'Practice-Changing' Data in Locally Advanced Cervical Cancer

— Strategies involving immunotherapy, induction chemo move the needle for first time in decades


MADRID -- Results from a pair of international phase III trials testing two distinct treatment strategies will usher in new standards of care for women with newly diagnosed, locally advanced cervical cancer, researchers reported here.

In the first study, integrating checkpoint blockade with pembrolizumab (Keytruda) into standard concurrent chemoradiotherapy plus brachytherapy significantly improved progression-free survival (PFS) rates at 2 years (68% vs 57% with placebo) and showed an early trend toward better overall survival (OS) as well (87% vs 81%, respectively), reported Domenica Lorusso, MD, PhD, of the Catholic University of Rome.

An absolute 11% more patients were potentially cured with the addition of the PD-1 inhibitor in the context of high-quality radiotherapy, said Lorusso, who argued that the "data support pembrolizumab plus chemoradiotherapy as a new potential standard of care" in high-risk patients.

Meanwhile, an induction regimen of weekly carboplatin and paclitaxel prior to the same chemoradiotherapy standard, as compared with chemoradiotherapy alone, led to significantly improved 5-year rates of PFS (73% vs 64%) and OS (80% vs 72%) in a lower-risk group of women, according to Mary McCormack, MD, PhD, of University College Hospital in London.

She concluded that this strategy, which is feasible across diverse healthcare settings, should be "considered the new standard in locally advanced cervical cancer."

Both trials -- KEYNOTE-A18 and INTERLACE, respectively -- were presented at the annual congress of the European Society for Medical Oncology (ESMO).

"Practice-changing," said INTERLACE-discussant Krishnansu Tewari, MD, of the University of California Irvine.

"This is the first phase III randomized trial in locally advanced cervical cancer to show a survival benefit in over 2 decades," he said. And given that the two drugs are readily available, "physicians taking care of these patients could consider induction chemotherapy with weekly carboplatin-paclitaxel tomorrow morning."

"This is a celebration," said Bradley Monk, MD, of the University of Arizona College of Medicine in Phoenix, who served as discussant for the pembrolizumab presentation. "We're challenging a treatment paradigm that has stood for more than 2 decades."

Since 1999, the standard of care in locally advanced cervical cancer has consisted of cisplatin-based concurrent chemoradiation followed by brachytherapy, a strategy considered curative for approximately 70% of patients.

"I hope people don't say, 'Which should I do? Neoadjuvant chemotherapy or immune checkpoint inhibitor?' It's not versus, it's plus," said Monk. If you like that improvement with the induction chemotherapy, "that's fine, just don't forget the pembrolizumab."


From 2020 to 2022, enrolled 1,060 previously untreated women with high-risk locally advanced cervical cancer at 176 sites in 30 countries. Patients had stage IB2-IIB node-positive disease or stage III-IVA disease, based on International Federation of Gynecology and Obstetrics (FIGO) 2014 criteria. Patients were randomized in a 1:1 ratio, and the median follow-up was 17.9 months, with a majority of patients still on treatment at data cutoff.

The PFS difference between arms amounted to a "clinically meaningful" 30% decrease in the risk for progression or death with pembrolizumab (HR 0.70, 95% CI 0.55-0.89, P=0.002), said Lorusso. Data for interim OS -- the study's co-primary endpoint -- were not mature, but appeared to favor the investigational arm (HR 0.73, 95% CI 0.49-1.07).

Findings from the trial -- also known as ENGOT-cx11/GOG-3047 -- have already been submitted to the FDA, drugmaker Merck , with an approval decision in this setting expected in January. Pembrolizumab currently holds two indications in PD-L1-positive cervical cancer, as defined by a Combined Positive Score (CPS) of ≥1: as a in combination with chemotherapy (with or without bevacizumab) for persistent, recurrent, or metastatic disease; and as monotherapy for recurrent or metastatic disease on or following chemotherapy.

Treatment in both arms of KEYNOTE-A18 consisted of concurrent external beam radiotherapy (EBRT) plus cisplatin followed by brachytherapy. Pembrolizumab (200 mg) or placebo were given every 3 weeks along with the five cycles of concurrent chemoradiotherapy; then afterwards, pembrolizumab (400 mg) or placebo were given every 6 weeks for 15 cycles.

Baseline characteristics were well-balanced, and the trial enrolled a diverse patient population. Participants had a median age of about 50, with 49% 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.

For disease stage, 44% had stage IB2-IIB node-positive cancers, while 56% had stage III-IVA disease. In terms of lymph-node involvement, 61% had pelvic-only involvement and 20% had both pelvic and para-aortic involvement. Most of the cancers (83%) were squamous cell carcinoma. "These are really high-risk patients," said Lorusso.

