Improvements in Clinical Outcomes for BRAFV600E-Mutant Colorectal Cancer

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Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer

Improvements in Clinical Outcomes for BRAFV600E-mutant Metastatic Colorectal Cancer

Authors: Van K Morris,1 Tanios Bekaii-Saab2

Affiliations: 1University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Mayo Clinic College of Medicine and Science, Phoenix, Arizona

Corresponding author: Name: Tanios Bekaii Saab Address: Mayo Clinic, 5881 E Mayo Blvd, Phoenix, Arizona, 85054 Tel: +014803422501 Email: [email protected]

Running title: BRAFV600E-mutant metastatic colorectal cancer

Acknowledgments

Publication of this article was supported by Pfizer Inc (formerly Array BioPharma), who were given the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the authors’ discretion.

All authors meet the authorship criteria of the International Committee of Medical Journal Editors, take responsibility for the integrity of the work and provided final approval of the version to be published.

Medical writing support was provided by Alex Lowe, PhD of Touch Medical Communications and subsequently by JD Cox, PhD of Mayville Medical Communications (funded by Pfizer

Inc).

Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer

Conflicts of interests

TBS is a paid consultant for Imugen and a paid IDMC member for Exelixis, Astra Zeneca, Silajen and

Armo. He is also a consultant for Array Biopharma, Bayer, Amgen, Incyte, Ipsen, Merck and Seattle

Genetics. VKM is a consultant for Array Biopharma and Incyte, and has research support from EMD

Serono, Astra Zeneca, Bristol Myers Squibb, and Array Biopharma.

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Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer

Abstract

Although the last two decades have seen a broad improvement in overall survival, colorectal cancer

(CRC) is still the second leading cause of cancer deaths worldwide. Patient populations continue to face poor disease prognoses due to the challenges of early detection and the molecular subtypes driving their CRC. Consequently, many patients present with metastatic CRC, which often limits options and shifts treatment focus away from curative interventions. BRAFV600E mutations are present in approximately 10% of CRC tumors and are associated with uninhibited cell proliferation, reduced apoptosis and resistance to standard therapeutic options. In CRC, BRAFV600E mutations are associated with decreased overall survival, poor treatment responses, and different patterns of metastatic spread compared to tumors with wildtype BRAF. Success in treating other BRAF V600E- mutant cancers with BRAF inhibitors as monotherapy has not translated into efficacious treatment of metastatic CRC. Consequently, combination therapy with inhibitors of BRAF, MEK, and epidermal growth factor receptor, which overcomes the innate treatment-resistant characteristics of BRAF

V600E-mutant CRC, is now recommended by treatment guidelines.

Keywords (Max 5): Colorectal cancer, biomarker, metastasis, MAPK signaling, BRAFV600E

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer

Introduction

Colorectal cancer (CRC) is a common cause of morbidity and mortality, and currently the second and third most common cancer worldwide in women and men respectively, accounting for 1.8 million new diagnoses and approximately 880,800 deaths in 2018.(1),(2),(3),(4) Given the inherent clinical challenges in diagnosing CRC including variable symptomatic presentation, natural history, rate of progression and tumor mutations, there is now a focus on the role of biomarkers in disease identification and predicting treatment responses.(5) Promising new treatments being explored for the treatment of CRC include inhibitors of critical oncoproteins in the MAPK signaling pathway, including MEK, BRAF and epidermal growth factor receptor (EGFR).(6)

A key pathway in the pathogenesis of CRC is the mitogen-activated protein kinase (MAPK) signaling pathway.(7) Dysfunction of this pathway, including the RAS, RAF, and MEK kinases leads to increased cell proliferation and survival by the disruption of apoptosis.(7) Activating point mutations of the RAS family genes (H-RAS, K-RAS, and N-RAS) are common and comprise up to 30% of all human cancers.14 In this pathway, BRAF is a serine/threonine kinase downstream of EGFR and RAS.(7)

Mutations in the BRAF gene most commonly result in a substitution of valine to glutamic acid at the

