Systemic Therapies of Advanced Inoperable Melanoma

Educational Session

work in progress

.....

New concept: possibility to stop treatment with Pembro for patients with complete response (Robert ASCO2016)

So the next question is: when can we stop treating?


Summary

Ipi

• durable effect for a few patients (20- 25%)
• dose-effect for efficacy and toxicity (the more drug, the more effect and the more side effects)
• infliction point at 3 years (patients who are alive at 3 years can be expected to be alive at 5 and 10 years)

Anti-PD1s 

• better than Ipi: higher response rate, fewer side effects 
• highest response for patients with high PDL1 levels

PDL1 is NOT a reliable biomarker

- its expression in the tissue is heterogeneous (uneven)
and it is inducible, so can changer over time.

Caroline Robert- does not use PDL1 testing for clinical practice as not established enough yet; she is experimentally testing for the contact between PD1 and PDL1 (as one can have PDL1 expressed but no T-cells in the tumour).

Combination of Ipi/ PD1 better than PD1 alone but coming with severe toxicity- this is the AACR data from Larkin.

The data is not mature yet, so the curves could separate further.

Question to Caroline Robert- what do you do upon progression on PD1 mono-therapy for BRAF wild-type patients?

Possibilities: Ipi or Ipi/Nivo- EORTC trial ongoing

Note
13% Ipi response rate when given after resistance to PD1, similar to what is seen as first-line
(find reference)


Robert- she would stop treatment with Pembro if the patient wants to stop but not enough data yet to be sure



Target therapies- next steps

Paul Chapman


Again- 

• BRAF plus MEK is better than BRAF alone
• Most patients become resistant but some patients stay on them for a long time (see yesterday)

Interesting combi of Phenformin with Dab/ Trab- he is running this in a trial.


3 classes of BRAF mutations- important as responding differently to treatment

RAS-independent
Class 1- V600E, functions are monomers 

Class 2- function as dimers to activate MEK/ERK

RAS-dependent
Class 3- activating RAS mutation

Zhan Yoa, Cancer Cell 2015, also just submitted



Options for patients who progress
Ragini Kudchadkar

3 groups of disease presentation

• primary progression in the brain
• rapid progression
• slow progression

What to do upon progression?

Chemo

can sometimes work

IL2

Surgery

Radiation

Intra-tumoral Approaches 
T-Vec
Ipi + T-Vec (abstract 9509)
Ipi + HF-10 (abstract 9510)

Re-challenge with earlier therapies

Ipi- same response rate upon re-challenge 
Q- maybe re-challenge with 10mg/kg instead of 3 mg/kg?


Prolonging time to resistance by intermittent treatment with targeted therapy  S1320

comment speaker: many patients inadvertently on intermittent regimens due to drug holidays for side effects

Interesting- find trial

Ascierto running a trial testing targeted short-term (3 months), followed by immune therapy versus immune therapy directly.