BRAF mutations have been identified as the most frequent mutation in cutaneous melanoma, with approximately 40-60% of cases carrying mutations in BRAF V600 kinase with higher frequencies observed in younger patients. Mutations in the BRAF V600 kinase leads to constitutive activation of the downstream MAPK pathway (Hoeflich et al, Cancer Res. 2009). BRAF and MEK Targeted therapies are only effective in tumours that are BRAF mutation positive.
BRAF mutations have been identified as the most frequent mutation in cutaneous melanoma, with approximately 40-60% of cases carrying mutations in BRAF V600 kinase with higher frequencies observed in younger patients. Mutations in the BRAF V600 kinase lead to constitutive activation of the downstream MAPK pathway (Hoeflich et al, Cancer Res. 2009). BRAF and MEK targeted therapies are only effective in tumours that are BRAF mutation positive.
Testing for the V600E BRAF mutation status: Single BRAF gene testing is available at the VCC-BCCA through the Molecular Genetics Laboratory and performed on paraffin-embedded formalin fixed tissue. BRAF mutation requests should only be performed in stage 4 metastatic melanoma or stage 3 unresectable melanoma as the role of BRAF inhibitors in the adjuvant setting is unknown at this time..In addition, OncoPanel, which tests a variety of targetable mutations across solid tumours, is also recently available as a preferred option for BRAF testing as it detects the more uncommon variants and also provides KIT and NRAS mutation status. Access the Pathology Request Forms through
Laboratory Services here.
Vemurafenib is an oral (960 mg twice daily) potent and selective inhibitor of mutated BRAF that has been shown to inhibit cell proliferation and induce cell death. Vemurafenib has demonstrated statistically significant clinical benefit and manageable safety profile in treatment-naïve and previously treated metastatic melanoma patients whose tumours (primary or metastatic) are positive for mutated BRAF V600. BRIM3, a randomized controlled study comparing vemurafenib to DTIC in untreated patients with unresectable or metastatic melanoma with the V600E mutation, demonstrated improvement in overall survival and progression-free survival (5.3 months vs 1.6 months P<.001) (Chapman et al, NEJM 2011). Overall survival was significantly prolonged with vemurafenib compared with dacarbazine (13.6 versus 9.7 months, HR 0.70, 95% CI 0.57-0.87). Progression-free survival was also significantly prolonged (6.9 versus 1.6 months, HR 0.38, 95% CI 0.32-0.46). The best ORR (BORR) was 48.4% in the vemurafenib arm versus 5.5% in the dacarbazine arm. The FDA approved Vemurafenib (trade name Zelboraf) for untreated and previously treated metastatic melanoma last year and in February 2012, Health Canada also approved the drug. Late 2012, the BCCA approved funding for vemurafenib through the Compassionate Access Program (CAP) in BRAF mutant metastatic melanoma. Patients receive vemurafenib until progressive disease or unacceptable toxicity.
Further support for the efficacy of vemurafamib comes from the phase II BRIM 2 multicenter trial evaluating the efficacy of vemurafenib in BRAF V600E mutation positive metastatic melanoma patients who have received at least one prior systemic therapy (n=132) (Ribas et al, JCO 2011). With a median follow-up of 12.9 months, (Sosman et al, NEJM 2012) the confirmed overall response rate was 53%, with a 6% complete response. The median DoR by IRC was 6.7 months and median PFS was 6.8 months and the median OS was 15.9 months (95% CI, 11.6 to 18.3).
In both studies, the most common side effects are photosensitivity, arthralgia, rash, fatigue, alopecia, nausea, and diarrhea as well as excisable keratoacanthoma or cutaneous squamous-cell carcinoma. Patients who haven’t had a recent skin evaluation should see a dermatologist. Rare QT prolongation can occur and patients require periodic ECG monitoring.
Dabrafenib is another BRAF inhibitor with significant activity in patients with advanced melanoma compared with dacarbazine chemotherapy. It was also Health Canada approved for the treatment of patients with advanced melanoma with the V600 BRAF mutation.
In the pivotal phase III trial (Hauschild et al., Lancet, 2012), patients with BRAF mutation positive unresectable stage III or IV melanoma were randomized to either dabrafenib (150 mg orally twice a day) or dacarbazine. Dabrafenib increased progression free survival compared with dacarbazine (median 5.1 vs. 2.7 months, HR 0.33, 95% CI 0.20-0.54). Overall survival favoured patients treated with dabrafenib but was not statistically significant, although crossover was allowed.
