Акценти от 2-ри ден

Neoadjuvant therapy, Biology and therapy of Merkel cell carcinoma, Targeting pathways in basal cell carcinoma: sonic hedgehog and beyond

Prof. Olivier Dereure

Dermatologist, Montpellier, France

Neoadjuvant therapy

Neoadjuvant immunotherapy in melanoma
Dr. Christian Blank (Dermatologist, Netherlands)

As expected, a number of presentations was made on the subject of neoadjuvant treatments for melanoma, following the recent significant advances in adjuvant therapy, particularly for stage III melanoma.

These neoadjuvant strategies are in fact quite diverse and respond to two main types of situations:

• either to allow resection for stage IV or stage III that is unresectable or “marginally” resectable
• or to address stage III that is resectable but with the ambition to increase the antitumour response and, therefore, the end result in terms of relapse prevention, in particular by increasing the stimulation of cytotoxic T cells in the remaining tumour while obtaining an early bio marker of treatment efficacy thanks to the analysis of the lymph node during the surgical procedure following the neoadjuvant period.

However, this strategy is not totally devoid of theoretical risk, including deterioration of the patient’s clinical state in the meantime, for instance by shifting the patient to an unresectable stage or a situation where surgery is more deleterious.

Moreover, it is not yet certain that this strategy is ultimately significantly more effective than conventional initial surgery followed by adjuvant treatment in terms of overall survival. Furthermore, these neoadjuvant strategies are not devoid of toxicity and are associated with heavier patient care load.

For immunotherapy, some data are already available, notably thanks to a trial comparing a neoadjuvant strategy using the ipilimumab/nivolumab combination with the same association in adjuvant treatment. In this trial, the pathological response rate to lymph node dissection is 78% after six weeks of neoadjuvant treatment. This rate is underestimated by the radiological response and independent of the tumour mutational burden. Imaging can even be disturbing, especially in cases of pseudo progression related to induced inflammation.

The updated results of this study show the consistent difference between neoadjuvant and adjuvant strategies for progression-free survival and overall survival and, as expected, the presence of an interferon-gamma signature is a good predictor of long-term outcome.

However, in this trial the neoadjuvant strategy proved to be more toxic than expected which led to trials using other doses of immunotherapy, in particular combining ipilimumab 1mg/kg + nivolumab 3mg/kg with then only 20% of grade 3 or 4 adverse events and, finally, results of progression-free survival were more or less identical with the other 2 arms using a higher dose of ipilimumab, even though the complete pathological response rate was higher in these two arms.

Once again, in this trial imaging underestimated the pathological response.

The emerging efficacy of these types of neoadjuvant immunotherapy raises several questions:

• whether or not this neoadjuvant period should be followed by adjuvant treatment in the event of complete or partial pathological remission,
• the need for lymph node dissection in case of complete pathological remission, but also in contrast
• to the benefits of adjuvant treatment by immunotherapy after dissection, if no pathological response is observed following lymph node dissection.

Neoadjuvant targeted therapy in melanoma

Prof. Peter Mohr (Dermatologist, Germany)

With regard to the targeted treatments, neoadjuvant therapy is also at the centre of attention with a trial comparing the “standard of care”, i.e. immediate dissection and dabrafenib + Trametinib for 12 weeks in resectable stage III, showing improved progression-free survival and survival without distant metastases in case of complete pathological remission where, once again, imaging underestimates the response, except perhaps if PET is used instead of volume rendering. According to the speaker, the best plan for targeted neoadjuvant treatment would be six weeks before surgery. It is unclear whether or not targeted adjuvant treatment should be continued if no pathological response to lymph node dissection is observed.

Neoadjuvant therapy and lessons from other tumor types and lessons to learn from former neoadjuvant trials in melanoma

Dr. James Larkin (Dermatologist, United Kingdom)

Finally, Dr. James Larkin notes that a large-scale trial is absolutely necessary for comparing neoadjuvant and adjuvant strategies before concluding that neoadjuvant therapy is of particular interest and that different trials would be required to answer different questions, identifying subgroups in advance, if possible, in order to better define the populations that would most benefit from the neoadjuvant or neoadjuvant/adjuvant combination (e.g. stage IIId) and by carefully selecting the questions that are asked given the number of patients required for obtaining a meaningful answer.

Finally, there is the question of the application of neoadjuvant strategy in stages preceding stage III, i.e. IIb and IIc, for example by using the interferon signature to predetermine the patients who would be the best potential responders.

Keynote lectures

Biology and therapy of Merkel cell carcinoma
Dr. Paul Nghiem (Dermatologist, United States)

Dr. Paul Nghiem in Seattle held an excellent plenary session that provided updates of the current data on Merkel cell carcinoma (MCC).

