Scientific highlights: Day 2
Management of advanced melanoma
Combining or sequencing targeted therapy and immunotherapy | Paolo ASCIERTO (Italy)
To treat cancer, several combinations of treatment are possible (immunotherapy, radiotherapy, chemotherapy, targeted therapy, etc.). Dr. Paolo ASCIERTO presented today his arguments for a concomitant or sequential administration of immunotherapy and targeted therapy in terms of efficacy. The studies presented by Dr. Paolo ASCIERTO showed that a single treatment in targeted therapy consisting of BRAF / MEK was less effective in the short term than a treatment associating this targeted therapy with an immunotherapy, in spite of stops necessary because of the toxicity. However, a primary study shows in parallel that a sequential administration of these treatments is equally effective when looking at the results in the longer term. Pending the phase III trials, these results are yet to be confirmed and, if confirmed, will likely leave the question unclear as to which approach to use in the future. It will certainly also be necessary to consider the differences in response between men and women among others, as well as other criteria specific to patients and their pathologies.
How to overcome primary and secondary resistance to immune checkpoint inhibitor | Thomas GAJEWSKI (United States)
While antibiotic resistance is a hot topic around the world, there is much less talk about the resistance of certain cancers to immunotherapeutic treatments. Yet these resistances are sometimes dead-ends for patients and medical staff. This is the subject of the conference that Professor Thomas Gajewski held this Thursday, April 25.
In the first place, it seems that there is a difference between T-cell inflamed versus non-inflamed tumor microenvironments that could find its origins with a molecular mechanism with distinct oncogene pathways activated in different patients.
T cell-inflamed tumor microenvironment serves as a predictive biomarker for response to anti-PD-1-based immunotherapies. However, this biomarker lacks precision and remains considered approximate. A new potential therapeutic target would correspond to the expression of regulatory receptors when dysfunctional TIL die.
In contrast, non-T cell-inflamed tumors might be amenable to de novo immune priming with STING agonists.
Professor GAJEWSKI concluded his presentation by addressing secondary resistance screens that are revealing new candidate mechanisms that could be potential new targets, specifying that a selection for resistant variants can require clonal cooperation.
How should we evaluate our patients in the era of immunotherapy? irRECIST, irRC, iRECIST? | Michael MAJER (France)
Imaging plays a major role in the objective evaluation of tumor response to anticancer treatments. Dr. Michael MAJER proposed a conference on the history of radiological evaluation of the response to immunotherapy in melanoma and its latest advances.
Since the establishment of conventional criteria for evaluating the response to immunotherapeutic treatments in 1981 by WHO, treatments have evolved considerably. It was therefore legitimate to review these criteria in accordance with different treatment responses.
These criteria were also extensively revised between RECIST 1.0 in 2000 and RECIST 1.1 in 2009. The main changes were the definition of the number of lesions to choose, the minimum size, the definition of non-targeted lesions and the one-dimensional way. In addition, three categories of lesions are taken into account: target lesions, non-targeted lesions and new lesions. Subsequent monitoring evaluates the three categories and the worst response among all categories prevails over the others to assess the overall response.
Other options have been studied, such as irRECIST or irRC. Due to the wide variability of clinical trials in the choice of respective evaluation criteria, the RECIST working group decided to create iRECIST as an official guide for clinical trials.
RECIST: Response Evaluation Criteria In Solid Tumors
How to prevent Melanoma Progression in tumor-free patients of…
Stage II | Jean-Jacques GROB (France)
Professor GROB discussed, this Thursday, April 25 on the difficulties to identify the kinetics of melanomas, echoing his speech of Wednesday, April 24. Indeed, the Breslow and sentinel lymph node tests do not differentiate indolent melanomas from aggressive melanomas. Even with early detection of melanoma, these tests do not provide enough information to define an effective and relevant treatment strategy.
Currently, we classify melanomas and we define a treatment according to the Breslow test and according to the number of affected lymph nodes. However, if one looks at the survival results, there is no longer a risk of having a death of a stage II-C patient than a stage III-A patient. The prognosis for a patient with stage II-A melanoma is not much better than for stage III-A, the prognosis of stage III-A is better than for stage II-B, while stage III-A remains much better than stage II-C. So why not treat stages II with the same application as stages III?
There are a lot of people in stage II with a low percentage of deaths, of course, but that's a lot of deaths at the end. With a higher death rate for Stage III but a much smaller group, this represents an overall lower number of deaths at the end.
Therefore, it appears essential to carry out additional studies to show that patients with stage II melanoma should be treated.
Stage III | Axel HAUSCHILD (Germany)
Professor HAUSCHILD presented this morning a conference that offers a concise comparison of different treatments.
He pointed out that a study on a treatment with ipilimumab in high doses versus a placebo had demonstrated an effectiveness, but this treatment was authorized only in the USA and that it was not proposed to the patients because of too much toxicity.
Another study showed that treatment with nivolumab reduced the risk of recurrence by 48%, which is very effective, regardless of BRAF status (mutated gene or wild type).
