Atezolizumab Plus Bevacizumab and Chemotherapy Fails to Provide PFS Benefit in Platinum-Sensitive Recurrent Ovarian Cancer

Atezo/Bev Plus Chemo in

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The addition of the PD-L1 inhibitor atezolizumab (Tecentriq) to bevacizumab (Avastin) and platinum-based chemotherapy did not result in a statistically significant progression-free survival (PFS) benefit among patients with recurrent epithelial ovarian cancer, according to findings from the phase 3 ATALANTE/ENGOT-ov29 trial (NCT02891824) published in the Journal of Clinical Oncology. The trial did not meet its coprimary end points of investigator-assessed PFS in the intention-to-treat (ITT) and PD-L1–positive populations.

At a median follow-up of 36.6 months (95% CI, 35.1-38.7), patients who received atezolizumab plus bevacizumab and chemotherapy in the ITT population (n = 410) experienced a median PFS of 13.5 months (95% CI, 12.2-14.2) compared with 11.3 months (95% CI, 11.0-13.5) for those treated with bevacizumab and chemotherapy alone in the placebo arm (n = 204; HR, 0.83; 95% CI, 0.69-0.99; P = .041). The 1-year PFS rates were 56% (95% CI, 51%-61%) vs 46% (95% CI, 39%-53%), respectively, and the 2-year rates were 20% (95% CI, 16%-24%) vs 12% (95% CI, 9%-18%), respectively.

Additionally, patients with PD-L1–positive disease who received atezolizumab (n = 156) achieved a median PFS of 15.2 months (95% CI, 13.6-17.3) vs 13.1 months (95% CI, 11.3-16.5) among those who received placebo (n = 77; HR, 0.86; 95% CI, 0.63-1.16; P = .30). The 1-year PFS rates were 64% (95% CI, 57%-72%) vs 55% (95% CI, 45%-68%), respectively, and the 2-year rates were 28% (95% CI, 22%-36%) vs 19% (95% CI, 12%-30%), respectively.

“These data show no benefit from the use of atezolizumab in patients with recurrent platinum-sensitive ovarian cancer, which is in line with multiple negative trials of immune checkpoint inhibition for patients with ovarian cancer treated in the frontline setting,” investigators noted.

ATALANTE was a double-blind, placebo-controlled study that enrolled patients in Europe and Israel with progressive nonmucinous epithelial ovarian cancer who experienced a first or second relapse after a platinum-free interval of more than 6 months. Eligible patients needed to have normal organ and bone marrow function and an ECOG performance status of 1 or less. The last chemotherapy that patients received had to contain platinum and new anticancer therapy in the 6 months between last platinum-containing therapy and study entry was not allowed, besides maintenance therapy up to 21 days prior to entry. Previous treatment with an immune checkpoint inhibitor (ICI) was not permitted as well.

In a 2:1 manner patients were randomly assigned to receive platinum-based chemotherapy and bevacizumab plus atezolizumab at a dose of 1200 mg daily once every 3 weeks or placebo. Platinum-based regimens were selected by investigators and consisted of: carboplatin area under the curve (AUC)4 on day 1, gemcitabine 1000 mg/m2 on days 1 and 8, and bevacizumab 15 mg/kg once every 3 weeks; carboplatin AUC5, paclitaxel 175 mg/m2, and bevacizumab 15 mg/kg once every 3 weeks all on day 1; or carboplatin AUC5 on day 1, pegylated liposomal doxorubicin (PLD) 30 mg/m2 on day 1, and bevacizumab 10 mg/kg on days 1 and 15 once every 4 weeks. Following 6 cycles of chemotherapy, all patients were treated with bevacizumab maintenance therapy at a dose of 15 mg/kg once every 3 weeks until objective radiologic disease progression per RECIST v1.1 criteria, unacceptable toxicity, or withdrawal.

After the initiation of ATALANTE and before the primary analysis, 3 phase 3 trials of immunotherapy in ovarian cancer failed to reach their primary end points. However, findings indicated that patients with PD-L1–positive disease may be more likely to benefit from treatment with ICIs. Thus, the design of ATALANTE was amended to included PFS among PD-L1–positive patients as a coprimary end point. Secondary end points included overall survival (OS), objective response rate (ORR), time from random assignment to start of second subsequent therapy or death (TSST), time to first subsequent therapy (TFST), and safety and tolerability, among others.

PD-L1–positive disease was defined as having tumor-infiltrating immune cell PD-L1 expression on at least 1% of tumor area. Patients were stratified by platinum-free interval (6-12 months vs > 12 months), PD-L1 status (negative vs positive vs noninformative), and chemotherapy (carboplatin-gemcitabine vs carboplatin-PLD vs carboplatin-paclitaxel).

The baseline patient characteristics in the ITT population were well balanced between the 2 arms; the median age was 63 years (range, 55-70) vs 64 years (range, 55-71) in the atezolizumab and placebo arms, respectively. Most patients in both arms had high-grade serous histology (84% vs 83%), an ECOG performance status of 0 (68% vs 64%), underwent 1 prior line of chemotherapy (75% vs 72%), and had a platinum-free interval exceeding 12 months (75% vs 78%); investigator-selected chemotherapy regimens consisted of PLD plus carboplatin (63% vs 63%), gemcitabine plus carboplatin (29% vs 28%), and paclitaxel plus carboplatin (8% vs 9%), respectively.

