WES-aneuploidy scores may identify patients with dMMR endometrial cancer who do not benefit from the addition of immunotherapy to chemotherapy.
Findings from a biomarker analysis of the phase 3 AtTEnd trial (NCT03603184) showed that high whole-exome sequencing (WES)–aneuploidy scores (W-AS) were associated with poorer outcomes with the addition of atezolizumab (Tecentriq) to chemotherapy in patients with mismatch repair–deficient (dMMR) advanced or recurrent endometrial cancer.1
Data presented at the
An analysis of progression-free survival (PFS) outcomes showed that patients with low W-AS treated with atezolizumab plus chemotherapy (n = 66) achieved a median PFS that was not evaluable (NE; 95% CI, 17.2-NE) compared with 7.1 months (95% CI, 6.2-10.1) for those given placebo plus chemotherapy (n = 34; HR, 0.28; 95% CI, 0.16-0.47; log-rank P < .0001). Conversely, in the high W-AS population, the median PFS was 4.2 months (95% CI, 1.9-6.5) in the atezolizumab arm (n = 4) vs 7.0 months (95% CI, 4.6-NE) in the placebo arm (n = 6; HR, 3.60; 95% CI, 0.71-18.29; log-rank P = .1006).
Additionally, in the low W-AS subgroup, the median overall survival (OS) was NE (95% CI, NE-NE) in the atezolizumab group compared with 37.2 months (95% CI, 10.1-NE) in the placebo group (HR, 0.40; 95% CI, 0.21-0.77; log-rank P = .0043). In the high W-AS subgroup, these values were 11.2 months (95% CI, 3.0-60.9) in the atezolizumab arm vs 31.8 months (95% CI, 8.9-NE) in the placebo arm (HR, 1.36; 95% CI, 0.25-7.55; log-rank P = .7238).
“The W-AS may actually identify approximately 10% [of patients with dMMR endometrial cancer] who do not benefit from the addition of immunotherapy [to chemotherapy],” lead study author Luca Mazzarella, MD, PhD, of DIMA, IEO IRCCS in Milan, Italy, said in a presentation of the data. “These cannot be considered definitive results because the size of the population is not very large, so we are in the process of validating these results in other cohorts.”
AtTEnd was a multicenter, double-blind, randomized, placebo-controlled trial that enrolled patients at least 18 years of age with advanced or recurrent endometrial carcinoma or carcinosarcoma, irrespective of MMR status.2 Patients were randomly assigned 2:1 to receive atezolizumab plus carboplatin at area under the curve of 5 or 6 and paclitaxel at 175 mg/m2 on day 1 of each 3-week cycle for 6 to 8 cycles; or placebo plus the same chemotherapy regimen. Treatment with atezolizumab continued until disease progression.
Previously reported findings showed that at a median follow-up was 28.3 months (IQR, 21.2-37.6), patients in the atezolizumab arm (n = 362) achieved a median PFS that was NR (95% CI, 12.4-NE) compared with 6.9 months (95% CI, 6.3-10.1) for those given placebo plus chemotherapy (n = 189; HR, 0.36; 95% CI, 0.23-0.57; P = .0005).
Investigators used collected 234 samples for WES, including 110 of 125 possible samples from patients with dMMR tumors (88%).1 Samples were also gathered from 121 of 409 patients with non-dMMR tumors, and work is ongoing in this group.
Researchers also examined genes associated with endometrial cancer from all collected samples in the dMMR and non-dMMR subgroups, and common genes included PTEN (63%), TP53 (35%), MSH6 (11%), BRCA2 (8%), MSH2 (5%), MLH1 (3%), BRCA1 (2%), CHEK2 (2%), MUTYH (2%), PMS2 (2%), SMARCA4 (2%), STK11 (1%), and EPCAM (1%). Notably, a POLE mutation was observed in only 1 patient (0.4%). Furthermore, 6.0% of samples were both dMMR and harbored a BRCA mutation.
Regarding dMMR samples only, the most common gene variants comprised PTEN (44%), PIK3CA (41%), TP53 (24%), KRAS (18%), CTNNB1 (15%), INPPL1 (15%), RNF43 (14%), MSH3 (13%), CRCF (12%), FGFR2 (11%), AP1S1 (9%), BAX (9%), FBXW7 (9%), PPP2R1A (9%), DAMTSL4 (8%), KMT2B (8%), MSH6 (8%), RAD50 (8%), and NF1 (7%).
In the dMMR population, 20.9% of tumors harbored CTNNB1 and/or APC mutations, which were associated with worse PFS (HR, 1.91; 95% CO, 1.10-3.33; P = .0201). Furthermore, MSH3 and/or MSH6 mutations occurred in 26.4% of dMMR samples.
What was the proportion of low vs high W-AS in the non-dMMR population?
Although investigators did not share in-depth biomarker data for the non-dMMR samples during the presentation, they did outline W-AS in this subgroup. Across both arms (n = 121), 47.1% of patients had low W-AS, and 52.9% had high W-AS. In the atezolizumab arm (n = 80), these respective rates were 58.5% and 41.5%. In the placebo arm, these rates were 41.3% and 58.7%, respectively.
Disclosures: Mazzarella reported receiving research funding from Tethis SpA.