600th amino acid (BRAFV600; approximately 90% of BRAF mutations) and are mutually exclusive from

KRAS/NRAS mutations.(6, 8, 9) BRAF mutations lead to a conformational change of RAF kinase, leading to the activation of BRAF kinase and the downstream MAPK pathway, subsequently driving increased tumor cell proliferation and anti-apoptotic behavior.(6) BRAFV600E mutations occur in approximately 10% of cases of CRC (estimates range from 5% to 21%),(6, 9-17) as well as being present in 51% of papillary thyroid cancers, 7% of non-small cell lung cancers and 40 to 60% of melanoma cases.(6, 8, 9, 14, 18-20) In recognition of the importance of BRAF V600E mutations in CRC, screening is recommended in the National Comprehensive Cancer Network (NCCN) guidelines.(21,

22) However, despite these recommendations, testing rates for BRAFV600E mutations may be as low

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer as 11.5% before first-line treatment initiation, once again highlighting the need for a more comprehensive screening effort.(23)

Understanding the clinical impact of BRAFV600E mutations

Due to their association with dysregulation of the MAPK pathway, the BRAFV600E mutation is an important prognostic biomarker and has predictive implications for patients with metastatic CRC.(6,

24, 25) In contrast, the less-common BRAFnon-V600 mutations, which are found in approximately 2% of patients with metastatic CRC, are associated with an improved disease prognosis compared with patients with BRAFV600E-mutant metastatic CRC.(26) The increasing incidence of BRAFV600E mutations with age in CRC may be a contributing factor to worse overall prognosis of patients with this mutation.(8) Additionally, mutations in BRAFV600E are associated with higher rates of bone, brain, and peritoneal involvement, a unique pattern of metastatic spread and worse health-related quality of life (HRQoL), relative to their BRAFV600E wildtype counterparts.(27-29)

A number of studies have demonstrated worse prognosis with BRAF V600E-mutant compared with

BRAF V600 wildtype CRC.(8, 30-33) In one study (n=229), patients with BRAF V600E-mutant/KRAS- wildtype CRC demonstrated significantly reduced overall survival (OS) compared with patients with

BRAF V600-wildtype/KRAS-wildtype tumors (11.0 months vs 40.6 months; HR 4.25, 95% confidence interval [CI]: 2.08–8.67; p<0.001).(30) Similarly, a separate study (n=504) evaluating the detection of mutant BRAF V600E as part of daily clinical practice found that regardless of time of first-line intervention, there was a significant reduction in OS (14.0 months vs 34.6 months; HR: 5.43; 95% CI:

3.60–8.18; p<0.001), in addition to worsened progression-free survival (PFS) (4.1 months vs 11.6 months; HR: 4.07; 95% CI: 2.66–6.20; p<0.001) with BRAF V600E-mutant compared with BRAF V600- wildtype CRC.(31) Additionally, 5-year OS of patients with stage I–IV BRAFV600E-mutant CRC has been reported to be 47.5% compared with 60.7% in patients with wildtype tumors.(32) These findings are

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer supported by a recent real-world analysis (n=503) that observed a median OS of 18.2 months for

BRAF V600E-mutant metastatic CRC compared with an OS of 41.1 months for patients with BRAF V600- wildtype CRC (HR 2.74; 95% CI: 1.60–4.70; p<0.001).(33) These results were observed despite both groups of patients receiving a median of 2 lines of systemic treatment (range 0–4) and a similar proportion of patients receiving up to three lines of treatment.(33)

In addition to poor disease prognosis, patients with BRAF V600E-mutant metastatic CRC also have poor disease outcomes in response to treatment. A retrospective database study (n=1,567) demonstrated that across a range of systemic therapies, the median PFS was 6.3 months following first-line treatment, dropping to 2.5 and 2.6 months following second- and third-line treatment.(34) Similarly,

OS was not significantly affected by standard first-line therapy, with the open-label, Phase III

Treating Patients with Metastatic CRC (TRIBE) study (n=508), with patients BRAF V600E-mutant compared with BRAF V600-wildtype CRC demonstrating significantly shorter OS (13.4 vs 37.1 months;