Additionally, in the atezolizumab and placebo arms patients had a sum of target lesions less than 5 cm in diameter (40% vs 51%), 5 cm or greater (37% vs 31%), or had no measurable target (23% vs 18%), respectively. Most patients did not have germline/somatic BRCA mutations (59% vs 58%); however, data was missing for 31% vs 26% of patients, and 10% vs 16% had mutations, respectively. Within 6 months of inclusion, 15% of patients in both arms underwent debulking surgery.

In the PD-L1–positive population, the median age in the atezolizumab and placebo arms was 64 years (range, 56-69) and 64 years (range, 59-72), respectively. Most patients in both arms had high-grade serous histology (87% vs 83%), an ECOG performance status of 0 (68% vs 66%), underwent 1 prior line of chemotherapy (81% vs 69%), and had a platinum-free interval exceeding 12 months (81% vs 78%); investigators selected PLD plus carboplatin (67% vs 62%), gemcitabine plus carboplatin (26% vs 29%), and paclitaxel plus carboplatin (7% vs 9%) as the chemotherapy regimens, respectively.

Due to the coprimary end points not reaching statistical significance, the secondary end points were not formally tested. However, the ORR in the ITT population was 62% in the atezolizumab arm vs 66% in the placebo arm and in the PD-L1–positive population was 62% compared with 61%, respectively. The median TSST in the ITT population was 23.9 months (95% CI, 22.6-26.5) in the atezolizumab arm vs 21.4 months (95% CI, 19.0-24.0) in the placebo arm (HR, 0.82; 95% CI, 0.67-1.01).

The median TFST in the ITT population was 14.6 months (95% CI, 13.8-16.4) in the atezolizumab arm vs 12.5 months (95% CI, 11.8-14.7) in the placebo arm (HR, 0.84; 95% CI, 0.70-1.01). In the PD-L1–positive population the median TFST was 17.5 months (95% CI, 14.6-20.2) vs 15.2 months (95% CI, 12.0-19.4) in the atezolizumab and placebo arms, respectively (HR, 0.97; 95% CI, 0.71-1.32).

The OS data were immature at the data cutoff, but there was a numerical trend in the ITT population in favor of the atezolizumab arm. The median OS was 35.5 months (95% CI, 32.4-41.3) in the atezolizumab compared with 30.6 months (95% CI, 27.9-33.6) in the placebo arm (HR, 0.81; 95% CI, 0.65-1.01). OS rates at 1 (89% vs 87%), 2 (67% vs 62%), and 3 years (49% vs 38%) were higher in the atezolizumab arm than the placebo arm, respectively. In the PD-L1–positive population, the median OS was 40.7 months (95% CI, 34.4-48.4) compared with 33.6 months (95% CI, 29.6-52.1) in the atezolizumab and placebo arms, respectively.

Findings from the PFS subgroup analysis showed that the median PFS favored the atezolizumab arm in most of the subgroups that were examined. The most pronounced benefit with atezolizumab was observed among patients with a baseline CA-125 level of less than 100 kU/L (HR, 0.62; 95% CI, 0.43-0.91), those who did not receive previous bevacizumab (HR, 0.67; 95% CI, 0.50-0.91), and those with a germline or somatic BRCA mutation (HR, 0.67; 95% CI, 0.41-1.09).

In terms of safety, adverse effects (AEs) of grade 3 or higher severity occurred at rates of 88% vs 87% in the atezolizumab (n = 408) and placebo (n = 201) arms, respectively. Treatment-related grade 3 or higher AEs (33% vs 35%) as well as fatal AEs (3% vs 2%) were also present and 25% and 18% of patients discontinued atezolizumab and placebo, respectively, due to AEs.

In the atezolizumab and placebo arms AEs of special interest occurred at any grade (27% vs 15%) as well as grade 3 or higher (13% vs 8%), respectively. Any-grade immune-related infusion reactions (8% vs 4%) and any-grade autoimmune disorders (22% vs 11%) were also present. Commonly occurring any-grade autoimmune disorders included hypothyroidism (11% vs 5%), hyperthyroidism (2% vs 2%), and colitis or severe diarrhea (1% vs 2%).

“An extensive biomarker program aims to deepen understanding of the immunologic landscape of platinum-sensitive disease. This may provide clues for new research avenues, perhaps generating hypotheses for new targets and approaches as alternatives to ICIs.This fifth negative trial of PD-(L)1 inhibition in epithelial ovarian cancer may dampen our enthusiasm for inhibiting this pathway in ovarian cancer using the strategies evaluated to date, but ongoing trials evaluating ICIs [including agents targeting other pathways] with PARP inhibitors and in different treatment settings and combinations may yet elucidate a role,” study authors wrote in conclusion.

Reference

Kurtz JE, Pujade-Lauraine 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. J Clin Oncol. Published online August 29, 2023. doi:10.1200/JCO.23.00529