Immunotherapy in melanoma -what other cancers could learn from us

J. Weber on the checkpoint inhibitors in Melanoma -what other cancers could learn from us

Relevant for us and other cancers:

-the pattern of response to immune therapy is generally slow; tumours can regress (shrink) over 6-12 months, responses can be mixed (some tumours respond, others grow) and then followed by regression, tumours can first progress and then regress.

-as the response  to immune therapy looks so different from e.g. chemotherapy, it is now also measured differently by irRECIST;

-if there is progression but the blood tests are ok, further measurements are required as this might not be TRUE progression (pseudoprogression)

- the duration of treatment is in most cases 2 years, but not less than one year- but we need more trials to find out the optimal length of treatment

- most patients with CR (complete response) stayed in remission after stopping treatment (see Caroline Robert's work), but even some with PR (partial response) achieved long term responses

- patients with partial response who progressed subsequently responded to a re-challenge with immunotherapy

- new profiles of toxicity (grade III/IV) need to be recognized as early as possible and managed by regimens of corticotherapy. This needs better training of oncologists and other physicians to make sure patients are treated correctly.

Hundreds of new trials started/will start in other cancers!

The article on J. Weber presentation can be found HERE

Wikipedia on irRECIST

A good explanation about the grading of side effects from the HIV community.

Treatment options for patients with localized metastatic melanoma -a study case

Overview on the subject HERE

Localized metastatic melanoma- a study case by Dr. Vervon Sondak

Study case of a patient, female , 43 years old

Diagnosed IIIC with melanoma-left buttock, 3 left inguinal limphnodes positive for melanoma;

Three options were considered by her team:

1)      Perform CLND (complete lymphnodes dissection)

This is reducing the risk of recurrence, but not difference in 3 years OS when compared CLND with only monitoring (see DeCOG-SLT trial on 483 patients); when macrometastasis present and more lymphnodes positive CLND is encouraged (high risk melanoma pts); it is offering a good control of disease but not increasing Overall Survival, see update by Faries et al, 2017 NEJM

Adjuvant radiotherapy- could lower the rates of relapse but increases the occurrence and complications of  lymphedema. In this case CLND (complete limphnode dissection) was refused by patient.

-          2) Recommend interferon (IFN alfa) or ipilimumab- not appropriate for patients with large relapsed limphnodes- unfortunately the patient in this study case received IFN

-          

-          3) Clinical trial with an anti-PD1 or targeted therapy

Patient was Braf negative. In one year unfortunately patient relapsed - stage IVM1b,

She was treated with the combination ipi/nivo;

Note: patients that could mostly benefit of combi are the ones with Braf mutation, high  LDH and low PDL1 expression/patients with rapid progression.

Options for patients progressing on targeted and immunotherapy

What to do when the best options are exhausted?

I. chemotherapy
- preferably lower toxicity regimens as the quality of life is important
- status performance should be carefully considered
- bridge to other treatments

II. IL2 - seems less toxic

III. Surgical resection whenever possible

IV. Radiation therapy
CNS disease -radiation or surgery
Shorted courses of radiations more recommended -the same effect like long course of radio

V. Intratumoral treatments
T-VEC - 16% RR
IPI+T-VEC 38% RR
IPI+ HF10 41%

VI. Re-initiation of previous systemic therapies 
a) Ipilimumab - the same response rate was observed at re-initiation
b) anti-PD1s
b) Braf/Mek- duration of re-challenge is shorter than first time
- intermittent dosing?

Discussions
Steroids use during immunotherapy
Efficacy of immuno on corticosteroids not known, so oncs prefer NOT to have patients on high dose corticosteroids at the start of immuno.
Why two years duration for the treatment with immuno (as no data behind)? Oncs prefer to stay on the safe side because is less likely that after 2 years patients will progress.

Caroline R.:
- education of radiologists, surgeons, and other specialists working together- a must for better management of pts.
-immunotherapy -61 pts stopped the immuno -so far 2 years no one relapse (data from real life -France -Caroline Robert)
- relapse should be well documented by biopsy and pathologic test
- data to come on sequential treatment from the trial run by Paulo Ascierto et al.,(stopping Braf/Mek and switch to immuno , SECOMBIT, NCT02631447).

