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.