Expert Discusses Latest Advancements in the Treatment Landscape of mCRC

Shubham Pant, MD

Shubham Pant, MD

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

Updated NCCN guidelines recommend a weekly regimen of regorafenib (Stivarga) in a dose-escalation strategy, starting with 80 mg and concluding with 160 mg in patients with CRC that have previously been treated. This decision is based on results from the ReDOS trial, a phase II dose-optimization study. The standard dose of 160 mg of regorafenib was compared to the dose-escalation treatment. In the experimental arm, the 6-month overall survival (OS) was 66.5% versus 49.8%. Results for the dose-escalation were also favored in the 12-month OS with 34.4% in the experimental arm and 26.7% in the standard.

A priority review was granted by the FDA to an sBLA for the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) for patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mCRC following progression on a treatment of fluoropyrimidine, oxaliplatin, and irinotecan. This decision is based on findings from a cohort of 119 patients in the phase II CheckMate-142 trial. Patients treated with the combination had a median follow-up of 13.4 months. The investigator-assessed overall response rate was 55% in the cohort while 31% of these patients had stable disease.²

Recently, findings from a phase Ib study also demonstrated that the combination of atezolizumab (Tecentriq) with cobimetinib (Cotellic) induced a 31% disease control rate in patients with heavily pretreated mCRC.³

In an interview withTargeted Oncology,Pant, associate medical director of the Clinical and Translational Research Center of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, discussed these trials and where he believes the treatment landscape of mCRC is heading.

TARGETED ONCOLOGY:Please provide an overview of your topic.

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. 

TAGRTED ONCOLOGY:What are the current regimens used for these patients with mCRC, and what is coming down the pipeline?

Pant: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 areBRAF, which has seen a lot of press recently, HER2/neu targeting, and a subset of CRC that benefits from immunotherapy.

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

Pant: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.

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

Pant: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.

TAGRTED ONCOLOGY:Could you speak to the dosing schedule changes for regorafenib?

Pant: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.

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

Pant: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.

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

Pant: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.

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

Pant: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 withKRAS-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).JClin Oncol.2018;36 (suppl 4S; abstr 560).