Neoadjuvant treatment of Melanoma

Session Monday 4pm


Re-cap
neo-adjuvant: treat with drugs first to shrink the tumour, then operate
adjuvant: operate, then treat with drugs

Rationale (reasons) for neo-adjuvant approach
- information about biology- how aggressive is the disease? Prognostic information
- gives information about how well therapy works
- downgrading/ downstaging surgery


A neo-adjuvant Dab/ Tram trial was stopped for efficacy
Lancet Oncology 2018- stopped for efficacy

T-Vec neoadjuvant for IIIB- IVM1a
pathological response 21%

Ipi vs Nivo neo-adjuvant
8% Grade 3/4 toxicity
has promise, impressive response but risk of progression - so needs close follow-up



Combination treatment of advanced Melanoma- IDOs or SD101 plus Pembro
Alex Menzie

Challenge remains: not all patients respond to PD1 or continue to respond to PD1 inhibition, so more treatment options are needed

Wolchok NEJM 2017- 39% OS at 3 yrs on Ipi+ Nivo


IDO plus PD1

Ph2 looked great for Epa plus Pembro

Another IDO-
Indoximod plus Pembro





Illuminate 301- Phase 3 study

A Study of IMO-2125 in Combination With Ipilimumab Versus Ipilimumab Alone in Subjects With Anti-PD-1 Refractory Melanoma (ILLUMINATE-301) (ILLUMINATE-301) https://clinicaltrials.gov/ct2/show/NCT03445533

IMO-2125 is a so-called TLR agonist (TLR = toll- like receptor, IMO-2125 blocks TLR9, agonist = it enhances the function of TLR9). TLR9 sits on the surface of dendritic cells and B-cells and once they are activated, these cells will activate T-cells.
In this trial, patients who progressed on PD1s will receive either Ipi 4 doses intravenously or Ipi iv plus IMO injected into the tumour.

IMO-2125 is produced by Idera and has received FDA fast-track designation for the combination with Ipi- so definitely something to keep an eye on.







5 year survival Pembro on Keynote 001

34% alive after 5 years
41% of treatment-naive patients were alive after 5 years


Biomarker to predict survival and durability of response in Melanoma

PFS after 1 year tm by CT vs PET

PET better than CT to predict durability of SD

Nice summary of adjuvant data recently presented at ASCO

This is a nice summary-
https://www.medscape.com/viewarticle/898327?src=wnl_edit_tpal&uac=250449EN&impID=1665305&faf=1

Take- home messages from ASCO 2018

This wasn't an ASCO of big Melanoma news but rather of a series of important updates, insights and 'keep-in-mind's



My (Bettina's) take-homes are here 

Stage 3 and earlier

• Nivo better than Ipi adjuvant and no one should talk about Interferon in this context anymore 
• Complete Lymph Node Dissection comes with side effects but is not better than observation when it comes to overall survival
• tumour burden </> 1mm in the sentinel node is an important prognostic factor for Stage 3A although it's not part of the new AJCC 8th classification
• adjuvant for Stage 2 is coming- so watch out for trials

Stage 4

• there is something about Ipi contributing to the long-term effect of immune therapy we need to keep an eye on
• several combinations have potential to work after resistance to PD1
• checkpoint therapy can be stopped upon complete response or stable disease, many patients remain stable but re-challenge works upon progression
• brain mets remain a major problem, still nothing satisfying for leptomeningeal disease

General

• We consider Stage 1 T1a and b Melanoma as the 'lucky ones' who are cured by surgery alone. However, there is more to the story and looking at 20 year overall survival is sobering- a figure G. Long showed:

Ref- https://link.springer.com/article/10.1245%2Fs10434-017-6325-1

• The idea that Melanoma first goes to the local lymph node and then spreads further is done with- Melanoma can unfortunately spread both via lymph and blood straight from the beginning. 
• There remains a lot of work to do in terms of multi-disciplinary teams: we were in sessions where the surgeons wanted to operate, the radiologist to irradiate and the oncologist to drug. I'd like to see a long-term strategy that ensures that patients survive with as little side effects and long-term damage as possible.

Education is more than information- and what do we educate for?

This year at ASCO again and in several meetings we had, there was a lot of talk about patient education. And I begin to notice that some of it just sits uneasily with me.

Firstly I believe that there is a confusion between information and education. A leaflet or a website can provide information- but unless a patient has understood the content and can act on it, it isn't education. It's just- information sitting there.

And then- what do we educate for in the first place? An awful many demands for 'patient education' reek of self-interest. 

'Education' for patients to follow a physician's instructions seems a contradiction in itself- you either demand uncritical obedience, that's an order but not education. Or you educate patients about the reasons why a physician makes certain demands. In that case, the educated patient might well disagree with a physician's judgement and act otherwise. There is maybe manipulation into obedience but education always offers more and not fewer options.