HR: 2.79; 95% CI: 1·75–4·46; p<0.0001) despite treatment with FOLFOXIRI (oxaliplatin, irinotecan, fluorouracil and leucovorin) or FOLFIRI (leucovorin, fluorouracil and irinotecan), both in addition to bevacizumab.(35)

Disease outcomes for patients with BRAF V600E-mutant CRC also remain poor following second-line or subsequent anti-EGFR therapy, with a significantly shorter median OS compared with patients with

BRAF V600E-wildtype CRC (4.3 months vs 17.4 months; p<0.0001) and worse PFS (2.2 months vs 6.0 months; p<0.0001).(31) These data are supported by a translational research study of 150 patients, which found patients with BRAF V600E-mutant compared with wildtype CRC had a median OS of 4.6 versus 14.5 months, respectively and PFS of 1.6 months, compared with 5.9 months despite anti-

EGFR therapy, respectively; although it should be noted that only nine patients with mutant BRAF

V600E were included.(36) Results of the latter study were observed despite patients having a wildtype

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer

RAS genotype, which have been associated with better responses to anti-EGFR therapy compared to mutant forms of RAS.(37) These results support the role of BRAF V600E mutation as a biomarker of anti-EGFR antibody monotherapy resistance. Mechanistically, BRAF V600E mutation confers poor outcomes with anti-EGFR therapy by activating the Ras-Raf-MAPK pathway downstream/independent of EGFR blockade.(10,35) similar to the impact of the RAS mutations, another known biomarker for anti-EGFR therapy resistance in metastatic CRC.

Underlying poor disease prognosis in patients with BRAF V600E-mutant CRC is the unique pattern of metastatic spread compared with wildtype BRAF V600 tumors. A number of studies have found that mutant BRAFV600E tumors are most likely to be right-sided and metastasize to the peritoneum rather than the lung or liver.(27, 28) Furthermore, survival following metastasectomy is significantly shorter for patients with BRAFV600E-mutant compared with BRAF V600E wildtype tumors.(28) An additional factor underlying poor prognosis may be distinct patterns of disease progression following first-line therapy in patients with mutant and wildtype BRAFV600.(24) A study using individual patient data from three clinical trials (n=2,530) found that one-third of patients with mutant BRAFV600E were more likely to progress rapidly through first-line therapy and then subsequently deteriorate rapidly, while patients with an initial good outcome to first-line therapy were more likely to progress after therapy ceased compared with patients with wildtype BRAFV600.(24)

On an individual patient level, BRAFV600E-mutant metastatic CRC is associated with worse HRQoL than for patients with RAS-mutated or BRAF/RAS wildtype tumors, with the former group of patients having worse social functioning and reduced daily function due to fatigue, dyspnea and diarrhea.(29)

Additionally, poor global HRQoL scores, and in particular physical functioning, pain and fatigue continued to be worse in patients with BRAFV600E-mutant compared with BRAF wildtype tumors across 12 treatment cycles of chemotherapy with or without cetuximab.(29) A number of case

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer studies of patients with CRC have highlighted the individual patient burden of the disease.(38-40)

These case studies include a 60-year-old women presenting with blood in her stool, a 45-year-old man presenting with a 3-month history of weight loss and anemia due to an adenocarcinoma involving the hepatic flexure of the colon and the liver, and a 55-year-old man presenting with poorly-differentiated stage IIIb adenocarcinoma of the transverse colon. All patients had BRAFV600E- mutant CRC and experienced disease progression despite multiple lines of therapy, indicating the high burden BRAFV600E-mutant CRC exerts on patients.(38-40) Underlying the further impact of poor

HRQoL is the finding that HRQoL is an independent predictor of survival, with every 10-point worsening from baseline global HRQoL score associated with a 7% increase in the risk of death.(41)

Furthermore, it has been proposed that HRQoL may directly influence tumor behavior and survival, or influence patient therapy adherence.(42)

Limited duration of response and acquired resistance to currently available therapies presents a challenge for the management of BRAF V600E CRC.(43-45) Feedback reactivation of receptor tyrosine kinase signaling causes insensitivity of BRAF V600E CRC to RAF inhibitors as monotherapy.

