Anita T. Shaffer is your lead editorial contact for 

®, a twice monthly clinical news publication. A 10-year veteran of MJH Life Sciences™, she has been at the helm of the publication since shortly after joining the company in 2010. Before becoming an oncology journalist, she held a variety of editorial positions at The Times of Trenton, including metro editor. Email: anitashaffer@onclive.com

 mutations have shown efficacy in several tumor types, these drugs have demonstrated limited success in studies involving patients with colorectal cancer (CRC).

 Now, investigators are combining BRAF inhibitors with other targeted therapies in an effort to establish a new chemotherapy-free standard in patients with metastatic disease.

One of the most promising avenues of research so far is a 3-pronged attack on the mitogen-activated protein kinase (MAPK) signaling pathway, alterations of which are involved in several processes that drive tumor formation, including cellular proliferation and suppression of apoptosis. The V600E mutation in 

 causes constitutive activation of the BRAF kinase, which is part of the MAPK network. This results in increased activity and activation of downstream kinases such as MEK and ERK, further driving oncogenic processes (

 One mechanism of CRC resistance to BRAF inhibitors is associated with incomplete suppression of MAPK signaling, investigators have found.

 Previous studies have shown that although BRAF inhibitors suppress MAPK signaling in CRC, they can also lead to suppression of negative feedback signals in the pathway, which causes reactivation through other signaling proteins, including RAS and CRAF.

The efficacy of BRAF inhibitors can be improved, however, when used in the context of triplet targeted therapy for 

 V600E-mutant CRC. Triplet targeted therapy is aimed at more complete suppression of the MAPK signaling pathway through targeting of alternative feedback mechanisms that keep the pathway active.

The most advanced triplet in development combines encorafenib (Braftovi), a BRAF inhibitor; binimetinib (Mektovi), a MEK inhibitor; and cetuximab (Erbitux), an EGFR inhibitor that is approved for 

-wild-type, EGFR-expressing metastatic CRC (mCRC).

The triplet targeted combination resulted in a significant improvement in overall survival (OS) compared with cetuximab and an irinotecan- containing regimen in patients with 

 V600-mutant mCRC, according to results of the phase III BEACON CRC study (NCT02928224) presented at the ESMO World Congress on Gastrointestinal Cancer 2019 (World GI).

In BEACON, the triplet regimen resulted in a median OS of 9.0 months compared with 5.4 months in the standard-of-care control arm, leading to a 48% reduction in the risk of death (HR, 0.52; 95% CI, 0.39-0.70; 2-sided 

 <.0001). Additionally, the objective response rate (ORR) was 26% with triplet therapy versus 2% for standard therapy (

The findings mark the first evidence of a survival benefit with a chemotherapy-free regimen in a prospective, biomarker-selected population of patients with mCRC, investigators said in the World GI presentation.

 Array BioPharma Inc, the company developing the combination, plans to submit the regimen for regulatory approval during the second half of 2019.

“These are very exciting results because we’ve been trying to target 

-mutant colorectal cancer for many years,” study author Scott Kopetz, MD, PhD, associate professor in the department of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center in Houston, said in a news release. “It’s encouraging to see such a significant improvement in overall survival and response in patients with such aggressive tumor biology.”

Despite the development of new combinations, the current consensus standard of care for patients with mCRC includes the use of combination chemotherapy. First-line treatment options include 5-fluorouracil (5-FU) and leucovorin in combination with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), as well as the use of oxaliplatin in combination with capecitabine (Xeloda).

The efficacy of these treatments can be improved through further combination, with a phase III clinical trial finding that the combination of 5-FU, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) significantly improved both progression-free survival (PFS) and OS compared with FOLFIRI treatment.

 More recently, the TRIBE study (NCT00719797) found that the addition of the anti-VEGF antibody bevacizumab (Avastin) to FOLFOXIRI could further increase the efficacy of therapy in regard to ORR and PFS.

However, despite improved outcomes, these treatments often come with an increased burden of adverse effects (AEs). Investigators with the Gruppo Oncologico Nord Ovest in Italy found that patients undergoing firstline treatment with FOLFOXIRI experienced significantly higher rates of grade 2 or 3 peripheral neurotoxicity compared with those on FOLFIRI treatment (19% vs 0%; 

 <.0001), as well as higher rates of grade 3 or 4 neutropenia (50% vs 28%; 

Similarly, the TRIBE study found higher rates of grade 3 or 4 AEs in the experimental (FOLFOXIRI) group, dominated by neutropenia, diarrhea, stomatitis, and peripheral neuropathy.

