Pembrolizumab-CRT: The New Standard of Care in Locally Advanced Cervical Cancer?

A pembrolizumab (Keytruda) combination led to an overall survival (OS) boost in patients with newly diagnosed, previously untreated, high-risk locally advanced cervical cancer, according to results from the KEYNOTE-A18 trial.

KEYNOTE paired pembrolizumab with concurrent chemoradiotherapy (CCRT) and then continued CCRT, and a second interim analysis showed that at a median follow-up of 29.9 months, patients randomized to receive pembrolizumab had significantly improved OS compared to those on placebo, with an HR 0.67 (95% CI 0.50-0.90, P=0.0040). That translated into a 33% reduced risk of death, reported Linda R. Duska, MD, of the University of Virginia in Charlottesville.

Median OS was not reached in either arm, and 3-year OS rates were 82.6% in the pembrolizumab group and 74.8% in the placebo group, she stated in a presentation at the Society of Gynecologic Oncology annual meeting in Seattle.

Updated progressive-free survival (PFS) results (co-primary endpoint) showed a sustained benefit for the pembrolizumab arm, with an HR 0.68 (95% CI 0.56-0.84). Three-year PFS rates came in at 62.7% in the pembrolizumab group and 54.5% in the placebo group. For the secondary endpoint of time to second disease progression or death (PFS2), PFS2 events occurred in 15.3% and 24.3%, respectively (HR 0.60, 95% CI 0.46-0.80). Median PFS2 was not reached in either group.

“These data support the use of this combination regimen as the new standard of care for patients with high-risk locally advanced cervical cancer, and is a potential appropriate control arm in future clinical trial,” Duska said.

Based on the first interim analysis of the trial, the FDA approved pembrolizumab plus CCRT for the treatment of patients with FIGO 2014 stage III-IVA cervical cancer.

KEYNOTE A-18 was a randomized, double-blind, phase III study conducted at 176 sites in 30 countries. The trial enrolled 1,060 patients with cervical cancer who had not previously received definitive surgery, RT, or systemic therapy. The trial included 596 patients with FIGO 2014 stage III-IVA cervical cancer and 462 patients with FIGO 2014 stage IB2-IIB, node-positive disease who were randomized to receive pembrolizumab 200 mg or placebo every 3 weeks for five cycles plus CRT, followed by pembrolizumab 400 mg or placebo every 6 weeks for 15 cycles.

Patients had a median age of about 50, 49% were white, 29% Asian, 15% multiracial, 4% American Indian or Alaska Native, and 2% Black. Nearly all (94%) patients were PD-L1-positive, as defined by a CPS of ≥1.

More than half (about 57%) had stage III or IVA disease, and 83% had positive retroperitoneal nodes, with 22% having positive para-aortic nodes. About 90% had intensity-modulated RT or volumetric modulated arc therapy, with 91% receiving a dose ≥ 70 Gy.

The median number of treatment cycles was 17 for pembrolizumab and 16 for placebo, and in both arms received a median of five doses of cisplatin.

The overall treatment time was a median of 52 days in both arms, and about 75% received their planned radiation within 56 days, “which is remarkable in an international trial that completely took place during the pandemic,” Duska observed.

As for safety, Duska reported that rates of all-cause and treatment-related adverse events (TRAE) grade ≥3, serious AEs, and AEs that led to treatment discontinuation, were generally similar between groups, with TRAEs leading to two deaths in each group. The most common TRAEs in both groups were anemia, nausea, and diarrhea.

Immune-related AEs occurred in 39% of patients in the pembrolizumab arm and 17% in the placebo group, most of which were grade 1 or 2, the most common of which were hypo- and hyperthyroidism.

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