Atezolizumab Before/Concurrent With CRT Enhances Immunogenicity in Cervical Cancer

Improved immunogenicity with neoadjuvant atezolizumab (Tecentriq) was observed in patients with locally advanced cervical cancer when comparing the anti-PD-L1 inhibitor atezolizumab before and concurrent with chemoradiation (CRT) for favorable outcomes for 2-year disease-free survival (DFS), according to results from the NRG-GY017 trial (NCT03738228).¹

Findings were presented at the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer and showed that with a median follow-up of 25.8 months, the proportion of patients on Arm A with 2-year DFS was 79% vs 59% in Arm B (P = .28).

In arm A, patients also had a 69% pathologically complete or partial response compared with 40% in Arm B of the 31 patients with day 28 post-treatment biopsy data available.

“In addition to the favorable results discovered in this data, it is also crucial to note that there was an early decrease in T-cell receptor diversity and potential killing of tumor-associated T-cell receptor clones with concurrent chemoradiation, which could imply harmful consequences for immune response. This information warrants further clinical studies navigating differential sequencing of chemoradiation and immune checkpoint blockade,” stated lead author Dmitriy Zamarin, MD, PhD, translational research director, Gynecologic Medical Oncology Service, and associate attending physician at Memorial Sloan Kettering Cancer Center in a press release.

In this analysis of the NRG-GY017 trial, patients were randomly assigned to receive either atezolizumab prior to and concurrently with CRT (arm A) or only atezolizumab concurrently with CRT on treatment (arm B). Data presented at SGO showed that patients had T-cell receptor (TCR) repertoire sequencing data from all timepoints. Patients in both arms had therapy that led to TCR clonal expansion, though the majority of the TCR clones were not found in tumors. In arm A, the fraction of tumor-associated TCR clones that expanded in peripheral blood in response to therapy was larger.

Additionally, atezolizumab led to initial peripheral expansion of tumor-associated TCR clones in Arm A. However, some of the clones contracted in response to the subsequent CRT after patients were given the first cycle of treatment.

No association was found between the baseline PD-L1 status and 2-year DFS among patients. In arm A, 80% of patients had an available baseline tumor and 80% compared with 75% in arm B who had positive PD-L1 immune infiltrate scoring (P = .59). Arm A had 30% positive tumor cell PD-L1 scoring compared with 83% in arm B (P = .02), both of which were defined as straining at 1% or above.

According to the press release, locally advanced cervical cancer remains an area of high need as recent trials have been unable to show evidence of benefit from adjuvant chemotherapy or immune checkpoint blockade administered concurrently with CRT.

As a result, the NRG-GY017 trial enrolled 36 patients with pelvic or para-aortic lymph-node-positive, locally advanced cervical cancer. Arm A administered atezolizumab on days -21, 0, and 21 with CRT, and Arm B gave atezolizumab to patients on days 21 and 42 with CRT.²

The primary end point of the study was to determine if the differences in sequencing of atezolizumab and chemoradiation led to differential immune activation, as determined by clonal expansion of TCRr beta repertoires in peripheral blood on day 21. Secondary end points consisted of feasibility of administration and determine the nature and degree of toxicity of atezolizumab as an immune primer and concurrent with CRT therapy, examine the changes in TCR clonality, diversity, and frequency in peripheral blood and tissue and correlate this with clinical outcomes, and assess the predictive value of baseline and on-treatment PD-L1 expression in the tissue in each treatment arm for clinical outcomes.

The exploratory end points of the trial were to explore baseline and on-treatment blood and tissue biomarkers that could predict response to the combination therapy, and to explore the response assessment on the exploratory and optional post-treatment week 12 PET-CT scan and the clinical 2-year DFS.

REFERENCES:

The utilization of atezolizumab as a primer for chemoradiation results in promising immune system alterations for women with locally advanced cervical cancer. News release. NRG Oncology. March 25, 2023. Accessed March 28, 2023. https://bit.ly/3ZnF6fR

Atezolizumab before and/or with chemoradiotherapy in immune system activation in patients with node positive stage IB2, II, IIIB, or IVA cervical cancer. ClinicalTrials.gov. Updated November 29, 2022. Accessed March 28, 2023. https://clinicaltrials.gov/ct2/show/NCT03738228