High-Quality Radiotherapy Delivery Not Affected by Durvalumab in High-Risk Locally Advanced Cervical Cancer

The addition of durvalumab (Imfinzi) did not appear to impact the delivery of high-quality radiotherapy in patients with high-risk locally advanced cervical cancer, according to findings from the phase 3 CALLA trial (NCT03830866) that were presented at the 2022 American Society for Radiation Oncology (ASTRO) Annual Meeting.

A total of 100.0% and 99.5% of patients in the durvalumab and placebo arms received chemoradiotherapy (CRT), respectively. In the durvalumab plus CRT arm, 51.7% of patients received 5 cycles of treatment with cisplatin/carboplatin, 35.3% received 6 cycles, and 0.3% received more than 6 cycles compared with 57.3%, 32.8%, and 0.0% of patients in the placebo plus CRT arm, respectively. External beam radiotherapy (EBRT) was completed per protocol in 96.4% of those in the durvalumab arm and 98.4% of those in the placebo arm. A total of 94.3% of those receiving durvalumab/CRT and 93.5% receiving placebo/CRT completed brachytherapy per protocol. Additionally, radiotherapy was administered in a timely manner of 59 days or less in 72.2% vs 72.5% of patients, respectively.

The median external beam dose was 5400 cGY in both arms, and the median EQD2 dose was 8387 cGy. Lymph node boost was given to 72.0% of patients in the durvalumab arm and 71.9% of patients in the placebo arm. Moreover, parametrial boost was delivered in 86.0% and 82.8% of patients in the durvalumab and placebo arms, respectively.

“The CALLA trial really sets a new benchmark for clinical trials for patients with locally advanced cervical cancer,” Jyoti S. Mayadev, MD, a radiation oncologist and professor of radiation medicine and applied sciences at the University of California, San Diego Health, said in a presentation on the findings.

The trial included a total of 770 patients aged 18 years or older with histologically confirmed cervical adenocarcinoma, squamous carcinoma, or adenosquamous carcinoma. Eligible patients had high-risk locally advanced disease that was either stage IB2 to IIB with 1 or more positive nodes or stage IIIA to IVA with no nodes or more. Patients also needed to have an ECOG performance status of 0 or 1 and were stratified based on disease stage and region.

Patients were randomly assigned 1:1 to receive either durvalumab at 1500 mg every 4 weeks totaling 24 doses followed by platinum chemotherapy, EBRT, and brachytherapy or a matched placebo with the same CRT backbone. The chemotherapy regimen consisted of 40 mg/m² of cisplatin or carboplatin every week for 5 weeks, and EBRT was given at a dose of 45 Gy in 25 fractions at 1.8 Gy per fraction and 5 fractions per week. High-dose brachytherapy consisted of 27.5 to 30.0 Gy and the low-/pulsed-dose rate was 35.0 to 40.0 Gy.

The study’s primary end point was PFS, with key secondary end points including overall survival, objective response rate, duration of response, incidence of local/distant progression, and safety.

Most patients included in the study in the durvalumab and placebo cohorts, respectively, were Asian (39.5% vs 38.4%), White (33.8% vs 32.5%), and American Indian/Alaskan Native (12.2% vs 14.5%). Moreover, less than half of patients were Hispanic or Latino (45.5% vs 42.6%). Most patients in the durvalumab arm and placebo arm had an ECOG performance status of 0 (68.8% vs 66.2%) and squamous histology (83.6% vs 83.1%). Additionally, most patients had stage III disease (58.4% vs 61.3%) and pelvic lymph node involvement (63.9% vs 69.6%).

At a median follow-up of 18.5 months vs 18.4 months respectively, the 12-month progression-free survival (PFS) rate was 76.0% in the durvalumab cohort compared with 73.3% in the placebo arm. Moreover the 24-month PFS rate was 65.9% compared with 62.1% in each respective arm (HR, 0.84; 95% CI, 0.65-1.08; P = .174). Mayadev also detailed PFS outcomes by radiotherapy subgroup.

“Within each subgroup analysis—brachytherapy, image guidance, IMRT, timely radiation—there was no difference with the addition of durvalumab,” she said.

In terms of radiotherapy quality control, detailed EBRT and brachytherapy guidelines were incorporated into the study protocol to ensure radiotherapy delivery was aligned across all regions.

“One key highlight of the CALLA clinical trial was the robustness of the radiotherapy quality control. The radiation therapy had robust site qualifications [and] needed to have a feasibility questionnaire, a benchmarking case, the plans were all reviewed, and CALLA had a radiotherapy steering committee to which I was the chair,” Mayadev explained. “The cases were reviewed in real time; we were always in communication and there was constant feedback.”

In particular, EBRT plan needed to be reviewed within 4 weeks of submission, and the first brachytherapy plan needed to be reviewed at each site within 1 week.

A total of 86.8% of patients in the durvalumab arm and 88.1% of patients in the placebo arm received intensity-modulated radiotherapy, and 79.6% and 82.2%, respectively, received image-guided radiation therapy. Additionally, volume-directed brachytherapy was given to 59.7% of patients in the durvalumab arm and 63.3% of patients in the placebo arm.

“This was truly a global technology trial for patients with cervical cancer,” Mayadev confirmed.

In terms of early– and late–onset radiotherapy toxicities, common grade 3 or higher early–onset toxicities in the durvalumab cohort included anemia (11.2%), white blood cell count decrease (9.6%), and neutrophil count decrease (5.7%) compared with white blood cell decrease (10.4%), anemia (8.3%), and neutrophil count decrease (7.0%) in the placebo arm. Common grade 3 or higher late–onset radiotherapy toxicities in the durvalumab cohort included radiation proctitis (0.3%) and urinary tract infection (0.3%), as well as gastroenteritis radiation (0.3%) and cystitis radiation (0.5%) in the placebo cohort.

“A major key highlight that the trial is telling us in terms of clinical practice is that the early– and late–onset radiotherapy toxicities were extremely low,” Mayadev stated.

Reference

Mayadev JS, Rong, Y, Toita T, et al. Durvalumab in combination with chemoradiotherapy (CRT) in locally advanced cervical cancer (LACC): radiotherapy (RT) delivery and subgroup analyses from CALLA. Presented at 2022 American Society for Radiation Oncology (ASTRO) Annual Meeting; October 23-26, 2022; San Antonio, TX; LBA 03. Accessed October 24, 2022.