Friday Five – This week’s key news stories

ASCO winners

Merck & Co. enhanced its lead in first-line metastatic non-small-cell lung cancer (NSCLC) thanks largely to positive data from the Keynote-407 trial; showing Keytruda and chemotherapy significantly prolonged survival versus chemotherapy alone in patients with harder to treat squamous disease.

See Physician Views Results: ASCO data strengthens Keytruda's position, say oncologists, but rivals can't be completely written off and ViewPoints: Keytruda rivals may be fighting for lucrative scraps in NSCLC

ASCO also provided the backdrop for further comparison of Keytruda with Bristol-Myers Squibb's competing PD-1 inhibitor Opdivo. "When you look at the totality of the data, there really is no difference between those two medicines,” said Bristol CEO Giovanni Caforio on the conference sidelines. This is likely not far from the truth, says Cancer Research Institute CEO Jill O'Donnell-Tormey, who argues that trial design, patient selection and crossover have probably resulted in Keytruda's superior survival data in lung cancer; a view echoed by discussants at the conference. 

This may be so but arguably makes for a more damning assessment of Bristol's execution. That said, there is clearly physician interest in using Opdivo with Yervoy if clinically applicable in certain first-line lung cancer patients which would allow use of chemotherapy to be spared. Having shown a progression free survical benefit in PD-L1 low/TMB-high patients at ASCO, Bristol now needs to deliver overall survival data.  

Also, for the second year in succession, Loxo Oncology was a hit in Chicago, presenting impressive response rate data for LOXO-292 in lung cancer patients with the rare RET-mutation (found in approximately 2 percent of patients). Precision medicine in oncology has arguably never looked this compelling - ViewPoints: Loxo chalks up another ASCO win.

Questions for CAR-T

The big ASCO reveal in CAR-T was bluebird bio and Celgene's bb2121 in multiple myeloma. New data, while impressive for heavily pre-treated patients, failed to fully meet the expectations of investors, who have been sold on the idea of CAR-T therapies being curative and likely moving into earlier lines of treatment in myeloma - ViewPoints: bluebird bio, Celgene’s bb2121 a victim of great(er) expectations.

Earlier use after diagnosis should facilitate longer-term durability of effect, said bluebird CEO Nicholas Leschly, but Bernstein analyst Ronny Gal argues new data presented at ASCO opens up the opportunity for alternative modalities to compete with first-generation CAR-T on efficacy (whilst also likely costing less and being more convenient to administer).

See KOL Views Results: Leading oncologist says bb2121 is an important foundation to build off of in MM

..and ViewPoints: Gilead keeps on growing- with a little help from the NCI

Caution for combos

Despite impressive momentum in the field of oncology research, the ghost of epacadostat also stalked the halls of ASCO this year; presentation of full results from the ECHO-301 study laid bare just how spectacularly Incyte and Merck's Phase III bet on an epacadostat/Keytruda combo in first-line melanoma fell short.

That story lplayed a part in spooking investors in Nektar Therapeutics, whose shares fell sharply in response to updated results looking at the combination of its immunotherapy agent NKTR-214 with Bristol-Myers Squibb's Opdivo in a number of tumour types.

Like Incyte and Merck before them, Nektar and Bristol-Myers Squibb have moved their combination into a number of Phase III studies based on a relatively small amount of response rate data in an early-stage single arm trial. Initial results from this study looked positive enough, but Nektar's ASCO update showed diminishing response rates as patient numbers increased. That's not an unusual trend when drug studies expand in size, and management agues the effect size could improve over time; but this was not reassurance enough for investors and the stakes for expensive-to-run Phase III studies have been raised.

"We don't want to squash innovation but we do need to find ways that are more efficient in producing translational data in smaller patient cohorts" says CRI's O'Donnell-Tormey on the issue of moving new approaches into pivotal stage trials on the basis of positive signals in small single arm studies. 

Madrigal delivers with NASH update

Madrigal Pharmaceuticals is the latest company to see its share price spike impressively on the back of exciting data in NASH. The combination of positive results and a subsequent fundraising should enable the company to design and fund a pivotal-stage study for MGL-3196.  The FGFR inhibitor received broadly positive assessment from NASH experts recently interviewed by FirstWord ahead of this latest data readout, despite limitations of 12-week Phase II data presented in December, showing that MGL-3196 reduced liver fat by at least 30 percent versus placebo.

Updated 36-week biopsy data from the same study showed meaningful reductions in liver fat were maintained while MGL-3196 led to two-point reductions in NAFLD Activity Score (NAS) in 56 percent of patients, which was significantly more than 32 percent for placebo, with the result being even more pronounced among 12-weeks responders (70 percent). On an important secondary endpoint, MGL-3196 achieved NASH resolution – the Holy Grail for treatment – in 27 percent of all treated patients, including 39 percent of the initial responders, which was significantly more than 6 percent for placebo.

What's more, all measures of blood lipids remained positive, with levels of LDL, HDL, Apo-B and triglycerides all directionally headed in the right direction. This, combined with a benign safety profile (no treatment-related serious adverse events), suggests that MGL-3196 will not be saddled with a problematic cardiovascular risk profile. Experts have suggested if the agent successfully negotiates Phase III studies and the regulatory arena, it will ideally be used in very early-stage NASH patients.

Olumiant finally reaches the market

Away from ASCO, Eli Lilly's JAK inhibitor Olumiant - once considered a potential best-in-class JAK inhibitor - has limped across the line in the US to make it to market as the newest therapy for rheumatoid arthritis. Concerned about safety issues, the FDA (as expected) approved a 2mg dose of Olumiant, but chose not to approve a 4mg dose.

To compensate, Eli Lilly's commercial strategy will now be heavily focused on undercutting Pfizer's JAK inhibitor Xeljanz on price. Rheumatologists predict this is a viable means to drive uptake (Pfizer's pricing of Xeljanz has always been a sticking point for key opinion leaders interviewed by FirstWord), but Olumiant's future role as a key growth driver looks likely to be diminished - ViewPoints: Olumiant makes it over the goal line- but only halfway.

To read more Friday Five articles, click here.

Reference Articles