medwireNews: Women with high-risk, locally advanced cervical cancer derive a progression-free survival (PFS) benefit from the addition of pembrolizumab to first-line chemoradiotherapy (CRT), indicate phase 3 data.
The researchers note in The Lancet that the improvement in PFS was “statistically significant and clinically meaningful,” and the early overall survival (OS) data support the PFS results.
Furthermore, “the safety profile was as expected, with adverse events that were clinically manageable with dose adjustments and use of concomitant medications,” they add.
The authors of a linked commentary say that “[t]he KEYNOTE-A18 investigators have made an important contribution to advancing immunotherapy for cervical cancer with considerable clinical ramifications.”
Krishnansu Tewari (University of California, Orange, USA) and Bradley Monk (Florida Cancer Specialists and Research Institute, West Palm Beach, USA) continue: “By virtue of pivoting immunotherapy to primary therapy, KEYNOTE-A18 is practice-changing and could reshape the therapeutic arena for individuals who relapse and are no longer checkpoint-naive.”
The trial enrolled 1060 women with a new diagnosis of high-risk, locally advanced cervical cancer, where high-risk disease was defined as FIGO 2014 stage IB2–IIB with positive nodes or stage III–IVA regardless of nodal status. Participants were randomly assigned to receive five cycles of pembrolizumab 200 mg or placebo every 3 weeks alongside CRT, followed by 15 cycles of pembrolizumab 400 mg or placebo every 6 weeks.
The first interim analysis, conducted at a median follow-up of 17.9 months, showed a significant reduction in the risk for progression or death of 30% with the use of pembrolizumab relative to placebo. The median PFS duration was not reached in either group, but the 24-month PFS rate was higher in the pembrolizumab group, at 68% versus 57%.
The hazard ratio for death was 0.73 in favor of the PD-1 inhibitor but “the observed p value did not cross the prespecified efficacy boundary at this interim analysis,” and follow-up will continue, say Domenica Lorusso (Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy) and associates.
The median OS was unreached in both pembrolizumab and placebo groups, and the 24-month rates were 87% and 81%, respectively.
“The safety profile of pembrolizumab–chemoradiotherapy was consistent with the known profiles of the individual treatment components,” note the researchers, adding that “[p]embrolizumab did not worsen the known toxicities associated with chemoradiotherapy, compromise exposure to cisplatin, or delay radiotherapy delivery.”
Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 67% of pembrolizumab-treated patients and 61% of those given placebo. The most common events of this severity in both arms were decreased white blood cell count (19 vs 21%), anemia (19 vs 16%), and decreased neutrophil count (15 vs 15%).
The rate of discontinuation of any treatment component due to TRAEs was similar in the pembrolizumab and placebo groups, at 15% and 13%, respectively, and there were two fatal TRAEs in each group.
The team therefore concludes: “The present findings expand on […] previous observations by showing the ability of pembrolizumab, when added to chemoradiotherapy followed by monotherapy, to improve outcomes even earlier in the treatment algorithm, in a potentially curative setting.”
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group
Lancet 2024; doi:10.1016/S0140-6736(24)00317-9
Lancet 2024; doi:10.1016/S0140-6736(24)00468-9