Then there is 'education' for patients to donate money, their time, their blood, their tissue samples and sometimes their lives- you just have to remember the series of equipoise-violating Melanoma trials we have had. 
These are valuable resources, so surely true education would provide patients with the knowledge to choose when, where and to whom to provide their support. 'For scientific progress' or 'the greater good of humanity' rather sounds like a poor sales pitch in this context, especially considering the normal distribution also replies to research- the good, the bad and the ugly are alive and kicking also here.

In my mind, you cannot 'educate to do', only 'educate to empower'- give patients and people in general the information and understanding to make informed decisions on their own behalf. One might sometimes agree, sometimes not. 
Patient education should provide knowledge and more options and with that, a higher degree of protection.

Options for those progressing on anti-PD1 - Early Clinical Trials and Reports

Here  - early agents in combinations, some promising for those progressing on anti-PD1 monotherapy!

Abstract 9514
Treatment after progression on monotherapy with anti PD1 (pembro)
Adding ipilimumab:
Complete Response rate (CR) 13%
Overal Response Rate (ORR) 45%

Abstract 9515
Tilsotolimod (TLR9 agonist) + IPI in patients progressing on anti-PD1 monotherapy
21 pts
Disease Control Rate -71%
Overall Response Rate 38.1%

Abstract 9513
SD-101 is a TLR9 agonist administered by local injection
By targeting TLR9, SD-101 helps dendritic cells to convert in APCs (Antigen Presentation Cells) and stimulates the anti-tumor activity of T-cells.

Trial SD-101 + Pembrolizumab
54 patients treated with SD-101 in an 8-mg dose in one lesion and 2-mg dose per lesion for two to four lesions beginning 21 days following the first dose pembrolizumab dose.

Efficacy
PFS 6 months -76%
ORR- 70% in naive patients (no previous treatment)
ORR -15 % in patients previously treated with an anti-PD1

Staging- particularly important for Stage 3 patients

Recent update from AJCC 7th to 8th edition


Stage 3 has now 4 substages


Study- externally validate new edition for prognosis and help with decision-making


Main take home- Stage 3D describes a patient group at very high risk

SN Tumour Burden 

cut-off of 1mm strongly correlated with survival- 


Stage 3A can be further stratified by Sentinel tumour burden 

< 1mm  91% 5 year OS
> 1mm  72%   5 year OS

Verver et al Eur J Cancer 2018

Hope that it will help avoid Complete Lymph Node Dissections in the future.



DECOG- SLT update-

CLND vs observation in patients with a positive Sentinel Lymph Node


Overall survival and Recurrence-free survival= no difference

MSLT II (publised NEJM 2017) confirmed findings

Now median follow-up 72 months- 24.5% died 

point to follow up- where does metastasis occur- pic

difference between < or > 1mm in SLN but still, no difference between observation and CLND

and original tumour thickness  most relevant factors for OS

The power was powered to detect a differences of 10% in the DMFS to date the difference is 2.7% in favour of observation.


Halstedian hypothesis (1907)
Stepwise metastasis

Data supports parallel metastasis, not step-wise fashion.

Therefore- they no longer recommend CLND in micro-metastasis


According to Lex Eggermont- 95% of patients staged correctly by tumor thickness and sentinel lymph node burden, so only 5% would benefit from a CLND for better staging


Weber 

Checkpoint 238: 24months follow-up

Most recurrences in Stage 3 occur within the first 3 years (slide for refs)

Ipi adjuvant- RFS plateaus at 3 years


Checkpoint 238 - pointless blinding yet again

Nivo 3mg/kg vs Ipi 10mg/kg

• post-surgery
• no uveal, but acral and mucosal allowed

Primary endpoint: RFS, new primary Melanoma or death


Results

24th months 63 vs 50%

18th 66% vs 53%

12 months 70 vs 60%


Important take-home 

• PDL-1> 5% do better than PDL-1<5% but the difference between Ipi vs Nivo remains in favour of Nivo
• again- 3 C (AJCC 7th) do worse than 3B
• no influence of BRAF status

Very valid question- how far is the rate of screening failure?

20% screening failure- as it takes 28 days to include in trial, some patients had metastasis 4 weeks later, so were staged incorrectly at beginning

Summary of orals

1. Recommendation Observation not CLDN should be the standard after positive SLND (Germany has US follow-up every 3 months)

caution

- head/ neck excluded from study

- patients who don't follow tight follow-up at risk

2. Adjuvant treatments

for BRAF neg: PD1 adjuvant more effective and less toxic than Ipi

for BRAF pos: targeted therapy remains an option

3. New staging

There is a group of patients at very high risk (Stage 3D)- but is there also a group that might be spared systemic therapy? 

The big question- IIIA: treat now or later?

Wolchok NEJM 2017- 58% at 3 years OS

Recommendation

for patients with Stage 3B and above

For Stage 3A- adjuvant should be discussed and offered, in particular with tumour burden > 1mm.

