World Lung preview – Astra takes on Roche

Astra’s Caspian study is the star of next week’s World Lung conference, which has also given targeted approaches important supporting roles.

Conferences

Biopharma watchers coming back from their summer breaks do not have long to get back into the swing of things. First up in the calendar is the World Conference on Lung Cancer, which kicks off in Barcelona, Spain, on 7 September.

One theme of 2018 will continue: last year’s instalment centred on Roche’s success in first-line small-cell lung cancer, on the back of which Tecentriq was later approved, and the highlight of 2019 will be Astrazeneca’s challenge to Roche in the same setting. Also closely watched will be targeted approaches against NSCLC, in particular Lilly’s data with LOXO-292.

Both the Astra data, from the first-line SCLC Caspian trial, and Lilly’s Libretto-001 study of LOXO-292 in Ret fusion-positive NSCLC feature in World Lung’s presidential symposium on Monday. Both studies are assumed to be positive, and could be used as the basis for US approval filings.

Astra announced in June that Caspian had read out positively for overall survival – but crucially only mentioned the study’s Imfinzi plus chemo cohort. In Roche’s pivotal Impower-133 trial Tecentriq plus chemo scored 12.3 months of median OS, versus 10.3 months for chemo alone.

A separate Caspian arm, testing Imfinzi plus tremelimumab and chemo, was not commented on, and bearing in mind tremelimumab’s disastrous track record is presumed to be a bust. Vantage understands that World Lung will see no Caspian data involving tremelimumab, a CTLA-4 inhibitor that in addition to being biologically inert has at times added toxicity leading to worse outcomes.

Selected presentations at 2019 World Conference on Lung Cancer
Treatment Company Study Setting Abstract/date Notes
Sunday, 8 September
AMG 510 Amgen NCT03600883 KRAS+ve NSCLC cohort PR02.01 Relevant for Mirati 
Enapotamab vedotin Seattle Genetics/Genmab NCT02988817 NSCLC OA02.05 Abstract states 19% confirmed ORR
Bemcentinib + Keytruda  Bergenbio NCT03184571 2nd-line NSCLC MA03.06 Abstract states 29% ORR
Tepotinib (+ Iressa) Merck KGaA Insight cMet+ve EGFR TKI-progressed NSCLC MA09.09 First OS data: abstract shows benefit vs chemo in cMet IHC3 & amplification, but not in overall cMet+ve pts
TAK-788 Takeda NCT02716116 EGFR exon 20 insertion NSCLC P1.01-127 Abstract lists same data as at Asco 2019
Monday, 9 September
Imfinzi + chemo cohort Astrazeneca Caspian 1st-line SCLC PL02.11 (presidential) +ve for OS at interim
LOXO-292 (selpercatinib) Lilly Libretto-001 Ret+ve NSCLC cohort PL02.08 (presidential) Relevant for Blueprint & Stemline
BLU-667 (pralsetinib) Blueprint Preclinical Ret+ve NSCLC P2.03-44 Poster on activity in tumour models
Tarloxotinib Rain Therapeutics Preclinical Her2 exon20 insertion NSCLC P2.14-16 Poster on in vitro data
Tuesday, 10 September
Keytruda + chemo Merck & Co Keynote-189, 407 & 021G 1st-line NSCLC MA25.01 Pooled analysis in PD-L1 non-expressers
Keytruda + chemo Merck & Co Keynote-189 & 021 1st-line NSCLC OA04.06 & OA04.05 Two analyses by TMB
Camrelizumab  Jiangsu Hengrui NCT03134872 1st-line NSCLC OA04.03 China study analysed by subjects with negative oncogenic drivers
Tecentriq + plat + tax/Abraxane Roche Impower-131 Squam NSCLC OA14.02 Final OS results; at interim study failed for mOS, but was +ve for mPFS

The rest of the investor-relevant World Lung presentations largely relate to NSCLC. Lilly’s Libretto-1 study is particularly important for followers of Blueprint Medicines and Stemline, which both have competing Ret-focused assets, pralsetinib and SL-1001 respectively.

At Asco a year ago LOXO-292, then still under the ownership of Loxo Oncology, yielded a 77% overall response rate, including 74% rate of confirmed CRs, among 39 evaluable Libretto-001 subjects with Ret fusion-positive cancers, most of which were NSCLC. Clinical data with pralsetinib featured at this year’s Asco, but at World Lung the Blueprint asset only gets a preclinical poster.

Among other small-molecule targeted therapy approaches an update covering Amgen’s KRAS inhibitor AMG 510 will feature in Sunday’s press briefing, and will be of interest to investors in Amgen’s overheated KRAS competitor, Mirati. At the last count there were five remissions (four confirmed) in 10 NSCLC subjects given AMG 510.

The potential of AXL inhibition will be scrutinised in presentations on Seattle Genetics/Genmab’s antibody-drug conjugate enapotamab vedotin and Bergenbio’s small molecule bemcentinib. And post-EGFR failure approaches will be on show from Merck KGaA’s tepotinib, with data relevant to Incyte and Chi Med, and Takeda’s TAK-788, which competes against Spectrum’s poziotinib.

Keytruda

In immunotherapy, of course, it will be impossible to escape the transforming effect of Merck & Co’s Keytruda on the treatment of first-line NSCLC.

Any threat to Keytruda, such as it is, is in patients whose tumours do not express PD-L1, and Merck has worked hard to shore up its franchise. A presentation on Tuesday will look at data from three different Keytruda studies that have been pooled to look specifically at PD-L1 non-expressers.

Finally, tumour mutation burden (TMB) has surprisingly had an entire Sunday session devoted to it. Bristol-Myers Squibb and, just last week, Astrazeneca have both shown that TMB is at best poorly understood; yet, while both feature, it is Merck that stars in this World lung session, by virtue of Keynote-189 and 021 trial data cut by TMB.

As Opdivo and Imfinzi’s attempts to challenge Keytruda on the basis that they work better in TMB-high patients have fallen flat, Merck’s best bet is to demonstrate conclusively that as the basis of treating NSCLC, TMB is not a useful biomarker.

This story has been amended to correct errors in the table relating to the Takeda and Merck & Co abstracts.

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