KEYNOTE-A18 Supports Pembrolizumab and CRT as New Standard in High-Risk Cervical Cancer

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Pembrolizumab (Keytruda) plus chemoradiotherapy and pembrolizumab monotherapy showed statistically significant and clinically meaningful benefits to survival vs chemoradiotherapy alone in patients with newly diagnosed, previously untreated, high-risk locally advanced cervical cancer, according to updated findings from the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study (NCT04221945) presented during a press briefing at the 2024 ESMO Congress.¹

The data, which were simultaneously published in The Lancet,² showed that at a median follow-up of 29.9 months (range, 12.8-43.0), the 36-month overall survival (OS) rate was 82.6% (95% CI, 78.4%-86.1%) with pembrolizumab plus chemoradiotherapy vs 74.8% (95% CI, 70.1%-78.8%) with chemoradiotherapy alone. The median OS was not reached (NR) in either arm (HR, 0.67; 95% CI, 0.50-0.90; 1-sided P = .0040). Notably, the hazard ratio for death was under 1 in all protocol-specified subgroups with the exception of those 65 years of age and older (HR, 1.35; 95% CI, 0.58-3.11).

“When we add pembrolizumab, the risk of death is reduced by 33%, and it is really remarkable for this tumor, which is among the worst among the gynecological malignancies; it involves younger patients,” Domenica Lorusso, MD, PhD, of the Gynaecology/Oncology Unit of Fondazione Policinico Universitario A. Gemelli IRCCS, Rome and Humanitas San Pio X, in Milan Italy, said in a press briefing at the congress where she initially shared some of the data. “It is a really painful tumor for women. In the locally advanced setting, it is our only opportunity to cure a larger number of patients and pembrolizumab is able to do it.”

The randomized, double-blind, placebo-controlled phase 3 study enrolled patients 18 years of age or older with newly diagnosed, locally advanced, histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. Patients needed to have high-risk disease, which was defined as having FIGO 2014 stage IB2 to IIB with node-positive disease or stage III to IVA regardless of nodal status.2 Patients were required to have an ECOG performance status of 0 or 1, evaluable disease by RECIST 1.1 criteria, acceptable organ function, and available tissue for sampling.

They could not have had other histological cervical cancer subtypes, FIGO 2014 stage IVB disease, have undergone prior hysterectomy, or have previously received systemic treatment, immunotherapy, definitive surgery, or radiation.

They were randomly assigned 1:1 to receive pembrolizumab plus chemoradiotherapy followed by pembrolizumab or placebo plus chemoradiotherapy followed by placebo. Those in the investigational arm received 200 mg of pembrolizumab every 3 weeks for 5 cycles plus chemoradiotherapy, followed by pembrolizumab at 400 mg every 6 weeks for 15 cycles. Those in the control arm received 5 cycles of placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of placebo every 6 weeks. Chemoradiotherapy comprised 5 cycles of cisplatin given at a dose of 40 mg/m2 once weekly paired with external beam radiotherapy followed by brachytherapy.¹

Stratification factors included planned external beam radiation therapy (EBRT) type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), disease stage at time of screening (FIGO stage IB2 to IIB node positive vs III to IVA), and planned radiotherapy dose according to EQD2 (<70 Gy vs ≥70 Gy). “We chose the cutoff of 70 Gy because this is a global trial with a huge number of Asian patients, and for Asian patients, 70 Gy is considered an appropriate dose of radiotherapy,” Lorusso said during the oral presentation.

The primary end points of the trial were investigator-assessed progression-free survival (PFS) by RECIST 1.1 criteria or histopathologic confirmation, and OS. “The two end points were analyzed in a hierarchical way—first PFS, and only if PFS was positive, all the α was recycled in OS,” Lorusso said. Secondary end points included 24-month PFS, 36-month OS, objective response rate, duration of response, patient-reported outcomes, and safety.

“When we designed the trial, we agreed since the beginning on the necessity to have a good quality radiotherapy. Otherwise, whatever the results of the trial, it would be difficult to interpret in the absence of an appropriate control arm. Therefore, a Quality Assurance Review Center provided site validation before study enrollment and reviewed and approved every single treatment plan before treatment initiation. Detailed guidelines were specified in the study protocol for radiotherapy,” Lorusso explained in the presentation. “The minimum acceptable cumulative dose was 80 Gy EQD for high-risk tumor volume. The intercalation of brachytherapy and EBRT was not allowed, and the overall treatment time was not to exceed 50 days, with an extension to 56 days for unforeseen delays.”

