Dabrafenib/Trametinib update Combi v.

Presentation of Caroline Robert (Abstract LBA40):

''In the COMBI-v study of 704 patients with BRAF V600E/K-mutant melanoma, results of an updated 3-year analysis revealed an increased rate of overall survival with first-line dabrafenib
plus trametinib compared with vemurafenib (45% versus 32%, respectively) with no apparent increase in toxicities.

Combination dabrafenib/trametinib   shows also a median overall survival of 26,1 months on combination versus 17, 2 months on vemurafenib.

Combi-v compared dabrafenib/trametinib with vemurafenib alone while Combi d compared the dabrafenib/trametinib with dabrafenib alone. Both trials demonstrated the superiority of combination (see figure bellow), thus combination Dabrafenib /Trametinib  is (highly) recommended as first line therapy in melanoma for Braf positive patients.

Important to start when LDH is still normal and the patient has few metastasis (<3 organ sites metastasis) -in this situation the response is impressive:  70% OS rate at 3 years.

Combinations are the future

Jeff Weber
Combinations in progress

Keynote 022 -Pembrolizumab in combination with Dabrafenib and Trametinib - safety and trial design reported at ASCO2016
Ipilimumab + IDO inhibitors
Pembrolizumab +Epacadostat (IDO inhibitor) phase I/II

Early clinical combinations -small studies including more cancers but signals for efficacy in melanoma.
Pembrolizumab + OX40
Pembrolizumab + atezolizumab

Summarizing

Future trials will combine immunotherapies with agents that are able to infiltrate cells into the tumors, generate T cells or T cells with improved features or increase the capacity to recognise tumors.

Jason  Luke -
Novel cytokine approach
Oncolytic viruses and innate immune tumor sensing
STING agonists
Immune system was design to eliminate the infections
Phase I trial Sting trial
viral therapies - local and distant effects
considered also for brain metastasis
Category of immunotherapeutic interventions
- PD1-IDO inhibitors -looks promising in clinical models-no increase in toxicity
- for the patients without T cell infiltration in tumours: T-VEC + Pembrolizumab

T cell inflamed env-predictive biomarker
TCR technology and novel antibody -promising

Most important combinations:

Joint Melanoma Simposium ESMO EORTC

Richard Marais
Where next with the next targeted therapies ?

Principles of advances
Combining laboratory with clinical research
Braf is mutated in 45 % in melanoma
Remarkable responses but relapses are coming
resistance mechanisms that are not completely  understood
PAN RAF inhibitors overcoming this resistence and are now in trials tested

Circulating tumour DNA to be evaluated -to measure what the tumour is doing and how the disease progressing , monitoring the disease.

Good study cases
To understand the disease and to send then the patient to the scan
then you look to the mutations

The case of a lady with mucosal melanoma
-DNA sequences in circulating DNA
- she had in two tumours kind -one with kit mutations responding to imatinib

Circulating Tumours DNA trials
Patient derived xenografts - close  relationship with pathologists
Problem is timing to take Braf inhibitors -is important for the time of progression
Rare Braf mutations + HRAS mutation

Study case
By DNA sequences in circulating DNA paclitaxel + trametinib = effective
They did not put the patient on it because of randomisation-
they decided to treat him with immunotherapy -patient died.

Study case
over 600 000 mutations - trametinib alone, crisotinib alone did not work
Trametinib+ crizotinib - discovered to be good in patient xenograft tumours
This combination -to be given to the patient when progress is arising

P. Ascierto
Immuno offers long survival

Clinical biomarker signature - orients the selection of patients

PD-L1 expression level to select treatment for the patients? Better not.

Consider an integrative approach
Gene expression and tumour burden at baseline- that means before patients start the treatment:
IFNy signature
Neoepitope signature and mutational load
Biochemical responses

Caroline Robert
Combinations and rationale for combinations

Braf inhibitors could induce T cells infiltrations in melanoma metastasis, facilitating further the action of immunotherapies

Advocacy track - clinical trials

1. Running your own clinical trials.The myeloma clinical trials network

Management team formed by patients
funded trough FP7
6 millions euro
got the grant
communication is the key
unit, focus and persistence

2. Drugs repurposing, by Pan Panziarka

Rare disease - not interesting for pharma
The REDO project
International collaboration
Going back with searching 20-30 years, with the clearly understanding of how they are working
Repurposing drugs -faster and cheaper, we know already a lot about-
They are drugs for chronic conditions
e.g. Ketorolac in Breast cancer - incidental research showed that women using Ketorolac were doing better.