Resistance also eventually develops when RAF and EGFR inhibitors are combined, limiting duration of response. The rapid acquisition of resistance, either due to dimerization problems, or to the activation of parallel pathways, needs to be addressed to improve the efficacy of RAF inhibitors. Of note, a recent study demonstrated that mechanisms of resistance converge on formation of RAF dimers and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant CRC.(43)

Further investigation to better understand the mechanisms of resistance to BRAF inhibition is an active area of research. For example, recent studies have suggested that sustained BRAFV600E tumor growth may be facilitated by increased Wnt pathway signaling in cooperation with MAPK pathway

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer signaling.(44) Pan-RAF inhibitors currently undergoing evaluation are also interesting, because they have been synthesized to be ‘paradox breakers’, by not inducing RAF paradoxical activation. New drugs, new combinations, and new targets are urgently required in this disease.(45)

Challenges in the treatment of BRAF V600E-mutant colorectal cancer

The NCCN Guidelines include a number of recommended therapies for the management of metastatic colon and rectal cancer.(21-22) The recommendations note that choice of therapy should consider a number of factors, including goals of therapy, the type and timing of previous therapies, the genomic profile of the tumor, and the safety profile of the potential agents. NCCN guidelines emphasize that their treatment recommendations represent a continuum of care and the lines of treatment in real-world practice are often blurred rather than discrete.(21-22)

For initial systemic therapy for patients with advanced or metastatic BRAF-mutant CRC who are appropriate candidates for intensive therapy, the NCCN guidelines recommend FOLFOX, CAPEOX,

FOLFIRI, FOLFOXIRI, 5-FU/leucovorin, CAPEOX, or capecitabine with or without either bevacizumab,

For first-line patients who are not appropriate for intensive therapy, NCCN recommends infusional

5-FU/leucovorin or capecitabine (with or without bevacizumab), as well as immunotherapy for dMMR/MSI-H patients as options (21, 22) For subsequent therapy after failure of initial therapy,

NCCN guidelines recommend a regimen with a BRAF inhibitor plus a MEK inhibitor, with either cetuximab or panitumumab for patients with BRAFV600E-mutant mCRC.(21, 22)

In the TRIBE study, FOLFOXIRI plus bevacizumab demonstrated benefit over FOLFIRI plus bevacizumab in patients with metastatic CRC including a small subset of patients with BRAFV600E- mutant CRC, raising the question of whether FOLFOXIRI plus bevacizumab should be considered as a first-line treatment.(35, 46, 47) However, there is debate about how widely the FOLFOXIRI plus

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer bevacizumab combination should be employed due to concerns about the general applicability of the results to all patients with metastatic CRC, including those with mutant BRAF V600E.(48)

Furthermore, a meta-analysis of the BRAF V600E-mutant subgroups of the STEAM, TRIBE and CHARTA trials found no significant difference in PFS between FOLFOXIRI, FOLFIRI, or FOLFOX, all in addition to bevacizumab in patients with BRAF V600E-mutant CRC.(49)

A number of BRAF inhibitors including vemurafenib, dabrafenib and encorafenib, are now available

V600E and have demonstrated clinical efficacy in BRAF -mutant melanoma, thyroid cancer and non- small cell lung cancer.(50-55) These findings have not translated into BRAF V600E-mutant CRC in studies of single-agent BRAF inhibitor.(56-58) In a Phase II open-label trial of 21 patients with

BRAFV600E-mutant metastatic CRC, vemurafenib therapy provided no complete responses, only one partial response, with seven patients maintaining stable disease for at least 8 weeks.(56) Median PFS and OS were 2.1 months and 7.7 months respectively.(56) Similarly, in a Phase I trial of dabrafenib in patients with various types of solid tumors, a partial response was observed in only one out of eleven patients with BRAFV600E-mutant CRC.(57) Finally, in a separate Phase I study, no partial responses were reported in 18 patients with BRAFV600E-mutant metastatic CRC across two different doses of encorafenib and median PFS was 4 months.(58) The lack of a meaningful clinical responses with the use of single-agent BRAF inhibitors in BRAF V600E -mutant metastatic CRC in contrast to BRAF

