Novel Strategies Progress Through mCRC Pipeline

Ryan B. Corcoran, MD, PhD

Several late-stage therapies, including targeted agents and immunotherapies, are being evaluated for patients with relapsed/refractory colorectal cancer (CRC) who have progressed on first- and second-line therapies, explained Ryan B. Corcoran, MD, PhD.

“There are a growing number of options for patients with CRC after passing first- and second-line therapy,” Corcoran said. “Many of these actually depend on key molecular features within the tumor. Comprehensive molecular characterization and sequencing are very important. While some of these targets may actually be rare, if they're found in that patient, they can open the door to some very successful and promising therapeutics.”

For example, the phase III BEACON CRC study looked at patients with BRAF V600E—mutant metastatic CRC (mCRC) who were randomized to receive the triplet regimen of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) versus encorafenib/cetuximab alone versus investigator’s choice of standard therapy with cetuximab plus either irinotecan or FOLFIRI. Results showed that the median overall survival (OS) was 9.0 months versus 5.4 months in the triplet and standard regimens, respectively, translating to a 48% reduction in the risk of death (HR, 0.52; 95% CI, 0.39-0.70; 2-sided&#8239;P <.0001).&#8239;

The FDA granted the triplet regimen a breakthrough therapy designation in August 2018 for the treatment of patients with BRAF V600E—mutant mCRC as detected by an FDA-approved test, following failure of 1 or 2 prior lines of treatment.&#8239;

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Corcoran, an associate professor of medicine of Harvard Medical School, and of Massachusetts General Hospital Cancer Center, discussed emerging therapeutics for patients with relapsed/refractory CRC.

OncLive: How is regorafenib (Stivarga) being used in CRC treatment?

Corcoran: Regorafenib is approved following failure of [prior therapy]. It was shown to extend OS by about 2 months compared with placebo in a trial. [Regorafenib] can be used at any point in late-line therapy. At times, there are some toxicities associated with regorafenib and there have been some alternative dosing strategies examined.

One of the trials is the ReDOS study, where we looked at the standard dose of regorafenib of 160 mg versus a dose-escalation strategy, in which you start a lower dose and escalate in increments over the course of a couple weeks until you get to a maximum dose—assuming that [regorafenib] is tolerated. [The dose-escalation strategy] was found to be slightly better tolerated and just as effective, which makes it a good option that can help with some of the potential toxicities associated with regorafenib.

Could you provide an overview of the BEACON CRC study?

The BEACON CRC study was the first randomized, phase III study specifically for patients with BRAF-mutant CRC, specifically for those with BRAF V600E mutations. This study was designed to address a big problem specific to BRAF CRC; other cancers [with a high rate of] BRAF mutations, such as melanoma, tend to respond very well to single-agent BRAF inhibitors or BRAF/MEK inhibitor combinations. However, CRC has a very robust adaptive feedback loop, meaning once you inhibit the pathway you get reactivation of pathway signaling through receptor tyrosine kinases, such as EGFR. This is fairly unique to CRC.

The BEACON study tested two experimental therapies. There was a BRAF plus an EGFR inhibitor arm—called the doublet—which was meant to interrupt EGFR specific feedback only. The triple regimen, which consists of a BRAF, MEK, and EGFR inhibitor, is able to interrupt EGFR specific and EGFR independent feedback.

[Both regimens were tested] in the second- or third-line setting against standard chemotherapy. The BEACON study showed that both the triplet and doublet therapy were significantly better than standard chemotherapy. The triplet, in particular, showed a response rate of 26% relative to 2% with standard chemotherapy, and a median OS of 9.0 months versus 5.4 months with standard chemotherapy arm.

How have the BEACON CRC data impacted the field?

The BEACON regimen has become part of the National Comprehensive Cancer Network guidelines since March 2019, which means it can be administered to patients. Based on these data, the company is taking this forward with a formal submission to the FDA. This could potentially represent the first FDA-approved option for patients with BRAF-mutant CRC, which would be an exciting development for the field.

What is the significance of HER2 amplification in CRC?

HER2 is amplified in about 4% of all mCRC cases. We know of HER2 as a target from breast cancer and gastric cancer, where it's more widely overexpressed and amplified. However, HER2 amplification occurs specifically in RAS and BRAF wild-type CRC.

Even though that is typically a group where EGFR-directed antibodies are given, research has shown that these cancers with HER2 amplification do not respond very well to EGFR antibodies either. Rather than being a mark of resistance, this has become a promising therapeutic target.

Three studies have combined the classic anti-HER2 agent trastuzumab (Herceptin) with either another antibody against HER2 called pertuzumab (Perjeta) or 1 of 2 small molecule inhibitors, lapatinib (Tykerb) or tucatinib (ONT-380). Some of these studies have shown response rates between 30% and 45% in this population with some very promising durability. [HER2], while a rare target, is something that is worth keeping an eye out when assessing for later-line options for patients with CRC.

How is immunotherapy currently being used in CRC?

Immunotherapy has had a dramatic effect in a lot of different cancer types. One of the special things about immunotherapy is that many of these responses can be durable—often more durable than some of our current therapies. Unfortunately, in CRC, the majority of patients haven't responded very well to checkpoint inhibitors.

That being said, there is a subset of cancers—about 4% to 5% of mCRC—that harbors microsatellite instability or mismatch repair deficiency. These cancers accumulate very high numbers of mutations due to this defect in DNA repair; thus, they have a lot of mutations that can be recognized by the immune system. In this population, there can be very high and durable response rates to checkpoint inhibitors.

Outside of that, we're still working very hard to figure out how to extend the benefit of immunotherapy to the 96% of patients with CRC who have microsatellite stable tumors. That has been a very difficult challenge. Right now, there are a lot of clinical trials looking at what we can combine with checkpoint inhibitors to enhance the immune adjusting of cancers. These include radiation, targeted agents, and other immune-based agents, including bispecific antibodies that engage an antigen on the tumor cell surface and the T cell, to bring those agents together to engender an immune response.

What studies of immunotherapy combinations would you like to highlight?

The bispecific antibodies, as a class, are very interesting right now. Some of these early studies have shown some interesting signals, particularly when given in combination with a checkpoint inhibitor. Unfortunately, some of these agents have also led to a bit of toxicity, which has limited their effect. A big focus right now is on how to modify these agents, regarding which antigens they're directed against and how to create elements that will allow for some degree of tumor specific activation.

We're learning that sometimes it's not all about the tumor cell. You can have, in the tumor microenvironment, the presence of several immunosuppressive cell populations. These are often recruited into the tumor by cytokines or chemokines produced by the tumor. There are agents directed against those, either the signals that recruit immunosuppressive populations or against the immunosuppressive populations themselves. In cooperation with checkpoint inhibitors, these have also shown some early promise in several clinical trials.

Tabernero J, A. Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E—mutant metastatic colorectal cancer: expanded results from a randomized, 3-arm, phase III study vs. the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). Ann Oncol. 2019;30(suppl_5):v851-v934. doi: 10.1093/annonc/mdz394.