Atezolizumab Does Not Improve PFS in Platinum-Sensitive Ovarian Cancer

Kathleen N. Moore, MD, MS

In patients with recurrent epithelial ovarian cancer (OC), treatment with atezolizumab (Tecentriq) failed to demonstrate significant improvements in progression-free survival (PFS) compared with placebo plus bevacizumab (Avastin), missing the primary end point of the phase 3 ATLANTE/ENGOT-ov29 trial (NCT02891824).¹

According to results from the study published in Journal of Clinical Oncology, the median PFS in the intention-to-treat population, which consisted of 410 patients in the atezolizumab arm and 204 in the placebo arm, according to a 2:1 randomization ratio, was 13.5 months (range, 12.2-14.2 months) with atezolizumab. In comparison, the median PFS was 11.3 months (95% CI, 11.0-13.5 months) in patients treated with placebo plus bevacizumab. In the PD-L1-positive population, which included 156 patients in the atezolizumab arm and 77 patients in the control arm, the median PFS was 15.2 months (95% CI, 13.6-17.3 months) with atezolizumab vs 13.1 months (95% CI, 11.3-16.5 months) with placebo plus bevacizumab.

ATLANTE/ENGOT-ov29 is a randomized, double-blinded, phase 3 study. The study follows multiple trials of immunotherapy used in first-line patients with OC. These trials were all negative.

The phase 3 IMagyn050/GOG 3015/ENGOT-OV39 trial [NCT03038100] was global trial explored the same experimental and control therapies in newly-diagnosed patients with stage III/IV OC.²

Cancer of the ovaries | Image Credit: © Lars Neumann -www.stock.adobe.com

“IMagyn050 was a frontline ovarian study that attempted to show improvement in PFS by adding the PD-L1 monoclonal antibody atezolizumab to bevacizumab, Kathleen N. Moore, MD, MS told Targeted Oncology. “This study demonstrated a statistically non-significant improvement in PFS from 18.5 to 20.8 months median PFS and a HR of 0.80. So, it was a 20% reduction in the hazard of progression with atezolizumab amongst tumors that were PD-L1-positive. The overall survival was just published in Gynecologic Oncology, and again, it shows a trend towards improvement in the PD-L1-positive cohort with a HR of 0.82. So, there is some modest separation in the overall survival tail that is interesting.”

Patients in ATLANTE/ENGOT-ov29 the study randomized to the experimental arm received atezolizumab 1200 mg or 800 mg for 6 cycles with carboplatin plus gemcitabine, paclitaxel, or pegylated liposomal doxorubicin. In the control arm, the dose level and schedule of placebo matched that of atezolizumab and was also combined with matching bevacizumab and platinum-based chemotherapy. In addition to PFS, patients in the study were evaluated for the secondary end point of overall survival (OS), time from randomization to second subsequent therapy or date of death (TSST), patient-reported outcomes, and the frequency of adverse events (AEs).³

“ATALANTE was performed in the platinum-sensitive, recurrent setting where tumors that are very resistant to everything and also tumors that do exceedingly well. The inclusion of both these groups in frontline studies may balance the impact but one could argue that the inclusion of resistant tumors may mute the PFS or OS benefit of an immune checkpoint inhibitor and inclusion of the roughly 15% who are cured may mute any evidence of OS. So, looking in a platinum sensitive recurrent setting may equalize the arms so that benefit if any is present can be seen, said Moore, associate director of clinical research, Virginia Kerley Cade Chair in Developmental Therapeutics, director, TSET Phase I Drug Unit, and co-director of the Cancer Therapeutics Program at Stephenson Cancer Center at the University of Oklahoma HSC.

Results for the secondary end points showed that even though atezolizumab yielded higher numbers, the benefit was not significant compared with the control. The median TSST in the ITT population was 23.9 months (95% CI, 22.6-26.5 months) with atezolizumab vs 21.4 months (95% CI, 19.0-24.0 months) with placebo (HR, 0.81; 95% CI, 0.67-1.01). The median OS was 35.5 months (95% CI, 32.4-41.3 months) with atezolizumab compared with 30.6 months (95% CI, 27.9-33.6 months) with placebo (HR, 0.81; 95% CI, 0.65-1.01).¹

Moore said “In the ATALNATE study, the alpha was split between PFS in the ITT and PD-L10positive subgroup. If one was positive, then the alpha could be shifted to the OS end point. But because neither was positive, no alpha could be passed to OS. Similar to what was shown in IMagyn050, the PFS HR was 0.83, so there was a 17% reduction in the hazard of progression in the ITT arm and 0.86 in the PD-L1-positive group [a 13% reduction in the hazard of progression]. Neither of these were statistically nor clinically positive. The OS is interesting though because here we see a HR of 0.81, which is almost a 20% reduction in the risk of death with use of atezolizumab in this setting, and no P value can be assessed because there is no alpha left to use. This is intriguing to me because the curves do maintain separation with 333/491 events expected, so I would want to see this followed out. We will not be able to call it positive because there’s was no statistical power, but there looks to be a signal here.”

Patients in the atezolizumab arm vs the placebo arm has a similar incidence of grade ≥ 3 AEs. Specifically, grade ≥ 3 AEs occurred in 88% of the atezolizumab arm compared with 87% of the placebo arm. Treatment-related grade ≥ 3 AE were observed in 33% of the atezolizumab arm vs 35% of the placebo arm. Fatal AEs occurred in 3% of patients treated with atezolizumab vs 2% of those in the placebo arm. Of the fatal AEs observed, those determined to be related to treatment with atezolizumab were cardiac arrest, peritonitis, and acute myeloid leukemia. Fatal AEs determined to be related to placebo were pulmonary embolism and bowel perforation.

The most frequently observed AE of special interest in the study was hypothyroidism, which occurred in 11% of the atezolizumab arm vs 5% of the placebo arm.In terms of health-related quality of life, there was no difference shown between the 2 treatment arms.

_REFERENCES:

_{1. Kurtz JE, Pujade-Laurine E, Oaknin A, et al. Atezolizumab combined with bevacizumab and platinum-based therapy for platinum-sensitive ovarian cancer: placebo-controlled randomized phase III ATALANTE/ENGOT-ov29 trial. [published online ahead of print, 2023 Aug 29]. J Clin Oncol. 2023;JCO2300529. doi:10.1200/JCO.23.00529}

_{2. ATALANTE: Atezolizumab vs placebo phase III study in late relapse ovarian cancer treated with chemotherapy+bevacizumab (ATALANTE). ClinicalTrials.gov. July 21, 2023. Accessed September 8, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT02891824}

_{3. Moore KN, Bookman M, Sehouli J, et al. Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J Clin Oncol. 2021;39;17:1842-1855. doi:10.1200/JCO.21.00306}