Frontline Atezolizumab Plus Chemotherapy Elicits PFS Benefit in Advanced/Recurrent Endometrial Cancer

Atezolizumab (Tecentriq) plus standard-of-care platinum-based chemotherapy, followed by maintenance therapy with atezolizumab monotherapy, improved progression-free survival (PFS) vs chemotherapy plus placebo, followed by placebo maintenance therapy, in the frontline treatment of patients with advanced or recurrent endometrial carcinoma particularly in those with mismatch repair–deficient (dMMR) disease, according to data from the phase 3 AtTEnd trial (NCT03603184) presented at the 2023 ESMO Congress.

“AtTEnd confirms the outstanding efficacy of immune checkpoint inhibitors, including PD-L1 inhibitors, in combination with chemotherapy in patients with advanced/recurrent endometrial carcinoma, particularly in those with dMMR status,” Nicoletta Colombo, PhD, director of gynecological cancer medical treatments, European Institute of Oncology, Milan, Italy, said during a presentation of the data.

Primary Analysis

After a median follow-up of 26.2 months, among the dMMR population, median PFS in the atezolizumab group was not evaluable (NE; 95% CI, 12.3-NE), compared with 6.9 months in the placebo group (95% CI, 6.2-9.0). Further, the 12-month PFS rates in the atezolizumab and placebo groups were 62.7% and 23.3%, respectively, while 24-month rates were 50.4% and 16.0%. The risk for disease progression was reduced by 64% with atezolizumab (HR, 0.36; 95% CI, 0.23-0.57; P = .0005).

Superiority with atezolizumab was confirmed in the all-comer population (median follow-up, 28.3 months), with a median PFS of 10.1 months (95% CI, 9.4-12.3), compared with 8.9 months (95% CI, 8.1-9.6) with placebo. The 12-month PFS rates were 44.9% vs 28.8%, respectively, while the 24-month PFS rates were 28.1% vs 17.0%. The risk for disease progression was reduced by 26% with atezolizumab (HR, 0.74; 95% CI, 0.61-0.91; P = .0219).

“The PFS improvement in all comers is mainly due to the large effect observed in the dMMR group in which a clear benefit is also seen,” Colombo said.

The investigators also conducted an interim overall survival (OS) analysis, with 43% data maturity; 236 deaths have occurred.

Among the all-comer population, median OS was 38.7 months (95% CI, 30.6-NE) with atezolizumab, compared with 30.2 months (95% CI, 25.0-36.1) with placebo. Twelve-month OS rates were 80.1%, compared with 74.9%, with atezolizumab and placebo, respectively, while 24-month OS rates were 62.2% vs 58.0%. Treatment with atezolizumab reduced the risk for death by 18% (HR, 0.82; 95% CI, 0.63-1.07; critical P value to state statistical significance, P = .024).

In total, 9.0% of the atezolizumab arm and 24.3% of patients in this analysis of the all-comer population went on to subsequent immunotherapy (IO).

Secondary Analysis

In the dMMR population, median OS was NE with atezolizumab (95% CI, NE-NE) compared with 25.7 months (95% CI, 13.5-NE) with placebo. The 12-month OS rates in the atezolizumab and placebo groups were 86.8% and 66.8%, respectively, while the 24-month OS rates were 75.0% and 54.2%. Treatment with atezolizumab reduced the risk for death by 59% (HR, 0.41; 95% CI, 0.22-0.76).

In total, 6.2% of the atezolizumab arm and 40.9% of the placebo arm in the dMMR population went on to subsequent IO.

Among patients in the proficient MMR (pMMR) population, median PFS was 9.5 months (95% CI, 9.0-10.4) in the atezolizumab arm, compared with 9.2 months (95% CI, 8.5-9.9) in the placebo arm. The 12- and 24-month PFS rates in the atezolizumab arm were 39.5% and 21.3%, respectively, compared with 30.2% and 16.4% in the placebo arm (HR, 0.92; 95% CI, 0.73-1.16). Median OS was 31.5 months (95% CI, 25.0-38.9) with atezolizumab, compared with 28.6 months (95% CI, 22.4-37.2) with placebo. In addition, the 12- and 24-month OS rates with atezolizumab were 77.8% and 57.4%, respectively, vs 77.3% and 58.3% with placebo (HR, 1.00; 95% CI, 0.74-1.35).

According to Colombo, based on these data, they could not find any PFS or OS benefit in the pMMR population. In total, of the pMMR population, 9.8% and 19.1% of the atezolizumab and placebo groups, respectively, went on to receive subsequent IO. However, when evaluating overall response rate (ORR) and duration of response (DOR), Colombo noted that they “were markedly improved in the dMMR population.”