Treatment was generally well tolerated. The most frequent grade 2 or greater toxicities were dermatologic. Other grade 2 or greater toxicities observed included arthralgia, fatigue, headache, and fever.
The BCCA has also endorsed funding for Dabrafenib and treating physicians can choose either Vemurafenib or Dabrafenib in BRAF mutant metastatic melanoma in untreated and previously treated patients with choice based on different side effect profiles. Although they have never been compared, efficacy across studies is similar.
Combination BRAF/MEK Inhibitors
There are two different combinations of BRAF inhibitors plus MEK inhibitors which have shown to yield a higher response rate, longer progression-free survival, and longer overall survival compared with BRAF inhibition alone.
One such combination is dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor). Two phase III studies have been conducted (COMBI-d trial and COMBI-v trial). The COMBI-d trial (Long et al., Lancet 2015) compared dabrafenib plus trametinib to dabrafenib plus placebo in treatment naive patients with advanced melanoma with a V600 mutation. ORR was significantly improved (69 vs. 53%) and the CR rate was 16 vs 13%, respectively. Progression-free survival (median 11.0 vs. 8.8 months, HR 0.67, 95% CI 0.53-0.84) and overall survival (median 25.1 vs. 18.7 months, HR 0.71, 95% CI 0.55-0.92) was improved with the combination. Cutaneous toxicities were more common in the dabrafenib arm including dry skin, pruritus, hyperkeratosis, hand-foot syndrome, alopecia, and skin papilloma. SCC were seen in 9% with dabrafenib vs. 3% with the combination. Combination therapy was associated with higher risk of diarrhea, fever, and chills.
The COMBI-v trial (Robert et al., NEJM 2015) compared dabrafenib plus trametinib to vemurafenib in BRAF mutated advanced melanoma. Overall survival was significantly increased with the combination arm (one-year survival rate 72% vs. 65%, HR for death 0.69, 95% CI 0.53-0.89). Median progression-free survival was significantly increased (11.4 vs. 7.3 months, 95% CI 0.46-0.69) as was the ORR (64 vs. 51%). The incidence of cutaneous SCC and keratoacanthoma was significantly decreased with combination therapy compared with vemurafenib alone.
Another combination therapy is vemurafenib and cobimetinib, as studied in the coBRIM clinical trial (Larkin et al., NEJM 2014). This trial evaluated patients with previously untreated advanced melanoma randomly assigned to vemurafenib plus cobimetinib or vemurafenib plus placebo. Progression-free survival was significantly increased with combination therapy compared with vemurafenib plus placebo (median 12.3 vs. 7.2 months, HR 0.58, 95% CI 0.46-0.72). The overall ORR was increased with combination therapy (70 vs. 50%) as was the CR rate (16 vs 11%). There was a trend toward longer overall survival with combination therapy although longer follow up is required.
In August 2016, the BCCA will launch funding of dabrafenib and trametinib in BRAF mutant metastatic melanoma and this is an option over BRAF monotherapy alone at the treating physicians discretion in previously treated or untreated patients. Vemurafenib and cobimetinib has been Health Canada approved for the same indication and currently, cobimetinib can be accessed through the drug company. Treatment with either dabrafenib and trametinib or vemurafenib and cobimetinib is at the discretion of the treating physician and largely guided by differences in the side effect profile.
Ipilimumab (trade name Yervoy) is an anti-CTL4A antibody, which counters host immunosuppression associated with advanced melanoma. Phase 3 trials in first and second-line therapy have demonstrated improved OS with Ipilimumab. In the previously treated population comparing Ipilimumab to Ipilimumab + GP100 vaccine and GP100 vaccine alone, the median OS was 10 months with Ipilimumab vs 6.4 months with GP100 alone with no improvement seen with drug combination (Hodi et al NEJM 2010). This was the first trial to demonstrate an overall survival benefit with any treatment for metastatic melanoma. The front-line phase III randomized trial used a higher dose of Ipilimumab (10 mg/kg) in combination with DTIC versus DTIC alone in addition to a maintenance phase in the Ipilimumab-containing arm and similarly showed a superior OS (11.2 vs 9.1 months) using Ipilimumab (Roberts et al, 2011).
