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Class II and III BRAF Alterations in Cancer
Expanding Therapeutic Horizons: Targeting Non-V600 BRAF Mutations in Solid Tumors

Released: August 02, 2023

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Key Takeaways
  • The treatment of class II and III BRAF alterations remains a huge unmet need for patients with advanced malignancies.
  • There are several drugs on the horizon with promising preliminary evidence of efficacy in early-phase studies for patients with class II and III BRAF alterations.

In this commentary, I describe the most relevant and up-to-date information on emerging novel agents targeting non-V600 BRAF alterations in solid tumors.

Overview

BRAF is a kinase downstream of RAS. It transduces signals via the MAPK pathway and is involved in the regulation of cell proliferation, growth, and survival. BRAF mutations occur across various cancer types but are relatively common in melanoma, colorectal cancer (CRC), non-small-cell lung cancer (NSCLC), and thyroid cancer. The most common BRAF mutations are BRAF V600 mutations, of which the incidence of BRAF V600E mutations accounts for the majority.

There are 3 classes of BRAF mutations: class I, II, and III (Figure). Class I BRAF mutations are limited to the alterations in the V600 locus. They are RAS-independent monomers. Class II mutations are non-V600 mutations, and they require the formation of homodimers with other BRAF oncoproteins for activation. These mutations activate BRAF in a RAS-independent manner. The homodimerization of 2 BRAF molecules activates the downstream ERK signaling without the need to activate upstream RAS kinase. If the homodimerization could be turned off, it would be possible to turn off the signaling pathway. Of note, class II BRAF mutations have intermediate kinase activity and include BRAF mutations, BRAF kinase duplications, and BRAF fusions. Lastly, the class III BRAF mutations require RAS activation to function and have low kinase activity or are “kinase dead” compared with the wild-type form of BRAF. Class III BRAF mutations upregulate MAPK signaling by forming RAF heterodimers that require an intact CRAF protein and at the same time carry oncogenic activity. The resulting BRAF-CRAF dimerization increases ERK activity.

Figure. Classes of BRAF alterations in cancer. 

 

The incidence of non-V600 BRAF mutations (class II/III) in patients with cancer is approximately 1% to 2%, and these mutations are common in NSCLC, CRC, melanoma, and prostate cancer. Although this accounts for a small percentage of patients with cancer, these activating mutations are targetable and actionable.

Current State of Treatment of Patients With BRAF-Mutated Cancers

Cobimetinib, binimetinib, dabrafenib, vemurafenib, encorafenib, and trametinib are FDA-approved agents that inhibit the MAPK/ERK/MEK signaling pathway. Several of these agents are effective at inhibiting BRAF V600 mutation‒positive cancer cell growth but have shown abysmal activity in non-V600 BRAF mutation‒positive cancer. Although several agents are approved for the treatment of patients with cancers harboring class I BRAF mutations, the treatment of patients with class II/III BRAF mutations is a huge unmet clinical need. There are no approved targeted therapies for patients with class II/III BRAF mutations. The clinical outcome for patients with class II/III  BRAF mutations is inferior compared with those with class I BRAF mutations. Clearly, for patients with non-V600 BRAF mutation‒positive cancers, the development of effective new agents and investigational approaches will be very helpful in targeting these non‑V600 BRAF mutations. With this in mind, the optimal drug will need to be highly selective for RAF family kinases and have broad coverage because in patients with cancer harboring these abnormalities, it is not a specific BRAF mutation, alteration, or gene fusion driving the disease. It is hoped that the optimal agent will be orally bioavailable, similar to most of the other BRAF inhibitors that are already approved in cancer.

Targeted Therapies in Development for Patients With Cancer Harboring Non-V600 BRAF Mutations

Several agents are currently being investigated in patients with non-V600 BRAF mutations and are coming down the clinical pipeline. These investigational agents include exarafenib (KIN-2787), tovorafenib, belvarafenib, and BGB-3245.

