Ocular Melanoma: Randomised phase 2 study of Trametinib +/- GSK2141795 in patients with advanced uveal melanoma

ASCO 2016: Poster Session

Alexander Shoushtari's team have investigated the value of adding an AKT inhibitor (GSK2141795) to the MEK inhibitor drug Trametinib in the expectation that it might mediate against acquired resistance.

Disruption of the MAP kinase pathway (MAPK) has been assoicated with immune response in other tumour types and hence the pursuit of responses with a MEK inhibitor which forms a part of this pathway.

This phase 2 trial concluded that there was no increase in PFS and that objective reponses were rare. Moreover, dose reduction because of side effects were frequent.

Adjuvant therapies for high risk Melanoma - Surgical Management

First speaker (Van Akkooi) discusses the surgical management for high risk melanoma




Wide Local Excision (WLE)

Findings:

• Haydu (2016): Difference only in Relapse Free Survival (RFS) when pT2 and comparing both arms in table above. No difference in Overall Survival (OS) however.
• Thomas (2004): Difference in Locoregional recurrence when comparing 1cm to 3 cm WLE (3cm is off course better than 1 cm)
• Hayes (2016), which is same dataset as Thomas (2004) but now longer follow up: Differences in Melanoma Specific Survival (MSS), again difference in OS is not sigificant

Is Sentinel Node Biopsy (SNB) of therapeutic value, or prognostic value?

According to Van Akkooi, the data supports the claim that SNB Positive (yellow line) and Observation with nodal recurrence (orange) have a significantly different Melanoma-Specific Survival. One could suggest that having a positive SNB is preferential compared to haven't executed a SNB and observe a nodal recurrence later. 

Adjuvant Ipilimumab: 20% relapse free survival benefit for Ipi adjuvant after CLND.

When looking to the Subgroups : positive SN (effect is highest) vs. palpable node

Most effect of Adjuvant Ipi : positive SN with ulcerated primary Melanoma

Van Akkooi is convinced no Complete Lymph Node Dissections (CLND) will be executed in the future unless one relapses. Instead of CLND => Adjuvant Therapy (e.g. Ipi) when Sentinel Node Biopsy positive.



Combinations of PD1 and Targeted Therapy

CTLA-4 blockade/ IPPI 

• 10 yr overall survival rate
• 1-3 month duration of treatment 
• 20-30% immune related toxicity 
• Retreat successful 
• Absence of predictive bio-marker 

PD1 Blockade 

• 3-5 yr Overall survival rate
• Superior OS to IPPI 
• DCR >50% Better Kinetics 
• Low immune related Toxicity 
• Up to 2 years continuous treatment 
• Retreat Appears Successful 
• PDL-1 Biomarker Sub Optimal 

Combined CTLA-4 and PD-1 have given results as follows 

• 2-3 years overall survival 60-70%
• 50% PFS plateau at 2 years 
• 1-6 months of treatment rapid Kinetics 
• 50-60% immune related toxicity 
• Retreatment success is unknown 
• PDL-1 marker encouraging 

In the combined treatment it has been proven that PD-1 followed by CTLA-4 sequence is Superior with a 1 yr overall response rate of 76% but with higher grade 3-4  Toxicity in 63%

But early treatment discontinuation does not effect efficacy so the question remains are patients being over treated?

A new era in of immunotherapy by combining therapies means 50% long term survival a reality toxicity management remains crucial and requires teamwork and experience. Toxicity can shorten duration of treatment but does not impare survival! 

The data overall survival rates with Dabrafenib/ Trametnib Combi-d are as follows
3 yrs OS 25% with elevated LDH levels and PFS 13%
3yrs OS 54% with normal LDH levels and PFS 27%
Presentation by Dr Keith Flaherty

Pembro  + IPPi  (Keynote 029) phase 1 153 patients treated
Pembro 2mg in combination with 4 doses of  IPPI 1mg has a manageable toxicity and provides robust anti-tumour activity
ORR was 57%
70% progression free at 6 months at data cut off point
Presentation by  Dr Georgina Long


There is a phase 2 study of Dabrafenib/Trametnib and Pembro combined (Keynote 022)
Recruitment is ongoing 

Ocular Melanoma: Disparity in PD-L1 expression between metastatic uveal and cutaneous melanoma

ASCO 2016: Poster Session 146

This study examined the presence of the PD-L1 ligand on both cutenous and uveal metastic tumours. PD-L1 expression has been considered as a possible biomarker to determine the likely efficacy of immune-modulatory drugs, although questions still remain as to its prognostic value and also what might acurately be considered a threshold value to indicate its presence.

In ocular melanoma however, PD-L1 is virtually non-existent in the metastatic setting and the authors suggest that this may explain the lower of response from drugs such as Pembrolizumab or Nivolumab.

Ocular Melanoma: Prognosticators of first line treatment of metastatic uveal melanoma (MUM)

ASCO 2016: Poster Session 175

A retrospective study, gathering data from previous UM cases including trial data, aiming to establish the best predictors of survival in the metastatic setting. Such tests exist for the primary melanoma but none as yet for metastatic patients.

