Durvalumab in Combination with Chemoradiotherapy (CRT) in Locally Advanced Cervical Cancer (LACC): Radiotherapy (RT) Delivery and Subgroup Analyses from CALLA

Abstract

<h3>Purpose/Objective(s)</h3> Concurrent platinum-based CRT has been standard of care in LACC for 20+ years. Simultaneously, RT techniques/technology have advanced, providing opportunity for improved treatment outcomes. In LACC, global standardization is critical to enhance RT quality and brachytherapy (BT) utilization. CALLA was the first global, placebo-controlled, Phase 3 study evaluating durvalumab (D), in combination with and following CRT, in LACC . We examine RT technological approaches, quality assurance measures, and related RT-based findings from CALLA. <h3>Materials/Methods</h3> Newly diagnosed, untreated patients (pts) with high-risk LACC (FIGO 2009 IB2–IIB node positive, IIIA–IVA any node status) were randomized 1:1 to D (1500 mg IV) or placebo (P) Q4W (total ≤24 doses), in combination with and following CRT. CRT comprised concurrent weekly IV platinum agent with external beam radiotherapy (EBRT) and BT. Detailed EBRT/BT protocol guidelines were included to ensure regional alignment. Prior to site qualification, a feasibility questionnaire and credentialing process confirmed compliance. A global RT subcommittee reviewed RT quality/compliance and created a scoring system to identify plan variations and potential clinical significance. RT quality was evaluated for each pt, including detailed review of contouring, EBRT plan dose/metrics, BT utilization/quality, RT completion, and treatment plan dose/quality variations. <h3>Results</h3> A total of 770 women (105 sites,15 countries; 44% Hispanic, 39% Asian) were randomized. The primary endpoint of PFS was not met (hazard ratio [95% CI] for D+CRT vs P+CRT: 0.84 [0.65–1.08]; <i>P</i>=0.174). PFS at 12 and 24 months for D+CRT vs P+CRT were 76.0% vs 73.3% and 65.9% vs 62.1%, respectively. EBRT and BT were completed per protocol in 96.4% and 94.3% of pts for D+CRT and 98.4% and 95.3% for P+CRT. RT was delivered in ≤59 days in 72.2% and 72.5% for D+CRT and P+CRT, respectively. Intensity-modulated RT was used for 86.8% (D+CRT) and 88.1% (P+CRT) of pts. A majority of pts received volume-directed BT (59.7% D+CRT, 63.3% P+CRT), and 87.4% and 88.1% of BT was high-dose rate. In both arms, median RT dose delivered was 5400 cGy and median equivalent dose was 8387.0 cGy (median BT dose/fraction 700 cGy, 4 fractions) (RT doses omit Japan). Clinically significant unacceptable variations in RT delivery were low; <25% of unacceptable variations were clinically significant. PFS by RT subgroups were generally aligned with the ITT population. <h3>Conclusion</h3> CALLA integrated an exceptional quality assurance/control strategy to ensure global protocol compliance, showing high-quality RT delivery is achievable with high compliance. Although D+CRT did not significantly improve PFS vs P+CRT, CALLA illustrates the importance of strong multidisciplinary collaboration for optimal CRT delivery in high-risk LACC. Funding: AstraZeneca