Michael J. Overman, MD
While PD-1/PD-L1 inhibitors have demonstrated encouraging activity in a subset of patients with gastrointestinal (GI) cancers, there are other drugs in the space that are currently in development, said Michael J. Overman, MD. The challenge lies in figuring out how to optimize the activity seen with this class of agents and bring them into the frontline setting.
“Immuno-oncology is currently a big area of development in GI cancers,” said Overman, who is a professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center. “It is revolutionary compared with our classic chemotherapy-based approaches.”
For example, the combination regimen comprised of the PD-1 inhibitor nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy) continues to be explored in colorectal cancer (CRC).
The phase II CheckMate-142 trial examined the combination in a cohort of 119 patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic CRC. In this cohort, 82 patients received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Results showed an overall response rate (ORR) or 46% (95% CI, 35%-58%).1
These data led to the FDA’s accelerated approval of the combination for the treatment of adult and pediatric patients 12 years and older with MSI-H mCRC.
Updated data, which were presented at the 2018 ESMO Congress, showed that the combination improves survival in treatment-naïve patients for MSI-high mCRC, highlighting its potential as a new first-line treatment in this population. In 45 patients with no prior treatment, the ORR with the combination was 60%, while the disease control rate was 84%. The complete response rate was 7%.2
In an interview with OncLive
during the 2018 ISGIO Meeting on Immune-oncology in Gastrointestinal Cancers, Overman highlighted new combination agents under investigation for the treatment of patients with GI cancers—specifically CRC—and challenges that still need to be addressed.
OncLive: Could you provide an overview of immune-oncology in the field of GI cancers?
: Immune-oncology is a current big area of development in cancer. There are many different drugs under development in this space, but the drugs that have had the most success have been these drugs targeting PD-1 or PD-L1. There are a number of different drugs that are FDA-approved for several different cancer types. The question is, “What other drugs are coming after the initial wave of multiple PD-1/PD-L1 agents?” There are a lot in development, and [we need to figure out] some of the bigger picture of how to decide which other targets are relevant.
What agents and targets are under investigation in this space?
One of the big ones is a target called CTLA-4, which is an immune checkpoint on T cells that inhibit an immune response; if you block this target, you can stimulate an immune response. There have been a number of studies looking at combinations targeting PD-1 and CTLA-4.
The classic combination that has been FDA approved is nivolumab and ipilimumab, a combination that has been approved for a while in melanoma. Recently, we had that combination approved in GI cancer, specifically for [patients with] MSI-high or dMMR CRC. We have this approval for patients after they had at least 1 or 2 lines of therapy. This combination really demonstrated pretty dramatic activity and appears to be potentially more active than just single-agent therapy, although it hasn't been compared in a randomized fashion.
However, when you look at the data, there is a refractory data set of patients with MSI-H CRC treated with nivolumab/ipilimumab where you see a 12-month PFS of around 80%, which is just really outstanding. At 1 year, only 20% of patients have progressed, which is a dramatic finding for us and a very high response rate.