Patients with advanced solid cancers treated with ERK inhibitors exhibit pseudo-progession in lymphatic nodes.

Abstract

3138 Background: ERK1/2 signaling is often overactivated in cancer, especially in patients with molecular alterations activating the MAPK pathway. MAPK pathway inhibition can result in the increase of CD8+ and CD4+ T-cells and decreased expression of immunosuppressive cytokines. Methods: This is a retrospective study of 52 patients with advanced solid cancers and oncogenic alterations in the MAPK pathway, who were treated in phase I/II clinical trials with five different single agent ERK1/2 inhibitors at MD Anderson Cancer Center. We reviewed serial PET and/or CT imaging obtained before therapy, on therapy, and after therapy completion. We evaluated dynamic changes in the lymphatic nodes (LN) in the context of overall response per RECIST 1.1 and other outcomes. Results: Of the 52 patients, 19 (37%) patients were evaluated with serial PET/CT and 33 (63%) with serial CT imaging only. Of the 19 patients evaluated with PET/CT, 12 (63%) demonstrated increased FDG uptake in LN compared to pre-treatment imaging (LN enlargement, n = 9; no LN enlargement, n = 3) discrepant from the known target and non-target lesions. These 12 patients were on therapy with ERK inhibitors (11 at doses > recommended phase 2 dose [RP2D]) for a median of 3.6 months (range, 1.8-12 months) with a best response per RECIST 1.1. as follows: partial response, n = 1; stable disease (SD), n = 10; progressive disease (PD), n = 1. Of interest, in 6 of those 12 patients, FDG uptake in LN decreased or resolved after treatment discontinuation. Further, one patient had a biopsy of an emerged LN, which showed lymphocytic infiltrate without tumor cells. Of the 33 patients evaluated with CT only, 5 (15%) demonstrated increased size of LN discrepant from the known target and non-target lesions compared to pre-treatment imaging. These 5 patients were on therapy with ERK inhibitors (all at doses < RP2D) for a median of 1.4 months (range, 1.1-3.5 months) with a best response per RECIST 1.1. as follows: SD, n = 2; PD, n = 3. Of interest, in 2 of those 5 patients, size of LN decreased or resolved after treatment discontinuation. In addition, one patient had a biopsy of an emerged LN, which showed lymphoid aggerates without tumor cells. Conclusions: Our data suggest that treatment with ERK inhibitors can result in activation of the lymphatic nodes, which can manifest as pseudo-progression. This can lead to an inconclusive assessment of their therapeutic benefit and further suggests exploration of the potential synergistic effects with immune therapy.