Neoadjuvant immune checkpoint blockade safe and effective in MMRd endometrial cancer

In mismatch repair-deficient (MMRd) endometrial cancer, neoadjuvant immune checkpoint blockade with pembrolizumab is safe and feasible, the first results of the phase 1 PAM study demonstrated.

Recent studies suggest neoadjuvant immune checkpoint blockade may be more efficacious than adjuvant treatment in (MMRd) cancers [1,2]. However, neoadjuvant immune checkpoint blockade in local MMRd has not been explored for endometrial cancer. The recent PAM study (NCT04262089) aimed to establish proof of concept for the use of immune checkpoint blockade as novel neoadjuvant therapy in patients with endometrial cancer characterised by either MMRd or mutations in the exonuclease (proofreading) domain of DNA polymerase epsilon. Dr Marco de Bruyn (University Medical Center Groningen, the Netherlands) presented results from the MMRd cohort [3].

Participants (n=4 stage I–II, n=6 stage III) at intent-to-treat with primary surgery (minimally a hysterectomy) were treated with 2 x 3-weekly cycles of pembrolizumab before standard of care resection and adjuvant treatment if indicated. The radiologic and pathologic response rates, treatment-related adverse events and immune correlates of treatment were assessed.

In participants with measurable disease on MRI (n=8), a partial radiologic response was observed in 3 of 8 participants (objective response rate [ORR] 37.5%). A pathological response (<90% viable cancer cells) was observed in 5 of 10 participants, with 2 major pathologic responses (<10% viable cancer cells). Up to the date of presentation of the results, no recurrences have been observed, with a median and longest disease-free survival of 17 and 26 months, respectively.

The safety profile was as to be expected. Grade 1–2 treatment-related adverse events were observed in 9 of 10 participants. A treatment-induced immunological response was detected in 9 of 10 participants with increased lymphoid infiltrates, clonal T cell expansion and diverse T cell phenotypes in post-treatment samples. Monoclonal T cell expansion of predominantly CD8-positive cells was observed in responding participants. In tumour-draining (sentinel) lymph nodes, a significant clonal overlap with treatment-induced intratumoral T-cell expansion was demonstrated.

“Neoadjuvant immune checkpoint blockade is safe and feasible in MMRd endometrial cancer,” concluded Dr De Bruyn. An investigation of extended neoadjuvant treatment (9 cycles) is currently being evaluated.

1. 
   
   1. Chalabi M, et al. Ann Oncol. 2022;33(suppl_7):S1389.
   2. Reijers ILM, et al. Nat Med. 2022;28:1178–1188.
   3. De Bruyn M, et al. Neoadjuvant immune checkpoint blockade in mismatch repair deficient endometrial cancer. Abstract 742MO, ESMO 2023, 20–24 October, Madrid, Spain.

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Posted on 19 December 202317 May 2024