Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade
- Study type
- Clinical trial
- Phase
- Phase 2
- Design
- Non-randomised phase 2 trial with three cohorts (an expansion of an earlier proof-of-concept study) evaluating PD-1 blockade in advanced mismatch repair-deficient cancers
- Sample size
- 86 patients with 12 tumour types
- Source
- Science · 2017
- Trial registration
- NCT01876511
In plain words
In some cancers, the cell's system for "repairing DNA mistakes" does not work, so the cancer cells build up a large number of mutations. This study showed that in patients with such advanced cancers, drugs that release the brakes of the immune system (the PD-1 pathway) can work. About half of the patients (53%) responded to treatment, and in 21% of them the tumour disappeared completely on scans. This effect was seen in cancers starting in many different organs, not just in one type of cancer.
Key results
Treatment arms and regimens
Pembrolizumab (MK-3475), an anti-PD-1 antibody, 10 mg/kg every 14 days. Patients stopped treatment after 2 years of therapy (11 patients with complete response; in 7 patients with residual disease pembrolizumab was also stopped on reaching 2 years or because of intolerance). Three cohorts in the trial registry: MSI-positive colorectal cancer, MSI-negative colorectal cancer and MSI-positive non-colorectal cancers.
Source of the regimen details: ClinicalTrials.gov NCT01876511 (pembrolizumab dose and interval, cohorts and inclusion criteria) and the full text of the paper (PMC5576142; treatment duration and adverse events)
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
Patients with advanced progressive mismatch repair-deficient cancer across 12 tumour types (86 patients; 78 with disease evaluable by RECIST). Inclusion criteria (ClinicalTrials.gov): measurable disease, ECOG 0 or 1, adequate organ function, at least 2 prior regimens in colorectal cancer and at least 1 prior therapy in other cancers, and consent to biopsy. Exclusion criteria: prior treatment with an anti-PD-1, PD-L1, PD-L2, CD137, OX-40, CD40 or CTLA-4 antibody, autoimmune disease, HIV or hepatitis B or C infection, interstitial lung disease, systemic corticosteroid use and active CNS metastases.
Endpoints
Efficacy of PD-1 blockade including objective radiographic responses, complete response, progression-free survival and overall survival. A functional analysis in one responding patient also examined neoantigen-specific T-cell responses. The primary endpoint is not specified in the abstract.
Safety and side effects
Adverse events were manageable and similar to other pembrolizumab studies: 74% of patients had an adverse event, mostly low grade. Endocrine disorders, mostly hypothyroidism, occurred in 21% and were easily controlled with thyroid hormone replacement.
Clinical significance and place in guidelines
Based on the abstract, this study shows that mismatch repair deficiency can predict response to PD-1 blockade in solid tumours, regardless of the tissue of origin. This finding provides the scientific basis for testing mismatch repair status in advanced cancers. Drug approvals and the place of this finding in treatment guidelines are not mentioned in the abstract and should be checked in official sources and current guidelines.
Limitations
The abstract gives no information on the number of patients, the exact study design, a comparison group, the drug and dose, or adverse events. The functional neoantigen analysis was performed in only one responding patient. Median progression-free and overall survival had not yet been reached, so long-term follow-up is needed.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.