V600E -mutant melanoma and other tumor types may be explained by the observation that, specific to

CRC, BRAF inhibition causes a rapid feedback activation of EGFR, permitting sustained MAPK activation and continued cell proliferation.(59, 60) Cancer cells with BRAF V600E mutations are highly dependent on MEK/ERK signaling and near-complete inhibition of phospho-ERK is required for tumor responses.(59, 60)

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer

The lack of clinical efficacy of either monotherapy with BRAF or EGFR inhibition in the treatment of

BRAF V600E-mutant CRC has driven a multi-target approach to treatment.(56-58) The potential benefit of this approach may lie in the interplay between BRAF and EGFR. Inhibitors of BRAF cause feedback activation of EGFR in mutant BRAF V600E-CRC, leading to continued cell proliferation, whereas EGFR- mediated MAPK pathway reactivation leads to resistance to BRAF inhibition.(59, 60) Consequently, a combination approach with BRAF inhibitors and anti-EGFR agents may overcome this feedback loop.(59, 60) This therapeutic combination has been examined in several studies of patients with

BRAFV600E-mutant CRC. In an open-label Phase I study (n=142) including 20 patients treated with the combination of dabrafenib and the anti-EGFR agent, panitumumab, the response rate in this arm was 10%, with a median PFS and OS of 3.5 and 13.2 months, respectively.(61) A total of 45% of patients in this arm had a grade 3/4 event. The most common adverse events (AEs) of all grades were dermatitis acneiform (60%), nausea (50%), fatigue (50%), and diarrhea (45%).(61) Similarly, in a pilot study (n=15) of vemurafenib plus panitumumab in 15 patients, a response rate of 13% was observed, and a median PFS and OS of 3.2 and 7.6 months, respectively.(17) A total of 54% of patients in this arm had a grade 3/4 event. The most common adverse events (AEs) of all grades were rash acneiform (53%), alkaline phosphatase elevation (33%), fatigue (27%), dry skin (27%) and arthralgia (26%).(17) The combination of encorafenib plus cetuximab demonstrated promising results in an open-label, Phase I dose-escalation trial (n=46), with an overall response rate (ORR) of

19.2%, an overall disease control rate of 76.9% and median PFS of 3.7 months.(62) In the follow-up

Phase II trial including 50 patients treated with dual therapy, initial results suggested that PFS and

ORR are 4.2 months and 22%, respectively.(63) In this study, 58% patients had a grade 3/4 AEs and the most common AEs of any grade were nausea (56%), diarrhea (54%), and vomiting (52%).(63) The addition of vemurafenib to the anti-EGFR and chemotherapy combination of cetuximab and irinotecan resulted in a numerical improvement in the response rate (16% vs 4%) and a significant improvement in median PFS (4.4 months) compared with cetuximab and irinotecan without

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer vemurafenib (4.0%, P=0.09; 2.0 months, p<0.001, respectively;).(64) Grade 3/4 AEs of neutropenia

(33% vs 7%), diarrhea (24% vs 13%) anemia (13% vs 0%), and nausea (20% vs 2%) were more common with vemurafenib add-on therapy than cetuximab and irinotecan alone.(64) Despite improvements in activity, these regimens did not demonstrated similar efficacy results observed in other tumor types and therefore new regimens with better profiles continued to be pursued.

Other strategies to overcome the lack of efficacy of BRAF inhibitors alone include combining these agents with a MEK inhibitor. As inhibition of the MAPK pathway with BRAF inhibitors alone in

BRAFV600E-mutant CRC is incomplete, the addition of a MEK inhibitor may result in more potent and sustained suppression of MAPK signaling and with it improved efficacy, as has been demonstrated in vitro.(65) MEK inhibitors may assist in overcoming MAPK reactivation that results from strong BRAF inhibition that may release upstream receptors from feedback inhibition. The reactivation of upstream receptors leads to MAPK signaling through RAS and the formation of RAF dimers. These

RAF dimers are insensitive to BRAF inhibitors, but may be sensitive to MEK inhibitors, which do not exhibit selectivity for BRAF V600E mutant cancer cells.