Unsurprisingly liver burden was key in predicting overall response and affects the viability of both surgical interventions and the efficacy of systemic approaches. Identifying the need for additional therapeutic approaches was concluded, although this might be mitigated by the fact that some of the patients from 2004-2012 would have likely missed out on an immunotherapy or new liver directed treatments.

Interstingly, the survival graph is plotted from diagnosis of metastic disease as opposed to post initial treatment. This is different from the usual curves we see for performance of immuntherapy drugs, say, which measure from time of first infusion.

Ocular Melanoma: The identification of novel genetic risk loci in uveal melanoma

ASCO 2016: Poster Session 366

Using blood tests to determine whether it is possible to more accurately determine risk of uveal melanoma. This may have uses in familial, or germline, mutations where particular markers can be associated with increased likelihood of disease occurence.

Multidisciplinary Management of Brain Metasteses

The session on Brain Metastases was not specifically melanoma but general Brain Mets studies - 

The brain is an immune privileged organ so there is a restrictive influence of the immune response which makes it harder to treat. They have recently discovered some kind of fluid transfer system but it lacks the normal lymphoid structure so antigen presentation and T-Cell infiltration is less well understood. Melanoma has more CD3+ and CD8+ TIL Density in Melanoma BMs and more FOXP3 TIL. The role of Microglial Macrophages (these are the main macrophages in Brain tissue and are the main form of active immune defence in the brain and central nervous system) in BMs is complicated : they are both tumour-promoting and tumour-suppressing depending on where in the metastatic cascade they are - brain tumour cells seem to co-opt them in some way - does inhibiting microglia reduce BM cell invasion ?



The Biology of Brain Mets : 

A couple of nice slides of the Venue of action of Checkpoint Inhibitors in BMs : 

And a summary :

(http://meetinglibrary.asco.org/content/50918?media=vm)

One Melanoma Abstract - 

Abstract 2071 - The retrospective analysis of Brain mets in Melanoma by the Boston team did show clinical activity on Brain Mets by Pembrolizumab - there is an ongoing study of patients with untreated BMs : NCT02085070

One Poster presentation :

Poster : Another retrospective study on the effect of Pembro using real world data from the french MELBASE registry - POSTER - the results were not that conclusive because results were complicated by radiotherapy treatment and pretreatment with Ipilimumab before  Pembrolizumab - but overall they concluded that Pembrolizumab PROBABLY better than Ipilimumab in Melanoma Brain Mets - apart from testing how to use registry data - there is not much we can take from this.

 Use of SRS  in treating BMs - Is there a role for Whole Brain Radiation ?

The initial treatment of most patients with limited brain metastases is stereotactic radiosurgery (SRS). SRS is a type of radiotherapy that aims beams precisely at the area of the brain tumor. After SRS, some patients also receive adjuvant whole-brain radiation therapy (WBRT).

The use of WBRT in patients with limited brain metastases has been controversial. Although WBRT does control tumor growth, it can have detrimental effects on quality of life. Preliminary findings from a federally funded study (NIH) have provided new insights into the impact of adjuvant WBRT on cognition 

Patients with one to three small brain metastases who received WBRT after SRS were more likely to experience cognitive decline within the first 3 months than those who received SRS alone. Specifically, those who received WBRT had a greater decline in memory and verbal communication. There was no significant survival benefit from WBRT, compared with SRS alone.

The results strongly suggest it may be preferable to forgo WBRT in favor of SRS, because SRS can preserve a patient’s cognitive function as long as possible. Longer-term follow-up to assess late neurocognitive effects of WBRT is pending.

Nonetheless, WBRT decreases recurrence of brain metastases, and it is possible that it may prolong survival in certain patients. A smaller Japanese study identified one such patient group. Patients with NSCLC who had one to four brain metastases and a favorable prognosis lived 6 months longer when treated with SRS and WBRT compared with SRS alone. No such survival advantage was observed among patients with a poor prognosis. Larger prospective studies are needed to confirm these findings.

1. (Brown PD, 
2. Asher AL, 
3. Ballman KV, 
4. et al.

 (2015) NCCTG N0574 (Alliance): A phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. J Clin Oncol 33, (suppl; abstr LBA4).)

A few slides on Adjuvant WBRT - basically dont do it ...

and is there ANY place for WBRT  :

From Melanoma perspective : this is 2015 but a useful summary :

http://cco.amegroups.com/article/view/6721/7550

The latest Melanoma updates - Monday abstract session

ORAL ABSTRACT SESSION

Melanoma/Skin Cancers

Mon, Jun 06 • 1:15 PM - 4:15 PM

Location: Arie Crown Theater


Abstract 9500 Results of NEMO: A phase III trial of binimetinib (BINI) vs dacarbazine (DTIC) in NRAS-mutant cutaneous melanoma.

Interesting to note that patients with prior immune therapy had better response than the ones who started on MEK inhibitor.

So unfortunately, not really great news for patients with NRAS mutant Melanoma:

Abstract 9501 A phase II trial of dasatinib in patients with unresectable locally advanced or stage IV mucosal, acral, and vulvovaginal melanomas: A trial of the ECOG-ACRIN Cancer Research Group (E2607).