Gut microbiome and the response of melanoma patients to anti PD1

Wargo Jennifer 
Retrospective study
Abstract 3008
work in progress

Responses to anti -PD1 (IT) are depending of  diverse factors
There was previous evidence that Microbiome could influence the response to IT (immunotherapy).

Tumor samples from 233 pts were collected.

Question 1:
Is an association between the diversity of microbioma and the response to the anti PD1?
Patients that have a higher diversity in gut microbiome were responders and the PFS or OS was better Patients that do not take antibiotics have a better OS (reference).

Question 2
The composition of microbioma is important?
Patients that had in the gut Clostridia are responders, but patients with Bacteroidia- non responders!
(slide 1 by Wargo, slide 2 presented by T. Gajewski)

Question 3
what relationship is between the microbioma and the anti tumor activity?
patients with ''good bacteria have also citotoxic T cells''

Question 4
Whats is the mechanism? Transnational research is in progress, manuscript under review (Gopalakrishnan et al.)
To test strategies and -fecal transplants to the nonresponders -in the mouse this strategy is working so far.


Discussions
During the study was perform also a dietary questionnaire -data to be published soon
The performance status of patients was excellent, no antibiotics, and their dietary habits were various.

Clinical trials to confirm the data obtained the retrospective studies will open soon, said Wargo.

More here !

Take home from ASCO

On my way back from ASCO 2017, so what do I take home?

Overall, no big surprises in Melanoma, unlike we had them in the last few years. Now it's rather drilling deep: how do we sequence therapies? Which patients are doing particularly well- or poorly- on which therapies? Can we minimise side effects? Nearly 200 posters to go through!

Brain mets remain the big challenge in Melanoma, so it was encouraging to see that Ipi/ Nivo also works in untreated brain mets and that better than Nivo alone. It is worth going through the next two abstract in details as the 2 studies are looking at different groups of patients- untreated brain mets, treated but locally progressing brain mets, lepto-meningeal disease  
abstract 9508

Pts with asymptomatic melanoma brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3W x4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets 1) that failed local therapy (new +/- progressed in previously treated met), 2) were neurologically symptomatic and/or 3) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed.

abstract 9507

From a historic perspective, this is important as patients with brain mets were first routinely excluded from clinical trials, so it took way too long out to find out whether these drugs also work in the brain. And that in a disease known for its unfortunate property to metastasise to the brain!
Question remains: if you had one or only a few lesions in the brain, would you want to take the risk to be treated with Ipi/ Nivo, fully knowing it does not work for everyone? Or rather get SRT (stereotactic radio therapy), just to make sure? Different case for many, many (miliary) mets- this could help avoid whole brain radiation that is widely feared due its long-term impact. So an important step!

Adjuvant treatment is a tempting concept but with the current level of side effects, the big question will be whether it improves overall survival and not only progression-free survival.

How to overcome resistance to immune therapy has become the next big topic after the initial excitement over immune therapies. Priming the body with higher levels of antigen- giving T-cells more material to train on- by e.g. intra-tumoral injections (like T-Vec, or HF10) or improving the environment for T-Cells (like IDO), both in combination with checkpoint inhibitors are currently tested approaches. Another topic is how the microbiome of the gut affects the response to immune therapy. 

Financial toxicity was at the forefront of any discussion- a large change from only very recently. Several times, people stood up after a presentation and asked: I have a patient with x, you said I should give y, but what do I do as I have no access to y? Hitting home the message that progress without access is meaningless.


