Catching up with Roche, Merck racks up positive data in frontline triple negative breast cancer
Merck’s Keytruda may not have qualified as a second- or third-line treatment of triple negative breast cancer, but the PD-1 inhibitor is showing promise for the first-line setting in a Phase III trial.
Investigators for the KEYNOTE-355 study report that Keytruda plus chemotherapy significantly improved progression-free survival for patients with metastatic TNBC whose tumors express PD-L1 compared to chemo alone, hitting a co-primary endpoint.
The topline result was from an interim analysis. The other primary endpoint, overall survival, is still being evaluated.
Frontline triple negative breast cancer — a particularly hard to treat form of the disease that accounts for 10% to 20% of all breast cancer cases — is one of the rare fields in which Roche’s PD-L1 Tecentriq has enjoyed a head start over Keytruda and Opdivo, the leaders in the checkpoint race. Tecentriq is approved in combination with Abraxane for this indication.
It didn’t help when Merck conceded failure in KEYNOTE-119, where Keytruda failed to help previously treated patients live longer.
But things soon took a turn for the better, as the company found that a neoadjuvant regimen of Keytruda and chemo — followed by Keytruda monotherapy after surgery — induced a higher pathological complete response rate. The control arm, which received chemo alone, saw a pCR of 51.2% versus 64.8% for the Keytruda group.
That’s a key marker for progression and recurrence, execs said.
But SVB Leerink analysts are less optimistic. In a note, Daina Graybosch pointed out that the trial had six primary endpoints, not all of which appeared to have been met. Only patients with PD-L1 Combined Positive Score (CPS) ≥ 10 benefited, but not those whose CPS was higher than or equal to 1.
Though they reported positive topline data for Keytruda (pembrolizumab) with chemotherapy in PD-L1 high patients, the regimen failed to show benefit in a broader TNBC population. By the time Merck enters the market, Roche will have a two-year lead, in addition to a more predictive biomarker for clinical benefit (immune-cell (IC) PD-L1). A launch for Keytruda in neo-adjuvant TNBC would mitigate this market risk, but we do not expect this until 2021 at the earliest, awaiting more mature disease-free survival data.
Roger Perlmutter, who oversees Keytruda’s expansive development program, highlighted that trial — KEYNOTE-522 — together with the new Phase III as he talked up the potential of registration.
While targeted therapies have benefited a number of breast cancer patients, the fact that TNBC is neither fueled by the hormones estrogen and progesterone nor by the HER2 protein renders it especially hard to treat.
“While detail data has yet to be announced, a PFS hit in this population is important given the lack of available therapies in this disease, and further indicates a role of checkpoint inhibitors in a subset (of) TNBC patients,” Mara Goldstein of Mizuho noted about KEYNOTE-355.
Roche is looking to expand its success with the Tecentriq and Abraxane regimen by adding their PI3K/AKT pathway drug ipatasertib to the mix — with some encouraging early data.
Other smaller players have zeroed in on new targets, such as protein kinase C, Lipocalin 2 and CD24.