Clinicians don’t understand what’s happening and why it’s happening- but they are trying to understand. How is immunotherapy working, what causes resistance, how will sequencing be undertaken, what does the future look like- will biomarkers increase predictably of which treatment strategies will be more effective for which patients, are there more biomarkers to be researched, what role will oncolytics play in the treatment of melanoma and what therapies will emerge in the neo-adjuvant and adjuvant setting. What is understood is that melanoma is not one disease but various diseases. And with so many variables existing when dealing with melanoma, the key will be to have a variety of treatment options to create the best possible patient outcomes.
Increasingly the notion of the right treatment for the right patient at the right time is being adopted, however an understanding of the biology of the tumour and its environment is necessary in order to put this into application. Immunotherapy is expected to work in 30% of the patient population- while there is not a clear understanding of why it works in some patients and not in others, it is clear that a better understanding of pathways and biomarkers are going to be an important area of research.
Targeted therapy will continue to have an important role to play in the treatment of metastatic melanoma and while targeted therapy activates an immediate response in a BRAF mutation population, sequencing is still not fully understood. When time is of the essence what will treatment will physicians use?
Biomarkers are going to be critical for future success of melanoma therapeutics- will there be a way to make predictions based on these biomarkers rather than waiting for three years for clinical benefit or loss to emerge for clinical trials. Research increasingly suggests that tumour expression can be scored prior to treatment, including PD-L1, CD8 T cells, and markers of activation or inactivity in the tumour cell.
BRAF inhibitor based therapies continue to be the most impactful by far. Currently all clinical evidence has been performed on the V600 mutation population which represents 45% of patients with advanced melanoma. Another 5% of BRAF mutations exists and are not currently being studied.
Updated results from three randomized trials of the recently FDA approved combination of vemurafenib (Zelboraf) in combination with cobimetinib (Cotellic) substantially improving overall survival rate as well as progression free survival and response rate. Similar results are seen in the Dabrafenib (Tafinlar) combination with trametinib (Mekinist) which was approved by the FDA two years ago and based on two large randomized trials. This data set is also allowing researchers to see longer term outcome data.
Factors affecting outcome include patient disease burden, serum LDH (which correlates with aggressiveness of the tumour). Patients with high LDH levels can benefit from the treatment but unlikely to be long-term respondents. Whereas patients with low disease burden are seeing great outcomes on this combination therapy. These factors hold true for both targeted therapies and immunotherapies as well.
LDH has a predictive ability and a lot of work needs to be done for patients presenting with high HDL levels.
While BRAF inhibitors have significantly enhanced melanoma treatment an understanding of BRAF resistance mechanisms to devise treatment regimens that provide durable tumour control is still necessary. Scientists are attempting to learn the mechanisms of resistance from static biomarkers before deploying patients to therapy. An understanding of the baseline features of tumours and adaptations of tumours during therapy that make them resistant will determine which patients are likely to develop resistance and should receive more aggressive treatments.
Despite recent advances in the treatment of metastatic melanoma through targeted and immunotherapy, the majority of patients do not achieve a durable response. Research efforts to better understand responses are underway, and numerous molecular mechanisms of resistance to targeted therapy have been identified.
See What Dr. Reinhard Dummer, University of Zurich has to say here
Dr. Winson Cheung, BC Cancer Agency presents Highlights from SMR here
Participation at the Society for Melanoma Research Congress was provided by funding received from Novartis Canada.