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Exceptional Responder to Pembrolizumab Guides Immunotherapy Progress in Leiomyosarcoma

Danielle Bucco
Published: Monday, Apr 24, 2017

Suzanne George, MD

Suzanne George, MD

Researchers at Dana-Farber Cancer Institute identified a treatment-naïve patient with metastatic uterine leiomyosarcoma who had a complete tumor remission for more than 2 years on pembrolizumab (Keytruda).1,2

A complete pathologic response to pembrolizumab was observed at all except 1 of the patient’s metastatic uterine leiomyosarcoma sites. To explore potential mechanisms of immunotherapy sensitivity and resistance, the researchers examined samples from the primary tumor, the sole treatment-resistant metastasis, and germline tissue.

In the resistant tumor, PD-1 cell infiltration significantly decreased (P = .039). Additionally, the resistant tumor uniquely harbored biallelic PTEN loss and had lower expression of 2 neoantigens that showed strong immunoreactivity with patient T cells in vitro.

In an interview with OncLive, lead study author Suzanne George, MD, assistant professor of Medicine, Harvard Medical School, clinical director, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, discussed the exceptional responder to pembrolizumab and the significance of these findings for further immunotherapy advances in leiomyosarcoma.

OncLive: Please describe your research.

George: The research that we recently published is a collaborative effort between the sarcoma and genomics team at Dana-Farber. We described a patient with an exceptional response to the PD-1 inhibitor pembrolizumab. This is a patient who received pembrolizumab as first-line therapy for metastatic recurrent uterine leiomyosarcoma. This patient had a dramatic response to the therapy in multiple sites of disease with the exception of a single site.

We were ultimately able to resect that resistance site of disease. We gathered tissue samples from her baseline tumor, which had a dramatic response, and the resistant tumor to attempt to determine the factors for resistance. With differences between the tumors at those 2 time points that might help us understand why the tumor became resistant. 

Is it unusual to have a resistant tumor left over that you can study?

It was quite a unique opportunity to have tissue sample from both the baseline and a resistant tumor. It also gave us the opportunity to study this more fully because we had the samples over time. Some of the information that we've learned from this experience is just highlighting the importance of biopsies and tissue acquisition in patients on treatments over time.

The specific work that we've done related to this case was looking at whole-exome sequencing, meaning looking at the gene profile of the tumor at baseline and compared to the resistant tumor. We also focused on changes of neoantigen expression, which we believe may be relevant in sensitivity and ability for responses to be seen in PD-1 antibodies.

The entire field of immunotherapy has dramatically changed the landscape of oncology in many areas but we know that there is a tremendous amount of work to be done to identify which patients are sensitive to these approaches and which are resistant. 

Entering this research would you have expected a patient with this diagnosis to respond to PD-1 inhibitors?

When we started, this patient began with pembrolizumab. We were unsure if sarcoma and specifically leiomyosarcoma would respond to this approach. This research occurred in the very early stages of using PD-1 antibodies in soft-tissue sarcoma and uterine leiomyosarcoma.

What we have since learned is that this case was an exceptional one. There have since been other studies that have been presented using pembrolizumab and nivolumab (Opdivo), that have shown almost no responses in leiomyosarcoma. Having that background further heightens the exceptional nature of this patient’s response. 

Have you learned anything from this exceptional, specific case that could be applied to the general patient population?

In my opinion, this work is very hypothesis generating. We've shown that the genomic landscape is modulated over time in leiomyosarcoma. We believe that the neoantigen expression is important in immunotherapy and is also modulated over time in exposure to these compounds. 

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