Immuno-oncology goes subcutaneous

The downside of having launched one of the best-selling drugs ever is the pain of seeing those sales fall away after patent expiry. In the case of Merck & Co’s Keytruda a subcutaneous formulation might extend market exclusivity, and a pivotal trial that could form the basis for a US filing is about to read out.

With $34bn of forecast 2028 Keytruda sales at stake, little wonder that analysts see the readout, of a lung cancer study called 3475-A86, as a hugely important catalyst. Still, when it comes to SC forms of anti-PD-(L)1 drugs, Roche looks set to get there first: the Swiss company’s SC Tecentriq could be approved as soon as September.

Of course, this is more important for maintaining Roche’s own market for Tecentriq, whose exclusivity could end in 2032, according to Evaluate Pharma, than to mounting a threat against Keytruda. But Roche does provide Merck with a sort of regulatory blueprint, having based its filing on the Imscin-001 trial, which was toplined positive last August.

Pdufa date

In December Imscin-001 data were quietly presented at the Esmo-IO meeting, and just as quietly Roche filed the SC form with the FDA. The filing has just been accepted under standard review, and the agency has set a September 15 action date, Roche told Evaluate Vantage.

A key detail: though Imscin-001 concerned second-line, post-chemo NSCLC, the data it generated are expected to support the registration of the SC formulation “across all approved indications of IV Tecentriq”, according to Roche’s statement. If this plan succeeds the same will apply also to Merck, whose phase 3 3475-A86 trial compares IV Keytruda plus chemo against SC Keytruda plus chemo in patients with front-line NSCLC.

The Merck trial’s co-primary measures concern bioavailability, in terms of area under curve and trough concentrations, while adverse events, PFS and OS feature as secondary endpoints. The co-primaries are broadly similar to those in Roche's trial, and the aim is to show SC to be non-inferior to IV dosing, just as Roche did in Imscin-001.

However, Merck has not spelled out the margin SC Keytruda needs to hit to demonstrate non-inferiority. In Imscin-001 the primary endpoints were both met, exceeding a non-inferiority floor defined as a lower bound of the 90% confidence interval of at least 0.80. PFS curves were virtually identical for IV and SC Tecentriq, and so was the occurrence of adverse events.

75% sales erosion?

Mizuho analysts reckon 2028 loss of exclusivity on IV Keytruda could erode over 75% of the drug’s sales within five years, but say successful launch of a SC form could limit the damage to just 30%. They base this claim on J&J’s multiple myeloma drug Darzalex, whose SC form captured over 80% of the IV’s market share within five years of launch.

For Roche less than a third of this sales number is at stake, but similar post-exclusivity dynamics probably apply. It is also important to remember that all the big PD-(L)1 players are pursuing SC formulations, and trials of Bristol Myers Squibb’s Opdivo and Astrazeneca’s Imfinzi are due to end late this year and early in 2024 respectively.

Another key player is Pfizer, which is developing sasanlimab as its SC contender, but a crucial difference here is that this is a new molecular entity, so a separate pivotal trial will be needed for every indication. And Bristol is pursuing an extra level of exclusivity protection, having coformulated Opvido and relatlimab as a single product, Opdualag.