In the dMMR population, ORR was 82.4% (95% CI, 71.0%-89.5%) in the atezolizumab group, including 31 complete responses (CRs; 19.1%) and 43 partial responses (PRs; 63.2%), compared with 75.7% (95% CI, 56.3%-84.7%), including 7 CRs (18.9%) and 21 PRs (56.8%), in the placebo group (HR, 0.27; 95% CI, 0.15-0.48). Median DOR with atezolizumab, vs placebo, was NE (95% CI, 15.0-NE) and 4.9 months (95% CI, 4.3-8.4), respectively.

In the pMMR population, ORR was 75.0% (95% CI, 65.5%-77.2%) with atezolizumab, including 27 CRs (13.2%) and 126 PRs (61.8%), compared with 74.6% (95% CI, 62.4%-78.6%), including 12 CRs (10.5%) and 73 PRs (64.0%) with placebo (HR, 0.89; 95% CI, 0.66-1.19). Median DOR was 7.8 months (95% CI, 6.9-9.7) with atezolizumab vs 7.0 months (95% CI, 5.6-7.9) with placebo.

“In the pMMR population, there was no benefit in the overall response rate and in the duration of response,” Colombo noted.

Of note, PFS benefit with atezolizumab in the dMMR population was consistent across all prespecified subgroups, namely geographic region, race, status of disease, histological type, previous chemotherapy, and PD-L1 expression, she added.

In total, 75.6% of adverse events (AEs) were related to atezolizumab, vs 63.8% with placebo, while 25.8% and 14.1%, respectively, of the arms were related to grade 3 or higher AEs. One death occurred in each arm as a result of treatment.

“The safety profile of the combination of chemotherapy and atezolizumab is manageable and consistent with expected toxicities,” Colombo noted.

In the atezolizumab and placebo arms, 290 and 158 patients, respectively, discontinued treatment due to progressive disease (191 vs 131), AEs (65 vs 9), deterioration of clinical condition or clinical decision (15 vs 7), patient refusal (8 vs 3), consent withdrawal (5 vs 4), death (3 vs 2), or another reason (3 vs 2).

Combining IO and Chemotherapy

Colombo explained that previous studies have demonstrated the effectiveness of immune checkpoint inhibitor monotherapy in patients with a high mutational burden, “particularly individual cancer with mismatch repair deficiency. There is a strong biological rationale for the combination of chemotherapy with immune checkpoint inhibitors and this synergistic effect has been further supported by recently published clinical trials,” she added.

In the double-blind, randomized, placebo-controlled phase 3 AtTEnd trial, the first of its kind, investigators randomized 551 patients 2:1 to receive either 1200 mg atezolizumab (n = 360) or placebo (n = 189) with carboplatin (AUC 5 or 6) and 175 mg/m2 paclitaxel, followed by maintenance therapy with 1200 mg atezolizumab (n = 356) or placebo (n = 185) until disease progression. As of the presentation, Colombo noted that 66 patients were still on maintenance with atezolizumab and 27 with placebo.

The study was conducted from October 2018 to January 2022 across 10 countries in 89 sites, which Colombo highlighted that, compared with other studies in this patient population, it included 20% of patients from Asia.

Patients were stratified by country, histotype (endometrioid vs other), recurrent vs newly diagnosed disease, and pMMR and dMMR vs non-evaluable patients.

To be eligible for the trial, patients had to have endometrial carcinoma or carcinosarcoma; stage III to IV, newly diagnosed or recurrent disease with no prior systemic chemotherapy for recurrence, an ECOG performance status of 0 to 2, and normal organ and bone marrow function. In patients with recurrent disease, 1 prior line of systemic platinum-based regimen was permitted with a platinum-free interval of 6 months or more.

The co-primary endpoints were comprised of PFS in the dMMR population, as well as PFS and OS in all comers.

In the atezolizumab and placebo groups among the all-comer population at baseline, 74.7% and 74.1%, respectively, had pMMR; 67.5% and 66.7% reported with recurrent disease; 70.3% and 68.3% did not previously receive chemotherapy; and 74.4% and 85.7% had measurable disease. Further, patients in the atezolizumab group were a median age of 67 years (range, 30-89), compared with 65 years (range, 30-89) in the placebo group; had a median body mass index of 27.3 (range, 15.1-61.5) vs 28.1 (range, 15.1-46.3), respectively; the majority were White (80.3% vs 75.7%), were PD-L1 negative (68.6% vs 68.2%), had intact ARID1A expression (68.9% vs 69.3%), reported with endometrioid cancer (63.1% vs 66.1%), and had grade 3 disease (48.3% vs 44.3%).

“The trial will continue as planned to assess OS,” Colombo concluded.

Reference:

Colombo N, Harano K, Hudson E, et al. Phase III double-blind randomized placebo controlled trial of atezolizumab in combination with carboplatin and paclitaxel in women with advanced/recurrent endometrial carcinoma. Ann Onc. 2023;34(S2):S1277. doi:10.1016/j.annonc.2023.10.034