Most patients (89%) underwent intensity-modulated radiation therapy or volumetric modulated arc therapy with a planned total dose of ≥70 Gy in 91% of patients. Median number of treatment cycles was 11 for pembrolizumab and placebo and five for cisplatin. About three-fourths of patients received their planned radiation within 56 days (median 52 in both arms), with a median total cervix EQD2 dose of 87 Gy in each arm.

Response rates were numerically higher in the pembrolizumab arm, at 79% versus 76% in the placebo arm, including complete responses in 51% and 49%. Responses of 12 months or longer occurred in 81% and 77% of the two arms, respectively.

The safety profile for the combination was manageable and "better than expected," said Lorusso, and "there was no negative impact on quality of life."

Common treatment-related adverse events (AEs) in both arms included anemia, nausea and vomiting, diarrhea, decreased white blood cell counts and neutrophil counts, leukopenia, decreased platelet counts, and neutropenia.

Grade ≥3 treatment-related AEs, serious treatment-related AEs, and immune-mediated AEs were all higher in the pembrolizumab arm:

  • Grade ≥3 treatment-related AEs: 67% vs 61%
  • Serious treatment-related AEs: 17% vs 12%
  • Immune-mediated AEs: 33% vs 12%

Immune-mediated AEs in the pembrolizumab arm included hypothyroidism in 19% of patients, hyperthyroidism in 11%, colitis in 3%, thyroiditis in 2%, pneumonitis and severe skin reactions each in 1% of patients, and adrenal insufficiency and nephritis each in less than 1%.

Five AEs from any cause led to death in the pembrolizumab arm versus six in the placebo arm.


From 2012 to 2022, the phase III randomized 500 women with locally advanced cervical cancer to five cycles of concurrent chemoradiotherapy alone or with 6 weeks of carboplatin and paclitaxel induction chemotherapy beforehand. In either scenario, brachytherapy was also recommended. Patients were enrolled across 32 centers in the U.K., Mexico, India, Italy, and Brazil, and randomized in a 1:1 fashion.

Dual primary endpoints were PFS and OS. Over a median follow-up of 64 months, the induction chemotherapy strategy led to a 35% reduction in the risk for disease recurrence or death (HR 0.65, 95% CI 0.46-0.91, P=0.013) and a 39% reduction in the survival hazard (HR 0.61, 95% CI 0.40-0.91, P=0.04), McCormack reported.

Local/pelvic relapse rates were a similar 16% in both arms, with the induction chemotherapy arm experiencing fewer distant relapses (6% vs 12% among controls).

Grade ≥3 AEs were reported in 59% and 48%, respectively.

Patients in the study had a median age of 46 years. While squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma subtypes were eligible, most participants (82%) had squamous histology. Stage II disease was most predominant (77%), followed by stage IIIB in 11% of patients, stage I (node-positive) in 9%, and stage IVA in 3%.

For radiotherapy, the trial mandated a minimum total EQD2 dose of 78 Gy, with each center undergoing quality assurance. Median overall treatment time for chemoradiotherapy was 45 days in the two arms.

In the induction chemotherapy arm, 92% of patients underwent at least five of the six weekly cycles of carboplatin plus paclitaxel, and the median time from induction therapy to the start of concurrent chemoradiotherapy was 7 days. Most of the patients underwent planned EBRT (97% in the investigational arm and 92% in the control arm) and brachytherapy (98% and 97%).

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    Ian Ingram is Managing Editor at app and helps cover oncology for the site.


The KEYNOTE-A18 study was funded by Merck.

Lorusso disclosed relationships (including research funding) with Merck, AstraZeneca, Clovis, Genmab, Immunogen, PharmaMar, Roche, and Tesaro.

McCormack disclosed relationships with Eisai, AstraZeneca, GSK, and Roche.

Monk reported relationships with Acrivon, Adaptimmune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Eisai, Elevar, Merck, Genmab/Seagen, the GOG Foundation, ImmunoGen, Karyopharm, Iovance, Laekna Healthcare, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, U.S. Oncology Research, VBL, Verastem, and Zentalis.

Tewari disclosed relationships with AbbVie, AstraZeneca, Eisai, GSK, Immunogen, Karyopharm, Merck, Morphotek, Regeneron, Roche/Genentech, and Seagen/Genmab.

Primary Source

European Society for Medical Oncology

Lorusso D "Pembrolizumab plus chemotherapy for high-risk locally advanced cervical cancer: The randomized, double-blind, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study" ESMO 2023; Abstract LBA38.

Secondary Source

European Society for Medical Oncology

McCormack M "A randomised phase III trial of induction chemotherapy followed by chemoradiation compared with chemoradiation alone in locally advanced cervical cancer: The GCIG INTERLACE trial" ESMO 2023; Abstract LBA8.