Abstract
Lessons Learned
This study suggests that trametinib has significant clinical activity in non‐V600 BRAF mutation and BRAF fusion metastatic melanoma, albeit in a small cohort.
All patients with metastatic melanoma should undergo sequencing of the BRAF gene to identify noncanonical BRAF mutations that may indicate benefit from treatment with trametinib.
Background
Non‐V600 BRAF mutations and BRAF fusions in aggregate occur in approximately 5% of all melanomas. Inhibition of the mitogen‐activated protein kinase (MAPK) pathway has been implicated as a possible treatment strategy for these patients.
Methods
In this open‐label, multicenter, phase II study, patients with advanced melanoma harboring mutations in BRAF outside V600 (non‐V600) or BRAF fusions received trametinib 2.0 mg daily. Patients were divided into cohorts based on the intrinsic catalytic activity of BRAF mutation (high, cohort A; low/unknown, cohort B). The primary endpoint was objective response rate (ORR) for patients in cohort A; secondary endpoints included ORR in cohort B, safety, and survival in both treatment arms.
Results
Among all patients, the ORR was 33% (three of nine patients), including 67% in cohort A and 17% in cohort B. Two patients had stable disease as best response, and six patients had some degree of tumor shrinkage. The median progression‐free survival (PFS) was 7.3 months. Treatment‐related adverse events occurred in all patients (100%); most (89%) were grade 1–2.
Conclusion
In contrast to recently described tumor‐agnostic studies in a genetically similar population, trametinib had considerable activity in a small population of patients with melanoma harboring BRAF non‐V600 mutations and fusions, providing rationale for sequencing in search of these genomic alterations.
Keywords: Trametinib, BRAF, Melanoma, Fusion, MEK
Discussion
Here, we report that trametinib appears to have substantial activity in a small cohort of patients with melanoma harboring non‐V600 BRAF mutations or fusions. The spectrum of mutations may impact response to trametinib; among patients with known/presumed “high activity” mutations (cohort A), ORR was 66%, compared with 33% ORR in cohort B (low/no activity BRAF mutations) (Fig. 1). Cohort A generally correlated with the newer class 2 mutation nomenclature (mutations that induce constitutively active dimerization of BRAF), whereas cohort B corresponded to class 3 mutations that retain low or no kinase activity. However, the patient with the best treatment response (−87% reduction; 19.3‐month PFS) harbored an unknown class/presumed class 3 BRAF mutation (BRAF T470R). Six of nine enrolled patients experienced clinical benefit, including four patients in cohort B. Median PFS for the full cohort was 7.3 months (Fig. 2). Most patients (7 of 9) discontinued therapy for progressive disease (Table 1).
Figure 1.
Response of BRAF non‐V600 mutant melanoma to treatment with trametinib. Abbreviations: amp, amplification; del, deletion; n/a, not applicable; PD, progressive disease; PFS, progression‐free survival; TLD, target lesion diameter.
Figure 2.
Progression‐free survival, all patients.
Abbreviation: PFS, progression‐free survival.
Table 1.
Patient characteristics, n = 9
| Variable | n (%) |
|---|---|
| Median age, years (range) | 52 (27–77) |
| Sex | |
| Male | 6 (66.7) |
| Female | 3 (33.3) |
| Primary tumor site | |
| Cutaneous | 4 (44.4) |
| Mucosal | 2 (22.2) |
| Unknown primary | 3 (33.3) |
| Mutation status | |
| BRAF class 2 | 2 (22.2) |
| BRAF class 3/unknown | 5 (55.5) |
| BRAF fusion | 2 (22.2) |
| ECOG PS | |
| 0 | 6 (66.7) |
| 1 | 3 (33.3) |
| Stage | |
| III | 1 (11.1) |
| IV M1a–b | 4 (44.4) |
| IV M1c | 4 (44.4) |
| Prior lines of systemic therapy | |
| 0 | 1 (11.1) |
| 1 | 6 (66.7) |
| 2+ | 2 (22.2) |
| Reason for discontinuation | |
| Progressive disease | 7 (77.8) |
| Toxicity | 1 (11.1) |
| Alternative therapy | 1 (11.1) |
Abbreviation: ECOG PS, Eastern Cooperative Oncology Group performance status.
