乌鸦传媒

An immunotherapy boost failed to improve outcomes in newly diagnosed advanced ovarian cancer compared with chemotherapy and bevacizumab (Avastin), a large international trial showed.

Progression-free survival (PFS) in the overall study population increased about a month with the addition of atezolizumab (Tecentriq) to carboplatin-paclitaxel chemotherapy and bevacizumab. Median PFS in the PD-L1-positive subgroup (≥1% expression) improved by 2.3 months (20.8 vs 18.5 months), but the difference did not meet prespecified criteria for statistical significance. An exploratory analysis suggested improved PFS with atezolizumab in the subgroup of patients with PD-L1 immune cell (IC) expression ≥5%.

A preliminary analysis of overall survival (OS) also suggested no benefit from the addition of atezolizumab to the standard regimen, Kathleen Moore, MD, of the University of Oklahoma Sciences Center in Oklahoma City, reported at the 2020 European Society for Medical Oncology (ESMO) virtual congress.

"Despite notable successes with incorporation of atezolizumab and bevacizumab in the treatment of other solid tumors, IMagyn50, the first such study in ovarian cancer, did not meet its first primary endpoint for extending progression-free survival in either the intention-to-treat or fully powered PD-L1-positive population," said Moore. "The signal of a clinical benefit for atezolizumab in the immune cell PD-L1-high subgroup may warrant further evaluation. The interim analysis of overall survival showed no differences between treatment groups, but a final analysis will be expected and presented in 2023."

The findings had a precedent in a trial reported earlier this year at a Society of Gynecologic Oncology webinar. A phase III trial of chemotherapy plus avelumab (Bavencio) not only failed to improve PFS versus chemotherapy alone but suggested a possible harm with the addition of anti-PD-1/L1 therapy. That trial was preceded by a negative randomized phase III study comparing pegylated liposomal doxorubicin (PLD) and avelumab versus PLD alone in patients with advanced platinum-resistant/refractory ovarian cancer.

Background and Trial Design

Atezolizumab has demonstrated efficacy in multiple solid tumors. Platinum-taxane chemotherapy is an established first-line regimen for advanced ovarian cancer, and combining angiogenesis inhibition with PD-1/L1 blockade has demonstrated antitumor efficacy in several types of advanced solid tumors, Moore noted. Collectively, the evidence supported a trial to evaluate the addition of atezolizumab to chemotherapy and bevacizumab.

The IMagyn050 trial involved patients with untreated stage III/IV epithelial ovarian, primary peritoneal, or fallopian tube cancer. Patients had postoperative macroscopic residual disease or planned neoadjuvant chemotherapy with planned interval surgery. All patients received carboplatin, paclitaxel, and bevacizumab and were randomized to placebo or atezolizumab.

The trial had co-primary endpoints: PFS in both the PD-L1-positive and intention-to-treat (ITT) populations (simultaneously tested) and OS in the same two populations, with hierarchical testing.

Data analysis included 1,301 patients, who had a median age of 59-60. A fourth of the patients had received neoadjuvant therapy and the rest underwent primary surgery. Moore said 60% of patients had PD-L1-positive tumors, and 69% had stage III disease.

Key Findings

The results showed a median PFS in the ITT population of 19.5 months with atezolizumab and 18.4 months without it. The slightly larger difference in the PD-L1-positive group was associated with conventional statistical significance (P=0.0376) but the point estimates for the two groups overlapped.

Median OS had yet to be reached for either group in the ITT or PD-L1-positive analyses. The 2-year event-free survival rate was about 80% for each group in the ITT analysis and about 82% for the PD-L1-positive analysis. A subgroup analysis did not identify any patients who appeared to benefit more with the addition of atezolizumab. An analysis of PFS by histology also failed to show a significant advantage for atezolizumab.

Investigators performed an exploratory analysis of PFS by the proportion of PD-L1-positive ICs and the presence or absence of tumor cell (TC) staining. The results yielded evidence of improved PFS with atezolizumab in the subgroup with IC ≥5%. Placebo-treated patients had a median PFS of 20.2 months, whereas the median had yet to be reached in the atezolizumab arm. The difference represented a 36% reduction in the hazard for progression or death (95% CI 0.43-0.96, P=0.0278). The subgroup accounted for 20% of the total study population, said Moore.

The analysis of TC staining also suggested a PFS benefit with atezolizumab (15.0 months vs not evaluable, HR 0.41, 95% CI 0.19-0.90), but the group represented only 5% of the study population, she added.

The safety profile was similar between the two groups, with a few exceptions, although atezolizumab was associated with more serious adverse events (47% vs 33% overall and 35% vs 21% considered treatment related) and more adverse events leading to discontinuation of atezolizumab versus placebo (15% vs 6%).

Despite the negative results from IMagyn050 and the avelumab studies, the death knell might not have sounded for PD-1/L1 in ovarian cancer, said ESMO-invited discussant Isabelle Ray-Coquard, MD, PhD, of Claude Bernard University in Lyon, France. Longer follow-up is needed in IMagyn050 for both PFS and OS. In the meantime, the first priority should be to learn more about the subgroup with PD-L1 IC expression ≥5% (BRCA and homologous recombination deficiency status, histology, surgical outcome).

Evaluation of immunotherapy should move beyond high-grade serous ovarian cancer to the more uncommon subtypes, Ray-Coquard continued. Different sequences of chemotherapy and immunotherapy require exploration, as well as the impact of integrating a PARP inhibitor. Finally, alternative chemotherapy backbones should be explored in the setting of relapsed platinum-sensitive disease.

Comment