Акценти от 3-ти ден

Dr Lise BOUSSEMART

Dermatologist, Rennes University Hospital, France

My third day of the congress focused on systemic treatment for advanced melanoma, including neoadjuvant, adjuvant and metastatic treatment.

Remember, since the discovery in 2002 of an oncogenic BRAF mutation in 1 out of 2 melanomas, targeted anti-BRAF and anti-MEK therapies, when combined with immunotherapy, have revolutionized the therapy landscape of metastatic melanoma over the past 8 years. We know that targeted therapies are effective and fast-acting for the majority of BRAF-mutated metastatic patients (approximately 80% of responders), but these responses are followed by almost systematic recurrence after a few months or years. Immunotherapy with anti-PD-1 results in less frequent responses (about 40%), but these responses last longer (5 years of regression for the first patients treated with anti-PD-1). Double immunotherapy with anti-PD-1 and anti-CTLA4 is more effective but potentially very toxic, and is not covered in the majority of European countries, including France.

News about targeted therapies was marked in 2018 by the European marketing authorisation of the new combination of encorafenib + binimetinib, which results in slightly longer responses than the already available anti-BRAF + anti-MEK combinations. It will still be a few months before it is covered and accessible to all patients. Georgina LONG pointed out that the tolerance of this new combination is generally better than the others, with less fever than from dabrafenib-trametinib and fewer rashes, diarrhoea, and phototoxicity than from vemurafenib-cobimetinib, without any new side effects. The dabrafenib-trametinib combination, taken for 1 year post-resection, made progress as an adjuvant treatment, with survival increasing to 3 years (86%) compared with the placebo (77%). Recurrence-free survival was reviewed at the 2018 ESMO Congress: it was 54% with targeted dual therapy vs 38% with the placebo. Surprisingly, even in the placebo group of this clinical trial, a high mutational load (number of mutations/DNA megabase, often following UV in skin cancers) and a strong interferon-γ signature were associated with better progression-free survival, as already established for immunotherapy. In the targeted dual therapy group, the interferon-γ signature was clearly associated with better progression-free survival, regardless of the overall mutational load. A strong mutational load would therefore favour natural immunogenicity, although it could be harmful due to selection pressure exerted by the targeted dual therapy. This is the first time I've heard about a link between mutational load/interferon-γ signature and targeted therapy. These biomarkers are usually studied with immunotherapy, but could help better select patients to benefit from one adjuvant treatment or another in the future. In neoadjuvant treatment, immunotherapy seems more relevant long-term than targeted therapies, but not with anti-PD-1 by itself, whose low response rate poses an unacceptable risk of becoming inoperable over the course of pre-surgical treatment. A double immunotherapy trial is therefore in progress with neoadjuvant treatment, with only 2 injections of ipilimumab instead of the usual 4, combined with 1 mg/kg of nivolumab. With this protocol, the first results reached 77% of histological response and 60% of radiological response. A strong interferon-γ signature was again a predictive biomarker for response. Neoadjuvant immunotherapy has the advantage of increasing the T-cell clone repertoire for a tumour that is still in place, gaining richer clonal diversity than with adjuvant immunotherapy. Strategically, it also helps determine if the patient is responding to immunotherapy in order to better select later adjuvant treatment.

In terms of side effects, the toxicities of immunotherapy are becoming better known and manageable, but the rarest are particularly serious (myocarditis, with 1/3 cases associated with myositis, myasthenia, etc.). Since neurological toxicities do not regress in 25% of cases, Lucie HEINZERLING, who maintains the European register of rare immunotoxicities, recommends high-dose corticotherapy at 1g/day for 2-3 days.

In stage IV, Reinhard DUMMER pointed out poorer responses to dabrafenib and trametinib when CDKN2A loss occurred (somatic but sometimes germinal), which is a new argument for favouring first-line immunotherapy in CDKN2A families in particular.