Exarafenib (KIN‑2787)
Exarafenib is an orally bioavailable and potent pan-RAF inhibitor. It has a high selectivity for RAF family kinases and is specific for the class II/III BRAF alterations and NRAS mutations. Exarafenib is being studied in a dose-escalation/dose expansion phase I clinical trial for patients with locally advanced or metastatic solid tumors harboring class I/II/III BRAF and/or NRAS mutations (NCT04913285). The primary endpoints are safety, tolerability, and the determination of the maximum tolerated dose (MTD). Preliminary results from this trial were presented at the 2023 American Association for Cancer Research (AACR) Annual Meeting. The study is investigating multiple types of BRAF mutations and fusions. In the dose-escalation phase of the trial, exarafenib doses of 25 mg twice daily to 400 mg twice daily were studied. Among 60 patients in the dose-expansion phase at the time of the data cutoff (February 28, 2023), 41.7%, 13.3%, and 30% had class I, II, and III BRAF alterations, respectively, whereas 15% of patients had NRAS alterations. The median number of prior therapies was 3 (range: 1-11). As expected, most of these patients had CRC (33.3%), whereas 28.3% had melanoma, 18.3% had NSCLC, 5% had biliary or papillary thyroid cancer, and 10% had other solid tumor types.

The dose‑limiting toxicities at 400 mg twice daily were acneiform rash and maculopapular rash, which is a class effect of inhibiting the MAPK/ERK/MEK signaling pathway. Treatment-related adverse events (AEs) of any grade were observed in approximately 73% of patients, of which 18% were grade 3/4. Besides rash, the grade 3/4 AEs observed were increased aspartate aminotransferase (AST) (6.7%) and increased alanine aminotransferase (ALT) (8.3%). The half-life of exarafenib was approximately 8 hours and demonstrated a dose-linear pharmacokinetic profile for the target. Of 28 efficacy-evaluable patients, 43% achieved a molecular response, including a complete molecular response rate of 11%. This is promising, considering the patient population and the median number of prior therapies received by these patients. Molecular responses were observed in 8 of 13 patients (62%) with class I BRAF mutations and 2 of 4 patients (50%) with class II BRAF mutations, and the only patient with class III BRAF and NRAS mutations had CRC and achieved a molecular response. The MTD for exarafenib was determined to be 300 mg twice daily, and this was chosen as the recommended phase II dose. At the MTD, the overall response rate (ORR) among patients with class II BRAF mutations was 33.3%. Overall, exarafenib was well tolerated and elicited promising responses in heavily pretreated patients with solid tumors harboring class II/III BRAF mutations.

Tovorafenib (DAY-101)
Tovorafenib is an orally bioavailable and selective pan-RAF inhibitor. Its efficacy and safety are being investigated in the multiarm, nonrandomized phase II FIREFLY-1 trial for pediatric and young adult patients with relapsed or progressive low-grade glioma and advanced solid tumors harboring activating BRAF or RAF alterations (NCT04775485). The primary endpoint is ORR. In this trial, patients were heavily pretreated with a median number of prior therapies of 3 (range: 1-9). Among 69 response-evaluable patients (of whom 59 had BRAF fusion‒positive disease), the ORR was 64%, with a clinical benefit rate of 91%, including a complete response rate of 4% and a partial response (PR) rate of 59%. The most common AEs included hair color changes (54%), anemia (46%), and maculopapular rash and fatigue (42% each). These promising results led to the initiation of the randomized phase III LOGGIC/FIREFLY-2 trial of first-line tovorafenib monotherapy vs standard of care chemotherapy for patients with low-grade glioma harboring activating RAF alterations (NCT05566795). This is an important registrational study for this population of patients in need of effective treatments.

