Expert Sheds Light on Recent Advances in mCRC

Shubham Pant, MD

The start of 2018 has brought about exciting developments in the treatment landscape of metastatic colorectal cancer (mCRC), explains Shubham Pant, MD.

The NCCN has updated its CRC guidelines, recommending a weekly regorafenib (Stivarga) dose-escalation strategy beginning at 80 mg and ending at 160 mg for previously treated patients. This was based on findings from ReDOS, a phase II dose-optimization study that compared the dose-escalation regimen with the standard dose of 160 mg of regorafenib daily. The 6-month overall survival (OS) rate was 66.5% in the dose-escalation arm versus 49.8% in the standard arm.¹ The 12-month OS also favored the dose-escalation arm at 34.4% versus 26.7%, respectively.

More recently, the FDA granted a priority review to a supplemental biologics license application (sBLA) for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of adult patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mCRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan. This sBLA was based on results from a cohort of 119 patients from the phase II CheckMate-142 trial who were treated with the combination. At a median follow-up of 13.4 months, the investigator-assessed overall response rate in the cohort was 55%, with 31% of patients having stable disease.²

Additionally, results from a phase Ib study recently showed that atezolizumab (Tecentriq) in combination with cobimetinib (Cotellic) induced a 31% disease control rate in patients with heavily pretreated mCRC.³

OncLive: Please provide an overview of your topic.

What are the current regimens used for these patients, and what is coming down the pike?

We have seen some interesting data with immunotherapy in MSI-H/dMMR tumors. Can you speak about some of that data?

Which patients may be better suited for nivolumab alone versus the combination?

Could you speak to the dosing schedule changes for regorafenib?

Atezolizumab and cobimetinib also look promising in mCRC. Can you speak to that as well?

Is there anything upcoming that you are particularly excited for in this landscape?

Looking ahead, what does the future of this landscape look like to you?

Pant, the associate medical director of the Clinical and Translational Research Center, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, discussed these studies in his presentation on mCRC at the 2018 OncLive^® State of the Science Summit^™ on Gastrointestinal Cancers. In an interview during the meeting, he shared his insight on the future direction of this treatment landscape.Pant: My presentation focused on how we treat patients in the third-line setting with mCRC. Unlike some other cancers, patients who are in the third-line setting with mCRC are still very sturdy, and they still have an excellent ECOG performance status, liver function, and white counts. They can tolerate the therapy. There is interest with targeted therapy and immunotherapy, and how we will fit them into the treatment paradigm. Current regimens that we do right now for patients are regorafenib and TAS-102 (Lonsurf). What we are trying to do is molecularly characterize the tumors. We do genomic profiling of the tumors and try find targets. The big targets that are actually targetable are BRAF, which has seen a lot of press recently, HER2/neu targeting, and a subset of CRC that benefits from immunotherapy. The study was presented by Dr Michael J. Overman of The University of Texas MD Anderson Cancer Center, and it essentially showed that both nivolumab by itself and nivolumab plus ipilimumab gives good response rates for patients who have MSI-H tumors. Nivolumab plus ipilimumab does have a higher response rate than nivolumab by itself, but it does have more toxicities. Nivolumab monotherapy would be better for patients who are a little bit older, and maybe whose performance status isn't that great. It depends on how we think their tolerance would be as far as side effects are concerned, because combination immunotherapy has a higher rate of side effects. It is truly based on the individual patient. The ReDOS study gave data on the way that a lot of physicians in the community were dosing regorafenib for these patients for some time now. ReDOS started regorafenib at a lower dose of 80 mg, and then the next week it was 120 mg, and then the following week was 160 mg. It showed improvement in quality of life and OS. You have to take that with a grain of salt, because it is a small study. It is very interesting. This is a smaller study, but it was instrumental. It is a pathway thing. Atezolizumab is a PD-L1 inhibitor, and cobimetinib is a MEK inhibitor. There is another MEK inhibitor out there called trametinib (Mekinist), which is also used in patients with melanoma. The interesting thing is that when you use a MEK inhibitor like cobimetinib, it actually aids in the immune infiltration of the tumor by increasing the lymphocytes. Then, you give the PD-1 agent and it causes response. We saw responses in a smaller study presented a couple of years back. We are now waiting for the bigger study to give us some data.One of the interesting trials is the SWOG S1613 (NCT03365882) trial of trastuzumab (Herceptin) and pertuzumab (Perjeta) in HER2/neu-positive patients. That will be very interesting to see in our patient groups. [I’m also looking forward to] longer-term data on immunotherapy for CRC. Toxicity and survivor data are all maturing, and we would love to see more data come out. The future looks very promising. If I looked at any non—small cell lung cancer slides from back when I started my fellowship, the specific translocations were not indicated. Now they are. I hope to have that for CRC, where we can take the “big pie” and break it up into MSI-H, BRAF mutations, etc.

We also must find new therapies for patients with KRAS-mutant CRC, and that is challenging. There are new KRAS inhibitors that are being developed. Downstream of KRAS is RAS, RAF, and MEK. Combinations may be something in the future; it’s a brave new world out there.

References

1. Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study. J Clin Oncol. 2018;36 (suppl 4S; abstr 611).
2. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773-779. doi: 10.1200/JCO.2017.76.9901.
3. Bendell JC, Bang YJ, Chee CE, et al. A phase Ib study of safety and clinical activity of atezolizumab (A) and cobimetinib (C) in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol. 2018;36 (suppl 4S; abstr 560).