Bettina

Overcoming resistance to Immune therapy

Last ASCO session this year and the session is jam-packed!

work in progress

Rational design of combination immune therapies
Michael Postow

Different ideas how to strengthen the immune response to tumours:

1. Increasing the 'visibility' of the tumour to the immune system

• Intratumoral oncolytic virus injection:
• T-Vec = Imlygic (Chesney et al.)
• Coxsackievirus A21 (Curti et al.)
• Entinostat (johnson et all)
• Cobimetinib + anti-PDL1

2. More T-Cells into the tumour

CD19 Chimeric antigenic receptor T-cells + Pembro (Maude et al)

CEA T-Cell bispecific antibody plust Atezo (Tabernero et al)- colon 

3. 'Force field'- make the environment more favourable for T-Cells

IDO- deletes tryptohpan, produces toxic kynurenine: inhibits T-Cells


4. Enhance T cell attack:

- block negative checkpoints
- activate positive checkpoints



How to test all possible combinations in a rational way?

- is there a reason to believe 2 agents work together?
- does the new treatment slow down tumour progression?





Resistance to Immunotherapy 
Tom Gajewski


Working model

T-cell inflamed versus non-flamed tumour environment

Vaccine-responders had a T-cell inflamed phenotype and favours response to checkpoint inhibitors (find old BMS study on Ipi)

source: Nature Immunology 2013 


CD8, FoxP3, PDL1, IDO present in T cell-inflamed, but absent in T cell non-inflamed


Primary resistance might by caused by absence of a T cell-inflamed environment. How can one create such a favourable environment?
The injections with viruses- like T-Vec- is thought to 'wake up' the environment


3 major hypothesis for primary resistance

- somatic differences (tumours are different)
- host differences (patients are genetically different- polymorphism in immune regulatory genes, so their immune systems react differently)
- environmental differences (like microbiota, pathogen exposure)

Most likely, all 3 factors are important



Biomarkers
Jeffery Weber

What can biomarkers tell you?

- risk prediction
- diagnostic
- monitor response to treatment
- predict response to treatment
- toxicity


Prognostic versus predictive?


Profiles associated with response to PD1 blockade

- high mutational load: better response to PD1
- Hugo Cell 2016- profiles of people who do not respond to PD1


AND AGAIN

PDL1 expression is associated with better response to PD1 blockade but it is not predictive. And in 30% of times, not even consistent in the SAME tumour. 

CD8 T cell infiltrate predicts response to PD1


JAK 1/2 mutations associated with acquired resistance to PD1-blockade

Literature
Daniel Sanghoon Shin et al. Cancer Discovery 2017
Hugo Cell 2016
Gao Cell 2016
Yusko, 2017 (unpublished)- mutational load associated with PD1 response but overlap huge, so clinical value limited right now
Huang et al. Nature 2017

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.

Checkpoint inhibitors by Caroline Robert

mmunotherapy
Presentation by Caroline Robert, on 5th June 2017

History
Ipilimumab
- a subset of pts cured
-re-induction is possible

-adding dacarbazine to ipi- no added efficacy!

Pembrolizumab and nivolumab
Pembro vs ipi - data update -
ORR 42% versus 16%
At 32 months
OS 50 % vs 39%
PFS 31% versus 14 %

Combi ipi+nivo Checkmate 067 update
OS 64% at 2 years vs 59% nivo - not a significant difference for now but researchers hope for a much higher OS on combi in time as data is still not mature.

Adverse effects
acute hypophisitis
pneumonitis
colitis
hypo and hyperthyroidism
increased ALT

-vitiligo is linked with a good response with anti PD1

-it is possible to stop the treatment after Complete Response! 

How long do we have to treat?
Response: 2 years is considered optimal; 10 months after stopping patients are still in remission.

Potential biomarkers

• PDL1- High level -high clinical response- patients with high PDL1  do well on combination but also with nivo alone.
• Mutational load - potential antigens might -not practical for use
• Gut microbiota -promising but not yet practical
• Genetical mutations-

Future
Anti PD1- will be the central drug of many combinations - lots of clinical trials in the following years

The decision to stop the treatment- there is no guaranty that if one stops the treatment, one will stay in remission or will respond again.

