Immune Checkpoint Inhibitors May Be Associated with High Activity in MSI-H Cancers

A meta-analysis of patients with pretreated microsatellite instability-high (MSI-H) cancers treated with immune checkpoint inhibitors (ICIs), published in JAMA Oncology, found that ICIs were correlated with high activity, independent of tumor type and drug used. 

Additionally, the researchers suggested that among molecular biomarkers for selection of treatment, mismatch repair (MMR) proteins may have a predictive value for the activity of immunotherapy.

“Although not currently approved worldwide, according to these findings anti-PD-(L)1 agents represent a potentially important treatment option for (deficient mismatch repair [dMMR]/MSI-H) tumors,” the authors wrote. 

Researchers used published articles that evaluated ICIs in the treatment of advanced MSI-H tumors from inception to December 2019; articles were identified by searching the PubMed, EMBASE, and Cochrane Library databases. Studies that were selected included prospective or retrospective studies which provided outcome data with ICIs in patients with MSI-H cancer.

The primary outcome was overall response rate (ORR). Secondary endpoints included median progression-free survival (PFS), median overall survival (OS), pooled rate of patients alive at 1, 2, and 3 years, and pooled rate of patients that attained disease control rate ([DCR] calculated as the sum of stable disease rate and ORR).

In total, 939 patients across 14 studies were analyzed mainly in the pretreated settings. The pooled ORR was 41.5% (95% CI, 34.9%-48.4%). The pooled DCR was 62.8% (95% CI, 54.5%-70.3%). Pooled median PFS was 4.3 months (95% CI, 3.0-6.8 months).

The pooled median OS was 24 months (95% CI, 20.1-28.5 months). Moreover, the pooled 1- and 2-year OS were 75.6% (95% CI, 61.8%-85.5%) and 56.5% (95% CI, 46%-66.4%), respectively. Since only 1 study provided 3-year OS data, a formal pooled analysis for 3 years was not possible.

“Despite the limitation of the nonrandomized design and the short follow-up, the pooled analysis provided evidence that MSI-H tumors, in various disease settings, were associated with benefit from ICIs in different lines of therapy,” the authors wrote. “Taking into consideration that ICIs were mostly offered in advanced lines of therapy, short-term OS (1- and 2-year) rates are encouraging.”

According to the researchers, the possible explanation of the positive outcomes after ICI treatment in MSI-H tumors relies on the potential association with PD-L1 expression and the high mutation burden of these disease types. For example, the higher mutational load of MSI-H colorectal cancer has been found to elicit an endogenous immune antitumor response, which is counterbalanced by the expression of immune inhibitory signals, such as PD-L1.

Based on these findings, the FDA has granted market authorization to pembrolizumab (Keytruda) for any solid tumors that have dMMR/MSI-H and that have progressed following prior therapies and who have no further treatment options. 

“Recently published trials have highlighted the high activity of ICIs in dMMR/MSI-H tumors and dMMR/MSI-H status has been approved by the FDA as an indicated for ICIs use for metastatic cancers, irrespective of the cancer types, likely due to the enhanced immune response related to the presence of increased somatic variations and the emergence of neoantigens in these tumors,” the authors wrote. “In addition, it seems appropriate to implement testing for dMMR/MSI-H patients with any advanced disease who have no more effective systemic therapies available.” 

Reference:

Petrelli F, Ghidini M, Ghidini A, Tomasello G. Outcomes Following Immune Checkpoint Inhibitor Treatment of Patients With Microsatellite Instability-High Cancers. JAMA Oncology. doi:10.1001/jamaoncol.2020.1046.