On Saturday one of the major announcements of the conference was made with the release of important new data from the phase III trial of Ipilimumab versus Placebo as an Adjuvant (preventative treatment) for the treatment of melanoma in High risk stage 3 patients. Dr. Alexander Eggermont from the Gustave Roussy France presented. The study had randomized 951 patients after complete resection to IPI 10 mg/kg every 3 weeks for four doses and then every three months for up to 3 years or a placebo. From the data presented at a follow up of 5.3 years the recurrence free survival (RFS) with the IPI arm showed significant improvements with 28% reduction in the risk of death and a 24% reduction in the risk of distant metastases. the 5 year Overall Survival rates (OS) was 11% higher in the IPI arm. Adverse reactions are unchanged at grade 3-4 gastric, hepatic and endocrine. Information was also reported from the first phase III study to directly compare IPI 10mg/kg and IPI 3mg/kg with stage 3-4 melanoma patients who did not have prior treatment with Braf inhibitior or checkpoint inhibitior Dr. Paolo Ascierto from Naples noted that there was a marked improvement in Overall Survival for patients receiving the higher dose although the patients receiving the higher dose also experienced higher level of Adverse effects.
On Saturday evening I attended an Industry Satellite Session called Living Beyond the Curve in Braf Mutant Metastatic Melanoma: Understanding the patients behind the data
It was presented by a very esteemed panel of Prof Grant McArthur Melbourne Australia, Dr.David Hogg Toronto Canada, Prof Bart Neyms Brussels Belgium and Prof Paul Lorigan Christie Manchester.
The topic of the talk was based around patients who are long term responders to Braf +Mek inhibitors as time goes by we are seeing more patients who fall into this category in fact 58% of patients are alive at 3 years in results released at ASCO in June with 22% having progression free survival. Pooled data from trials show OS flatten out when patients get out past two years of treatment. Factors that can be an indicator of how well a patient will respond are the number of disease sites less than 3 being best, normal LDH level and good clinical prognosis. Of course the big question remains should patients switch treatment to Immunotherapy once they stabilise but at the moment there is no clinical data to support saving someone with Dab/Tram and then coming in with a change to Immuno being successful. So at the moment patients carry on for indefinitely on treatment, however this may not be the case as some new evidence is emerging of a very small set of 4 patients who have decided to come off treatment under very close medical supervision. These patients have remained disease free except for one who had a small reoccurrence of a 1cm sub cutaneous mass at 12 months after discontinuation removed and remains no evidence of disease since, it opens up the idea that targeted therapy may in fact have some effect on Tcell activity which previously hadn’t been understood, exciting news if proven to be true.
Also up for discussion at this session was how do we predict patients that will have relapse and what role does Circulating Tumour DNA play in helping to predict a relapse at a earlier time than perhaps CT/PET scan. There is no doubt the potential for using CTdna as a marker for relapse is potentially going to be a reliable one, but we are not there yet in terms of data to confirm this, so more trials are needed for confirmation also there is the problem of frequency of testing and the fact that many countries are not equipped yet to carry out testing. What happens if a patient progress is the next problem there is always the possibility of Immuno therapy to be used second line but it carries no guarantees of success some patients will of course respond well while some will not some evidence of an abstract poster presentation by Prof Bart Neyns amongst others of evidence that some patients even after progression and resistance on Dab/Tram and IPI or anti PD1 they may respond again with a rechallenge after a 12 week break from treatment it may only be a tempory response but might get the patient some valuable time.
On Monday new abstracts to be investigated further were discussed at a packed auditorium these included abstracts 1108 + 1110 which consider immunotherapy combined with Chemotherapy and abstract 1109 considering immuno + radiotherapy + Targeted.
The potential for combining Tvec with immune-checkpoint inhibitors to help create a immunogenic tumour micro environment such as Tvec followed by IPI compared to IPI early results show an improved response rate on the combination arm of this trial. It is too early to give any OS or Progression free survival stats, and with the presence now of PD1 antibodies this trial may prove to be unattractive.
Early response results of 16 patients receiving Pembro +Tvec showed a 56.% response rate but it was only 16 patients so very small result pool so far from the masterkey-265
Also a possibility is a phase III trial combination of Vermurafenib+Cobimetnib+Atezolizumab. Also discussed was the Keynote 253 Pembro + Epacadosat randomized Pembro + Placebo trial it shows potential from the viewpoint that Epdo does not cause toxicity so maybe a possible better in terms of toxicity combo than those presently in use if the results can match up. Still too early to say.
It has also been confirmed that low PDL1 expression means patients do not see any added benefit from having IPI/Nivo instead of Nivo Mono so testing for PD1 expression prior to commencing treatment may spare those patients the toxicity of the anti CTLA-4 agent. Also anti PD 1 therapies appear to be safe and effective to use in elderly patients, toxicity is the same but adverse effect management might be more challenging.
The one big challenge seems to be Brain Metastases when treated with Anti PD1 they are still worrisome and may require treatment with other checkpoint inhibitors or targeted therapies and unfortunately patients with Symptomatic Brain Mets or using corticosteroids have even worse outcome so regular brain CT\MRI is essential observation in patients receiving treatment at stage 4, who will be a risk of developing Brain Mets.
My own personal conclusions on the medical information at this years conference was a lot of positivity, when patients can access the correct treatments, sometimes the amount of checkpoint pathways that potentially offer a way of infiltrating the tumour can be disheartening you just want them to find the correct one now but of course it is never going to be that simple and ultimately it will probably be a combination of treatments to block or connect these pathways that offers the best outcomes, there have been huge advances in the last five years since 2011 there have been 8 new melanoma drugs in total and many more are in the pipeline it will be finding the right combinations and sequences of these drugs that will offer the best hope for patients in the future, it does feel like we are on the cusp of a possible cure but it is important to also manage patients expectations properly as unfortunately as of now Melanoma still remains a deadly prognosis for many patients.