Clinically, this combination has been investigated in a number of studies of patients with BRAFV600- mutant melanoma.(66-69) Improved patient response rates, PFS and OS, with a similar incidence of

AEs were demonstrated with dabrafenib plus trametinib, and vemurafenib plus cobimetinib in the

Phase III COMBI-d (n=423) and coBRIM studies (n=495), respectively.(66, 67, 70) Additionally, the randomized, open-label, Phase III COLUMBUS study (n=577) demonstrated that the combination of encorafenib and binimetinib significantly improved PFS and OS compared with encorafenib or vemurafenib monotherapy, respectively.(68, 69) BRAF/MEKi therapies are associated with characteristic adverse events, but each of the established combinations has a distinct safety profile with unique toxicities. Within the limitations at evaluating across melanoma phase 3 trials,

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer encorafenib + binimetinib appears to have a distinct safety profile as compared relative to other anti-BRAF/MEK targeted therapies, with much less pyrexia than dabrafenib/trametinib and less photosensitivity than vemurafenib/cobimetinib.(71, 72) In BRAF V600E-mutant metastatic CRC, results so far have been less impressive than in melanoma. An open label, Phase I/II study of 48 patients found that the combination of dabrafenib plus trametinib resulted in a response rate of 12% and a median PFS of 3.5 months, with 56% of patients achieving stable disease.(73)

Overall, these results suggest that even with dual MAPK pathway blockade, suppression of this pathway is still suboptimal in CRC and highlights the complex treatment challenges of treating BRAF

V600E-mutant metastatic CRC.(61) Therefore, the disease may require an evolving approach to overcome inherent and acquired resistance to the current treatment options.

Expanding the treatment horizon: New data on BRAF/EGFR +/- inhibition in BRAF V600E

CRC

Several new treatment options are emerging in the pursuit of improving outcomes in difficult-to- treat CRC, including targeting EGFR activation to overcome the resistance to BRAF and MEK inhibition observed in BRAF V600E-mutant metastatic CRC. Preclinical and clinical data have suggested that combination therapy could play a key role in improving treatment outcomes.(59, 60) In addition, MEK inhibition may mitigate some BRAF associated toxicities and vice versa. For example,

BRAF inhibitors have been associated with keratoacanthomas/SCC/melanoma but this risk is decreased when given with MEK and/or EGFR inhibitors, while conversely the acneiform rash of MEK and/or EGFR inhibitors is less severe when these drugs are combined with BRAF inhibitors.(74, 75)

To date, two combinations of BRAF, MEK and EGFR inhibitors have been explored: dabrafenib plus trametinib plus panitumumab and encorafenib plus binimetinib plus cetuximab, although the patient

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer populations were different (first-line patients were enrolled in the dabrafenib/trametinib/panitumumab study, whereas encorafenib/binimetinib/cetuximab study was

nd rd 2 and 3 -line patients only).(61, 76) In an open-label, Phase I study of patients with metastatic

BRAF V600E CRC, dabrafenib/trametinib/panitumumab therapy (n=91), dabrafenib /panitumumab

(n=20), or trametinib/panitumumab (n=31) resulted in objective response rates of 21%, 10%, 0% and median PFS of 4.2, 3.5, and 2.6 months, respectively, assessed by local investigator review.(61) Of note, OS was lower for the dabrafenib/trametinib/panitumumab arm, with median OS of 13.2 months (95% CI, 6.7–22.0 months) in the dabrafenib/trametinib arm, 8.2 months (95% CI, 6.5–9.4 months) in the trametinib/ panitumumab arm, and 9.1 months (95% CI, 7.6–20.0 months) in the dabrafenib/trametinib/ panitumumab arm (estimable but not mature).(61) Grade 3/4 AEs were observed in 70%, 45%, and 67%, in dabrafenib/trametinib/panitumumab, dabrafenib