UPDATE ON COMBI-D

Genomic analysis and 3-y efficacy and safety update of COMBI-d: A phase 3 study of dabrafenib (D) + trametinib (T) vs D monotherapy in patients (pts) with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma.

1:39 PM - 1:51 PM

Abstract  9502  

Keith Flaherty, MD

Good overview over targeted therapy:

And again- patients with lower LDH do better-

Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.

2:15 PM - 2:27 PM

Abstract  9503  

Caroline Robert, MD, PhD - Presenter • Disclosure 
Gustave Roussy and Paris-Sud University

most important take-home message: most patients with complete response continue to respond even after stopping treatment

A very nice write-up from ASCO can be found here.

Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival analysis of KEYNOTE-006.

2:27 PM - 2:39 PM

Abstract  9504  

Jacob Schachter, Prof, MD - Presenter • Disclosure 
Ella Institute for Research and Treatment of Melanoma, Sheba Medical Center

Pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma: Results of the KEYNOTE-029 expansion cohort.

2:51 PM - 3:03 PM

Abstract  9506  

Georgina V. Long, BSc, PhD, MBBS, FRACP - Presenter • Disclosure 
Melanoma Institute Australia, The University of Sydney, Mater Hospital, and Royal North Shore Hospital

Combination of targeted and immune therapy- discussion between Ribas and Flaherty

Ribas-

'The ultimate targeted therapy: Your own antitumor T-cells'

Nice overview comparing targeted and immune therapy:


Interesting argumentation to give checkpoint blockage before targeted (BRAF and MEKi) therapy.

Contrary to common belief, patients with high LDH also profit less from targeted therapy but can respond to anti-PD1.

Why give checkpoint blockage before BRAFi plus MEKi- it seems that acquired resistance also confers resistance to PD1 blockage.

and Ribas' conclusion:

Flaherty

And yet again- No patients should be getting BRAF monotherapy-

And an interesting algorithm on how to identify patients at higher risk, based on LDH level and the number of disease sites- patients will normal LDH and less than disease sites do best.

So the discussion which therapy to start with and how to continue is far from resolved but the possible cross-resistance between targeted therapy and immune therapy is something to worry about.

Metastatic Melanoma 2016- Georgina Long

Overall survival is continuously increasing in Melanoma, from 25- 35% in 1990 to above 70% at 1 year after diagnosis, both on immune therapy and targeted therapy.

Wolchok session- Melanoma Immunotherapy- How we got here

Always a pleasure to listen to J.Wolchok- Some history on immune therapy- IL2 approved in 1995 and already showed the 'tail' of the immune therapies that we like to see so much. Unfortunately not for many patients and coming with considerable toxicity.

'Pseudoprogression'- tumours seem to grow but are in effect infiltrated by immune cells. For that reason, immune RECIST were developed to distinguish progression from something that looks like progression but in reality is a response by the immune system.


Long-term survival on Ipi- 20%

from Schadendorf et al. 2015

the full publication is available here.


PDL1 as biomarker

as rather not as Wolchok was very vocal on PDL1 NOT being suitable to make treatment decisions whether to give an anti-PD1 antibody (Keytruda, Opdivo) or not. Even patients without PDL1 expression can respond to anti-PD1 antibodies and PDL1 is not a stable biomarker- it can be induced and change over time.

This is besides the fact that tests for PDL1 are not consistent, so different tests on the same tissue sample will not give the same results!

Hard to see but top curve is overall survival for patients whose tumours were PDL positive, the next lower one patients whose tumours who are PDL1 negative- and then come the DTIC ones..... which should have never been there in the first place!!


Combination of IPI plus PD1
Very interesting point on IPI plus PD1 given together or after each other- it appears that the concentration of how much Ipi is present in the blood matters: patients with more Ipi left do better.

67.5% of patients 81/120 who discontinued Nivo + Ipi due to side effects developed a response.

Gadget time...Mobile App for improving Cross-Referral and Recruitment to Melanoma Clinical Trials....

(From the poster session Saturday the 4th of June)


..although this Mobile App is focused on Australia....useful to think about the need for a European focused Melanoma Trial App...


Userinterface ....compare this to clinicaltrials.gov

Results (1/2)

Google analytics report - peak around May 2015 probably due to ASCO2015 results / attention (own interpretation red.)

Results (2/2) .....127% (!) increase in clinical trial participation

I would suggest to add the conclusion "use the app technology for all Melanoma in Europe"

Gr. Koen

Pembro and Ipi and PDL1 expression ....

Progression free survival on Pembro or Ipi ...

But in the Combined Ipi and Pembro ....

And a bit for the Uveal Patients ....

For The Acral and Mucosal Patients ....

Anti PD1 and pre-existing Autoimmune problems - can you treat them ?

Basically with careful management it is fine in most cases :

Interesting poster on Prediction of response for PD1 Monotherapies

Red is poor Response , Green is better  - not that women fare worse than men - they are now looking to see if there are sex hormone related reasons ....