Melanoma management

Risk calculator

https://www.melanomarisk.org.au/

 Adjuvant

1. CheckMate 238: Adjuvant Nivolumab vs Ipilimumab in Stage III-IV High-Risk Melanoma

5 year update from this study demonstrated sustained long term improvement in median RFS with nivolumab at 61.0 months vs 24.1 months (HR: 0.72). The OS data remain immature.

50% vs 39% nivo versus ipi 5 yr RFS.

2. KEYNOTE-054: Adjuvant Pembrolizumab vs Placebo for Stage III Melanoma

The 5-year RFS rates were 55% with pembrolizumab and 38% with placebo (HR: 0.61).

3. KEYNOTE-716: Adjuvant Pembrolizumab vs Placebo in High-risk, Resected, Stage II Melanoma

The 36-month RFS rate was 76.2% with pembrolizumab and 63.4% with placebo, and the median RFS was not reached in either arm. Although OS analyses remain immature, results from this study reinforce the SoC to consider adjuvant therapy with anti–PD-1 in this patient population.

4. CheckMate 76K: Adjuvant Nivolumab vs Placebo in Resected Stage IIB/IIC Melanoma

CheckMate 76K demonstrated an RFS benefit with nivolumab (HR: 0.42).

In patients with stage IIB melanoma, 12-month recurrence-free survival was 93% with adjuvant nivolumab therapy, and 84% in stage IIC melanoma (vs 84% and 72% in the placebo group).

5. COMBI-AD: Adjuvant Dabrafenib/Trametinib vs Placebo in BRAFV^600E/K-Mutant Melanoma

5 yr RFS 52% ( Dab Tram) vs 36% ( placebo)

Discussion:

Risks versus benefits of treatment, different options, duration of treatment, route of administration, chances of relapse with observation alone, patient preferences were all discussed.

Neoadjuvant

1. SWOG S1801: Adjuvant Pembrolizumab ± Neoadjuvant Pembrolizumab in Resectable Stage III-IV Melanoma

event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant–adjuvant group and 49%

2. OPACIN-Neo: 3 different doses of ipi nivo for stage 3 melanoma ; phase 3 ongoing. high pathologic responses of 78% was observed in the neoadjuvant arm with a 2-year relapse-free survival (RFS) rate of 80% No difference between 3 arms.

3. Neoadjuvant Relatlimab + Nivolumab for Resectable Stage IIIB/C/D or IV Melanoma :phase 3 ongoing.

Metastatic 

1.  CheckMate 067: OS and PFS at 7.5-Year Follow-up

The 7.5 year follow-up of this trial found ongoing OS and PFS benefits in the nivolumab containing arms compared with ipilimumab.¹⁸ The median OS was 72.1 months, 36.9 months, and 19.9 months for nivolumab plus ipilimumab, nivolumab alone, and ipilimumab, respectively. These results reinforce the SoC for this patient population, which is using an anti–PD 1–containing regimen as upfront therapy.  

2. RELATIVITY-047: PFS by BICR

The study met its primary endpoint of an improvement in PFS with relatlimab plus nivolumab.²¹ At a median follow-up of 25.3 months, the median PFS was 10.2 months vs 4.6 months with nivolumab alone. OS not significant.

Discussion:

wild-type BRAF metastatic melanoma who is treatment naive: nivolumab in combination with either ipilimumab or relatlimab. While ipi nivo has not been compared head to head with nivo relatlimab, if the disease burden is low and patient frail,the latter combo has 10% grade 3 toxicity

3. BRAF V600 E mutated: Pooled Analysis of COMBI-d and COMBI-v Trials of Dabrafenib + Trametinib: 5-Year OS

5 year OS rate was 34% in this patient population, with a median OS of 25.9 months. The 5-year PFS rate was 19%, with a median PFS of 11.1 months

4. coBRIM: OS With Vemurafenib ± Cobimetinib in BRAF-Mutant Advanced Melanoma

Results from this study were similar to those seen with COMBI-d and COMBI-v, with a 5 year OS rate of 31% with the combination and a median OS of 22.5 months.

5. COLUMBUS:  phase III COLUMBUS study looked at encorafenib plus binimetinib in comparison with vemurafenib or encorafenib monotherapy in patients with unresectable stage IIIB/C/IV melanoma and a BRAF^V600E/K mutation.

Results similar to #3 and #4.

Metastatic melanoma treatment sequence : DREAMseq

This study established that the sequence beginning with combination nivolumab/ipilimumab resulted in a 20% absolute improvement in 2-year overall survival (72% v 52%) compared with the sequence beginning with dabrafenib/trametinib. A trend toward 2-year overall benefit was seen across all patient subsets, and other efficacy end points (progression-free survival and duration of response) also favored first-line immunotherapy

Clinical pearl: Dacarbazine is recommended in certain circumstances where patients are not eligible for immunotherapy or targeted therapy

How would you approach: BRAF wild-type melanoma who received first-line ipilimumab/nivolumab and now has progressive disease?

•  Relatlimab with Nivo
• Pembro with lenvatinib
• TIL therapy once approved or on clinical trial
• Dacarbazine

Melanoma with CNS mets

If asymptomatic -Ipi nivo

If symptomatic: steroids,local Rx and ipi nivo rather than combination BRAFMEK even for BRAF mutated melanoma

AE management BRAK MEK

• Derm: skin exam at baseline, q2 months, then upto after 6 months after stopping treatment
• Eye: baseline retinal exam, then as needed. Hold if grade 2 or higher
• Cardiac: EKG baseline, Echo baseline. At 2weeks- another EKG. At 1 month- echo. Then repeat EKG and echo q 3 m
• LFT monthly- hold if grade3 or higher
• Fever- hold, tylenol, steroids

Pearls:

1. BRAF mutant melanoma stage 4: symptomatic. Paraneoplastic are rare. Retinal manifestations may be seen. Use ipi nivo based on Dream seq data. 20% OS benefit in 2 yr.

2. MSLT II- therapeutic LND does not improve survival.

3. Steroids- small amount for short duration OK, more than 10 mg for longer term not good on IO.

4. Orthostatic hypotension in immunotherapy: rule out endocrine disturbances, but consider autonomic neuropathy. Could be directly drug induced although rare.