/panitumumab, or trametinib/panitumumab arms, respectively.(61) In the largest clinical study in this patient population, the triple therapy combination encorafenib plus binimetinib plus cetuximab has been investigated in 665 patients with BRAFV600E-mutant CRC after 1 or 2 prior treatment regimens in the randomized Phase III BEACON trial.(76) This was a global, multicenter, randomized, open-label, phase 3 trial comparing encorafenib (300 mg daily) plus binimetinib (45 mg twice daily) plus cetuximab (400 mg/m2 initial dose, then 250 mg/m2 weekly) (triplet combination), encorafenib plus cetuximab (doublet combination), or investigator’s choice of either cetuximab combined with irinotecan alone (180 mg/m2 on days 1 and 15), or cetuximab combined with FOLFIRI (folinic acid, 5- fluorouracil and irinotecan; control regimens). Eligible patients were randomized in a 1:1:1 ratio and stratified by ECOG performance status, prior use of irinotecan, and cetuximab formulation (United

States-licensed vs. European-approved). Primary endpoints for the BEACON CRC study were overall survival and independently reviewed confirmed objective response rate for the triplet combination compared to the control. Secondary end points included overall survival for the doublet arm compared to the control arm as well as progression-free survival, duration of response, and safety.

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer

The BEACON CRC trial also included an initial safety lead-in (SLI) to determine the safety of triple therapy and an initial assessment of treatment activity before the Phase III section of the study was initiated. Preliminary data (n=30), released as part of the protocol SLI, suggested promising benefits for this treatment approach. The triple combination had a relatively high confirmed ORR (48%), a median PFS of approximately 8 months, and a median overall survival of 15.3 months, with a median

18.2 months duration of follow-up.(76, 77) The safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen was deemed manageable and acceptable for initiation of the randomized portion of the BEACON CRC study. Reflecting these results, the 2019 NCCN guidelines update added encorafenib plus binimetinib plus cetuximab as a subsequent treatment recommendation for patients with BRAF V600E-mutant metastatic CRC after failure of one or two prior lines of therapy.(21, 22)

In the randomized portion of BEACON CRC, the triplet regimen significantly improved OS relative to the control group, with a median overall survival of 9.0 months (95% confidence interval [CI] = 8.0–

11.4 months) for the triplet regimen compared with 5.4 months (95% CI = 4.8–6.6 months) for the control regimens (hazard ratio = 0.52, 95% CI = 0.39–0.70; P < .0001).(78, 79) The OS results were consistent across a broad range of subgroups. The objective response rate for the targeted triplet therapy was 26%, compared with 2% for the controls (p<0.0001). The response rate for patients with only 1 prior line of therapy was 34% (95% CI: 23, 47) for the triplet therapy and 2% (95% CI: 0, 9) for the control, suggesting increased efficacy in earlier lines of therapy. The triplet combination also significantly prolonged progression-free survival by central review relative to the control arm

(median progression-free survival was 4.3 months (95% CI: 4.1, 5.2) for triplet arm and 1.5 months

(95% CI: 1.5, 1.7), for the control arms). The triplet combination was generally well tolerated, with no unexpected toxicities. Efficacy results favored the doublet regimen over the control as well. The safety and tolerability profile of both triplet and doublet combinations were consistent with the

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer known profiles of the component agents. Grade 3 or higher adverse events were seen in 58% of patients who received the triplet regimen, 50% of those in the doublet group, and 61% of those in the standard-therapy group. Quality of life (QOL) assessments favored the triplet regimen over the control, with no impact on maintenance of QoL for the triplet compared to the doublet.(80). An updated analysis of the BEACON CRC study that includes 6 months of additional follow-up and response data for all randomized patients was presented at the 2020 ASCO Gastrointestinal Cancers