By contrast, in the BEACON trial, the most frequently reported grade ≥3 AE occurring in at least 2% of patients in either combination therapy arm was diarrhea, reported in 10% of participants in both the triplet and standard therapy arms. Other grade ≥3 AEs included abdominal pain (6% vs 5%), nausea (5% vs 1%), and pulmonary embolism (4% vs 4%) in the triplet and standard therapy arms, respectively.

Overall, the occurrence of serious AEs was reported in 42% of patients in the triplet arm, which had a median 21-week duration of exposure, compared with 37% in the standard therapy group, which had a median of 7 weeks of therapy. The rate of discontinuation of all drugs due to any AE was lower in the triplet arm at 7% than in the control group at 11%.

Table. Findings for Primary Endpoints in BEACON CRC Trial

In commenting on the World GI data, Andrés Cervantes, MD, PhD, noted the advantages of chemotherapy-free treatment. “The fact that we can give this targeted combination without the need for chemotherapy is very good news for patients, not least because of the side effects that they typically experience with chemotherapy,” said Cervantes, director of INCLIVA Health Research Institute and professor of medicine at the University of Valencia in Spain.

Overall, an estimated 10% to 15% of patients with mCRC harbor the 

 V600E mutation, according to Kopetz and colleagues.

 mutation are particularly prognostic of poor patient outcomes.

“Sometimes patients who have this mutation have an overall survival that is about one-third of what we would normally expect,” Christopher Lieu, MD, director of gastrointestinal medical oncology at the University of Colorado Cancer Center, Anschutz Medical Campus, in Aurora, said in a recent interview with 

. “A lot of this is simply due to the fact that it is an aggressive cancer and our standard therapies do not work for it.”

Although chemotherapeutic options improve the survival prognosis for patients with CRC overall, patients with 

-mutant CRC still experience worse outcomes on treatment. The TRIBE study found that, despite the observed improvements in outcomes, mutations in 

 were still prognostic of worse PFS and OS.

 A retrospective study that analyzed the association between 

 mutations and response to bevacizumab treatment for mCRC found that although patients with 

-wild-type tumors responded similarly to treatment, 

 mutations were still prognostic of decreased OS.

Efforts to improve outcomes for patients with 

 mutations by combining a BRAF inhibitor with an EGFR inhibitor have shown only modest response rates, which ranged from 4% to 23%, according to analyses of preliminary findings from several studies.

Investigators have also tried adding chemotherapy to targeted therapy doublets, which has also shown promise in this treatment setting.

In a randomized phase II trial, patients with 

 V600-mutant treated with cetuximab and irinotecan exhibited improved median PFS (4.4 vs 2.0 months; 

 <.001) and a trend toward improved response rate (16% vs 4%; 

 = .08). Improvements in PFS and response rate upon the addition of vemurafenib (Zelboraf), a BRAF inhibitor.

Similarly, a recent case report revealed a promising response to treatment with vemurafenib and cetuximab in combination with 5-FU and irinotecan; the patient experienced a complete response, with full recession of metastases and decreased serum levels of tumor antigen.

The use of MEK inhibitors in combination with BRAF inhibitors has also been investigated for activity against CRC because MAPK pathway reactivation was found to be MEK-dependent as well.

 Similar to the response rates seen with the addition of EGFR inhibitors, a phase I/II study of dabrafenib (Tafinlar), a BRAF inhibitor, in combination with trametinib (Mekinist), a MEK inhibitor, found a modest response to treatment, with a partial response or better in 12% of patients and a reduction in target lesion size in 37% of patients.

The clear involvement of multiple arms of the MAPK signaling pathway has led to the emergence of triplet targeted therapy studies, with a focus on combinations of BRAF/MEK/ EGFR inhibitors.

The results of a phase I/II study (NCT01750918) investigating the safety and efficacy of dabrafenib plus trametinib in combination with panitumumab (Vectibix), an EGFR inhibitor that is approved for 

The triplet combination exhibited a confirmed ORR of 21% and an unconfirmed ORR of 32%, compared with ORRs of 10% and 15%, respectively, for the combination of dabrafenib and panitumumab and 0% and 1% for trametinib plus panitumumab.

The findings for the triplet were not as favorable by other measures. The median PFS was 4.2 months with the triplet, compared with 3.5 months with dabrafenib and panitumumab and 2.6 months with trametinib and panitumumab. The median OS (estimable but not mature) in the 3 arms, respectively, was 9.1 months, 13.2 months, and 8.2 months.

“Collectively, these data support the need to inhibit both EGFR-dependent and -independent feedback signals in 

 “Our data suggest that rapid emergence of resistant subclones harboring MAPK-activating alterations may be a major driver of treatment failure and that future strategies aimed at suppressing or overcoming these resistance mechanisms may help to sustain clinical benefit.”

