The Presidential Symposium and the poster sessions at the European Society for Medical Oncology (ESMO) 2014 were mostly focused on melanoma studies. The meeting was held in Madrid, Spain, where studies demonstrated that inhibiting two molecular pathways is better than one, and where the data of the first ever performed phase 3 trial of a PD-1 inhibitor were presented. Melanoma, a specific type of skin-cancer that occurs when melanocytes become cancerous, had all the attention.
Intralesional injections to induce local and systemic immune responses in cutaneous melanomas were a highlighted field at the poster session; in turn, COMBI-v and CoBRIM studies were referenced in the second Presidential Symposium showing that two pathway inhibitors prove better than one in advanced melanoma patients with BRAF mutations.
“While monotherapy with a BRAF inhibitor is currently considered as a standard of care for patients with BRAF-mutated advanced melanoma, the data from these two trials, along with trial data presented earlier this year, provide convincing evidence that combination therapy with either dabrafenib and trametinib or vemurafenib and cobimetinib will be the standard systemic therapy for this patient population,” Reinhard Dummer from the University of Zurich and European Society for Medical Oncology (ESMO) faculty coordinator for melanoma commented in a Medical News Today interview.
The CoBRIM study included two groups of patients (randomly selected); the first group (254 patients) was treated with vemurafenib plus the MEK inhibitor cobimetinib and the second (239 patients) was treated with vemurafenib alone. Patients treated with the combination (first group) achieved a progression-free survival of 9.9 months and patients treated with vemurafenib alone (second group) achieved 6.2 months. The study showed that the combination treatment reduced in 35 percent the risk of death, based on the frequency of complete and partial responses. The complete response (meaning the total disappearance of the disease) scored 10 percent with the combination treatment and 4 percent with vemurafenib alone; the combination therapy reduced the rate of cutaneous squamous cell carcinoma from 11 percent to 3 percent and of keratoacanthoma from 8 percent to 1 percent.
The author of the study Grant McArthur from the Peter MacCallum Cancer Centre in Melbourne, Australia stated “not only does the MEK inhibitor make the melanoma respond better, but it actually reduces this particular side effect.”
Caroline Robert from the Institut Gustave-Roussy in Paris, France, presented data regarding the COMBI-v trial (LBA4). A group of 704 patients with advanced BRAF-positive melanoma were randomly divided in two groups: the first one (352 patients) treated with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib and the second (352 patients) with vemurafenib monotherapy. The median overall survival was 17.2 months with vemurafenib alone and, at the time of the presentation, it had not yeat been reached for the combination arm. The median progression-free survival was 11.4 months for the combination and 7.3 months for the monotherapy. Combination therapy showed a 64 percent response versus 51 percent with vemurafenib, which could be translated in improved tolerance to the combination. Cutaneous malignancies occurred in 1 percent of patients treated with the combination and in 18 percent of the patients treated with monotherapy.
In the third study (LBA3) nivolumab was adressed in patients suffering with advanced melanoma who have progressed on the approved agents ipilimumab and BRAF inhibitors; these are limited options for this kind of disease.
Nivolumab is a PD-1 (programmed death-1) immune checkpoint inhibitor that has the capability of binding himself to the checkpoint receptor PD-1 protein on the surface of activated T-cells. Cancer cells can produce the PD-1 ligands (PD-L1) which “shields” them from an efficient immune response; Nivolumab prevents the cancer’s PD-L1 from deactivating T-cells. In the phase 3 of the trial, 405 patients suffering from advanced melanoma who progressed on or after anti-CTLA-4 therapy and a BRAF inhibitor for BRAF V600 mutation positive diseases cases, were randomly selected to receive nivolumab (208) or a chemotherapy chosen by the reearchers (ICC): dacarbazine or carboplatin plus paclitaxel.
Results showed that the response rate of nivolumab was 32% while the chemotherapy rate was 11%. Also, treatments with the PD-1 inhibitor were associated with a lower frequency of discontinuation due to side effects: 2.2 percent with nivolumab versus 8 percent with chemotherapy.
Olivier Michielin, from the University of Lausanne, commented “these results demonstrate that PD blockade, contrary to a common and old dogma of immunotherapy, can produce rapid and deep responses even in advanced and bulky disease. This opens exciting new opportunities to widen the scope of application of immune-oncology for the treatment of stage I melanoma.”
At the poster session “Melanoma and other skin tumours” two intralesional therapies for cutaneous melanoma were presented as leading to tumor regression. Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-derived investigational oncolytic immunotherapy and PV-10 is a 10 percent solution of Rose Bengal.
Results showed that injections lead to tumor regression in the injected regions and in bystander lesions. A total of 80 patients suffering with stage IIIB-IV melanoma were injected with PV-10, which has a local chemoablative effect, since it enters lysosomes causing local necrosis and, in some patients, a systemic immunologically mediated effect. T-cells increased in peripheral blood after the injection including CD8+, CD4+, CD3+ and NKT. Twenty-eight patients that were injected with PV-10 had an overall response rate of 71 percent with 50 percent achieving complete response. These patients showed a progression-free survival of 9.8 months compared with 7 patients with a median of five untreated lesions that had a progression-free survival of 6 months.
An extension of the phase 3 OPTIM study in patients with unresected Stage IIIB-IV melanoma was also reported; the median overall survival was 23.3 months in the T-VEC treatment group, and 18.9 months in the granulocyte macrophage colony-stimulating factor (GM-CSF) treatment group. This eextension was available for patients who didn’t have clinically relevant progressive disease or had a complete response and proceeded to develop new lesions within 12 months from the end of their last treatment. A total of 31 patients were enrolled in the trial and the best overall responses improved in 7 patients receiving the T-VEC treatment.
We were able to show that in some patients whose disease had returned we could get them back into remission by re-challenging them with the agent. We also showed that T-VEC was very tolerable with no additional toxicity burdens for reinjection,” study author Kevin Harrington, from the Institute of Cancer Research in London, UK, concluded in the interview.