The approved dose in previously treated patients is Ipilimumab 3 mg/kg given each 3 weeks for 4 doses. Although Ipilimumab is not associated with a higher response rate than standard therapies, some patients have prolonged disease control. Collectively, prior studies support that approximately 20% of patients achieve durable remissions and even cure with Ipilimumab. Due to interference with T-suppressor cell function, the main side effects are autoimmune in nature with a predictable time course. Rash occurs early followed by diarrhea which can progress to colitis, with pathologic changes reminiscent of Crohn’s disease, peak at 7 weeks and early steroid administration is critical or patients can be at risk of colonic perforation and even death. Other side effects can include endocrinopathy (panhypopituitarism, thyroid abnormalities, adrenal suppression), dermatologic (rash, rare severe Stevens-Johnson syndrome), hepatitis and neurologic dysfunction. It is critically important that patients meet protocol eligibility criteria for Ipilimumab therapy and that it is given by oncologists at centres knowledgeable about adverse event management. Ipilimumab is not suitable for patients with rapidly progressive disease and/or performance status 2-4. Some patients with disease control after Ipilimumab may be eligible for re-treatment at the time of progression.
Ipilimumab was originally approved in pre-treated patients with metastatic melanoma in 2012 and in July 2015 it was launched at the BCCA in previously untreated with unresectable or metastatic melanoma. However, with the approval and funding of the PD1 inhibitor pembrolizumab at the BCCA in June 2016, Ipilimumab is no longer funded in patients previously treated with these agents due to a lack of efficacy data in this population and poor cost effectiveness. Ipilimumab remains a treatment option for previously untreated patients, however, with the superior efficacy of PD1 inhibitors in this setting, there will be little role for ipilimumab in this group of patients.
Nivolumab and pembrolizumab are antibodies that target PD-1 (programmed death 1 protein), an immune checkpoint receptor expressed by activated T cells. Activation of the PD1 pathway through interaction with the PDL ligands expressed on tumour cells results in melanoma tumour evasion. By blocking this receptor, these agents restore the anti-tumour T-cell response against melanoma. Similar to Ipilimumab, autoimmune (AI) toxicities can occur, however, the frequency of severe AI toxicities is much less. In addition, as a class, PD1 inhibitors can also cause pneumonitis.
Pembrolizumab is an anti-PD-1 antibody that has been studied in both the ipilimumab naïve and previously treated patients. In a phase I study (KEYNOTE-001), patients were treated with pembrolizumab in 4 cohorts using one of 3 dose schedules (10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks). The ORR was 33%. The median OS was 24 months and the 3 year survival rate was 40%. There was no significant differences in outcomes between dose schedules. Side effects were manageable with the most common toxicities being fatigue, rash, diarrhea, and arthralgias.
Two phase III trials were conducted. In the KEYNOTE-002 study, patients with ipilimumab refractory advanced melanoma were randomized to pembrolizumab or chemotherapy. By central review, PFS was significantly improved with pembrolizumab compared with chemotherapy. ORR was higher for pembrolizumab when compared to chemotherapy. Pembrolizumab was well tolerated with the most common adverse events being fatigue, pruritus, and rash. Serious immune related toxicities were rare. In the pivotal KEYNOTE-006 study, patients were randomized to pembrolizumab at a dose of 10 mg/kg every 2 weeks or every 3 weeks or four doses of Ipilimumab at 3 mg/kg every 3 weeks. The estimated 6 month PFS rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for Ipilimumab. Estimated 12 month survival rates were 74.1%, 68.4%, and 58.2%, respectively. Response rates were improved with pembrolizumab every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%). Efficacy was similar in the 2 pembrolizumab groups. Treatment related events were lower in the pembrolizumab groups than in the ipilimumab group.
Nivolumab is not yet funded at the BCCA for metastatic melanoma.
Updated results from the phase I/II study looking at nivolumab showed that the median overall survival was 17 months and the objective or partial responses were observed in 32% (Hodi et al., 2016 AACR Meeting). Based on the earlier studies, three phase III studies were conducted.
The CHECKMATE 066 study was conducted in previously untreated patients with BRAF wild type metastatic melanoma. Patients were randomly assigned to nivolumab (3 mg/kg every 2 weeks) or dacarbazine chemotherapy (1000 mg/m2 every 3 weeks) (Long et al., NEJM 2015). Overall survival was significantly increased in those treated with nivolumab. The one year survival rate was 73% vs. 42%, HR 0.42. PFS was also increased with nivolumab (median 5.1 vs. 2.2 months). The ORR was 40% vs. 14%.
The CHECKMATE 037 study randomized previously treated patients to receive either nivolumab or investigator’s choice chemotherapy (Weber et al., Lancet Oncology 2015). All patients had received prior anti-CTLA-4 therapy and a BRAF inhibitor if a V600 mutation was present. Interim analysis showed that objective responses were higher with nivolumab (32% vs. 10%). Median duration of response was longer with nivolumab (not reached versus 3.7 m) although median PFS was only marginally better with nivolumab (4.7 m vs 4.2 m). Responses were also seen in patients with BRAF mutation positive metastatic melanoma who had progressed on a prior BRAF inhibitor.
