Add-on immunotherapy prolongs survival in advanced endometrial cancer

In the treatment of patients with advanced or recurrent endometrial carcinoma, adding the PD-L1 inhibitor atezolizumab to chemotherapy helps lower the risk of progression or death, according to the phase III AtTEnd trial.

Final data from the intention-to-treat population showed that the median progression-free survival (PFS) was superior with atezolizumab than with placebo both in the subgroup of patients with deficient mismatch repair (dMMR) status (median PFS, not evaluable vs 6.9 months; hazard ratio [HR], 0.36, 95 percent confidence interval [CI], 0.23–0.57; p=0.0005) and in all patients (median PFS, 10.1 vs 8.9 months; HR, 0.74, 95 percent CI, 0.61–0.91). [ESMO Congress 2023, abstract LBA40]

“At 2 years, we had 50.4 percent of patients alive without progression in the atezolizumab arm and 16.0 percent … in the placebo arm,” according to Dr Nicoletta Colombo of the European Institute of Oncology in Milan, Italy, who spoke at ESMO Congress 2023.

In the interim analysis of overall survival (OS) in all patients (data maturity: 43 percent), a signal of benefit with atezolizumab emerged, with the median OS being 38.7 months as opposed to 30.2 months with placebo (HR, 0.82, 95 percent CI, 0.63–1.07; p=0.0483). This was despite the fact that 24.3 percent of placebo-treated patients received subsequent immunotherapy, Colombo pointed out.

The safety profile of the combination of atezolizumab plus carboplatin and paclitaxel was manageable and consistent with expected toxicities, she said.

Any grade ≥3 adverse events (AEs) considered related to the study drug were documented in 25.8 percent of patients in the atezolizumab arm and in 14.1 percent in the placebo arm. Neutropenia was the most common AE, followed by anaemia, thrombocytopenia, peripheral sensory neuropathy, fatigue, diarrhoea, nausea, and arthralgia. One patient in each arm had a treatment-related AE that led to death.

“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 those with dMMR status,” Colombo said.

Asian representation

The intention-to-treat population included 549 patients with advanced or recurrent endometrial carcinoma/carcinosarcoma who were enrolled in 89 sites across 10 countries. Colombo highlighted that 20 percent of these patients were from Asia (ie, Japan, South Korea, and Taiwan). A total of 360 patients (mean age 67 years, 80.3 percent Caucasian, median BMI 27.3 kg/m²) were assigned to the atezolizumab (1,200 mg) arm, while 189 were assigned to the placebo arm (mean age 65 years, 75.7 percent Caucasian, median BMI 28.1 kg/m²). The study drugs were given in addition to paclitaxel (175 mg/m²) and carboplatin (AUC 5 or 6).

Of the patients, 125 (22.8 percent) had dMMR tumours and 352 (64.1 percent) had endometrioid carcinoma; 369 (67.2 percent) had recurrent disease and 148 (82.2 percent) of newly diagnosed patients had a stage IV disease.

For the secondary endpoints, the atezolizumab vs the placebo arm had significantly better OS (HR, 0.41, 95 percent CI, 0.22–0.76), objective response rate (ORR; 82.4 percent vs 75.7 percent), and duration of response (HR, 0.27, 95 percent CI, 0.15–0.48).

On the contrary, in the subgroup of patients with proficient MMR, the two treatment arms did not differ in terms of PFS (HR, 0.92) and OS (HR, 1.00).

Practice-changing therapy

“Clearly, the molecular classification of endometrial cancer is now leading us into areas that we didn't think before was possible,” according to study discussant Dr David Tan of National University Cancer Institute, Singapore. “The first sense of this was obviously in the single immunotherapy studies where you selected patients with deficient mismatch repair, where we were seeing response rates of 50 percent in patients who have recurrent endometrial cancer, which you never thought you'd ever see.”

Tan lauded the effort of AtTEnd investigators to recruit Asian patients, given the huge number of endometrial cancers in Asia. “If we really want to think about whether these treatments work on a global perspective, it is important to have proper demographic representation in these trials.” [https://gco.iarc.fr/tomorrow/en/dataviz/bars]

The AtTEnd trial, Tan said, “continues to validate this practice changing therapy that immunotherapy plus chemo really works for the dMMR patients, and it doesn't matter if you give them a PD-L1 inhibitor or a PD-1 inhibitor.”

Then again, whereas the primary PFS endpoint was met for the overall population, the proficient MMR subpopulation presents an unmet medical need, he pointed out.

Tan called for a combined translational analysis across GY018, RUBY, and AtTEnd trials in order to generate valuable data on predictive biomarkers for immunotherapy plus chemotherapy in both proficient- and deficient-MMR endometrial cancer populations.