In addition, patients without concurrent mutations in key cell signaling pathways seemed to have increased benefit: three of five patients with clinical benefit had no other mutations identified, whereas all four patients with progressive disease had tumors with concurrent mutations in known oncogenic drivers or tumor suppressors, including KIT, NF2, ERBB4, and PTEN. These genes activate parallel signaling networks, thus potentially circumventing MEK inhibition. This suggests that MEK inhibition for non‐V600 BRAF mutations may be more effective in the absence of mutations in other core cell signaling pathways. However, the patient with the longest duration of benefit (stable disease for 22.3 months) had a concurrent KRAS G12V mutation, demonstrating at least one exception. Our findings could have been strengthened, but the study was closed early because of slow accrual.
These data are in juxtaposition with the recently published NCI‐MATCH subprotocol assessing trametinib in patients with BRAF non‐V600 mutations and fusions. This histology‐agnostic population only demonstrated a 3% ORR [1]. In contrast, our data and several case series have shown a much higher degree of activity for MEK inhibition in advanced melanoma, with most responses occurring in so‐called class 2 mutations or fusions [2]. This suggests that histology remains a key feature of treatment response and may relate to high MAPK dependence observed in melanoma.
Over the past decade, patients have benefited from advances in immunotherapy and targeted therapy [3, 4]. Such treatments can lead to durable responses or, rarely, complete remissions, but such outcomes remain the exception. As such, it is essential that we continue to deepen our understanding of the biology of genetic drivers of melanoma, translate this understanding to the clinical setting, and continually re‐evaluate old paradigms to benefit more patients. In total, this study highlights the importance of obtaining next‐generation sequencing data (rather than targeted BRAF V600 sequencing) on patients with advanced disease, as a small but substantial subset of patients with non‐V600 mutations or BRAF fusions may benefit from MEK inhibition.
Trial Information
| Disease | Melanoma |
| Stage of Disease/Treatment | Metastatic/advanced |
| Prior Therapy | No designated number of regimens |
| Type of Study | Phase II, single arm |
| Primary Endpoint | Overall response rate |
| Secondary Endpoint | Overall response rate, progression‐free survival, safety |
| Additional Details of Endpoints or Study Design | |
| The trial was open for accrual from January 19, 2015, through July 20, 2018. The study was planned as a two‐stage, two‐cohort design with up to 25 patients per arm (50 total patients). In each arm, if at least one response was observed in the first 15 patients, an additional 10 patients would be accrued. If 4 patients of 25 patients had experienced a response in cohort A, the primary endpoint would have been met. | |
| Investigator's Analysis | Active and should be pursued further |
Drug Information: Trametinib
| Generic Name | Trametinib |
| Trade Name | Trametinib |
| Company Name | Novartis |
| Drug Type | Small molecule |
| Drug Class | MEK |
| Dose | 2.0 milligrams (mg) per flat dose |
| Route | Oral (p.o.) |
| Schedule of Administration | Trametinib 2.0 mg daily on days 1–28 of 28‐day cycle, repeated until progression or unacceptable toxicity, with dose adjustments based on tolerability |
Patient Characteristics
| Number of Patients, Male | 6 |
| Number of Patients, Female | 3 |
| Stage |
III: 1 (11.1%) IV M1a–b: 4 (44.4%) IV M1c: 4 (44.4%) |
| Age | Median (range): 52 years (27–77) years |
| Number of prior systemic therapies | Median (range): 1 (0–2) |
| Performance Status: ECOG |
0 — 6 1 — 3 2 — 0 3 — 0 Unknown — 0 |
| Other |
Primary tumor site: Cutaneous 4 (44.4%) Mucosal 2 (22.2%) Unknown primary 3 (33.3%) BRAF mutation status: BRAF class 2: 2 (22.2%) BRAF class 3: 5 (55.5%) BRAF fusion: 2 (22.2%) |
Primary Assessment Method
| Title | Response Rate |
| Number of Patients Screened | 9 |
| Number of Patients Enrolled | 9 |
| Number of Patients Evaluable for Toxicity | 9 |
| Number of Patients Evaluated for Efficacy | 9 |
| Evaluation Method | RECIST 1.1 |
| Response Assessment CR | n = 0 (0%) |
| Response Assessment PR | n = 3 (33.3%) |
| Response Assessment SD | n = 2 (22.2%) |
| Response Assessment PD | n = 3 (33.3%) |
| Response Assessment OTHER | n = 1 (11.1%) |
| (Median) Duration Assessments PFS | 7.3 months |
| (Median) Duration Assessments Duration of Treatment | 9.1 weeks |
| Outcome Notes | |
