Bekaii-Saab Highlights Targeted Therapy Advances in CRC

Tanios S. Bekaii-Saab, MD, FACP

Although targeted therapy developments have lagged behind in colorectal cancer (CRC), molecular subtyping of patients is pushing the field toward an era of targeted treatment, said Tanios S. Bekaii-Saab, MD, FACP.

"I hope we can continue along the track of other cancers where identifying these subgroups has transformed survival outcomes for some patients," said Bekaii-Saab, who is a medical oncologist at Mayo Clinic. "I am not scared of saying the word 'cure' for stage IV colon cancer anymore because we are getting close to that. In some patients, we are achieving it."

One of the most recent examples of the emergence of targeted therapy is the April 2020 FDA approval of the combination of encorafenib (Braftovi) and cetuximab (Erbitux) for the treatment of previously treated adult patients with metastatic CRC who harbor a BRAF V600E mutation.

The approval was based on findings from the phase 3 BEACON CRC study, in which the combination was evaluated with or without binimetinib (Mektovi) in this subgroup of patients. The study demonstrated improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) with the doublet and triplet regimens.

Targeting other aberrations found in patients with CRC, such as KRAS mutations, HER2 amplifications, and NTRK fusions, could provide additional pathways toward personalizing treatment to specific subgroups of patients.

In an interview with OncLive, Bekaii-Saab, who is also medical director of the Cancer Clinical Research Office, and vice chair and section chief of Medical Oncology in the Department of Internal Medicine at Mayo Clinic, discussed the growing role of targeted therapy in CRC.

OncLive: Could you discuss the emergent role of targeted therapy in CRC?

Bekaii-Saab: For the longest time, most of our questions in CRC have revolved around [treatment selection]. Should we give FOLFOX or FOLFIRI? What about bevacizumab (Avastin) or cetuximab? Do we move to triplet regimens? Those were relevant questions.

For 2 or 3 decades, we had lagged behind in the era of biologic and immune-based therapy. Now, we are seeing a trickling in a lot of these targeted agents that are transforming how we treat and will continue to treat patients with CRC.

We know the story of microsatellite instability—high (MSI-H) and PD-L1 inhibitors, specifically pembrolizumab (Keytruda) and nivolumab (Opdivo) plus or minus a CTLA-4 [inhibitor]. That [approach] applies to about 4% of patients with CRC. NTRK fusions are present in about 0.5% of colon cancers. We have 2 agents, entrectinib (Rozlytrek) and larotrectinib (Vitrakvi), to target that fusion, and [those agents] have [led to] many patients into remission.

Could you shed light on some of the targeted therapies that are available for patients with BRAF mutations?

The subgroup of patients with BRAF V600E mutations typically [have a poor prognosis] with an average survival of about 1 year compared with a survival of closer to 3 years in the general population of patients with colon cancer. BRAF-mutant CRC accounts for 8% of all patients with CRC; that is not an insignificant number.

Over the last few months, we have seen a combination of a BRAF inhibitor such as regorafenib (Stivarga) plus cetuximab with or without the MEK inhibitor binimetinib transform the way we care for those patients. The traditional wisdom had been that EGFR inhibitors like cetuximab do not have activity [in BRAF-mutant disease]. That makes sense because BRAF is in the RAS [pathway], so EGFR inhibition is not as relevant.

Unlike in melanoma, if we block RAF in colon cancer, we see less than a 5% response rate of responses that are barely durable. This is because of the loop mechanism that makes EGFR relevant again. Therefore, we have to block EGFR and BRAF.

Could you discuss the BEACON CRC study?

The BEACON trial looked at whether we could combine cetuximab and encorafenib or the same combination with the addition of a MEK inhibitor, which is below the RAF pathway and perhaps controls for some of the escape mechanisms through MEK and pathways that feed through MEK. That was compared with standard chemotherapy of FOLFIRI and cetuximab.

The results of the BEACON study came back positive. Every end point was met, including OS, PFS, and ORR. Surprisingly, the toxicity with the 2-drug regimen was lower than expected, despite some relative overlap. The quality of life in patients was better with the doublet [compared with standard chemotherapy].

The BEACON study was done in the refractory setting, which means that patients had progressed on at least 1 and up to 2 lines of therapy. Interestingly, patients who received this regimen in the second-line setting did much better than those who received it in the third-line setting. Now, we are moving this [combination] to the first-line setting to see if we can achieve the same transformational activity.

If you look at the tail of the curve, about 20% to 30% of patients have not progressed and are alive after at least 1 year. That is remarkable for this patient population who traditionally do not do very well.

I believe this [combination] is perhaps transforming the [disease] biology for some patients. Unfortunately, [it has not been as effective] for all patients with this alteration. There is still a lot to learn.

Could you highlight the progress that has been made regarding HER2-targeted strategies?