The combination of nivolumab and ipilimumab was studied in the phase III CHECKMATE 067 study in previously untreated BRAF mutant and BRAF WT metastatic melanoma, (Larkin et al., NEJM 2015). The median PFS was longer for the combination compared to ipilimumab (11.5 vs 2.9 months) and numerically higher than nivolumab alone (6.9 months) although the study was not statistically powered for this comparison. Similarly the ORR was also higher with the combination (57.7% vs 19%) (43.7% for nivolumab). However, combination therapy was associated with a rate of 55% grade 3 and 4 toxicities and the need for treatment discontinuation. Interestingly, the outcome was comparable in patients who had to stop treatment due to toxicity. Combination therapy is currently available through an expanded access program.
On June 1 2016, pembrolizumab was launched at the BCCA in previously untreated patients with metastatic melanoma and is accessed through the CAP program. Subsequently, for BRAF mutant positive patients, pembrolizumab can also be used in patients who have been previously treated with BRAF +/- MEK inhibitors with the sequence chosen at the discretion of the treating physician. For legacy patients who have been previously treated with ipilimumab and develop recurrent disease, pembrolizumab can be requested through CAP. However, currently, for all other patients, pembrolizumab is not funded in patients who have previously received ipilimumab after June 2016.
Dimethyl triazeno imidazole carboxamide (DTIC) is the only approved chemotherapy agent for the management of metastatic melanoma, however, it has never been shown to have an overall survival benefit. The effectiveness of treatment is influenced by the site and extent of disease, but the overall response rate ranges from 9-29% with more recent trials with stringent response criteria showing responses of only 5-10% and complete remissions of < 3% (Cochrane review 2009). Patients with good performance status and non-visceral metastases are more likely to respond. Patients with mucosal and ocular primaries rarely respond to DTIC in the metastatic setting. Combination chemotherapy regimens have not proven superior to single agent DTIC in comparative trials.
Temozolomide, like DTIC, is a pro-drug of MTIC. However it does not require metabolism, has 100% oral bioavailability and penetrates the blood brain barrier. A randomized study showed a superior PFS but not OS and thus use is limited to patients with CNS metastases or intolerance to DTIC through the Compassionate Access Program.
Previous phase 2 studies have also shown a modest response rate of carboplatin and taxol in metastatic melanoma and may have a higher ORR than DTIC although these treatments have never been directly compared. CCNU has limited efficacy with CNS penetration and can be used in the relapsed setting. Physicians can request carboplatin/taxol and CCNU can be accessed through CAP.
Interferon has shown modest activity in malignant melanoma. The single agent response rate is modest (15%) and there is significant associated toxicity. Combinations of DTIC with interferon have not proved superior to DTIC alone. Select cases may be considered through the Compassionate Access Program.
Prior to Ipilimumab, IL-2 was used, particularly in the U.S. The composite results of 8 clinical trials have previously demonstrated that high dose Interleukin 2(IL-2) has a low overall response rate (16%) with rare complete remissions (5%). A limited number of highly select patients with predominantly subcutaneous metastases demonstrated durable remissions (Atkins MB et al, J Clin Oncol 1999). However, these results have never been confirmed in a phase 3 trial. Further, IL-2 is associated with severe toxicity including hypotension, capillary-leak syndrome, sepsis, renal insufficiency and myocarditis, thus requiring ICU support. Bio-chemotherapy, which combines DTIC-based chemotherapy regimes with IL-2 and interferon has not fulfilled its early promise of superior survival, in spite of yielding higher response rates (Ives NJ et al., Proc ASCO 2007). IL-2 is not approved for use at the BCCA.
Whole limb perfusion/infusion may be worthwhile for selected patients with unresectable in-transit metastases. This procedure is associated with significant morbidity and referral to Cancer Centre should be arranged prior to treatment. Whole limb perfusion/infusion should only be performed by surgeons/institutions with extensive experience in this type of treatment. Currently, B.C. patients are referred to Calgary after approval at the multidisciplinary melanoma conference.
The use of biological response modifiers in metastatic melanoma remains investigational.
Topical imiquimod cream may be considered for large/non-surgically resectable lentigo maligna where radiotherapy would not be appropriate.
Intra-lesional BCG has been employed in the treatment of isolated cutaneous metastases from melanoma. Care must be taken with BCG treatment as fatal anaphylactic reactions have occurred.
