A pre-planned translational analysis of the MITO END-3 study shows significant interactions of avelumab efficacy with the molecular characteristics of the collected tumour samples. Patients with microsatellite instability-high (MSI-H) endometrial cancer largely benefit from the addition of avelumab to concomitant chemotherapy and then as maintenance, while in patients with microsatellite stable (MSS) tumours, the presence of TP53 mutation is not associated with a benefit from the avelumab treatment.
Patients with MSS endometrial cancers, including those with TP53-mutated tumours, show several different targetable mutations, suggesting that new targeted agents can be investigated in first-line treatment for advanced disease according to Prof. Sandro Pignata of the Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale in Naples, Italy and colleagues who published the findings on 2 May 2024 in the Annals of Oncology.
Endometrial cancer is molecularly catergorised in four different subgroups: POLE ultramutated, MSI hypermutated, copy number low and copy number high. This new molecular classification of endometrial cancer has significantly changed the treatment in the early setting. The new classification has been incorporated in the risk classification after surgery being part of the decision algorithm. In particular, the presence of a POLE mutation downgrades the risk of recurrence, while the mutation of TP53 upgrades the risk and prompts a more aggressive adjuvant therapy.
In the copy number-high subgroup, a high frequency of TP53 mutation (85%), serous morphology (73.3%), older age, a more advanced stage, and poor prognosis has been observed. A p53-abnormal signature is also present in the vast majority of carcinosarcomas (73.9%), and almost half of clear-cell endometrial carcinomas (42.5%).
However, in advanced endometrial cancers, few data are available on the response to treatment according to molecular data, particularly when immunotherapy is used. Preliminary results of the GARNET study in the second-line setting, with dostarlimab, showed fewer responses to the drug in patients with tumours carrying TP53 mutation. No data are available in the first-line treatment with regard to immunotherapy efficacy.
Immunotherapy has been recognised as an effective treatment in recurrent endometrial cancer with dostarlimab, pembrolizumab, and pembrolizumab/lenvatinib approved by FDA and EMA. The activity is higher in patients with high mutational load, as in POLE-mutated and MSI-H subtypes, which constitute only 25% of the cases.
Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer, with a much larger effect size in MSI-H cases. New biomarkers might help to select patients that may have benefit among those with MSS tumours. In a pre-planned translational analysis of the MITO END-3 study, the study investigators assessed the significance of genomic abnormalities in patients randomised to standard carboplatin/paclitaxel without or with avelumab.
Among 125 randomised patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 MSI-H cases, 26 MSS TP53 wild-type (wt), 47 MSS TP53-mutated, and one case with POLE mutation. Four mutated genes were present in more than 30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation of whom five in MSI-H and six in MSS subgroup. High tumour mutation burden (≥10 muts/Mb) was observed in all MSI-H cases, in four out of 47 MSS/TP53-mutated, and no case in the MSS/TP53 wt category.
The effect of avelumab on PFS significantly varied according to TCGA categories, being favourable in MSI-H and worst in MSS/TP53-mutated (p interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A p interaction = 0.01; PTEN p interaction = 0.002).
The MITO END-3 study results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced endometrial cancer. TP53, PIK3CA, ARID1A and PTEN were the mutations more frequently identified. PIK3CA, ARID1A and PTEN mutations were observed in all TCGA categories. Furthermore, TP53, PIK3CA, and PTEN were prognostic for PFS when considering the entire population. A statistically significant interaction was found for TP53 mutation with avelumab treatment, suggesting that TP53 mutations can be associated with resistance to immunotherapy.
Despite not fully clear mechanisms of the poor efficacy of immunotherapy in p53-mutated endometrial cancers enrolled in the study, these patients show a complex molecular profile that includes several potentially targetable mutations. The study team observed PIK3CA mutations in 44% of the MSS cases and 44 of the TP53-mutated cases. In addition, PTEN and ARID1A mutations have been observed in 21% and 14% of the TP53-mutated cases.
These data confirm that other targetable mutations are present in MSS endometrial cancers, thus suggesting that new targeted agents or combinations of these drugs with immunotherapy could be explored. Targeted therapy is under investigation in Endomap study in recurrent endometrial cancer with drugs affecting the PIK3CA and PTEN pathways.
This study was partially funded, and avelumab was supplied by Pfizer as part of an alliance between Pfizer and Merck.
Reference
Pignata S, Califano D, Lorusso D, et al. MITO END-3: Efficacy of Avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy. Annals of Oncology; Published online 2 May 2024. DOI: https://doi.org/10.1016/j.annonc.2024.04.007