| Among three patients in cohort A, the ORR was 66%. Among six patients in cohort B who tumors harbored BRAF mutations with presumed or demonstrated low sensitivity to trametinib, ORR was 17%. ORR for defined class 2 mutations was 50% (one of two patients), 0% (zero of three patients) for known class 3 mutations, 50% (one of two patients) for unknown class, and 50% (one of two patients) for fusions. Of four patients with primary progressive disease, all had concurrent mutations in other key cancer cell signaling pathways, including KIT (n = 2), NF2 and PTEN, and MET. Of five patients with response or stable disease, three had no other concurrent mutations identified, although two did have KRAS G12V and NF1 mutations, respectively. Of two patients with mucosal melanoma, one had durable stable disease, and one had primary progression. Among all patients, median PFS was 7.3 months. Among three responders, one had progression‐free intervals of 19.3 months, 8.3 months (ongoing and changed to immunotherapy), and 1.8 months (ongoing and discontinued therapy for side effects). Two additional patients had stable disease lasting 22.3 and 7.3 months, respectively. | |
Adverse Events
| Cycle 1 | |||||||
|---|---|---|---|---|---|---|---|
| Name | NC/NA, % | Grade 1, % | Grade 2, % | Grade 3, % | Grade 4, % | Grade 5, % | All grades, % |
| Rash maculo‐papular | 11 | 11 | 67 | 11 | 0 | 0 | 89 |
| Fatigue (asthenia, lethargy, malaise) | 56 | 22 | 22 | 0 | 0 | 0 | 44 |
| Diarrhea | 56 | 22 | 11 | 11 | 0 | 0 | 44 |
| Vomiting | 78 | 0 | 22 | 0 | 0 | 0 | 22 |
| Anorexia | 78 | 11 | 11 | 0 | 0 | 0 | 22 |
| Alanine aminotransferase increased | 89 | 0 | 0 | 11 | 0 | 0 | 11 |
| Aspartate aminotransferase increased | 78 | 11 | 11 | 0 | 0 | 0 | 22 |
| Distension/bloating, abdominal | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Hair loss/alopecia (scalp or body) | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Dry skin | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Headache | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Confusion | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Edema limbs | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Edema face | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Creatinine increased | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Dyspnea (shortness of breath) | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Pruritus/itching | 89 | 11 | 0 | 0 | 0 | 0 | 11 |
| Irritability | 89 | 0 | 11 | 0 | 0 | 0 | 11 |
Adverse Events Legend
Treatment‐related adverse events occurred in all patients (100%). Most were low‐grade, with only one patient (11%) experiencing grade 3 adverse events. No grade 4 or 5 events occurred. Consistent with previously reported data on trametinib [5], the most common toxicity was rash (89%). Six of nine patients required dose reduction secondary to rash (four patients’ dose reduced to 1.5 mg, two patients’ dose reduced to 1.0 mg). Other common toxicities included fatigue (44%), diarrhea (44%), aspartate aminotransferase/alanine aminotransferase (AST/ALT) elevations (22%), and anorexia (22%). One patient discontinued treatment because of toxicity; this patient experienced grade 3 rash as well as diarrhea, elevated AST/ALT, and fatigue (Table 2).
Abbreviation: NC/NA, no change from baseline/no adverse event.
Assessment, Analysis, and Discussion
| Completion | Did not fully accrue; study terminated before completion |
| Investigator's Assessment | Active and should be pursued further |
Over the last two decades, advances in genetic sequencing have transformed cancer therapeutics through the identification of specific driver mutations with sensitivity to targeted inhibitors [6]. Mutations in the BRAF gene have been implicated as oncogenic drivers in numerous tumor types, including approximately half of melanomas as well as lung cancer, gastrointestinal cancers, thyroid cancer, hairy cell leukemia, and more [3, 7, 8, 9, 10, 11]. Over 200 mutant alleles of the BRAF gene have been identified. The most common BRAF mutation lies at the V600 codon, which alters BRAF activity such that it signals as an active monomer to robustly activate downstream mitogen‐activated protein kinase (MAPK) signaling. These mutations, classified as “class 1” mutations, have well‐characterized sensitivity to BRAF/MEK inhibitors, both alone and in combination [3]. In contrast, “class 2” mutations are known to induce constitutively active dimerization of the BRAF protein, which exhibits similarly high intrinsic catalytic activity with downstream MAPK activation. A “class 3” group of BRAF mutations is known to retain low or no kinase activity and appears to facilitate MEK/ERK signaling via upstream growth factors [12]. Class 2 and 3 mutations are thought to make up approximately 5% of all BRAF‐mutant melanomas. Beyond point mutations, numerous fusions have been reported between BRAF and over 30 unique partner proteins; such fusions remove the inhibitory RAS‐binding domain but maintain the kinase domain of BRAF, facilitating uninhibited activity [13]. BRAF fusions are thought to be found at a frequency of 1.2%–6.7% of melanomas [14, 15, 16, 17].
