Balancing RAF, MEK, and EGFR Inhibitor Doses to Achieve Clinical Responses and Modulate Toxicity in BRAF V600E Colorectal Cancer

INTRODUCTION

Recent years have seen dramatic clinical advances in targeting the ERK pathway with the US Food and Drug Administration approval of several selective inhibitors of RAF and MEK.^1-5 Clinical trials of these agents indicate that near-complete inhibition of pathway signaling is necessary to effectively inhibit tumor growth.⁶ Targeted approaches have been most successful in BRAF V600E tumors because of the relatively wide therapeutic index of RAF inhibitors (vemurafenib and dabrafenib), which inhibit signaling in cells with BRAF V600 mutants but cause paradoxical activation of ERK signaling in normal cells that are wild type for RAF kinases. In contrast, MEK inhibitors (trametinib and cobimetinib) suppress ERK signaling in all cells, and their clinical activity has been limited by a narrow therapeutic index. Combining these agents (with RAF and MEK inhibitors for BRAF V600E melanoma or lung cancer and with RAF, MEK, and epidermal growth factor receptor [EGFR] inhibitors for BRAF V600E colorectal cancer) to profoundly inhibit ERK signaling has led to improved antitumor activity.⁷ Combination therapy has also been shown to offset the toxicities caused by RAF inhibitors, such as the development of keratoacanthoma and squamous cell carcinoma, resulting from paradoxical ERK activation with these agents.

The role of RAF inhibitors in offsetting MEK inhibitor toxicity and the need for dose intensity to modulate opposing toxicities is less clear. Recent observations in clinical trials have suggested that RAF inhibitors offset dermatologic toxicity resulting from MEK or EGFR inhibitors. In the phase III trial of trametinib in melanoma, grade 3 or 4 acneiform dermatitis occurred in 8% of trametinib-treated patients, whereas in the phase III trial of the combination of dabrafenib and trametinib, no patient had grade 3 or 4 acneiform dermatitis.^8,9 Combinations of RAF and EGFR inhibitors have also had a lower incidence of acneiform rash than seen with EGFR inhibitors alone.^7,10,11 This is also likely because of the opposite effects of RAF and EGFR inhibitors on MEK activation in normal cells. However, the doses of RAF inhibitors needed for these clinically opposing effects and how these doses compare with clinically efficacious doses have not been studied. We now report the course of a patient with BRAF V600E colorectal cancer treated with dabrafenib, trametinib, and panitumumab in a phase II clinical trial and characterize the effect on toxicities of different dose levels of these agents in this patient. Furthermore, we find that within the clinical dose range, there is a RAF inhibitor dose that is an inflection point for the toxicity and efficacy of this regimen.

CASE REPORT

The patient, a previously healthy 61-year-old woman, underwent a right hemicolectomy for a mucinous right colon adenocarcinoma (pT4N2M0) in 2014. She received 6 months of adjuvant FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy, and imaging 3 months after completion of adjuvant therapy showed recurrent disease with peritoneal carcinomatosis (primarily omental caking) and ascites. Omental biopsy confirmed metastatic adenocarcinoma consistent with colorectal primary, mismatch repair proficiency by immunohistochemistry, and KRAS wild type and BRAF V600E by polymerase chain reaction. Subsequently, she was treated with FOLFIRI (folinic acid, fluorouracil, and irinotecan) plus bevacizumab. Within 6 months, she experienced progression of peritoneal disease. She then provided written informed consent to participate in a clinical trial for patients with BRAF V600E colorectal cancer and was started on the combination of dabrafenib (150 mg orally twice daily), trametinib (2 mg orally once daily), and panitumumab (6 mg/kg intravenously every 2 weeks), all at the full US Food and Drug Administration–approved single-agent doses (Fig 1A), with prophylactic doxycycline (28-day cycles). This study was approved by the local institutional review board and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. During the first cycle, she developed grade 2 neutropenia that was attributed to dabrafenib; therefore, the dose of this drug was decreased one dose level to 100 mg orally twice daily. In the second cycle, she required additional supportive medications for a grade 1 pustular acneiform rash. During the third cycle, she developed grade 3 febrile neutropenia attributed to dabrafenib, and the dabrafenib dose was further reduced to 75 mg orally twice daily. One week after this dose reduction, she developed grade 2 pustular acneiform rash on her face, arms, chest, and abdomen (Fig 1B). Trametinib was reduced one dose level to 1.5 mg orally once daily and panitumumab to 4.8 mg/kg intravenously every 2 weeks for worsening rash. Despite these modifications, during the fourth cycle, the rash became grade 3; skin cultures were positive for methicillin-sensitive Staphylococcus aureus, and she was treated with sulfamethoxazole and trimethoprim. Given the lack of response of the rash to medical treatment, with sponsor approval, the dose of dabrafenib was escalated to 100 mg orally twice daily during the fifth cycle, which was followed by clinical improvement of skin toxicity to grade 1. In terms of clinical efficacy, her disease was difficult to measure on imaging, but Response Evaluation Criteria in Solid Tumors review was consistent with stable disease on the computed tomography evaluations at the 6-, 12-, and 18-week assessments. With treatment, she had clinical improvement of ascites and a decrease of carcinoembryonic antigen from 140 to 7.9 ng/mL. During the fifth cycle, the patient developed ascites again, and computed tomography scan confirmed large-volume ascites; there were no new sites of disease. The patient died as a result of disease progression 1 month after stopping the study treatment.