Treatment with pembrolizumab also gives good results with a reduction in the risk of recurrence of 43%, also regardless of BRAF status. The nivolumab and pembrolizumab treatments cause little toxicity with 10 to 14% of stops. However, sequelae toxicities and a few rare deaths come to tarnish these beautiful results.
Thus, despite good results with immunotherapy, cases of toxicity prompt the consideration targeted therapies.
Pr. HAUSCHILD reverted to the results of a study with Dabra/Tram treatment. The probability of survival without recurrence was 88%, a spectacular result, however this result decreases over time by 53% after 4 years.
Therefore, it seems necessary to carry on studies to identify the best treatment, according to short-term and long-term efficacy, without forgetting to consider toxicity problems.
Stage IV | Nicolas MEYER (France)
Professor Nicolas MEYER painted a picture of the effectiveness of possible treatments for people with stage IV skin cancer, a balance that remains so dramatic given the few solutions.
Pr. MEYER proposes to administer these patients an adjuvant treatment by arguing in his speech the following elements:
1- Stage IV patients have a very poor prognosis, especially those with elevated LDH
2- Stage IV patients with complete resection also have a poor prognosis
3 - Adjuvant treatment also works in stage IV patients.
If one is satisfied with surgery for stage IV patients, the recurrence rate is 90%, demonstrating that surgery alone is totally inadequate. In contrast, a study associating adjuvant treatment after surgery to this type of patient shows a risk of recurrence down by 30% only. However, this study only covered a small cohort of just over 80 patients. In parallel, the tracks of other additional treatments, for example neoadjuvants or radiotherapy, will be studied for comparison.
Biomarkers in melanoma
Microbiome | Beth HELMINK (United States)
At a time when the microbiome is being studied in all areas of health, it seems obvious to ask the question of its role in carcinogenesis and in the responses to anticancer treatments. This is the work that Dr. Beth HELMINK led with her team.
She showed that patients with high microbial diversity survived better in case of stem cell transplantation.
She also found that patients with this intestinal characteristic and metastatic melanoma responded better to anti-PD1 therapy. Patients with fecal microbial diversity also had significantly prolonged SPP. More specifically, patients with a high abundance of Faecalibacterium greatly extended their SSP.
Dr. HELMINK's team also investigated the relationship between the microbiome and the microenvironment of the tumor. The team observed a group of bacteria (including faecalibacterium) associated with a strong anti-tumor immune response. A high abundance of faecalibacteria correlates with a higher immune cell density, as well as an increase in myeloid and lymphoid compartments (including a higher number of antigen presenting cells).
It is thus clear that bacterial taxons of the intestine are associated with the response to anti-cancer and toxicity. However, a major question remains unresolved: by modulating the microbiome, can we improve the patients responses to immunotherapy? If Dr. Beth HELMINK is certain, there are studies to be done in the context of clinical trials.
Immunotherapy alone or in combination with RT in melanoma CNS metastases | Hussein TAWBI (United States)
Brain metastases are peculiar in many ways. Dr. Hussein TAWBI has studied the administration of an immunotherapeutic treatment alone or in combination with a targeted therapy in the context of metastases of the central nervous system. He presented the results of this work on Thursday, April 25.
Initially, he noted that patients with intracranial metastases and T-cells in the brain had a better response to immunotherapy and better survival rates than patients with extra-cranial metastases. He was also able to conclude from his research that the response to corticosteroids was low for patients treated with ipilimumab, unlike nivolumab patients.
PD1 alone had little effect on brain metastases, but was more effective in combination with ipilimumab treatment.
In addition, a combination ipilimumab + nivolumab allowed a fast and durable response with a classic toxicity.
More generally, targeted therapies allow progression-free survival but responses are short. In contrast, immunotherapy causes prolonged intracranial responses to intracranial metastases.
For Dr. TAWBI, the combination of immunotherapy and targeted therapy is the key to hopefully increasing the effectiveness of treatments. Another promising avenue is an association between radiotherapy and immunotherapy, but it remains to define in what order and to what extent to associate them.
Challenges in the design of CNS metastases trials | Emilie LE RHUN (France)
Cerebral metastases are relatively rare cases. Because of its low frequency, it is difficult to study. Dr. Emilie LERHUN outlines the various criteria to be taken into account in order to carry out the most reliable research possible on the subject.
To develop a good study, it is necessary to list the eligibility criteria very carefully. We must think about the very definition of brain metastases to determine the scope of metastases that can be included in a study. It is also necessary to establish the definition of lepto-meningeal metastases to be included in a study and to determine the characteristics of active metastases (recent or progressive). In addition, it is necessary to identify the population to be targeted: type of cancer, treatment, general condition, etc.
The desire to be selective is legitimate, but this selectivity may limit the possibilities of extrapolating future results to other patients and other situations.
Finally, in order to develop a satisfactory study, it is also essential to specify the objective: overall survival or progression-free survival, in addition to assessing the toxicity and quality of life of patients.