A total of 1562 patients entered the screening period of the trial; of these patients, 1060 were randomly assigned at 176 clinical sites spanning 30 countries. A total of 529 patients were allocated to the pembrolizumab/chemoradiotherapy arm, and they comprised the intention-to-treat (ITT)/efficacy population; 528 were treated, and they represented the as-treated/safety population. At the time of data cutoff, 16.3% remained on treatment, 41.5% completed treatment, and 42.2% discontinued; the main reason for discontinuation in this group was radiographic progression (n = 108). A total of 531 patients were allocated to the placebo/chemoradiotherapy arm, and they comprised the ITT/efficacy population; 530 were treated and they represented the as-treated/safety population. At cutoff, 16.0% remained on treatment, 39.4% completed treatment, and 44.5% discontinued; radiographic progression was also the most common reason for discontinuation in this group (n = 158).

“This is a global trial; 50% of patients were White race; 30% came from Asia. However, basically, all the races living in the world were represented in the trial,” Lorusso said. “More than 95% of patients had PD-L1–positive tumors [defined as having a] combined positive score of 1 [or higher.] Fifty-six percent of patients had stage III and IVA [disease], 85% had positive lymph nodes, and in particular, 62% in the pelvis and [about] 20% in the pelvic and para-aortic area.” Just under 90% of patients received IMRT or VMAT, and most patients had a planned radiotherapy dose of 70 Gy or higher (91.1 % in the pembrolizumab arm and 91.3% in the placebo arm).

With regard to treatment exposure, the median number of pembrolizumab or placebo cycles in the respective arms was 17 (range, 1-20) and 16 (range, 1-20). The median number of cisplatin cycles in both arms was 5 (range, 1-7). Overall treatment time for radiotherapy in the pembrolizumab and placebo arms was 52 days. In the pembrolizumab arm, radiotherapy was completed within 50 days for 35.5% of patients and within 56 days for 74.2% of patients. “This is remarkable considering it is a global trial in 146 patients during the [COVID-19] pandemic,” Lorusso noted. In the placebo arm, these respective rates were 36.8% and 74.7%. The median duration of EBRT and brachytherapy was 37 days and 12 days, respectively, in both arms.

Lorusso also shared additional information about radiation treatment exposure. The median HR-CTV D90% total EQD2 dose was 87 Gy (range, 83-92) in the pembrolizumab arm and 87 Gy (range, 83-92) in the placebo arm. Most patients in both arms received IMRT or VMAT (89.4% vs 87.5%). “The total [EQD2] dose in the cervix was 44, and on the lymph node, 56,” Lorusso said. “High-volume brachytherapy was received by [about] 90% of patients, HDR by [about] 94% of patients, at an appropriate dose of 41 Gy. In terms of technique, most of the patients received intracavitary brachytherapy, and in 23% of cases, interstitial was also provided.

PFS data were shared at the time of the first interim analysis, which had a median follow-up of 17.9 months. The 24-month PFS rate with pembrolizumab plus chemoradiotherapy was 67.8% (95% CI, 61.8%-73.0%) vs 57.3% (95% CI, 51.2%-62.9%) with chemoradiotherapy alone. The median PFS was NR in both arms (HR, 0.70; 95% CI, 0.55-0.89; P = .0020); the 30% reduction in the risk of disease progression was determined to be of statistical significance.

“Considering that the PFS end point [met] successful criteria at the first interim analysis, we did not [formally] analyze at the second interim analysis,” she added. With a median follow-up of 29.9 months, the 36-month PFS rate in the pembrolizumab arm was 69.3% (95% CI, 62.7%-75.0%) vs 56.9% (95% CI, 50.4%-62.9%) in the placebo arm. The median PFS was still NR in both arms (HR, 0.68; 95% CI, 0.56-0.84).

“The subgroup analysis reported consistent benefit of pembrolizumab according to all prespecified subgroups. This was reported in the interim analysis and was confirmed in the second interim analysis,” Lorusso said.

