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'

ASCO/ ESMO joint session on access to cancer care- value scales

ASCO VALUE FRAME WORK
Lowell Schnipper

Interest to listen to Lowell Schnipper- their primary motivation was to reduce out-of-pocket expenses for patients.

ASCO framework includes costs, but only rudimentarily and focuses on the out-of-pocket costs of the patients.

Should frameworks differ according to purpose? Lowell Schnipper says YES.

Should patients bear the cost if they derive no benefit from the therapy? NO.



ESMO Magnitude of Clinical Benefit Scale 
Elisabeth De Vries

earlier study could only score comparative studies- needs to be able to grade single arm studies for 'orphan disease' and 'high unmet need'

There will be a workshop for patients (rather patient advocates though ;-))

Where the scale is used:

1. ESMO organisation
- included in the ESMO Guidelines (so this will affect Melanoma patients)
- also used for mapping access: valuable drugs not available, not valuable drugs were available 

2. Doctors in patient care
Physicians use the scale to explain the benefit of medicines to patients

3. Training of oncologists

4. Academic groups 

5. Industry
'uses the scale to advertise for drugs. When the scores are good'

6. Organisations

WHO considers it a valuable tool
Countries begin to use the scale for policy decisions
EHA performing field-testing
Tested for radio-therapy


The Value of Pathways
Russell Hoverman

Aetna Medicare Project reduced hospitalisation and costs with the same outcomes. 

• Pathway planning
• Tight follow-up
• Advanced care planning

Five interesting scientific abstracts to be followed at ASCO

Five interesting scientific abstracts that will to be followed at ASCO in a Medscape interview with Dr. Jeffrey Weber, a medical oncologist at the New York University Langone Medical Center in New York City:

1) KEYNOTE-006 clinical trial update: 50% of patients with inoperable metastatic disease treated with pembrolizumab lives up to 3 years. Also, data suggest that patients who stopped because of toxicity or after 2 years of treatment could continue to respond to the therapy (Caroline Robert, Institut Gustave Roussy in Paris, France);

2) Combi-d update: 28% of the patients receiving the combination Dabrafenib /Trametinib are alive after 5 years. A higher overall survival rate of 51% could be seen for patients that started the treatment with normal levels of LDH and three or fewer sites of disease (LDH or lactate dehydrogenase is here a biomarker for the progress of the disease), (Georgina Long, University of Sydney, Australia).

3) Combi-MB trial update shows a response rate of 55% and a median overall survival of 10,5 months for patients with brain metastasis treated with the combination dabrafenib/trametinib. So, patients with brain metastasis will do well on the combination, but ‘’probably not so well as the patients who start the treatment without brain metastasis (Mike Davies from MD Anderson Cancer Center in Houston, Texas).

4) CheckMate 204 study update will be presented by Hussein Tawbi, from MD Anderson Cancer Center. 
In this study, 40% of the patients with brain metastasis, treated with a combination of immunotherapy (ipilimumab/nivolumab) responded to the therapy.

5) And finally, the ECOG/intergroup 1609 clinical trial has (unplanned!) shown no significant differences in the Relapse Free Survival at 3 years, between 10 mg/kg (54%) and 3-mg/kg ipilimumab (56%). This result could lead to using the 3 mg/kg ipilimumab dose as adjuvant therapy, but not 10 mg/kg, with a higher toxicity (ECOG Intergoup 1609 trial compares ipi versus interferon- but data not out yet).

Short Update on Screening and Early Detection

Melanoma Screening: Review of Current Evidence and Guidelines
SancyAnn Leachman

The guidelines are not providing the optimal number of check per year. For the population at risk 3-12 months or in Germany, every 2 years.

An overview of melanoma detection methods: 

no one is perfect.

Defining patient who should be considered at risk

Example: proposed criteria to define the patients that could be at high risk to get skin cancer and therefore could qualify for the a monitoring program UPSTF (US preventing Service Task Force)

Some Melanoma Previews before ASCO2017

Jeff Weber on what to look forward to at ASCO : Targeted therapy Updates, High Dose Pembro updates, Ipi/Nivo updates and what is doing well for Brain Mets ...

Preview of melanoma at ASCO 2017

2 more weeks and abstracts are out!

Only 2 more weeks till the next trip to the windy city

so high time to check the ASCO abstracts here

Same procedure as every year, so please add the talks, abstracts and posters that you find particularly relevant as comments to this very post. 

And we will do our best to cover them on the blog!