Tailoring Targeted Therapies in Metastatic CRC

Syed Kazmi, MD

Metastatic colorectal cancer (mCRC) may be incurable in most patients, but Syed Kazmi, MD, said established combinations that are tailored toward specific subsets can help drive progress further. These include encorafenib (Braftovi) plus cetuximab (Erbitux) for those with BRAF mutations and trastuzumab (Herceptin) plus pertuzumab (Perjeta) for patients with HER2 amplifications.

“mCRC is still an incurable disease for most patients. In order to optimize a patient’s goals, which includes prolonging their life with a good quality of life, those patients [need to] go through all the known FDA-approved treatments. Following those guidelines and using [treatments] more effectively in the right patient population can allow a person to achieve those goals,” said Kazmi. “[We need to] learn about the disease itself, use that information to choose lines of therapies, and line them up for a patient so that they go through all the effective treatments. It can make a huge difference.”

The personalized approach cascades through multiple lines of therapy, and responses to prior treatment can be used as a factor in deciding the next course of action, he added.

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Kazmi, an oncologist at UT Southwestern Medical Center, highlighted the go-to regimens for patients with mCRC.

OncLive^®: How do you navigate between trifluridine/ tipiracil (TAS-102; Lonsurf) and regorafenib (Stivarga) in the advanced setting? What is the rationale behind choosing one vs the other?

Kazmi: After a tumor has been exposed to 5-fluorouracil [5-FU], leucovorin, and oxaliplatin or to 5-FU, leucovorin, and irinotecan and it becomes refractory, both of these options are excellent. I do not differentiate significantly between the 2 regimens; both are actually very good options to consider. It just depends upon a patient’s performance status and [additional factors]. If a patient has low burden of disease and lung metastases and is otherwise healthy [and has] a good performance status, regorafenib can be a good choice.

There have been data about improving the tolerability of regorafenib by slowly tapering it up compared with starting at the full dose and then [de-escalating the dose]. That has made a big difference. If a person has a high disease burden and significantly worse performance status, then regorafenib can add to some of those adverse effects.

Having said that, on the opposite end, you have TAS-102, [which] is also an effective FDA-approved treatment [that can be used] in this [setting]. That medication definitely has a role in mCRC. If a patient has had a good response previously to 5-FU–based therapy or maintenance, then switching to TAS-102 is also a great option.

[Additionally], recent data [emerged from Denmark] concerning TAS-102 with bevacizumab [Avastin]. It was a randomized study [demonstrating] that adding an antiVEGF therapy to TAS-102 led to improved progression-free survival. I have incorporated that into my practice as well.

What targeted regimens have changed the way you approach your patients?

We do not consider CRC to be a homogeneous disease; it is heterogeneous. For example, we talked [in the webinar] about the presence of mutation in the BRAF gene and alterations in HER2—more specifically, amplification—and fusions in NTRK. Those subsets are treated differently in the second-line setting and beyond.

Patients with microsatellite instability–high [MSI-H] disease are treated differently with immunotherapy now in the first and subsequent lines of therapy. When we reach that third-line option, we try to tease out if the cancer belongs to any specific group.

Ideally, that information should be available up front when a patient receives a diagnosis of stage IV disease, but the utility becomes more relevant in the third- or later-line setting.

If a patient has a BRAF mutation and has not received a BRAF-targeted therapy, that will be important to consider. Most recently, the phase 3 BEACON study [NCT02928224] looked at encorafenib along with cetuximab; another arm [utilized] encorafenib, cetuximab, and binimetinib [Mektovi].

However, the updated analysis [indicated] that the doublet arm was equal to the 3-drug arm; [therefore], a 2-drug combination is now the standard for BRAF-mutated CRC.

Similarly, for HER2-amplified CRC, clinical trials are looking at a combination of anti–HER2-based therapy—more specifically, trastuzumab [Herceptin] and pertuzumab [Perjeta]—which is being studied compared with irinotecan and cetuximab. We are participating in that clinical trial.

A patient with HER2-amplified CRC who has not received anti-EGFR therapy in the first- or second-line setting is eligible for that clinical trial. There are other data with trastuzumab plus lapatinib [Tykerb], and also, a recent antiHER2-based antibody-drug conjugate has been listed in the National Comprehensive Cancer Network guidelines based on some recent positive data.

For MSI-H disease, if a patient has not previously received immunotherapy, then [one should] definitely consider immunotherapy at that point. [Additionally], a large group of patients may not have any such option available. In those patients, regorafenib, TAS-102 with or without bevacizumab, or a clinical trial is very relevant to consider.

Could further identification of biomarkers help answer some of the ongoing questions in CRC?

Some biomarkers we already know about, such as RAS and PIK3CA. For PIK3CA, some inhibitors are available and are used in other tumors, but they have not panned out so far in CRC.

However, people are looking at other interesting biomarkers. Slowly and gradually, we will tease out more subsets in CRC and provide more specific therapies to each [individual patient], but that is yet to come.

What other patient populations should be an area of focus for research?

Another important group that we definitely need to pay attention to is young-onset CRC. These patients may have mutations present that may be different vs those who have standard-onset CRC. Secondly, in my practice, [I confirm multiple ways to determine if a patient has microsatellite stable [MSS] disease].

If [MSS status is confirmed]—for example, [through] immunohistochemistry [IHC] in a young person—I do a polymerase chain reaction [PCR] test as well. If a PCR-based test has been done first, then I also do an IHC test. [This is] because there is a small—5% to 10%— discrepancy in those tests. Immunotherapy, which has [demonstrated] some durable, long-term responses, is worthwhile to consider. Taking that extra step to confirm if this tumor is MSS or not can make a big difference for those patients.