The other target of interest is HER2 amplification, which is present in about 3% to 4% of patients. It is only relevant in RAS wild-type patients. When RAS is mutated, it counteracts the meaningfulness of a HER2 amplification.

Patients who have a HER2-amplified tumor do not respond to EGFR inhibitors. That is important to note because we can spare those patients EGFR inhibitors. It turns out that HER2-amplified patients have a better biology than the average patient. However, chemotherapy may not be effective [in these patients]. We knew from breast cancer and gastric cancer that HER2-targeting agents could change outcomes for patients. We've seen that happen with trastuzumab (Herceptin) plus lapatinib (Tykerb) or pertuzumab (Perjeta) at a 20% to 30% response rate and interesting PFS and OS. Those were certainly important studies that established added guidelines [for HER2-targeted therapy].

We presented data with the oral TKI tucatinib (Tukysa). That agent is more specific to targeting HER2 and is very well tolerated when added to trastuzumab. At the 2019 ESMO Congress, we presented data on 26 patients. We are [planning] to update those data to include 45 patients. To date, we've seen a 55% response rate—the highest response rate reported [in these patients]—as well as ease of administration and long PFS with tucatinib in patients with HER2 amplifications. We see those trends continue.

Interestingly, once patients achieve a complete response in their symptoms, biochemical responses occur within 3 to 6 weeks. While tucatinib has not been compared head-to-head with other regimens, we are hopeful this will become another targeted strategy available to our patients.

Have we seen the same success with targeted agents for patients with KRAS mutations?

We have had an incredibly difficult time due to confirmation issues and an inability to find the key to [unlock treatment for patients with] KRAS mutations. We could not target KRAS, which is present in about 2% to 3% of patients with CRC. We see a higher rate in appendiceal cancer, which is a rare subset of colon cancer. In those patients, agents targeting KRAS G12C are being developed.

KRAS mutations seem to be immunomodulatory. As such, strategies that target KRAS plus immunotherapy are being explored preclinically. That may bring immunotherapy into non—MSI-H tumors.

It is an exciting time in colon cancer. There are other [strategies] as well. We are starting to piecemeal colon cancer into subgroups.

What role do antibody-drug conjugates (ADCs) play in CRC?

Overall, there is a whole platform being developed for these agents that is based on a delivery of cytotoxic agents directly into tumor cells. Some of these targets are being developed in CRC with fam-trastuzumab deruxtecan-nxki (Enhertu). The agent looks promising in a number of cancers.

The principle [of ADCs] is a bit different because rather than targeting the receptor directly, the agent delivers a killing dose of cytotoxic therapy into the tumor. One may argue that the target itself is also affected by this because we are essentially preventing dimerization or other effects that [the target] typically has. In turn, there may be some direct-targeting effects.

Those agents are also interesting because they deliver these cytotoxic agents intratumorally, sparing the patient the toxicities associated with systemic chemotherapy. It is a promising way to target tumors.

Interestingly, these agents may fit [into sequencing] for patients who progress on trastuzumab and tucatinib, for example. Today, we don't have any evidence that targeting HER2 beyond HER2 failure works, but with these agents it makes sense. [When a patient progresses on another agent], we are specifically shutting down the receptor dimerization and receptor activity. When that fails, the receptor is still there. If we take advantage of this through this ADC-specific mechanism, we won't be as concerned with chasing down the activity of the receptor and instead, will use the target as a docking station to deliver the chemotherapy into the cancer cell.

Where do you see the future of targeted therapy headed?

At this point in time, I am excited about these targeted strategies. As we start moving the knowledge that we have acquired into the metastatic setting to see how we are transforming biology with BRAF-targeted strategies, immunotherapies, and now with emerging HER2-targeted strategies, we have to ask, "How do we bring those therapies into the adjuvant setting?" We already have studies [ongoing] with atezolizumab (Tecentriq) in MSI-H patients. We have planned studies [for patients with] BRAF-mutated colon cancer in earlier stages with the hope of inducing a more favorable biology and ultimately, curing more patients with early-stage colon cancer.

The last area of research that is being actively looked at in adjuvant colon cancer is the role of minimal residual disease (MRD) as measured by circulating free DNA (cfDNA) assays. Prognostically, we know that if a patient has some cfDNA, the likelihood of recurrence is higher. However, we do not know what that means in terms of predicting for [response to] chemotherapy or intensifying follow-up [treatment].

Overall, we are seeing great improvements in understanding subtypes of colon cancer, moving [effective agents] to the adjuvant setting, continuing to define oligometastatic disease and the role of locoregional therapies, and understanding risk stratification. In the next few years, we will move the needle in a very positive direction, in which we cure a lot of patients even with later-stage disease.

Editor's Note: This interview took place before the 2020 ASCO Virtual Scientific Program. A posthoc updated analysis of the phase 3 BEACON CRC trial was presented during the ASCO virtual platform.

Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632-1643. doi:10.56/NEJMoa1908075