Evidence-Based Oncology July 2016
Zeroing in on Predictive Biomarkers for Cancer Immunotherapy
Mismatch Repair Deficiency in CRC
During his talk, Programmed Death-1 Blockade in Mismatch Repair Deficient Colorectal Cancer, Luis A Diaz, Jr, MD, medical oncologist, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, provided an update on the progress of using mismatch repair (MMR) deficiency as a marker for predicting response to PD-1 receptors. A presentation at ASCO last year by his group generated a lot of interest, because it indicated that a patient’s MMR status can be used to predict their response to the PD-1 inhibitor pembrolizumab, in colorectal cancer (CRC).1
Microsatellite instability resulting from genetic and epigenetic MMR is responsible for the development of CRC, Diaz said, adding that a majority of patients who participated in their trial were young and had Lynch syndrome or hereditary colon cancer.
MMR-deficient colon cancers are densely infiltrated with CD8+T cells and regress when treated with anti–PD-1 antibodies. This antitumor response is thought to be potentiated by somatic mutations, which when expressed as proteins, result in immunogenic neo-antigens that can be recognized by the patient’s immune system.
The current study recruited patients diagnosed with CRC who were either deficient (n = 28) or proficient (n = 25) in MMR. Patients were treated with the anti–PD-1 antibody, pembrolizumab, at a dose of 10 mg/kg, every 2 weeks. The median age of MMR-deficient participants was significantly younger (49 years) compared with those who had MMR-proficient tumors (62 years).2
An immediate biochemical response to treatment was observed in those with MMR-deficient tumors, measured as the levels of carcinoembryonic antigen. At 30 months follow-up, median overall survival (OS) in the MMR-proficient cohort was 5.98 months, while the MMR-deficient cohort is yet to reach a median OS. Additionally, progression-free survival (PFS) in MMR-proficient patients was 2.3 months, but PFS was not reached in the MMR-deficient patients. The objective response rate was 0% and 57% in the MMR-proficient and MMR-deficient patients, respectively, while the disease control rate was 16% and 89%, respectively.
Diaz said that 50% of patients presented with complete and durable response. Five of the 28 MMR-deficient patients had reached the 2-year mark following initiation of treatment and were no longer being treated with pembrolizumab. “They are on active surveillance,” Diaz said.
He had several thoughts on what this data would mean in the long term:
- Is it time to think of treating MMR-deficient tumors with anti–PD-1 agents in a histology-independent manner?
- How do we evaluate the management of patients who have a stable response following 2 years on a PD-1 inhibitor?
- Do we need to figure the molecular etiology of primary and secondary resistance in these tumors?
However, there is a trend indicating that there is a critical threshold for mutation burden for specific disease (including melanoma)—higher mutation burden can improve patient response. “Why does mutation burden matter?” Charen asked. Mutations create neo-antigens, which create abnormal proteins which are then presented to the immune system by antigen presenting cells (APCs).
Charen pointed out several questions that remain unanswered:
- Does mutation load matter in dual checkpoint blockade–treated patients?
What factors lead to primary and acquired resistance in tumors expected to respond to checkpoint blockade?
- Do they upregulate other checkpoints or are the APCs modified or missing pathways?
Charen is hopeful that peripheral testing, using blood-based biomarkers could help make progress in the field. However, a significant challenge remains integration of this multivariable data in a statistically and biologically meaningful manner in the clinic.