Asco preview – Loxo shines amid small-molecule effort

Bayer might be kicking itself this morning for not taking a bigger bet on Loxo Oncology – encouraging data from the US drug developer’s follow-on candidate, which was not included in last year's licensing deal between the two companies, emerged as one of the highlights of the Asco abstract release last night.

The first look at data on Loxo-292 sent shares in Loxo up 19% in early trade today, marking out the small molecule as one to watch in an Asco that will be much more squarely focused on immuno-oncology combinations. Other targeted approaches should also deliver some interesting news in Chicago next month – most notably Merck KGaA’s c-Met kinase inhibitor tepotinib, which yielded impressive response rates in a genetically defined lung cancer subset.

Merck is focusing its efforts with tepotinib on patients with a Met exon 14 deletion, a specific form of alteration in the Met receptor that is thought to drive around 3-4% of adenocarcinomas. The Met-targeting space is notable for its failures – of both small molecules and antibodies – and Merck hopes to improve its chance of success by using a specific biomarker to find patients.

At Asco the company will present data from an ongoing phase II trial in advanced non-small cell lung cancer; a response rate of 60% was revealed in the abstract, among 15 investigator-assessed patients. In 13 independently assessed patients the ORR dropped to 46%, though the trial intends to go on to recruit 120 subjects, so these results are far from the end of the story.

Merck is not alone in pushing on with a Met inhibitor – Novartis and Mirati have both signalled an interest in Met exon 14 deletion with their candidates, capmatinib and glesatinib – but the German conglomerate appears to have the most strategically focused programme running here.

Of course the market potential is small – Bernstein analysts reckon sales could peak at around €500m ($589m) – but the Asco data would appear to show Merck moving in the right direction.

Tumour agnostic

Loxo is also targeting a small cancer niche with Loxo-292, which takes aim at tumours driven by Ret fusions. This oncogene is implicated in around 2% of non-small cell lung cancers, 10-20% of papillary thyroid cancers and 60% of medullary thyroid cancers, an opportunity that analysts put at around $1bn. 

A similar tumour-agnostic approach with Loxo’s Trk inhibitors snared Bayer as a partner last year – the German company paid $400m up front for two assets – leaving Loxo to focus on ’292 (Loxo’s Bayer deal falls short of bullish expectations, 14 November 2017).

The first look at results from an ongoing phase I trial is encouraging – a response rate of 52% across patients evaluable so far points to good activity in a heavily pretreated group. And in a press release the company said the data that will be presented in Chicago represent an improvement over those in the abstract.

Confirmation that these responses have been evaluated by independent assessors remains an important issue. This took the shine off data from a rival project, Blueprint Medicine’s BLU-667, at the AACR conference last month.

Targeting Ret – the responses so far
NSCLC ORR PTC ORR MTC ORR Trial details
Loxo-292* 65% (17/26) 83% (5/6) 14% NCT03157128 (seeking 180 patients)
BLU-667 50% (7/14, 5 confirmed) Data pending 40% (10/25, 6 confirmed) NCT03037385 (seeking 115 patients)
Notes: *of the 32 NSCLC and PTC responses, 21 confirmed. Confirmed response rate among MTC patients not specified in abstract. ORR = overall response rate, NSCLC = non-small cell lung cancer, PTC = papillary thyroid cancer, MTC = medullary thyroid cancer. Source: ASCO abstracts, analyst notes. 

The 8% fall in Blueprint’s shares this morning shows that Loxo is perceived to be moving into the lead in this space, and the table above would appear to show superior efficacy with Loxo-292. However, both trials remain a long way from completion, and there remains the chance that differences between the compounds could emerge, for example around activity in the brain.

Still, these results – and Loxo’s previous partnering success – look certain to make this company a big story of Asco, at least in the small-molecule space.

Other targeted agents with updates include the PI3k inhibitors. MEI Pharma is presenting several abstracts on ME-401 in lymphoma/leukaemia, while Roche’s taselisib features as a late breaker; the results of the Sandpiper study should confirm these agents’ potential in breast cancer.

Updates from those pushing on with epigenetic approaches are also due, though are unlikely to be earth moving. A number of abstracts have been released on Karyopharm’s selinexor, which the company must hope will build confidence in the asset before more important releases. Meanwhile, Epizyme looks like it might come under more pressure, as Asco data in mesothelioma appear to cast more doubt over tazemetostat’s chances of reaching the market any time soon.

These and other small-molecule approaches will struggle to fight for much attention among the big themes of this year’s Asco – lung cancer and combination therapies – but progress in this area should not be overlooked.  

Product Company NCT ID Abstract
Tepotinib  Merck KGaA NCT02864992 9016
Loxo-292 Loxo NCT03157128 102
Tazemetostat Epizyme NCT02860286 8515
ME-401 MEI Pharma  NCT02914938 7519
Taselisib  Roche NCT02340221 LBA1006
Selinexor Karyopharm NCT02606461 11512

This story has been amended to show to correct ORR for Loxo-292 in MTC.

EP Vantage will be reporting from Asco, which begins in Chicago on June 1. For live tweets follow @ByAmyBrown and @ByJonGardner on Twitter.

To contact the writer of this story email Amy Brown in London at AmyB@epvantage.com or follow @ByAmyBrown on Twitter. 

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