T cells. This is a promising start, but stronger efficacy data are still needed.

Grail’s liquid biopsy today became the third pan-cancer blood test to be launched in the US. But it is being sold for a slightly different use versus the two approved tests. Galleri, which is not approved by the FDA but sold under a Clia waiver, is on sale as a screen, and can be used to test people aged over 50 at elevated risk of cancer. The other two tumour-agnostic liquid biopsies are used in patients who already have a confirmed cancer diagnosis, as a way to assess the mutations a tumour carries and therefore help assign targeted drugs. Grail is pitching its Galleri test at $949, quite a bit cheaper than both its rivals: Roche’s FoundationOne Liquid CDx sells at $5,800 and Guardant’s Guardant360 around $1,000 more than that. But the latter two have formal FDA approval, granted last August, making reimbursement easier – no reimbursement is yet in place for Galleri. Meanwhile Illumina’s $8bn bid to acquire Grail is no nearer closing. The FTC recently withdrew a lawsuit seeking to block the acquisition, which sounds like good news, but is in fact the opposite. The suit will likely be refiled later, delaying the deal's close further.

Those fretting about the magnitude of Keytruda’s disease-free survival win in Keynote-564, the first positive phase 3 trial of an adjuvant immunotherapy in renal cancer, need not have worried. The study’s just unveiled Asco late-breaker has shown a 32% reduction in risk of disease progression versus placebo (p=0.0010), the likely approvable primary endpoint. Just as important is the secondary endpoint of overall survival, which is showing a 46% reduction in risk of death. True, at p=0.0164 this was not statistically significant – but this was a result of a high bar set at this early interim analysis, corresponding to a December 14, 2020 cutoff. In reality, the strong hint is that Keytruda really is helping renal cancer patients live longer when given as adjuvant for a year within 12 weeks of surgery. The results further underscore the Merck & Co drug’s widening lead against its kidney cancer rivals, in particular Opdivo, though it should be stressed that competitor phase 3 adjuvant studies are under way and start reading out next year.

Last month ended with a flurry of US FDA decisions and one, the green light for Amgen’s Lumakras, came over two months early. The accelerated approval in NSCLC patients with a Kras G12C mutation was given to the 960mg dose; a 240mg dose is the subject of a postmarketing study to see whether it has a similar clinical effect. Two other oncology drugs gained first-time accelerated approvals: J&J’s Rybrevant and Bridgebio’s Truseltiq. Both have confirmatory trials under way. After two previous complete response letters it was finally good news for Heron’s pain therapy Zynrelef, an extended-release bupivacaine combined with the anti-inflammatory meloxicam. To try and gain market share Heron is pricing Zynrelef at a 22-28% discount to Pacira’s Exparel; Evercore ISI analysts note that this price will also allow Heron’s drug to compete with generic bupivacaine. With May now over all eyes rest on aducanumab’s June 7 Pdufa, the biggest regulatory event of the year (Go or no go? Aducanumab’s day of reckoning, May 27, 2021).

Friday’s US approval as a companion diagnostic for Amgen’s Kras inhibitor Lumakras is the third such nod for Guardant360 CDx. Guardant’s liquid biopsy can be used to pick out patients with advanced non-small cell lung cancer whose tumours harbour the Kras G12C mutation, thought to be present in around 13% of this population. But Guardant360 CDx is some way behind Roche’s FoundationOne Liquid CDx, approved in the US for no fewer than seven drugs in four different cancers. A look at forecast sales, compiled by Evaluate Pharma, for these targeted therapies gives a loose indication of how the two tests might sell: the drugs with which Roche’s test may be used are forecast to generate $14.5bn of collective revenue in 2026, whereas the corresponding figure for Guardant’s assay is a comparatively paltry $10.8bn. Naturally not all patients with these cancers will respond to these therapies – the Alk arrangements amenable to treatment with Alecensa occur in just 3-7% of advanced NSCLC cases, for instance – but many more patients will undergo liquid biopsy testing.

This article has been corrected to remove a misattributed approval for FoundationOne Liquid CDx.