Symposium.(81) The results of this analysis confirmed that encorafenib + cetuximab with or without binimetinib improved overall survival and objective response rates in previously treated patients with BRAFV600E mCRC compared with standard chemotherapy. Median OS was 9.3 months (95% confidence interval [CI]:8.2, 10.8) for triplet and 5.9 months (95% CI:5.1-7.1) for control (hazard ratio

[HR] (95% CI): 0.60 (0.47-0.75)). Median OS for doublet was also 9.3 months (95% CI: 8.0-11.3) (HR vs. control: 0.61 (0.48-0.77), with no difference in survival benefit with the addition of binimetinib to encorafenib and cetuximab. These outcomes represent an improvement over the current standard of care, in addition to an improvement over other BRAF inhibitor triple-therapy combinations.(49,

61, 64, 76) These data also represent the first time a targeted therapy combination for patients with

BRAFV600E-mutant metastatic CRC has demonstrated survival benefit compared with standard treatment options. Taken together, the results of the BEACON CRC study provide support for a new standard of care in patients with previously treated BRAF V600E-mutant mCRC. A trial to evaluate the triplet regimen in the first-line setting was recently initiated (ANCHOR, NCT03693170).

Immunotherapy in BRAFV600E metastatic CRC

Co-occurrence of BRAFV600E mutations has been characterized in as many as 40-50% of patients with sporadic MSI-H CRC.(32) Here, microsatellite instability arises not from Lynch Syndrome but rather from somatic hypermethylation across the tumor cell genome, including gene silencing by methylation of the MLH1 promoter. Data in metastatic CRC indicate that approximately 20-30% of

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer

BRAF mutant tumors have beaco.(79, 82, 83)

Use of immune checkpoint blockade agents targeting proteins like programmed death-1 (PD-1) and cytotoxic-T lymphocyte-associated protein 4 (CTLA-4) have demonstrated sustained antitumor activity in patients with MSI-H metastatic CRC, with 12-month survival rates reported in >70% of patients.(84-86) In the KEYNOTE-164 study using the anti-PD-1 antibody pembrolizumab as single agent therapy, 14 of the 124 patients with MSI-H metastatic CRC had BRAFV600E mutations.(84) In the

CHECKMATE-142 study, patients with MSI-H metastatic CRC were treated with the anti-PD-1 antibody nivolumab with or without the anti-CTLA-4 antibody ipilimumab.(85, 86) In the nivolumab monotherapy group, 29% of patients harbored BRAFV600E mutations, as well as 12 of 74 (16%) of patients in the combination cohort. Durable responses were seen among patients with BRAFV600E

MSI-H metastatic CRC in all of these treatment groups. These results imply that immunotherapy alone is a reasonable and effective choice for patients with treatment-refractory, BRAFV600E MSI-H metastatic CRC. For patients with BRAFV600E microsatellite stable (MSS) metastatic CRC, multiple ongoing trials are examining the efficacy of targeted agents against MAPK signaling in combination with immunotherapy: dabrafenib + trametinib + spartalizumab (NCT03668431), encorafenib + cetuximab + nivolumab (NCT04017650); and encorafenib + binimetinib + nivolumab (NCT04044430).

Concluding remarks

Despite broad improvements in diagnosis and management of CRC in recent decades, challenges remain to be addressed. There is a clear need to reduce the rate at which patients present with metastatic disease, placing an emphasis on improved awareness and screening practice. Poor prognoses for patients with BRAF V600E-mutant metastatic CRC, due to the innate treatment resistance associated with this mutation, require new treatment approaches to improve disease

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer outcomes. Currently there is an evolving treatment landscape, with recent additions to the NCCN guidelines; however, to date only modest advances in response rate and PFS have been observed with BRAF inhibitors alone. BEACON CRC phase 3 data for the triplet therapy combination of encorafenib (BRAF inhibitor), binimetinib (MEK inhibitor), and cetuximab (EGRF inhibitor) represent promising advances in the treatment of metastatic CRC, with significant improvements over existing standard of care therapy.

Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer

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Improvements in Clinical Outcomes for BRAFV600E-mutant Metastatic Colorectal Cancer

Van K. Morris and Tanios Bekaii-Saab

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