ELCC 2025 – subQ Keytruda heads towards approval
On key measures Keynote-D77 shows subcutaneous delivery to be the equal of IV.
On key measures Keynote-D77 shows subcutaneous delivery to be the equal of IV.
Judging by results of the Keynote-D77 trial just unveiled at the European Lung Cancer Congress Merck & Co appears headed for first approval of a subcutaneous formulation of Keytruda, today revealed as having an FDA action date of 23 September.
With Merck's subcutaneous rivals, Tecentriq Hybreza from Roche and Opdivo Qvantig from Bristol Myers Squibb, already approved, much is riding on Keynote-D77's ability to back SC Keytruda's use across all current IV solid tumour settings. In contrast to the other two players, however, Merck's study still involved an IV element because it combined SC Keytruda with chemo.
While Keynote-D77 is designed to back approval across IV Keytruda's existing solid tumour uses, it was carried out in first-line NSCLC irrespective of PD-L1 status. The standard of care in PD-L1 non-expressers is Keytruda plus chemo, hence the need to give active cohort patients platinum-doublet chemo, which is dosed IV, in addition to SC Keytruda; this was compared against IV Keytruda plus chemo.
Pharmacokinetics & efficacy
Keynote-D77 primarily analysed pharmacokinetics, in terms of area-under-curve and steady-state trough concentration. On both primary endpoints SC Keytruda comfortably cleared prespecified non-inferiority margins versus the IV form, with p values under 0.0001, according to a presentation at ELCC.
Perhaps of greater interest will be typical efficacy endpoints of survival and response rate, listed as secondaries in Keynote-D77, as well as SC Keytruda's safety profile. On all efficacy metrics the two forms looked nearly identical, while showing similar rates of serious and severe adverse events, and treatment discontinuations.
Though Keynote-D77 was a non-inferiority trial it will be noted that SC Keytruda showed a numerical 67% increase in trough concentrations. A comparison might be drawn with Opdivo Qvantig, whose Checkmate-67T study showed trough concentrations up to twice as high for SC versus IV dosing – data Evercore ISI analysts described as “almost too good” – and a numerical response rate benefit.
Checkmate-67T, in second-line renal cancer, was a straight comparison of SC versus IV dosing, with no chemo, and the same goes for Roche's Imscin-01 trial, carried out in second-line NSCLC. Merck will have its chance to show a similarly clean comparison in the Keynote-F84 trial in front-line PD-L1 ≥50% NSCLC, which also uses monotherapy, but only recently got under way.
Registrational trials of SC anti-PD-(L)1 MAbs
Merck & Co | Bristol Myers Squibb | Roche | |
|---|---|---|---|
| Status | SC pembrolizumab has 23 Sep 2025 PDUFA date | Opdivo Qvantiq US approved 29 Dec 2024 | Tecentriq Hybreza US approved 13 Sep 2024 |
| Trial | Keynote-D77 (1L NSCLC) | Checkmate-67T (2L renal cancer) | Imscin-001 (2L NSCLC) |
| Design | SC Keytruda + IV chemo, vs IV Keytruda + IV chemo | SC Opdivo vs IV Opdivo | SC Tecentriq vs IV Tecentriq |
| Trough concentration | Geometric mean ratio 1.67 | Geometric mean ratio 2.10 | Geometric mean ratio 1.15 |
| mPFS | 8.1mth vs 7.8mth | 7.2mth vs 5.7mth | 2.9mth vs 2.9mth |
| ORR | 45.4% vs 42.1% | 19.0% vs 13.6% | 11.0% vs 10.5% |
| Grade 3-5 TRAE | 47.0% vs 47.6% | “Similar or lower for SC vs IV” | 5.3% vs 5.6% |
| Serious TRAE | 21.1% vs 19.8% | Not published | 2.0% vs 3.2% |
Source: ESMO & ELCC.
While Merck first disclosed that it had filed Keytruda's SC form in the US and EU at this month's TD Cowen conference, nothing more was said about timelines. In a press release on Thursday the company revealed that the FDA had set a 23 September PDUFA date, implying that the BLA was accepted in February.
Regulatory action will come at a time when Merck is fending off a patent challenge from Halozyme. All three SC anti-PD-(L)1 drugs use modified hyaluronidase, Roche and Bristol having licensed a product called Enhanze from Halozyme, while Merck has rights to Alteogen’s Hybrozyme.
On the basis of several recently issued patents Halozyme claims that SC Keytruda infringes its IP, while Merck is seeking to have seven of these patents invalidated. However, the dispute seems likely to end up being settled through a simple licensing deal.
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