With immunotherapy, Véronique BATAILLE advised against taking antibiotics or even probiotics because they disturb the microbiome. There are, however, some types of microbiomes that aid immunotherapy. Consuming Processed/industrial foods and red meat is also discouraged, in favour of a diet rich in fibre, fruits and vegetables. Trials of faecal transplantation from responders to non-responders is promising.

In the event of multiple brain metastases, Brigitte DRÉNO  emphasized the superiority of the ipilimumab + nivolumab combination (56% of responses, the vast majority of which – 47/52 responses – last up to one year) over anti-PD-1 by itself (22% of responses). Jean-Jacques GROB insisted on the benefits of stereotactic radiosurgery when centres are equipped. Stereotactic radiotherapy, like surgery, can be done simultaneously with immunotherapy. Radionecrosis can occur 2 years after radiotherapy, and is a differential diagnosis of local recurrence that is important to know. Unanimously, in toto brain radiotherapy (whole-brain radiotherapy) should be banned (toxic, ineffective).

New targets such as eIF4F, CDK4, p53, HGF, sox 10 and EZH2 are being studied.

Finally, uveal melanoma remains a very specific case in clinical, genetic and therapeutic terms. Since it almost never expresses PD-L1 on its surface, immunotherapy is not efficient enough, so the anti-PD-1 and anti-CTLA4 combination is preferred when accessible (11.5% of responses vs. 6% with ipilimumab by itself and 3.6% with anti-PD-1 by itself).

In conclusion, new treatments for metastatic melanoma are starting earlier and earlier, while indications for surgery continue to lose ground. Pre-therapeutic biomarkers such as mutational load and interferon-γ signature seem essential for the future.

Dr Oriol YÉLAMOS PENA

Dermatologist, Hospital Clínic & Centro Médico Teknon, Barcelona, Spain

SYMPOSIUM: Treatment of advanced BCC & SCC MELANOMA

Chairs: N. BASSET-SEGUIN - A.STRATIGOS - R. VIEIRA

Classification of advanced BCC: J. J. GROB

Classically basal cell carcinomas that were not amenable to surgery were considered advanced. However, currently with the advent of new hedgehog inhibitors some of these BCCs are now treatable. Hence, the term of advanced BCC should probably be replaced for difficult to treat basal cell carcinomas. Also, a challenge with these difficult to treat BCCs is that no classifications exist and actually many different realities exist. In this sense, through the EADO a new classification for difficult to treat BCCs has been created: BCC located in cosmetic areas that can be surgically removed completely, multiple BCCs which are difficult to treat due to multiplicity (>10 small ones, or >5 medium-large ones), giant BCCs, BCCs with distant metastases, and BCCs which may be operated but leaving unacceptable defects for the patient.

Update in the management of HhI in the treatment of advanced BCC: N. BASSET-SEGUIN

In the last years two systemic drugs that inhibit the sonic hedgehog pathway have been developed: vismodegib and sonidegib. Both drugs are comparable in terms of efficacy and adverse events. Regarding adverse events they normally appear at 21 months of treatment with both drugs and mostly include alterations in the taste, alopecia and muscle cramps. In addition, these drugs can lose activity due to resistance. Two forms of resistance exist: intrinsic resistance (happens in 6% of cases) and external resistance (happens in 9.5% of cases). Intrinsic resistance is the one that is related to the tumor which basically prevent the tumor to respond (meaning, no response exists from the beginning), whereas external resistance is when a tumor that has responded to hedgehog inhibitors then starts growing again. This type of relapse is known to happen because different mutations happen which are not in the hedgehog pathway but in the Wnt pathway.

Management of advanced SCC: A. STRATIGOS

Squamous cell carcinoma (SCC) rarely produces metastases but this happens in around 4% of cases. However, the mortality that occurs with cutaneous SCC is not related to metastases, but mostly is related to locally invasive cSCC.

High risk SCC include as those that require aggressive management. But which is the management of such cases? The treatment strategies for advanced SCC includes surgery, radiotherapy, chemotherapy, antiEGFRs and recently immunotherapy. All the treatments work but since SCC has a very high mutational rate, immunotherapies such as antiPD1 seem very promising. In this sense, a new immunotherapy specific for cutaneous SCC has been developed, known as cemiplimab.