Belvarafenib (HM95573/GDC-5573)
Belvarafenib is an orally bioavailable, potent and selective type II pan-RAF inhibitor. It has demonstrated activity in patients with BRAF V600E‒mutant and NRAS-mutant melanoma. Belvarafenib is one of the agents being investigated in the ongoing phase II TAPISTRY platform study evaluating the efficacy and safety of immunotherapy or targeted therapies as monotherapy or in rational, specified combinations for patients with unresectable locally advanced or metastatic solid tumors harboring oncogenic genomic alterations or patients with high tumor mutational burden (NCT04589845). In the TAPISTRY trial, belvarafenib will be investigated in patients with class II/III BRAF mutation‒positive and/or BRAF fusion‒positive tumors.

BGB‑3245
BGB-3245 is an orally bioavailable, potent and selective small-molecule inhibitor of RAF monomer and dimer forms. With its mechanism of action, it is expected that BGB-3245 will be active in class I/II/III BRAF-mutated cancers. It has shown activity in preclinical models against class II/III BRAF mutations, BRAF fusions, and BRAF splice isoforms. Its safety, pharmacokinetics, and antitumor activity are being investigated in a dose-escalation/dose-expansion phase I trial for patients with advanced or refractory tumors, including those with disease harboring class I/II/III BRAF mutations and/or fusions (NCT04249843). The primary endpoints include safety, tolerability, MTD, and ORR. Preliminary results from this trial were presented at the 2023 AACR Annual Meeting. Among 33 efficacy-evaluable patients, the disease control rate was 48%, including 1 complete response, 5 confirmed PRs, 2 unconfirmed PRs, and 8 patients with stable disease lasting ≥24 weeks. Of 42 safety-evaluable patients, grade ≥3 treatment-related AEs were reported in 29%, including decreased platelet counts, maculopapular rash, increased ALT/AST, and fever.

Lifirafenib (BGB-283)
Lifirafenib is a RAF dimer inhibitor. In a phase I trial, lifirafenib demonstrated manageable safety and antitumor activity in patients with BRAF V600‒mutant solid tumors. Its safety, pharmacokinetics, and antitumor activity are being investigated in combination with the MEK inhibitor mirdametinib in patients with advanced or refractory solid tumors (NCT03905148). This agent has the potential to be active in non-V600 BRAF mutation‒positive cancers.

Clinical Implications and Future Directions

I see many patients with lung cancer in my clinic. In the lung cancer world, we sometimes debate about whether to give immunotherapy upfront vs BRAF‑targeted therapy in patients with BRAF V600‒mutant disease. In melanoma, on the other hand, it is recommended to give first-line immunotherapy because response is comparable to that observed with BRAF-targeted therapies, and in a large subset of patients, durable response or even “cure” can be achieved with upfront immunotherapy. In my clinical practice, however, I tend to use BRAF-targeted therapy as soon as I can in patients with BRAF V600‒mutant lung cancer. In general, most patients benefit significantly from the earlier use of targeted therapies, and the safety profiles of these agents are typically manageable. Because targeted therapies turn off signaling pathways and do not wait for immune responses to effect cancer cell kill, I prefer to administer these therapies in my patients with symptomatic disease, a high tumor burden, or substantial bone metastases. Responses with these agents can be elicited rapidly—sometimes in 1 week. Nonetheless, whether the recommendation is to use targeted therapies in the first or second line, we need to develop targeted drugs that are effective for patients with class II/III BRAF mutation‒positive cancers. These are exciting times for patients with non-V600 BRAF mutations, fusions, and/or splice isoforms. At least 4 of these agents are being developed and studied in patients with cancers harboring non-V600 BRAF alterations, with some a little farther down the development pipeline than others. It is hoped that in the near future, we will have further evidence of antitumor activity of these agents in randomized clinical trials that will provide a new treatment paradigm for these patients.

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What are the challenges you experience in your practice when it comes to treating patients with cancer harboring class II or III BRAF alterations? Answer the polling question and join the conversation in the discussion box below. 

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