Pembrolizumab Plus CCRT Improves Overall Survival

BARCELONA, Spain — Adding pembrolizumab to standard concurrent chemoradiotherapy (CCRT) significantly improves overall survival in patients with high-risk, locally advanced cervical cancer, according to results of a phase 3, randomized, double-blind trial.

Domenica Lorusso, MD, PhD, director of Gynecological Oncology at Humanitas San Pio X and professor at Humanitas University, Milan, Italy, presented these findings of the ENGOT-cx11/GOG-3047/KEYNOTE-A18 study at the European Society for Medical Oncology (ESMO) Annual Meeting 2024. The results were published online ahead of print in The Lancet on the day of the presentation.

During her presentation, Lorusso, the first author of the paper, emphasized the need for new and more effective therapies for high-risk locally advanced cervical cancer.

“For more than 20 years, the standard treatment of locally advanced cervical cancer has been concurrent chemoradiation plus brachytherapy, based on the results of five randomized trials that reported a 6% increase in overall survival when we combined chemotherapy with radiation,” Lorusso said.

Study Design and Patient Population

The study enrolled 1060 patients with newly diagnosed, previously untreated, high-risk locally advanced cervical cancer, defined as FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of the lymph node status.

Patients were randomized 1:1 to receive either pembrolizumab or placebo in combination with standard CCRT. Patients in the pembrolizumab arm received 200 mg every 3 weeks for five cycles during CCRT, followed by 400 mg every 6 weeks for 15 cycles.

According to Lorusso, the trial is particularly notable for its use of modern radiotherapy techniques. Over 85% patients were treated with intensity-modulated external beam radiotherapy, and a similar proportion received volume-based brachytherapy, she said.

The median total equivalent dose in 2-Gy fraction (EQD2 dose) to the high-risk clinical target volume was 87 Gy.

R.A. Nout, MD, PhD, professor of radiotherapy at Erasmus MC, Rotterdam, the Netherlands, said giving this dose reflects contemporary best practices in radiation oncology for cervical cancer.

In her talk, Lorusso highlighted the importance of quality assurance in radiotherapy for the trial.

“When we designed the trial, we agreed since the beginning on the necessity to have a good quality radiotherapy; otherwise, it would be difficult to interpret the results of the trial in the absence of appropriate [quality assurance].”

Effect of Pembrolizumab Plus CCRT on Overall Survival

At a median follow-up of 29.9 months (range, 12.8-43.0 months), the study met its primary endpoint, demonstrating a statistically significant improvement in overall survival with pembrolizumab plus CCRT vs placebo plus CCRT. The 36-month overall survival rate was 82.6% in the pembrolizumab arm vs 74.8% in the placebo arm (hazard ratio [HR], 0.67; 95% CI, 0.50-0.90; P = .0040).

Lorusso emphasized the clinical significance of these results: “A statistically significant and [clinically] meaningful overall survival benefit was reported in patients treated with pembrolizumab, with a hazard ratio of 0.67, suggesting a 33% reduction in the risk of death.”

The benefit of pembrolizumab was consistent across prespecified subgroups, including FIGO stages IB2-IIB (HR, 0.89; 95% CI, 0.55-1.44) and III-IVA (HR, 0.57; 95% CI, 0.39-0.83).

Progression-free survival (PFS), a co-primary endpoint, also showed significant improvement. At 2 years, 67% patients in the pembrolizumab arm were free of progression compared with 57% patients in the placebo arm (HR, 0.65; 95% CI, 0.53-0.79; P < .0001).

Safety of Pembrolizumab Plus CCRT

According to Lorusso, the safety profile of pembrolizumab plus CCRT was manageable and consistent with known toxicities of the individual therapies. Grade ≥ 3 treatment-related adverse events occurred in 69.1% patients in the pembrolizumab group vs 61.3% patients in the placebo group. Immune-related adverse events were more common with pembrolizumab (40% vs 17%) but were mostly grade 1-2.

During her talk, Lorusso emphasized that none of the patients experienced colitis. “We pay particular attention to digestive adverse events because of possible overlapping toxicity of immune-related colitis post-radiotherapy colitis,” she explained.

Clinical Implications and Future Work

Commenting on the clinical implications of their findings, Lorusso stated, “In our opinion, these data support pembrolizumab in combination with chemoradiation as the new standard of care in patients with locally advanced high-risk cervical cancer.”

Nout, who was not involved in the KEYNOTE-A18 study and served as a discussant on the findings presented by Lorusso, echoed the clinical significance of the results. At 3 years, there was a 12% PFS benefit and 8% overall survival benefit, he said.

“I think these are clinically meaningful and should be considered as practice-changing improvements.”

Nout also highlighted the strengths of the study.

“This was a well-designed randomized double-blind placebo-controlled, adequately powered, phase 3 trial. Importantly, it included not all locally advanced cervical cancer patients, but a defined high-risk population,” he said.

During the discussion session, Nout also raised some points for consideration. He noted that the recent phase 3 CALLA trial investigating another immunotherapy agent, durvalumab, in a similar setting provided negative results, highlighting the need to understand potential differences between PD-1 and PD-L1 inhibition or patient populations.

Nout also suggested areas for further investigation, stating, “I think we know now [the effects of pembrolizumab plus chemoradiotherapy on] progression-free survival, but what are the differences in local, regional and distant recurrence?”

He explained that more data are needed to better understand the patterns of recurrence, treatment effects on long-term survival, which patients are more likely to benefit from treatment, and the optimal duration of pembrolizumab treatment.

Lorusso reported financial relationships with AstraZeneca, Clovis Oncology, Corcept, Daiichi Sankyo, Genmab, GSK, Immunogen, MSD, Oncoinvent, Novocure, Seagen, and Sutro (advisory board); AstraZeneca, Clovis Oncology, Daiichi Sankyo, Genmab, GSK, Immunogen, MSD, Novocure, and Seagen (invited speaker); MSD and Novartis (consultancy); AstraZeneca, Clovis Oncology, Pharma&, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, PharmaMar, Roche, Seagen, Alkermes, and Corcept (institutional funding, grants, or contracted research); and AstraZeneca, Menarini, GSK, and MSD (grants for traveling).

Nout reported financial relationships with Elekta, Varian, Accuray, Sensius, Sennewald, and Oceanz (institutional funding, grants, or contracted research); Elekta (invited speaker); and MSD (advisory board).