Moderna takes on IO Biotech

In the battle of the IDO/PD-L1 immunotherapies, IO Biotech so far seems to have the edge with its peptide-based project Cylembio, although Moderna reckons it can challenge with its mRNA contender mRNA-4359.

Data presented at the recent ESMO meeting with both assets suggest that Cylembio could be more effective in PD-L1-negative patients, while mRNA-4359 might be restricted to PD-L1 positives. However, Moderna’s head of development, Kyle Holen, claims that this difference has been overblown. “I think they’re actually more similar than dissimilar,” he told ApexOnco during ESMO.

He pointed out the different settings studied – first-line melanoma for Cylembio in the Keynote-D18 study, and checkpoint inhibitor-refractory melanoma for mRNA-4359 in its phase 1/2 trial. 

Holen highlighted that, in a phase 1/2 trial of Cylembio plus Opdivo, there were no responses among a 10-patient-strong PD-(L)1-refractory arm.

A combination of mRNA-4359 and Keytruda, meanwhile, produced six responses among nine PD-L1 positive post-checkpoint inhibitor patients, ESMO heard. However, there were no responses among 12 PD-L1-negative patients. Another four patients included in the ESMO update weren't evaluable for PD-L1 status.

First-line expansion

A more straightforward comparison could come soon: Moderna plans to open a first-line melanoma cohort of the same trial, in which mRNA-4359 will be tested alongside Opdivo and Yervoy in around 45 patients.

Another cohort will evaluate mRNA-4359 plus Keytruda in around 50 first-line NSCLC patients with PD-L1 expression of 50% or greater. Data from these cohorts could be available in 2027, Holen estimated.

Meanwhile, Moderna wants to confirm the signal in PD-L1-positive post-checkpoint inhibitor melanoma, and to this end will expand the existing cohort to around 80 patients in total. The company isn't giving details of the dose(s) it's taking forward in this or the other cohorts; the ESMO data concerned mRNA-4359 dosed at 400µg and 1,000µg every three weeks, with five of the six responses seen in the 400µg arm.

Overall, Holen reckons “there may be a more robust immune response from mRNA technology than what you get from a peptide”, although he conceded that it was still early days.

mRNA-4359 and Cylembio are both off-the-shelf immunotherapies, but Cylembio comprises the IDO and PD-L1 peptide antigens imsapepimut (IO102) and etimupepimut (IO103) respectively, while mRNA-4359 delivers mRNA encoding IDO and PD-L1 antigens. The idea is, once manufactured and displayed by antigen-presenting cells, these antigens will activate T cells that can then eliminate tumour cells.

Will they, won’t they?

Cylembio’s future in first-line melanoma looks uncertain: in Keynote-D18 a Keytruda combo led to a 23% reduction in the risk of progression or death versus Keytruda alone, but the trial looked underpowered, and narrowly missed hitting statistical significance with a p value of 0.056.

Efficacy looked particularly strong in PD-L1 negatives, where median PFS was 16.6 months for Cylembio plus Keytruda versus 3.0 months for Keytruda control.

Still, the FDA has advised IO not to file, and the agency might also be troubled by the fact that Keynote-D18 enrolled just 17 US patients from a total 407. However, investors recently took hope from the similar case of Replimune, which recently refiled a project once spurned by the agency.

Holen believes that Moderna can sidestep any such drama. When it comes to a pivotal trial of mRNA-4359, “we need to power our study appropriately, number one”. Before that, the group has to confirm the benefit in post-checkpoint inhibitor melanoma patients, and see if there’s also a signal in the front line.