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'

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).