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NYU Expert Examines Emerging Agents in Colorectal Cancer

Gina Columbus @ginacolumbusonc
Published: Thursday, Dec 31, 2015

Jennifer Wu, MD

Jennifer Wu, MD

With the FDA approval of a novel therapy and the discovery of a possible biomarker to predict which patients are likely to respond to a PD-1 inhibitor, 2015 proved to be a positive year for the treatment paradigm of colorectal cancer (CRC).

The oral nucleoside TAS-102 (Lonsurf) was approved by the FDA in September for the treatment of patients with metastatic disease who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biologic product, and an anti-EGFR monoclonal antibody, if RAS wild-type. This provides a second single-agent option for patients, as regorafenib (Stivarga) was approved in 2012 for patients with metastatic disease who had prior therapy.

The TAS-102 approval was based on results from the phase III RECOURSE trial, which examined 800 patients with refractory metastatic CRC.1 In the study, the overall survival (OS) for those who received TAS-102 was 7.1 months compared with 5.3 months with placebo (HR, 0.68; P <.0001). The median progression-free survival (PFS) in the TAS-102 arm was 2 months versus 1.7 months with placebo (HR, 0.48; P <.0001).

Earlier this year, at the 2015 ASCO Annual Meeting, data showed that individuals with CRC who have high levels of deficiency in DNA mismatch repair (MMR) have a higher production of neo-antigens and are potential candidates for immunotherapy.2 In the study, patients with MMR deficiencies who received pembrolizumab (Keytruda) had an objective response rate of 62% compared with 0% in patients with MMR-proficient tumors. These findings suggest that MMR could be a biomarker for PD-1 inhibition.

In an interview with OncLive, Jennifer Wu, MD, an assistant professor of Medicine in the Department of Medicine at Perlmutter Cancer Center and NYU Langone Medical Center, sheds light on TAS-102, as well as some emerging agents likely to play a role in the treatment of patients with CRC.

OncLive: What are some of the most promising emerging agents in CRC right now?

Wu: Currently, there is a focus on two single agents. One is regorafenib, which is a non-chemotherapeutic agent that showed OS benefits in refractory CRC. The other one was actually approved in September—TAS-102—and, as a single agent, it also showed an OS benefit.

Both of these are oral agents and they have shown a pretty impressive survival benefit in similar patient populations, except that TAS-102 includes patients who had received prior regorafenib. The agents each have their own side effect profile.

I think those are very good choices for our patients now. We have two options, and the choice of one versus the other depends on patient preference, prior patience experience, or prior chemotherapy. We can choose one or the other. Sometimes, it is even possible to do it sequentially.

Secondly, we now have EGFR inhibitors for RAS and RAF wild-type patients. We have realized that it’s not adequate to just inhibit BRAF. In contrast to melanoma, we have EGFR feedback activation in CRC. If we just inhibit a single-agent BRAF inhibitor, it doesn’t really work.

Therefore, there are ongoing studies that combine both BRAF and EGFR inhibitors with pretty good results, although it is preliminary data. There are also data indicating that, by combining all 3 BRAF, MEK and EGFR inhibitors, patients had either stable disease or a response rate of 80% in the refractory setting.

There is also the fact that when patients are treated with therapy, they acquire resistance. Acquired resistance actually increases in patients with HER2 amplification, so there has been a study combining EGFR and HER2 agents in patients who have received 5 prior lines of therapy, and the response rate was 35%. That is pretty impressive.

There are also some agents being combined with chemotherapy agents, such as a SYK inhibitor and an Hsp90 inhibitor. Although they are small studies, the OS is 16 months, and that is very exciting.

Stem cell inhibitors are also being investigated in CRC. What can you share about this?

This is the most exciting one to me. We understand that there are stem cells for all kinds of cancers, and there are a couple stem cell inhibitors that are ongoing with CRC treatment right now.

One of them inhibits a transcription factor in the stem cell pathway called Nanog. In patients who were positive for this biomarker, their PFS was approximately 16 weeks in fifth-line therapy versus 6 weeks in patients without the stem cell marker. It is a small study, but perhaps we now have a biomarker about stem cells.

Another study examined a stem cell inhibitor that inhibited STAT3 and β-catenin pathway when combined with an EGFR inhibitor in the second- or third-line setting. One group includes patients who have never been treated with an EGFR inhibitor before; the other group is made up of patients treated with EGFR inhibitors, but now in combination with the stem cell inhibitor.

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