What is new in melanoma systemic therapies

Ahmad A. Tarhini, Adjuvant therapy in melanoma, Abstract 9500
Interferon is not a options anymore!
What drugs are the best?
What endpoints we will use: present endpoint is RFS; needs to be changed for OS

Ipilimumab 10 mg /kg showed benefit for high-risk melanoma patients in the previous research

In the present study, abstract 9500: lower dose gives financial advantages but most important less side effects grade III and IV;

New: 10 mg is similar with 3 mg/kg in terms of survival ! (RFS- relapse-free survival)

The question:  is this the same for OS (overall survival)?

In metastatic melanoma OS 10 mg showed benefit- thus researchers suspect the same will be seen in the adjuvant setting; conclusion: we have to wait for data on OS in order to decide the dose..

Ipi after Pembro Keynote 006
Caroline Robert, Abstract 9504
Pembro arms -
What is happening with pts that stop -not because of toxicity but simple because they had benefit;
median follow-up-
104 patients in total 
64 ongoing
10 SD (stable disease)
not only the Complete Responses are lasting but also Partial Responses 
-2 years was administrated
-efficacy
-safety
Patients received previous immuno in both
Patients were fallowed 9,7 months after completing the treatment with pembro.

''Responses were durable in pts who completed pembro; 9.7 months after completion of pembro, estimated PFS was 91% in all 104 pts, 95% in pts with complete response and  91% in pts with partial response and 83% in pts with stable disease.''

Pembro -duration of response higher.

Jeff Weber (for Georgina Long) Abstract 9505
Dabra/Mek- superior to monotherapy is known
Long term OS in a subset of pts -phase II study
3 arms -the second with lower dose of trametinib (1 mg)
5 years follow up
Patients- treatment naive, BM stable (a subset), LDH was above normal
half pts > 3 metastases
-subsequent therapy-anti PD1 or ipi
RR combi- 76%
RR dabra 54%

OS- 28% at 5 years for all
OS -45% at 5 years for pts with LDH normal
LDH normal - median survival of 4 years.

A. Menzies  -Long term survival -what is known?
the main issues:
-do we have long term survivors or cured patients?
-can the treatment be stopped
-who are the ones surviving?

I. long term follow up trial ipi after pembro
keynote 006-most mature data
3 years 50% pembro -with the tendency to form a plateau
primary resistance and secondary
71% DoR
Pembro- is not depending of dose like ipi
Treatments duration of 2 years is not based of scientific data-just clinical observations- a trial is needed to see the optimal duration? (C.Robert)
Characterization of the complete respondents- a must!


Who are the survivors - in general the ones with LDH normal, less disease sites, performance status 0 and CR (complete response); we need for better biomarkers.

Can we stop?- with immuno is clear that after some time (2 years ) could be stopped, with Braf/Mek not  known!

Re-challenge- again differences - with immuno there is not enough data showing that can work in case of re-initiation, but with combi Braf/Meks there is evidence re-challenge is working.

Combi MB (Brain Metastasis), Abstract 9506
A. Davies
Break -MB -4 groups of patients  A, B, C, D
A- not simptomatic
B -simptomatic
C -ECOG 0-1
D 0-2
intracranial response -primary endpoint 58% in Cohort A
median duration of reponse 6,5 months obs shorter then for extracranial disease (12-14 months)
See the article in The Lancet.

Check Mate 204- faze II study MB (for patients with brain metastasis), Abstract 9507
Nivo+ipi
No previous treatment!
primary end points -intracranial response
secondary- OS, PFS etc
109 treated
70 patients followed

efficacy Nivo/Ipi
53% global response (intra+extracranial)
67%PFS -at 6 months
time to response of 2,8 months

23 pts stopped because of toxicity

Georgina Long - Trail ABC (BM), Abstract 9508
76 pts
18 months follow up
most patients were male,
younger in cohort A, Braf mutated
previous combi Braf/Mek was permited

Best intracranial response-
A- 42%  ipi/nivo; 6 months PFS 46%
B- 20 % nivo alone
C- 6 % leptomeningeal on nivo

46% PFS -6 months

16% response with prior therapy Braf/Mek
Some patients could respond in the brain , but not extra-cranial

Bellow most relevant data from the Brain Metastasis studies - best results are obtained on asymptomatic patients and the response of patients with leptomeningeal disease remains poor. Clinical trials for the patients with symptomatic disease are considered.