• Best adjuvant for BRAF pos remains to be seen
• Neo-adjuvant vs adjuvant 
• Treatment of even earlier stage disease needs to be investigated

To note- Stage 3 not always tested for BRAF

fertility and endocrinopathies to be considered with immune therapies, in particular in young patients


The big question- can we stop Pembro?

4- ys OS after 2 yrs of Pembro KEYNOTE 006
Georgina Long


all patients were treatment-naive for Ipi, PD1, PDL1 but could have had targeted therapy. Patients with elevated LDH or tumour-related symptoms had to have targeted first

2 yrs of Pembro and 2nd dose of Pembro was permitted upon progression


3 yr 41.7% on Pembr 34.1% Ipi

Interesting to note that the duration of response was similar between Pembro and Ipi 

86% patients are progression-free after 20 months after completing 2 years of pembro

re-challenge is possible and works
slide



Columbus trial

Dummer

Enco - very long on target dissociation time- leads to sustained target inhibition


And yet another ugly bridesmaid design 1:1:1 
considering we know BRAF+ MEK is better than BRAF alone, so the combo can only look better than mono 

Enco 450 mg/ Bini  45mg vs Vem vs Enco 300mg

Immunotherapy biomarkers- beyond PDL1

PD-L1- Prognostic and Predictive State of the Science
Charles G. Drake

-normally is a negative prognostic biomarker in cancers
-as a predictor to the treatment response in melanoma -if you have a PDL1 the treatment could work

-in bladder cancer -PDL1 expression correlates with response to atezolizumab;
- unfortunately, within same cancer, same treatment we get different responses for the 1st line and second line, so different conditions could impact the ability of PDL1 to be a right predictor


Limit Utility
1) spatial Heterogeneity
2) which cells type to quantify
3) competing assay and metrics

In lung cancer is clinically used and recently was announced as a predictor in the blade cancer.
Translational research- in mouse models conflicting results.
Message-  still we cannot rely on it as a single biomarker, so in melanoma PDL1 cannot guide the treatment decision.


Tumour Mutational Burden (TMB)
Timothy An-thy Chan 
Memorial Sloan Hospital

TMB promising as biomarker to identify those people responding to immunotherapy; as seen bellow still we have a consistent percentage of non responders- unmet medical need

Human T-Cells - two important features to remember:
Tumour is part as non-self for our body (that is helping T-cells to recognize the tumor and attack it)
Immune system has memory, so what was recognize as enemy first time could be identified the second time too.
Having antigens and neo-antigens within tumors is helping the immune system to recognize the tumors as non self.

Multiple cancers benefiting: melanoma, urothelial, lung,, renal etc but we still have negative trials, so..what are the genetic determinants of benefit from immunotherapy (anti CTL4 and anti PD1)?
- mutation and neoantigen burden predict response in lung cancer to anti-PD1
- in melanoma- mutational burden a good indicator of response to ipi (for example)
- melanoma is highly immunogenic - got a number of modified proteins as a consequence of DNA damage (environmental factors)

High TMB (Tumor Mutational Burden)  and low TMB - in Checkmate 038, Keynote 012, 028 (solid tumors) (to be checked)
So- Hypermutated tumors - respond to anti-PD1
Clonal neoantigens - predict a better response
Patients with HLA +high TMB - do better on immuno
but how to integrate different biomarkers is the challenge in the future

Future Directions in Immunotherapy Biomarkers

Kurt Schalper

Challenges in developing biomarkers
foto
rules of cell functionality don't apply for the tumor cell
measure the metrics of T-cells

Tumors tissue biomarkers
CD3, CD8
Low TIL infiltrations
Patients with dormant TIL - DO the best
Active TILs did not so good on immuno (see foto)
By different techniques - we understand the imune compositions -effector  memory T cells, T cells activation, candidate targets etc.

Liquid biopsy
foto
TMB could be measured in blood too!
More in 2 abstracts (foto)

Serum IL-level in melanoma
BMS company validate this biomarker
low levels low responses and OS

Circulating immune cells and the response to blockers- good metric in patients with melanoma (foto)
Mieloid Derived Suppressors Cells - could be also measured -predict outcomes in certain cancers.

Integration and implementation in clinical practice - remains a challenge
No one could study alone the multitudes of biomarkers- so collaboration between labs is essential.

Questions:
1)Microbiome -promising but the mechanisms are not yet understood
and How we can we use that clinically?

2)PDL1 and TMB - they are independent predictors, what is the best?
-not yet convincing data what is the better- must be judged in context (first line, second line); and is not actually important what is better because they could be used together

3) Imaging - as biomarkers

4)TMB - could be different but responses to therapies could be sometimes similar -that means that there are also other factors involved (such as tumor microenvironment -hostile conditions for T-cells infiltration).

5)calculating TMB from liquid biopsy -how accurate is?

Related literature - Manson et al., 2016