Trametinib, the only MEK inhibitor monotherapy approved by the U.S. Food and Drug Administration, is a selective allosteric inhibitor of MEK1/2. It has been well studied in the BRAF V600–mutant melanoma setting, and a number of case reports have suggested its activity in the non‐V600 mutant melanomas, with supporting preclinical data [18, 19, 20]. We therefore conducted a multicenter phase II trial in patients whose melanomas harbor BRAF fusions or non‐V600 mutations in BRAF. The objective of this study was to determine the efficacy of trametinib among patients whose melanoma tumors harbor mutations with demonstrated/predicted BRAF kinase activity or fusions (cohort A), as well as a broader cohort of patients whose tumors harbor mutations conferring lower or unknown kinase activity (cohort B).
In this study, we observed that trametinib had significant clinical activity in a small cohort of patients harboring non‐V600 BRAF mutations and fusions. Of nine patients, three had objective responses, and two other patients had stable disease. Particular activity was observed in cohort A, with two of three patients responding.
These data can be juxtaposed against the recently published NCI‐MATCH subprotocol assessing trametinib in patients with BRAF non‐V600 mutations and fusions. This histology‐agnostic population only demonstrated a 3% objective response rate (ORR) (1 of 32 patients) [1]. In contrast, our data and a wealth of case reports have shown a much higher degree of activity for MEK inhibition in advanced melanoma, with most responses occurring in class 2 mutations. This suggests that histology remains a key feature of treatment response and may relate to particular MAPK dependence found in melanoma.
The spectrum of mutations does appear to have some import within the melanoma histology. Among patients with known/presumed “high activity” mutation involving BRAF (cohort A), ORR was 66%, compared with ORR of 33% among the expanded cohort of high and low or no activity BRAF‐mutant tumors. However, the patient who enjoyed the best response to treatment (−87% reduction with 19.3‐month progression‐free survival) harbored a class 3 BRAF mutation and was in cohort B. Six of nine enrolled patients experienced clinical benefit, including four patients in cohort B. In addition, there seemed to be a trend toward increased benefit in patients without concurrent mutations in key cell signaling pathways: three of five patients with clinical benefit had no other mutations identified, whereas all four patients with progressive disease had tumors with concurrent mutations in known oncogenic drivers or tumor suppressors, including KIT, NF2, ERBB4, and PTEN. This suggests that MEK inhibition in non‐V600 BRAF mutations may be more effective in the absence of mutations in other core cell signaling pathways. However, the patient with the longest duration of benefit (stable disease for 22.4 months) had a concurrent KRAS G12V mutation, demonstrating at least one exception to this trend.
This study leaves several unanswered questions. It was slow to accrue (and incompletely accrued) because of the uncommon nature of these genetic alterations and the widespread advent of immunotherapy during the study time frame. It is not clear whether this population of melanomas may be more likely to respond to immunotherapy compared with nonselected populations, as non‐V600 mutations seem to occur across the spectrum of mutation burden and immune activation profiles, and small studies have suggested seemingly equivalent response rates [21, 22]. Finally, only two patients with melanomas harboring BRAF fusions were accrued. These fusions remove the inhibitory RAS‐binding domain, although preclinical evidence suggests that their response to MEK inhibitors may be influenced by their fusion partners [23]. Larger studies or case series may help address these questions.