Search retrospectively and put the drug in trial prospectively
In angiosarcoma -propranolol showed efficacy
130 of drugs show evidence of working in cancer
Cimetidine - Cochrane reviews -show efficacy as adjuvant treatment in colorectal cancer;
Aspirin in colorectal cancer

Patient view: efficacy is the FIRST!!
Non commercial trials -should have their role
Rare disease -uninteresting for pharma companies
influence the decision makers to support repurposing drugs
Looking to generics
- no support from pharma or generic companies

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Adaptive licensing - MAPPs

Regulatory perspective on MAPPs
Francesco Pignati

Sara Garner
MAPPS from HTA perspective
Fix ''menu is not working for everybody
RCTs are ''not working for everybody
Current framework is not giving all the data we need and we have a lot of decision uncertainty

We have not the evidence we need
Slow innovation=slow access
So the adaptive licensing needed

Discussion should start earlier
Not lowering the evidence; we just change the timing
Is the commercial pressure or the scientifical pressure


Speaker
we will use existing tools: existing design models?
early approval
paying for the volume should be replaced by paying for the health outcome and this requires good data;
-what kind the data we need -and which data will prove what .

Adaptive licensing
Paolo Casali

How EMA   approves
How national rules applied are variate
Joint scientific advise - between the eu regulator and the national authorities
The problem in rare cancers is the companies are not interested to develop the drugs for those disease
The clinical advise is to centralise the care- to refer the patients to centres of excellence and that is a matter of networking (crucial in rare disease-crucial also for melanoma in fact).

Bettina Ryll
MAPPS -
using melanoma as a study case
two classes of drugs
in phase I we could already see efficacy which we never were seen
tumours were actually
access to the new drugs was the only way
but these drugs are not a cure/meant we need systematic learning

Seeking early scientifically advice
the value of drug should be assess
early agreements between the payer and companies
sharing the responsibility

Bettina to Francesco
question: why the change is so  slow?
different organisation, different pathways
people that do not understand what is about -people are not confident
how to best design networks that can generate evidence
Timing of the evidence

Poster discussion session Melanoma

T-vec against Ipi trial phase 2
Ipi 3mg
82 patients had 48 weeks of follow up median 61 weeks
35% for combo against 17 for Ipi
CR the same
Side effects - Ipi tox 17 % grade 3-4
Improved ORR and same CR rates
efficacy better on low tumour burden
Masterkey 265 now recruiting
Pembro with Tvec had 56% in phase 1/2 - going to see phase 3 trial now




Atelizomab PDL1- 1b study  cobi and vem triple 
21 day run in of targeted and then atelizomab
ORR 83% unconfirmed
CD8+ infiltration followed the vem/cobi run in
single agent atelizumab is 33%
questions :
are these data good enough for phase 3 ?
biomarkers ?
TKI first or second ?
Trilogy trial starting soon - cob and vem plus/minus atelizumab - vem combo 21 days - (strange week of placebo to replace the cobi cos vem is 3 weeks and cobi 2) ??


IDO/Pembro
26% CR - small sample
but encouraging
IDO high  & low expressors
LDH and number of organ sites is still a dilemma for all these trials - there is nothing good for the high LDH people

what do we know of all these therapies : duration of response is 2-3 years need 2 more years but PFS is good
should we do phase 2s in clever ways rather than risking failed phase 3s as  happened in Lung

Christian Blank

Pooled data of PDL1 expression in Ipi/Nivo - PDL1 is not good enough

PDL1 in elderly patients
PFS and OS similar small number (38) of >75

If you have 4  of the favourable biomarkers on Pembro - this leads to 60% response
CRP  should be used more often in these trials as a biomarker

anti PD1 and brain mets

Poor PD1 efficacy in BMs  - do corticosteroids  influence this fresh/old tissue difference in PDL1 ? no  -
Melbase showed 11 months of PFS on corticosteroids -
Leptomeningeal disease rarely lasts 3 months



multi morbid patients still  need thinking about

Melanoma abstracts

1. Christian Blank -Combi IPI/NIVO as neoadjuvant -OpACIN trial

Combi ipilimumab and nivolumab produces more side effects in neoadjuvant setting.
Small study, 20 patients
-for stage III, rezectable, with palpable limphnodes




Main goals of neoadjuvant therapies
- to reduce the microscopic disease.
- to better control the local disease

Too small to get relevant results, still promising - Recurrence Free Survival (RFS), 1 year 56%.

2. A. Ribas. Genomic features of complete responders versus fast progressors in patients with Braf mutated melanoma treated with Vemurafenib/cobimetinib versus vemurafenib alone.  

Mutational load predictor was the same in patient with complete response and the ones who were progressing- analyzing biopsies.

Interesting - Disease Progression (PD)
was related to keratinization or keratine signature

Complete responses (CR) were seen in patients with multiple gene signatures

To be continued..