Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition

Abstract

Background: Novel therapeutic agents have improved survival outcomes in patients with advanced solid tumors. In parallel, the development of predictive biomarkers to identify patients who are likely to benefit from a certain treatment has also contributed to the improvement of survival. Recently, clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. In Japan, a PD-1 inhibitor for dMMR advanced solid tumors, regardless of the primary tumor site, has been approved. However, there are some issues related to administering immune checkpoint inhibitors in the clinical practice setting, making it necessary to develop the guidelines.

Methods: Clinical questions (CQs) regarding medical care were formulated for patients with dMMR advanced solid tumors, and evidence to the CQs was collected by manual search to prepare recommendations. Then, the committee members voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other factors.

Results: The current guideline, which we consider a provisional clinical opinion at this point, describes the 11 requirements to be considered in terms of patients for whom dMMR testing is recommended, the timing and methods of dMMR testing, and clinical care systems required to perform dMMR testing properly and to administer immune checkpoint inhibitors safely.

Conclusion: This provisional clinical opinion proposes the requirements for performing dMMR testing properly to select patients who are likely to benefit from immune checkpoint inhibitors and administering them safely.

Keywords: MSI-H; Mismatch repair-deficient advanced solid tumor; PD-1/PD-L1 inhibitor; Provisional clinical opinion; dMMR.

Fig. 1

MSI analysis of BAT26. Area with a gray background was QMVR of BAT26. In tumor tissue, the sizes of microsatellites (patterns framed by red lines) are different from those seen in normal tissue

Fig. 2

MSI-H case (colorectal cancer). Microsatellite instability (MSI)-positive (↓)

Fig. 3

MSI-H case that need attention in decision (endometrial cancer). In tumor tissue, there were two markers (↓) that need attention in decision. In comparison with markers in normal tissue, these patterns were defined as MSI positive. Moreover, there was one additional marker that defined as MSI-positive compared with normal tissue

Fig. 4

MMR protein human MutLα/MutSα complex

Fig. 5

Objective response rate with PD-1/PD-L1 inhibitors by cancer type and trial. Note: each bar represents one clinical trial (green bar: dMMR tumor)

Fig. 6

Recommendations by cancer type. *Since biomarkers, such as expression of PD-L1, have different priorities, you should note to perform biomarker testing and dMMR testing at the same time or sequentially