Adjuvante fotemustine versus surveillance in high risk uveal melanoma- no benefit of fotemustine! Abstract 9502

-median OS 1 year -lack of treatments
-fotemustine- alkylating agent: RR and PFS  in 171 liver metastatic was previously used in metastatic melanoma
primary endpoint- MFS (Metastatic Free Survival)
secondary endpoints- OS and quality life
arm A-fotemustine
arm B -monitoring
---------
302 patients enrolled
Patients -genomic High Risk in both of arms
3 years- 60,9% MFS and 59,3%
83, 1 OS at 3 years

Fotemustine fail to improve MFS (metastatic free survival) 3 year (60,9 vs 59,3).
Interimar analysis and trial stopped for futility!

Brain mets

work in progress

Background
Metastasis to the brain is one of the big challenges in Melanoma- cancer with the highest risk to spread to the brain  (43% in clinical studies and 75% in autopsies).


This session looked on therapies and how they worked on Melanoma brain mets:

COMBI-MB

Does Dabra/ Tram work in brain mets?

58% intracranial response, so response in brain mets
6.5 months time till progression, so less than extra-cranial

most common pattern progression: in the brain 47%

Results are now published in the Lancet here




CheckMate 204

Ipi/ Nivo in untreated brain mets

• 0.5- 3cm brain mets
• not symptomatic
• SRT on < 3 brain mets

good number of responses were already visible at 6 weeks


Conclusion

• Ipi/ Nivo works in the brain, but not quite as good as outside the brain.
• Need to find approaches sequencing with radiotherapy
• patients with brain mets need to be included into clinical trials

ABC trial- nivo vs ipi/nivo in active brain mets

Georgina Long

Interesting- small extra cohort of leptomeningeal disease

(pic)

Nivo and Nivo/Ipi have activity in brain mets

Activity is high when Ipi/Nivo is given up front


Conclusion

• Ipi/ Nivo high activity in brain mets when given upfront
• how to combine with radiotherapy

Discussion- Lynn Schuchter

This is about Melanoma patients with brain mets upfront who were often excluded from clinical trials.

Summary slide

Questions that remain
This data allows to consider upfront systemic therapy.

But which therapy first? How to sequence? How to combine with radiotherapy?

BUT
Ipi/ Nivo past Dab/Tram does not seem to work well for brain mets

Combination of Local therapy and Systemic therapy

principal take home messages

• systemic therapy as initial treatment has become an option

• honest discussion about prognosis important

Question from the audience-
anecdotal evidence: flare of brain mets after starting immune therapy? Occurs but not often.

Discussion point with G. Long

'Bulk control' for BRAF mut Melanoma- treat with targeted therapy for a short time to reduce tumour burden and then switch to immune therapy 'extremely attractive' as patients who switch to immune therapy AFTER progressing on targeted therapy do very poorly.




Abstracts


Abstract  9506  

COMBI-MB: A phase II study of combination dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600–mutant (mut) melanoma brain metastases (MBM).
Read full abstract here

Abstract  9508  

A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC).
Read full abstract here

Surviving Melanoma- overal survival data

work in progress

Background

Melanoma therapies have evolved enormously over the last very few years. From only 12% patients surviving the first year after diagnosis- Alexander Menzies just called this 'the dark ages'- we are now looking at the possibility of true survival. What is still unclear is in which order therapies should be used, so looking how these medicines are working long-term is important.


Alexander Menzies- the BIG questions to ask:

- do we have true long-term survival- cure...? 
- who are the survivors?
- can we stop treatment?


Not long ago, 2-year OS would have been considered 'long-term survival'- not anymore.



This session gave updates from two different therapeutic classes: 
Immune therapy (Pembro) and 
Targeted therapy (Dabra + Tram).