First, he mentioned that this is a particularly dangerous tumour whose mortality rate in the United States is approximately 40% with a steadily increasing incidence, about 95% over the past 15 years. Unlike other tumours, whose relative frequency tends to decline after age 80, the incidence of MCC continues to increase steadily with age. Clinical diagnosis is not that simple and should be systematically evoked after age 60 before any recent asymptomatic pink nodular lesion.

The topic of excision margins remains highly debated. Dr. Paul Nghiem believes that a 1cm margin should be sufficient even if the excision margins are unhealthy, if a sufficient dose of radiotherapy is performed postoperatively. Thus, not all patients require wide excision. In addition, direct closure should be preferred to flaps and grafts.

Is it possible to avoid radiation therapy in some cases? This is a possibility, if six low risk criteria are absolutely met. Monitoring should take into account the relapse rate, which is approximately 40% overall, and should not be too frequent or too infrequent.

Stage-dependent relapse-free survival curves should be used, provided that relapse generally occurs within 3 to 4 years after initial excision, and earlier in advanced local stages. This monitoring is clinical and morphological but could also easily be based on a MCPyV antibody assay that could be completed every three months. If the initial assay is positive, a decrease in rates has an excellent negative predictive value with respect to the absence of subsequent relapse and, conversely, an increasing rate after excision has an excellent positive predictive value with respect to relapse and should encourage increased vigilance.

According to Dr. Paul Nghiem, this biological monitoring would allow imaging savings and result in less radiation exposure for patients.

Regarding systemic treatment, it must now be considered that chemotherapy must definitely be replaced by anti-PD-1 immunotherapies which, naturally, makes sense in a tumour that is linked either to the presence of a virus with viral
antigens or UV-induced mutations with the appearance of neoantigens. The clinical trial mainly concerned pembrolizumab, presenting responses that are often long lasting when they appear, which is not the case for chemotherapy, as well as lower toxicity. Unfortunately, for regulatory reasons, reimbursement is often allowed only for second-line therapy following chemotherapy. Finally, the existence of forms resistant to anti-PD-1 should encourage trials using combinations such as anti-PD-1 + ipilimumab, anti-PD-1 + radiotherapy, anti-PD-1 + intralesional treatment with TLR agonist, oncolytic virus or Sting agonist, anti-PD-1 + targeted treatment such as MDM2 inhibitors or histone deacetylases.

Targeting pathways in basal cell carcinoma: sonic hedgehog and beyond

Prof. Nicole Basset-Seguin (Dermatologist, France)

In an equally excellent plenary session, Prof. Nicole Basset-Seguin delivered a remarkable presentation on the treatment of advanced BCC including hedgehog pathway inhibitors, vismodegib and sonidegib.

These two inhibitors have approximately the same efficacy and a similar side effect profile. The two main limiting factors to these treatments are represented by the numerous side effects that very often require a temporary or permanent cessation of treatment and, more rarely, by primary or secondary resistance. Nevertheless, 40% of patients can obtain an extended response, apart from those with Gorlin syndrome.

To improve treatment adaptation to adverse effects, intermittent regimens have been proposed which, apparently, do not modify the overall efficacy of these molecules and can therefore be proposed in case of limiting adverse effects. As far as Gorlin syndrome is concerned, these molecules demonstrated sustained efficacy, but their continuous long-term use is practically impossible due to those side effects and the lesions systematically reappear after stopping the treatment. Intermittent regimens can be useful yet again.

It should be noted that there are no specific trials for cases of xeroderma pigmentosum, but it may be necessary to pay attention to the appearance of cutaneous squamous cell carcinoma (cSCC) even if its high risk seems to have been ruled out despite a number of published observations, except perhaps in some special cases, such as the appearance of a SCC in the area affected by the BCC in treatment.

The use of hedgehog pathway inhibitors in neoadjuvant therapy is also quite possible, for instance, for reducing the tumour volume and, therefore, the tissue sacrifice.

With regard to primary or acquired secondary resistance, this happens quite rarely and concerns only about 15% of cases. This resistance may be related to the amplification of GLI2 or to mutations, e.g. of Smoothened (SMO), NOTCH, MYCN or MNT, and the use of another inhibitor naturally does not solve the issue. In contrast, a new SMO antagonist that has recently been the subject of a stage 1 trial could overcome the resistance to currently used hedgehog inhibitors.

Itraconazole has also been used in advanced basal cell carcinoma, which means that this molecule should not be overlooked.

In conclusion, basal cell carcinoma is associated with a significant mutational load that, of course, paves the way for immunotherapy alone or associated with a hedgehog inhibitor; several early trials are currently underway.

Lastly, the hedgehog-dependent pathway is certainly not the only signalling pathway involved in the pathophysiology of basal cell carcinomas and it is very likely that in the relatively near future a number of other targeted therapies will be developed to interfere with these different signalling pathways, thus broadening the therapeutic scope for advanced BCC treatment.