Pembrolizumab plus chemoradiotherapy had a manageable safety profile. “We were surprised of the good tolerability of pembrolizumab in combination with chemoradiation,” she said. “There were no new safety signals.” With longer follow-up, 78.2% of those in the pembrolizumab arm and 70.0% of those in the placebo arm experienced grade 3 or higher all-cause adverse effects (AEs); grade 3 or higher treatment-related AEs (TRAEs) occurred in 69.1% and 61.3% of patients, respectively. All-cause serious AEs were experienced by 32.6% of those in the pembrolizumab arm vs 28.5% of those in the placebo arm; they were treatment related in 19.3% and 13.4% of patients, respectively. Any treatment discontinuation due to AEs was reported in 20.6% and 14.9% of patients in the respective arms. “Of note, only one patient in the pembrolizumab arm discontinued all treatment for a non–pembrolizumab-related AE,” Lorusso said.

The most common TRAEs experienced by 20% or more patients in the pembrolizumab and placebo arms, respectively, were anemia (60.0% vs 55.8%), nausea (57.6% vs 59.8%), diarrhea (50.8% vs 51.1%), decreased white blood count (32.8% vs 34.5%), decreased neutrophil count (29.5% vs 27.9%), vomiting (25.6% vs 28.3%), leukopenia (23.7% vs 17.4%), decreased platelet count (22.0% vs 20.6%), neutropenia (21.6% vs 17.7%), and hypothyroidism (21.2% vs 5.7%).

“We pay particular attention to diarrhea because of a possible overlapping toxicity between autoimmune-related colitis and post-radiotherapy colitis. However, no signals [were observed],” Lorusso noted.

The most common immune-mediated AEs experienced by 3 or more patients in the pembrolizumab or placebo arms were hypothyroidism (22.5% vs 6.8%), hyperthyroidism (12.1% vs 2.8%), gastritis (4.2% vs 3.8%), colitis (3.0% vs 2.1%), thyroiditis (2.3%; 0.4%), pneumonitis (1.9% vs 0.9%), severe skin reactions (1.3% vs 0.9%), adrenal insufficiency (0.8% vs 0%), nephritis (0.6% vs 0.2%), and pancreatitis (0.6% vs 0.2%).

“Quality of life [QOL] was not impacted—no clinically meaningful between-group differences were reported in this trial at week 36 when we use the EORTC QOL Questionnaire Core 30,” Lorusso concluded.

Disclosures: Dr Lorusso disclosed the following: Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: GSK, Clovis Oncology, PharmaMar; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: AstraZeneca, MSD; Financial Interests, Personal, Other, Consultancy: PharmaMar, AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen, Novartis; Financial Interests, Personal, Advisory Board, Invited member of advisory board and invited speaker: Seagen, Immunogen, Genmab; Financial Interests, Personal, Advisory Board, Invited member of advisory board: Oncoinvest, Corcept, Sutro; Financial Interests, Institutional, Funding, Grant for founding academic trials: MSD, Clovis Oncology, GSK, PharmaMar; Financial Interests, Institutional, Coordinating PI, ENGOT trial with institutional support for coordination: Clovis Oncology; Financial Interests, Institutional, Coordinating PI, ENGOT trial with institutional support for coordination: Genmab, MSD; Financial Interests, Institutional, Funding, Clinical trial/contracted research: AstraZeneca, Clovis Oncology, GSK, MSD, Seagen; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab, Immunogen, Incyte, Novartis, Roche; Non-Financial Interests, Principal Investigator, PI of several trials, no compensation received: GSK; Non-Financial Interests, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca, Genmab; NonFinancial Interests, Principal Investigator, PI in several trials, no personal compensation received: MSD; Non-Financial Interests, Principal Investigator, PI of clinical trial, no personal compensation received: Immunogen, Clovis Oncology, Roche, Incyte, Seagen; Non-Financial Interests, Principal Investigator, PI of several trials, no personal compensation received: Novartis; Non-Financial Interests, Principal Investigator, PI of clinical trials, no personal compensation received: PharmaMar; Non-Financial Interests, Member, Board of Directors: GCIG; Other, Other, Grants for traveling: AstraZeneca, Clovis Oncology, GSK.

REFERENCES:

1. Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab plus chemoradiotherapy high-risk locally advanced cervical cancer: Overall survival results from the randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. Presented at: 2024 ESMO Congress; September 12-17, 2024; Barcelona, Spain. Presentation 7090.

2. Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. Published online September 14, 2024. doi:10.1016/S0140-6736(24)01808-7