Immune therapy

Caroline Robert on KEYNOTE-006
update results and outcomes of patients who stopped treatment with Pembro

(pic)


interesting to note

• Some (but few) patients get a complete response AFTER stopping treatment
• 91% of patients who completed 2 years of Pembro are progression-free after a medium follow up of 9.7 months

Targeted therapy

Jeff Weber (instead of G. Long)

LDH level and number of organ sites associated with overall survival 

Comment on trial design
treated brain mets could be included but stable for 3 months
by consequence, not many brain met patients in the trial (pic)

Cross-over allowed (but we know that adding MEK to BRAFi at resistance is too late- Ribas at previous ASCOs), so lame

Combination better than monotherapy- 76 vs 54% but also, lower the dose of Trametinib reduces to 50% (check data, add pic)

interesting to note

• NOT all patients receiving targeted therapy will progress
• normal LDH level = better prognosis
• <3 sites of metastatic disease = better prognosis

5 year overall survival all patients together: 28% 
but 5 year overall survival with patients with normal LDH and < sites of disease: 51%

13% PFS at 5 years on D/T- impressive- but only 4% patients are still on therapy

Conclusions
(pic)

Alexander Menzies' summary

On survival vs cure

• 50% OS at 3 years with Pembro and a plateau seems to be forming, similar to Ipi
• 
  
• 31% patients remain progression-free at 32 months 
• but primary vs acquired resistance also exists for PD1

Can we stop treatment upon response?
Complete responders do better than partial responders or stable disease


Can we recover? So if we stop treatment, does the tumour respond again when we give the drug again upon progression.

Seems to work with MAPK but is less clear with PD1 less- not because it's not happening but because the data is not collected.

Is there something particular about the responders?
Seems so but we have to find out what it is.

General comment

'overall survival in the modern era'  with a number of effective therapies available, any OS data is affected by subsequent therapies, so therefore
PFS better endpoint to evaluate TRUE benefit



Abstracts

Abstract  9504  

Long-term outcomes in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in the phase 3 KEYNOTE-006 study who completed pembrolizumab (pembro) treatment. 

Full abstract here 

Abstract  9505  

Five-year overall survival (OS) update from a phase II, open-label trial of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600–mutant unresectable or metastatic melanoma (MM).

Full abstract here

Adjuvant Therapies in Melanoma- update

Adjuvant therapies are given before the Melanoma has widely spread, so in Melanoma Stage 3.

work in progress

Sophie Piperno- Neumann on 
FOTEADJ: randomised adjuvant Phase 3 clinical trial of fotemustine versus observations in high-risk UM patients


Uveal Melanoma (Melanoma of the eye)

• 3-5% of all Melanoma cases
• 20% of patients will develop mestastasis within 5 years after being diagnosed, median OS is 12 months
• TNM staging is important as important for prognosis

aim: 5 year progression-free survival

Reason for the study:

previous EORTC study had shown that Fotemustine given directly to the liver improved OS in Stage 4 patients (find study) 

(pic study design)

The trial was stopped for futility- no difference between chemo (fotemustine) and observations. The study was therefore stopped and changed to an intensive surveillance program.

Peter Mohr discussing adjuvant therapies in Melanoma-

What is the standard of adjuvant therapy in Melanoma?

After 25 randomised adjuvant Interferon trials-

Michael Atkins ASCO 2016: only 30% Stage 3 patients today get adjuvant therapy in US (Interferon)
Even less in Europe.

No agreement on treatment in adjuvant setting- guidelines internationally do not agree 

(pic)

What is the right endpoint for adjuvant trial?

so what should we be looking for?

- relapse free survival benefit?

- distant met free survival?

- overall survival (most likely today as we have effective therapies in Stage 4)

'chemotherapy should no longer be applied in the adjuvant setting' P. Mohr

Intergroup E1609

EORTC 18071  65% vs 54% 5 yrs OS adjuvant Ipi 10mg/kg

(presented by Lex Eggermont at ESMO2016)

OS in Stage 4 - Ipi 10mg vs 3mg begins to differ after one year, with patients on Ipi 10mg/kg - so we need to wait for OS data in the adjuvant setting

Up to now NO STANDARD based on efficacy, toxicity and cost

upcoming: PD1- based adjuvant therapies

(pic)

Eggermont: 'I see no future for Ipi/Nivo in the adjuvant setting'