Fig 1.

(A) Timeline showing doses of dabrafenib, trametinib, and panitumumab; severity of acneiform rash; and carcinoembryonic antigen (CEA) levels. Also shown is inferred phosphorylated ERK (p-ERK) level in skin with inflection point from mild to severe ERK inhibition occurring at the dabrafenib dose of 75 mg orally twice daily. (B) Grade 2 acneiform rash, paronychia, and splinter hemorrhages.

DISCUSSION

This case shows the opposing effects of RAF inhibitors and EGFR and MEK inhibitors on skin and the importance of RAF inhibitor dose-intensity for clinical efficacy and for offsetting toxicity in combination regimens with other ERK pathway inhibitors. As the dose of dabrafenib was reduced, skin toxicity resulting from the EGFR and MEK inhibitors became more pronounced, and when the dabrafenib dose was raised, the toxicity improved, confirming that dabrafenib was modulating skin toxicity resulting from the EGFR and MEK inhibitors. Therefore, although counterintuitive, skin toxicity decreased when the dose of dabrafenib was ultimately increased after failure of maximal supportive care. Differences in RAF signaling underlie the differing effects of RAF inhibitors seen in normal and tumor tissues; in normal tissues, RAF signals as homo- and heterodimers activated by RAS, whereas BRAF V600 mutants, which lead to high ERK activation and feedback suppression of upstream signaling and RAS, signal uniquely as constitutively activated monomers. At clinically achievable doses, RAF inhibitors bind to one site in RAF. In BRAF V600–mutant tumors, this leads to suppression of activated monomers, and in tissues with wild-type RAF kinases (functioning as dimers), this leads to transactivation of RAF dimers.^12,13 Thus, clinical efficacy and the modulation of toxicity in combination regimens are linked; inhibition of BRAF V600E monomers and paradoxical activation of ERK occur at the same doses. The absence of clinically appreciable opposing effects to EGFR or MEK inhibitors in normal tissues, as occurred in this case, thus suggests inadequate occupation of the first site of RAF dimers in normal tissues as well as of BRAF V600E monomers.¹⁴

This case shows the fine balance of the RAF inhibitor dose in the clinical range for treatment efficacy and adverse effects. When the RAF inhibitor was reduced to a dose level of 50% of the recommended dose, toxicities from unopposed ERK inhibition resulting from the MEK and EGFR inhibitors became problematic, and the tumor began progressing through treatment. The inflection point for RAF inhibitors will vary with different tumor types and patients as toxicity varies among patients and efficacy varies by tumor type.¹⁵ This case suggests reescalation of RAF inhibitor dose can rapidly improve toxicity but may not overcome resistance that has developed to treatment. Although tumor progression in this case was likely multifactorial, incomplete inhibition of BRAF V600E at a lower dose of dabrafenib and the likely higher threshold to reestablish ERK suppression after incomplete pathway inhibition may have contributed to the short duration of clinical benefit of approximately 4 months. This case report shows the importance of dose intensity of the RAF inhibitor in combination regimens and, following skin toxicity, the dramatic change in RAF inhibitor effect within the clinical dose range.

AUTHOR CONTRIBUTIONS

Conception and design: Sebastian Mondaca, Rona Yaeger

Administrative support: Jonathan Hersch

Provision of study material or patients: Mario Lacouture, Jonathan Hersch

Collection and assembly of data: All authors

Data analysis and interpretation: Sebastian Mondaca, Rona Yaeger

Manuscript writing: All authors

Final approval of manuscript: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Sebastian Mondaca

Travel, Accommodations, Expenses: Roche

Mario Lacouture

Consulting or Advisory Role: Novartis, Novocure, Legacy Healthcare Services, Janssen Research & Development, Adgero Biopharmaceuticals, Galderma, Amryt Pharmaceuticals, Lindi, Debiopharm Group, Merck, Legacy Healthcare Services, Helsinn Healthcare, Celldex, Menlo Therapeutics, Johnson & Johnson, Roche

Research Funding: Veloce, US Biotest

Jonathan Hersch

No relationship to disclose

Rona Yaeger

Research Funding: Array BioPharma, GlaxoSmithKline, Novartis

Travel, Accommodations, Expenses: Array BioPharma