Earlier this year, the National Comprehensive Cancer Network (NCCN) added 2 targeted therapy triplet combinations to the guidelines for patients with the 

 V600E mutation: (1) encorafenib plus binimetinib and either cetuximab or panitumumab; and (2) dabrafenib plus trametinib and either cetuximab or panitumumab. Both triplet combinations are category 2A additions to the list of potential treatment recommendations for patients with mCRC after prior therapy.

In BEACON, the investigators randomized 665 patients to treatment with the encorafenib/ binimetinib/cetuximab triplet (n = 224); doublet therapy with encorafenib and cetuximab (n = 220); or the chemotherapeutic combination of FOLFIRI or irinotecan plus cetuximab (control; n = 221). The primary endpoints were OS and ORR by blinded central review in the triplet versus the standard therapy arm.

The study recruited patients with histologically or cytologically confirmed mCRC with a 

 V600E mutation whose disease had progressed after 1 or 2 prior regimens in the metastatic setting. Patients who had been previously treated with RAF, MEK, or EGFR inhibitors were not eligible.

In the triplet arm, the median age was 62 years (range, 26-85 years), and 64% had liver metastases; regarding previous therapy, 65% had 1 line and 35% had more than 1. In the control arm, the median age was 60 years (range, 27-91 years), and 58% had liver metastases; 66% had 1 prior line of therapy and 34% had more than 1.

After a median follow-up of 7.8 months, the median OS for the triplet therapy was 9.0 months (95% CI, 8.0-11.4) compared with 5.4 months (95% CI, 4.8-6.6) for the control, which translates into an HR of 0.52 (95% CI, 0.39- 0.70; 2-sided 

 <.0001). The median OS in the doublet therapy arm was 8.4 months (95% CI, 7.5-11.0), which was also significantly higher than that in the control group (HR, 0.60; 95% CI, 0.45-0.79; 2-sided 

The study was not powered to formally compare the outcomes of the triplet and doublet therapies, Kopetz and colleagues said. Nevertheless, the OS HR data indicated a trend toward superiority of the triplet regimen to the doublet therapy among all randomized patients (HR, 0.79; 95% CI, 0.59-1.06) and among the first 331 patients randomized during the study (HR, 0.74; 95% CI, 0.53-1.04).

PFS was also longer with triplet therapy than with the control treatment. Among all randomized patients, the median PFS was 4.3 months (95% CI, 4.1-5.2) with the triplet compared with 1.5 months (95% CI, 1.5-1.7) in the control arm (HR, 0.38; 95% CI, 0.29-0.49; 2-sided 

Furthermore, the ORR for the first 331 randomized patients was higher in both targeted therapy arms than in the control group: 26% for triplet therapy (n = 111), 20% for the doublet regimen (n = 113), and 2% for the control arm (n = 107), translating into 

 <.0001 for each targeted therapy arm vs the control arm. The complete response rates for the 3 arms were 4%, 5%, and 0%, respectively.

Among participants who received a targeted combination, ORRs were higher for those who had 1 prior line of therapy versus >1: 34% versus 14% for the triplet and 22% versus 16% for the doublet, respectively. (There was no difference by line of therapy in the control arm’s ORR, which was 2% in both cases.)

Kopetz and colleagues concluded that both targeted therapy combinations have a safety and tolerability profile that should enable most patients to maintain a high dose intensity. Moreover, the triplet regimen offers improved efficacy compared with the doublet, with added but manageable toxicity.

The findings also suggest that triplet therapy is effective in earlier treatment settings, according to Kopetz and others. “At present, targeted therapy should probably be limited to the patient group treated in the BEACON CRC trial who had progressed after 1 or 2 previous lines of chemotherapy,” said Cervantes. “However, it is important that we investigate its use in other settings where more patients with BRAF mutations may also benefit, including those with less advanced metastatic disease and possibly in the adjuvant setting after primary surgery with curative intent.”

The data also underscore the importance of mutation testing in mCRC. NCCN guidelines recommend that all patients with mCRC should have tumor tissue evaluated for 

 mutations, either as a singlegene test or as part of a next-generation sequencing panel.

“We now have a specific treatment that can change the natural course of the disease in patients with 

 mutations and is better than previous therapy, so it is essential that patients are routinely tested,” Cervantes said.

Lieu also stressed the importance of mutation testing. “If 5% of our patients have a 

 mutation, and we have an effective [approach] for those patients and another 5% have 

 amplification, and we find an effective targeted therapy combination for that, just 5% here or 5% there by itself may be a small percentage. But, as you start to chip away at the ‘pie,’ you start to see better personalization of therapy for our patients,” Lieu said. “The next frontier is identifying these subsets where we can find effective therapeutic strategies for patients with particular biomarkers.”

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