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823 Spatial analysis of tumor-infiltrating lymphocytes correlates with the response of metastatic colorectal cancer patients treated with vactosertib in combination with pembrolizumab
  1. Tae Won Kim1,
  2. Keun-Wook Lee2,
  3. Joong Bae Ahn3,
  4. Young Suk Park4,
  5. Gahee Park5,
  6. Kyunghyun Paeng5,
  7. Chan-Young Ock5,
  8. Hyejoo Park6,
  9. Jiyeon Ryu6,
  10. Bitna Oh6,
  11. Bo-Kyoung Kim6,
  12. Sunjin Hwang6,
  13. Ki Baik Hahm6 and
  14. Seong-Jin Kim6
  1. 1Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic of
  2. 2Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea, Republic of
  3. 3Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic of
  4. 4Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of
  5. 5Lunit Inc., Seoul, Korea, Republic of
  6. 6MedPacto, Inc., Seoul, Korea, Republic of


Background Previously, we presented a promising anti-tumor efficacy (ORR: 16%, mOS: 15.8 months, RECIST) of the combination of vactosertib, a potent and selective TGF-β receptor I, and pembrolizumab (vac+pem) in patients with microsatellite stable metastatic colorectal cancer (MSS mCRC, MP-VAC-204 study). Recent reports showed immune-excluded TIL located in stroma would be closely related to TGF-β signature, which may harbor the primary resistance of pembrolizumab. In this study, we performed an exploratory biomarker analysis of TIL resided in either intra-tumoral or stromal area in pathology slides, and we hypothesized that spatial features of TIL would correlate with the response of vac+pem.

Methods Pathology slides stained with H&E were obtained from 31 patients at baseline and 14 patients at cycle 2 in MSS mCRC patients in MP-VAC-204 study. For spatial TIL analysis, we applied an artificial intelligence -powered H&E analyzer, named Lunit SCOPE IO, which automatically detects TIL, tumor and stroma. It calculates the proportion of immune phenotype consists of inflamed, as high TIL density inside tumor area, or immune-excluded, as high TIL density in stroma in whole-slide images. Additionally, PD-L1 and CD8 were stained using multiplex immunohistochemistry to validate immune phenotype assessed by Lunit SCOPE IO.

Results At baseline, the proportion of immune-excluded area (immune-excluded score, IES) was positively correlated with the density of CD8-positive cells in stroma area measured by mIHC (coefficient = 0.349), but it was not related to the density of PD-L1-positive cells (coefficient = -0.226). Area under receiver operating characteristics to predict the responder as partial response by RECIST v1.1 by IES and PD-L1 were 0.741 and 0.528. The overall response rate of vac+pem in the patients with high IES > 42.3% was 25% (4 out of 16), while no response was observed in those with low IES (0 out of 15). Overall survival (OS) of vac+pem was significantly prolonged in those with high IES > 42.3% compared to low IES (median OS: not reached versus 6.8 months, P = 0.0097), but it was not different according to PD-L1 level. After treatment of vac+pem, while IES was decreased regardless of treatment response, the proportion of inflamed area was increased in the responders (N=3) but decreased in the non-responders (N=11).

Conclusions Immune-excluded score which reflects TGF-β-driven TIL exclusion into stroma is correlated with anti-tumor response of vac+pem in MSS mCRC. Further investigation on spatial TIL analysis as a potential biomarker should be warranted. (Clinical trial information: NCT03724851)

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