Over the past decade, patients with melanoma have benefited from advances in immunotherapy and targeted therapy. Such treatments can occasionally lead to durable responses or, rarely, complete remissions, but such outcomes remain the exception. As such, it is essential that we continue to deepen our understanding of the biology of genetic drivers of melanoma, translate this understanding to the clinical setting, and continually re‐evaluate old paradigms to benefit more patients. In total, this study highlights the importance of obtaining next‐generation sequencing data (rather than targeted BRAF V600 sequencing) on all patients with advanced melanoma, as a small but substantial subset of patients with non‐V600 mutations or BRAF fusions may benefit at high rates from thoughtfully chosen MEK inhibition.
Disclosures
Douglas B. Johnson: Bristol Myers Squibb, Catalyst, Iovance,Merck, Novartis, Oncosec (C/A); Ryan J. Sullivan: AstraZaneca, BristolMyers Squibb, Eisai, Iovance, Merck, Novartis, OncoSec, Pfizer (C/A), Merck(RF); Roda N. Amaria: Nektar, Iovance (C/A), Iovance, Bristol Meyers Squibb,Novartis, Genentech (RF); Keith T. Flaherty: Loxo Oncology, Clovis Oncology, StrataOncology, Vivid Biosciences, Checkmate Pharmaceuticals, Kinnate Pharmaceuticals(Board of Directors), X4 Pharmaceuticals (Corporate Advisory Board), PICTherapeutics, Sanofi, Amgen, Asana, Adaptimmune, Aeglea, Shattuck Labs, Tolero,Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros, Vibliome(SAB), Lilly, Novartis, Genentech, Bristol‐Meyers Squibb, Merck, Takeda,Verastem, Boston Biomedical, Pierre Fabre, Debiopharm (C/A), Novartis, Sanofi(RF), Clovis Oncology, Strata Oncology, Checkmate Pharmaceuticals, KinnatePharmaceuticals, X4 Pharmaceuticals, PIC Therapeutics, Shattuck Labs, Apricity,Oncoceutics, Fog Pharma, Tvardi, xCures, Monopteros, Vibliome (OI). The otherauthors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Figure and Tables
Table 2.
Toxicity (n = 9)
| Event | Any grade, n (%) | Grade 3+,a n (%) |
|---|---|---|
| Dermatologic | ||
| Rash | 8 (89) | 1 (11) |
| Skin ulceration | 1 (11) | 0 (0) |
| Dry skin | 1 (11) | 0 (0) |
| Alopecia | 1 (11) | 0 (0) |
| Gastrointestinal | ||
| Anorexia | 2 (22) | 0 (0) |
| Nausea | 1 (11) | 0 (0) |
| Vomiting | 1 (11) | 0 (0) |
| Diarrhea | 4 (44) | 0 (0) |
| Elevated AST/ALT | 2 (22) | 0 (0) |
| Bloating | 1 (11) | 0 (0) |
| Neurologic | ||
| Headache | 1 (11) | 0 (0) |
| Pain | 1 (11) | 0 (0) |
| Confusion | 1 (11) | 0 (0) |
| Vascular | ||
| Peripheral edema | 1 (11) | 0 (0) |
| Facial edema | 1 (11) | 0 (0) |
| Genitourinary | ||
| Elevated creatinine | 1 (11) | 0 (0) |
| Respiratory | ||
| Dyspnea | 1 (11) | 0 (0) |
| Constitutional | ||
| Fatigue | 4 (44) | 0 (0) |
| Cold intolerance | 1 (11) | 0 (0) |
| Pruritis | 1 (11) | 0 (0) |
| Irritability | 1 (11) | 0 (0) |
All grade 3 toxicities occurred in a single patient.
Abbreviation: AST/ALT, aspartate aminotransferase/alanine aminostranferase.
Acknowledgments
Funding for the study was provided by the National Comprehensive Cancer Network (NCCN)‘s Oncology Research Program (ORP) from general research support provided by Novartis Pharmaceuticals Corporations (formerly GlaxoSmithKline, LLC). Drug supply was provided by Novartis. D.B.J. was supported by the American Society of Clinical Oncology and NCCN Career Development Awards during conduct of the study, and by National Institutes of Health (NIH) National Cancer Institute grant K23 CA204726. C.A.N. was supported by NIH National Cancer Institute grant F32 CA254070.
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Footnotes
- ClinicalTrials.govIdentifier: NCT02296112
- Sponsors: Vanderbilt‐Ingram Cancer Center, in collaboration with the National Cancer Institute and the National Comprehensive Cancer Network
- Principal Investigator: Douglas B. Johnson
- IRB Approved: Yes
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