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MADRID -- Patients with advanced endometrial cancer had less disease progression and lived longer when they received the immune checkpoint inhibitor (ICI) atezolizumab (Tecentriq) in addition to chemotherapy, a multicenter randomized trial showed.

The addition of the PD-L1 inhibitor reduced the risk of progression by 64% in patients with mismatch repair-deficient (dMMR) cancer and by 26% in all patients. Overall survival (OS) improved by more than 8 months, which translated into an 18% reduction in the hazard ratio. The OS benefit was driven by a 59% reduction in the hazard among the dMMR subgroup.

A consistent PFS benefit in favor of atezolizumab emerged from a subgroup analysis, reported Nicoletta Colombo, MD, PhD, of the European Institute of Oncology in Milan, during the (ESMO) congress.

"The safety profile of the combination of chemotherapy and atezolizumab is manageable and consistent with expected toxicities," she said in conclusion. "The confirmed 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."

The results of the trial continued to build on the groundbreaking work made possible by The Cancer Genome Atlas, which showed that treatment beyond chemotherapy was possible, said ESMO-invited discussant David S.P. Tan, MD, of the National University Cancer Institute of Singapore.

"Clearly, the molecular classification of endometrial cancer is now leading us into areas that we didn't think before was possible," he said. "The first sense of this was obviously in the single IO [immuno-oncology] studies where you selected patients with deficient mismatch repair, where we were seeing response rates of 50% in patients who have recurrent endometrial cancer, which you never thought you'd ever see."

The rationale for combining immunotherapy with chemotherapy came from observations that chemotherapy's cytotoxic activity is partly dependent on immune activity, Tan continued. The rationale was confirmed earlier this year by trials pairing pembrolizumab (Keytruda) and dostarlimab (Jemperli) with chemotherapy in advanced/recurrent endometrial cancer.

"[The AtTEnd trial] continues to validate the practice of changing therapy, that IO 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," said Tan. "Importantly, the primary PFS endpoint was met for the all-comer population, but the [MMR-proficient] population remains an unmet need."

Ongoing trials will determine whether chemotherapy is really necessary, he added.

When AtTEnd was designed, standard first-line treatment for advanced/recurrent endometrial cancer was carboplatin and paclitaxel, Colombo noted. Multiple studies showed that single-agent ICI treatment was effective in tumors with a high mutational burden, such as endometrial cancer, and particularly in cancers with dMMR/microsatellite instability-high status.

The AtTEnd trial included patients with newly diagnosed stage III-IV or recurrent endometrial cancer and no prior systemic chemotherapy for recurrence. Investigators randomized 551 patients 2:1 to carboplatin-paclitaxel chemotherapy with or without atezolizumab, followed by maintenance atezolizumab or placebo.

The primary endpoint was progression-free survival (PFS) in the dMMR population. If that was positive, the trial's hierarchical design called for assessment of PFS in all patients and, if positive, OS in all patients.

After a median follow-up of 26.2 months, the primary analysis showed a median PFS of 6.9 months with chemotherapy-placebo, whereas the median was not yet evaluable for the atezolizumab arm but had a lower confidence interval of 12.3 months (P=0.0005). Landmark PFS analyses favored atezolizumab at 12 months (62.7% vs 23.3%) and 24 months (50.4% vs 16.0%).

The all-comer PFS analysis yielded median PFS values of 10.1 months with atezolizumab and 8.9 months with chemotherapy alone (P=0.0219). The OS analysis produced median values of 38.7 months with atezolizumab and 30.2 months with chemotherapy alone (P=0.0483).

An OS analysis in the dMMR subgroup yielded median values of 25.7 months with chemotherapy versus not evaluable with the addition of atezolizumab. The difference translated into an HR of 0.41, despite the fact that 41% of patients in the chemotherapy arm crossed over to atezolizumab, Colombo noted.

Patients with MMR-proficient (pMMR) disease did not derive a significant PFS or OS benefit from the addition of the ICI. Duration of response (DOR) in the dMMR subgroup had yet to reach the median value but had a lower confidence interval of 15.0 months, as compared with a median of 4.9 months with chemotherapy-placebo. In contrast, median DOR in the pMMR subgroup was 7.8 months with atezolizumab versus 7.0 months without, a nonsignificant difference.

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