To conclude, it is necessary to better classify advanced cutaneous SCC, no standards of care exist, radiotherapy plus chemotherapy +- antiEGFRs is the most used scheme, although new drugs such as cemiplimab may be the best way to treat advanced cSCC.

Surgical treatment in advanced tumours: R. VIEIRA

Surgery is still a very important in the management of advanced non-melanoma skin tumors.

However, there are now new aspects to consider. One the most important one is the use of targeted therapies and immunotherapy in the neoadjuvant setting for non-melanoma skin cancers. Since SCC has a high mutational rate, they respond nicely to antiPD1 and then can make the tumor smaller prior to surgery. The same situation is true for advance BCC and the use of hedgehog inhibitors such as vismodegib or sonidegib. It is also important to remember that, although virtually every tumor is ressectable, sometimes we need to acknowledge that sometimes surgery is not necessary. In certain cases, especially old patients with poor performance status, surgery may not be the option, and sometimes radiotherapy or a more conservative approach may be better in order to provide good quality of life.

PLENARY SESSION:

Chairs: S. PUIG - C. ROBERT

How to combine target and immunotherapy?: G. LONG

Before targeted therapies and immunotherapy the overall survival for advanced melanoma was 5%. Now, with the combination of targeted therapies and immunotherapy survival increased to 40%. In terms of efficacy, this combo is unprecedented and has set the bar.

Still the main problem in melanoma is that some patients in immunotherapy progress very fast and we cannot do anything to save them. So, why there is resistance to immunotherapy? We are still doing research to identify biomarkers that may predict the responders vs the non-responders. For now we are still identifying these biomarkers. A way to increase response is to combine immunotherapy and targeted therapies. Some trials evaluating triple therapy (ie pembrolizumab + dabrafenib + tametinib vs dabrafenib + tametinib) show very high response rates (around 40%) with long duration of response. What’s also important is that with triple therapy the adverse events that force stopping the drugs were high with triple therapy (42% with triple therapy vs 22% with dabrafenib + trametinib).

To summarize, it is not recommended to wait a patient to progress under BRAF+MEKi in order to start antiPD1, new evidence seems to show that administering these drugs before surgery may be beneficial, and that the combination of all drugs works best but can be toxic and expensive.

Can we cure advanced metastasic melanoma patients?: A. HAUSCHILD

Although melanoma in metastatic stage is very deadly, not all patients die. Also, with the new drugs many patients live longer. First, before considering melanoma can be cured we need to acknowledge what is curing melanoma. Curing melanoma would be obtaining an expectancy of life similar to the general population so people will die of other causes than melanoma.

Patients can be cured of melanoma now, but it’s not us physicians who cure them but it’s the fact of chance since there are different tumor biology. Also, before drugs can cure melanoma, studies should be performed correctly without running too fast. An example of a deceptive drug are IDO inhibitors such as epacadostat which have shown zero benefit since they switched from phase 2 to phase 3 trials too fast with small sample sizes. So, current available data with 5 year survival is nivolumab: 5-year overall survival around 48%, and for pembrolizumab 34-41% of overall survival. These responses are very good but still far from considering “cure”, since more than 50% of patients will die from melanoma in the next 5 years.

Another aspect that is important is not only response but is for how long the response is maintained. For example, 20 years ago when the studies using IL2 for melanoma showed that the response rate was very low (less than 10%) but the patients who responded survived for more than 10 years! So, virtually those who responded were “cured”. This type or responses are the ones we need to achieve to cure melanoma. Finally, is cure possible through adjuvant therapy? It is possible but we need to long term data to see for how long the response is maintained.

What is to do to make our treatments more efficacious? Understand better the tumor biology and identify biomarkers that may be useful to select the adequate drug and predict which patients will get cured with a given treatment strategy (most likely combination treatments). However, now we can identify biomarkers but some of them are still not targetable with drugs.