Cancer Res Treat.  2020 Oct;52(4):1135-1144. 10.4143/crt.2020.218.

A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair–Deficient/Microsatellite Instability–High or POLE-Mutated Metastatic or Unresectable Colorectal Cancer

• Kim JH
• Kim SY
• Baek JY
• Cha YJ
• Ahn JB
• Kim HS
• Lee KW
• Kim JW
• Kim TY
• Chang WJ
• Park JO
• Kim J
• Kim JE
• Hong YS
• Kim YH
• Kim TW

• KMID: 2507939
• DOI: http://doi.org/10.4143/crt.2020.218

Abstract

Purpose
We evaluated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with metastatic or unresectable colorectal cancer (mCRC) with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations.
Materials and Methods
In this prospective, open-label, multicenter phase II study, 33 patients with mCRC harboring dMMR/MSI-H or POLE mutations after failure of ≥1st-line chemotherapy received avelumab 10 mg/kg every 2 weeks. dMMR/MSI-H was confirmed with immunohistochemical staining (IHC) by loss of expression of MMR proteins or polymerase chain reaction (PCR) for microsatellite sequences. POLE mutation was confirmed by next-generation sequencing (NGS). The primary endpoint was the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors ver. 1.1.
Results
The median age was 60 years, and 78.8% were male. Thirty patients were dMMR/MSI-H and three had POLE mutations. The ORR was 24.2%, and all of the responders were dMMR/MSI-H. For 21 patients with MSI-H by PCR or NGS, the ORR was 28.6%. At a median follow-up duration of 16.3 months, median progression-free survival and overall survival were 3.9 and 13.2 months in all patients, and 8.1 months and not reached, respectively, in patients with MSI-H by PCR or NGS. Dose interruption and discontinuation due to treatment-related adverse events occurred in 4 and 2 patients, respectively, with no treatment-related deaths.
Conclusion
Avelumab displayed antitumor activity with manageable toxicity in patients with previously treated mCRC harboring dMMR/MSI-H. Diagnosis of dMMR/MSI-H with PCR or NGS could be complementary to IHC to select patients who would benefit from immunotherapy.

Keyword

Colorectal neoplasms; Mismatch repair deficiency; Microsatellite instability; mutation; Avelumab

Figure

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  Fig. 1. Status of mismatch repair by immunohistochemistry (IHC) or microsatellite instability (MSI) by polymerase chain reaction (PCR) and POLE mutation. dMMR, mismatch repair deficiency; MSI-H, MSI-high; MSS, microsatellite stable; NGS, next-generation sequencing; p-MMR, proficient-microsatellite instability. a)Six of nine were MSS by PCR or NGS, b)One of eight was p-MMR by IHC, c)p-MMR by IHC.

• 

  Fig. 2. Antitumor activity of avelumab in patients with metastatic or unresectable colorectal cancer harboring deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations. (A) Treatment duration of avelumab for all patients. (B) Best change from baseline in target lesion size after avelumab. CR, complete response; IHC, immunohistochemistry; NGS, next-generation sequencing; PCR, polymerase chain reaction; PD, progressive disease; p-MMR, proficient-microsatellite instability; PR, partial response; SD, stable disease.

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  Fig. 3. Median progression-free survival (PFS) (A, B) and overall survival (OS) (C, D) in all patients (A, C) and patients with microsatellite instability high (MSI-H) (B, D) by polymerase chain reaction (PCR) or next-generation sequencing (NGS). CI, confidence interval.

• 

  Fig. 4. Median progression-free survival (PFS) (A, B) and overall survival (OS) (C, D) in all patients (A, C) and patients with microsatellite instability high (MSI-H) (B, D) by polymerase chain reaction (PCR) or next-generation sequencing (NGS). CI, confidence interval.

Reference

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