Staging- particularly important for Stage 3 patients

Recent update from AJCC 7th to 8th edition


Stage 3 has now 4 substages


Study- externally validate new edition for prognosis and help with decision-making


Main take home- Stage 3D describes a patient group at very high risk

SN Tumour Burden 

cut-off of 1mm strongly correlated with survival- 


Stage 3A can be further stratified by Sentinel tumour burden 

< 1mm  91% 5 year OS
> 1mm  72%   5 year OS

Verver et al Eur J Cancer 2018

Hope that it will help avoid Complete Lymph Node Dissections in the future.



DECOG- SLT update-

CLND vs observation in patients with a positive Sentinel Lymph Node


Overall survival and Recurrence-free survival= no difference

MSLT II (publised NEJM 2017) confirmed findings

Now median follow-up 72 months- 24.5% died 

point to follow up- where does metastasis occur- pic

difference between < or > 1mm in SLN but still, no difference between observation and CLND

and original tumour thickness  most relevant factors for OS

The power was powered to detect a differences of 10% in the DMFS to date the difference is 2.7% in favour of observation.


Halstedian hypothesis (1907)
Stepwise metastasis

Data supports parallel metastasis, not step-wise fashion.

Therefore- they no longer recommend CLND in micro-metastasis


According to Lex Eggermont- 95% of patients staged correctly by tumor thickness and sentinel lymph node burden, so only 5% would benefit from a CLND for better staging


Weber 

Checkpoint 238: 24months follow-up

Most recurrences in Stage 3 occur within the first 3 years (slide for refs)

Ipi adjuvant- RFS plateaus at 3 years


Checkpoint 238 - pointless blinding yet again

Nivo 3mg/kg vs Ipi 10mg/kg

• post-surgery
• no uveal, but acral and mucosal allowed

Primary endpoint: RFS, new primary Melanoma or death


Results

24th months 63 vs 50%

18th 66% vs 53%

12 months 70 vs 60%


Important take-home 

• PDL-1> 5% do better than PDL-1<5% but the difference between Ipi vs Nivo remains in favour of Nivo
• again- 3 C (AJCC 7th) do worse than 3B
• no influence of BRAF status

Very valid question- how far is the rate of screening failure?

20% screening failure- as it takes 28 days to include in trial, some patients had metastasis 4 weeks later, so were staged incorrectly at beginning

Summary of orals

1. Recommendation Observation not CLDN should be the standard after positive SLND (Germany has US follow-up every 3 months)

caution

- head/ neck excluded from study

- patients who don't follow tight follow-up at risk

2. Adjuvant treatments

for BRAF neg: PD1 adjuvant more effective and less toxic than Ipi

for BRAF pos: targeted therapy remains an option

3. New staging

There is a group of patients at very high risk (Stage 3D)- but is there also a group that might be spared systemic therapy? 

The big question- IIIA: treat now or later?

Wolchok NEJM 2017- 58% at 3 years OS

Recommendation

for patients with Stage 3B and above

For Stage 3A- adjuvant should be discussed and offered, in particular with tumour burden > 1mm.

• Best adjuvant for BRAF pos remains to be seen
• Neo-adjuvant vs adjuvant 
• Treatment of even earlier stage disease needs to be investigated

To note- Stage 3 not always tested for BRAF

fertility and endocrinopathies to be considered with immune therapies, in particular in young patients


The big question- can we stop Pembro?

4- ys OS after 2 yrs of Pembro KEYNOTE 006
Georgina Long


all patients were treatment-naive for Ipi, PD1, PDL1 but could have had targeted therapy. Patients with elevated LDH or tumour-related symptoms had to have targeted first

2 yrs of Pembro and 2nd dose of Pembro was permitted upon progression


3 yr 41.7% on Pembr 34.1% Ipi

Interesting to note that the duration of response was similar between Pembro and Ipi 

86% patients are progression-free after 20 months after completing 2 years of pembro

re-challenge is possible and works
slide



Columbus trial

Dummer

Enco - very long on target dissociation time- leads to sustained target inhibition


And yet another ugly bridesmaid design 1:1:1 
considering we know BRAF+ MEK is better than BRAF alone, so the combo can only look better than mono 

Enco 450 mg/ Bini  45mg vs Vem vs Enco 300mg