Melanoma studies dominated both the Presidential Symposium and poster sessions at the European Society for Medical Oncology 2014 meeting. Practice changing trials endorsed the “precision medicine” theme of the meeting, held in Madrid, Spain, September 26-30, with studies demonstrating inhibiting two pathways was better than one and the first ever phase 3 trial data of a PD1 inhibitor.

Abstracts in the poster session highlighted the emerging field of intralesional injections to induce local and systemic immune responses in cutaneous melanomas. Taken together, the COMBI-v and CoBRIM studies, featured in the second Presidential Symposium on Monday, showed that for advanced/metastatic melanoma patients with BRAF mutations, two pathway inhibitors prove better than one.

Commenting on the results of the two phase 3 studies, Reinhard Dummer, from the University of Zurich and European Society for Medical Oncology (ESMO) faculty coordinator for melanoma, said:

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.”

The rationale for combination therapy is that tumours develop resistance to BRAF inhibitors via the MAPK pathway that can be blocked by a MEK inhibitor.

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This year’s ESMO conference focused on the latest melanoma studies.

For the CoBRIM study (LBA5), 495 patients were randomized 1:1 to vemurafenib plus the MEK inhibitor cobimetinib (n=254) or vemurafenib alone (n=239). Results show patients in the combination arm achieved a median progression-free survival of 9.9 months, compared with 6.2 months with vemurafenib alone (HR=0.51, 95% CI, 0.39 to 0.68 P<.0001).

The frequency of complete and partial responses was 68% for the combination arm versus 45% for vemurafenib (P<0.0001), and an interim overall survival analysis showed a 35% reduction in risk of death favoring the combination arm (HR=.65; P<.05).

The complete response (total disappearance of the disease) was 10% with the combination arm versus 4% with vemurafenib alone. While the rate of grade >3 adverse events were greater for those receiving combination treatment (65% versus 59%), no difference was found in the rate of adverse events leading to study drug discontinuation.

Combination therapy reduced the rate of cutaneous squamous cell carcinoma from 11% to 3%, and of keratoacanthoma from 8% to 1%.

“Not only does the MEK inhibitor make the melanoma respond better, but it actually reduces this particular side effect,” said study presenter Grant McArthur from the Peter MacCallum Cancer Centre in Melbourne, Australia.

For the COMBI-v trial (LBA4), presented by Caroline Robert from the Institut Gustave-Roussy in Paris, France, 704 patients with advanced BRAF-positive melanoma were randomized to the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib (n=352) or to vemurafenib monotherapy (n=352).

The trial was stopped for efficacy when the one-sided p value exceeded <0.0107, and the interim analysis became the primary analysis. The median overall survival was 17.2 months with vemurafenib alone and had not been reached for the combination arm (HR 0.69, 95% CI 0.53-0.89 p=.005). The median progression-free survival was 11.4 months for the combination arm versus 7.3 months for monotherapy arm (HR 0.56, 95% CI 0.46-0.69, P<0.001).

Furthermore, the best confirmed response was 64% with the combination arm versus 51% with vemurafenib alone (P<0.001). Again, patients tolerated the combination well.

Grade 3 toxicities were 48% in the combination arm versus 57% with the single agent, and cutaneous malignancies occurred in 1% of patients in the combination arm versus 18% in monotherapy.

A third study (LBA3) addressed nivolumab in patients with advanced melanoma who have progressed on the approved agents ipilimumab and BRAF inhibitors, for whom there are limited options. Nivolumab is an investigational, fully-human PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 (programmed death-1) protein on the surface of activated T cells. If a programmed cell death 1 ligand (PD-L1) – produced by cancer cells – binds to PD-1, the T cell dies to avoid over activation. Nivolumab works by preventing PD-L1 from binding to PD-1, thereby stimulating the immune system.

In the phase 3 open-label trial, 405 patients with advanced melanoma who progressed on or after anti-CTLA-4 therapy and a BRAF inhibitor in the case of BRAF V600 mutation positive disease were randomized 2:1 to receive nivolumab (n=268) or investigators’ choice chemotherapy (ICC), either dacarbazine or carboplatin plus paclitaxel.

Results showed that the objective response rate of nivolumab was 32% compared with 11% for chemotherapy, and the median duration of response was 3.6 months in the chemotherapy arm and had not been reached in the nivolumab arm.

Responses were observed regardless of pre-treatment PD-L1 expression status, BRAF mutation status and prior anti-CTLA-4 benefit. Treatment with the PD1 inhibitor was associated with a lower frequency of adverse events compared with ICC, with discontinuation due to drug side effects occurring in 2.2% of the nivolumab group versus 8% of chemotherapy patients.

“The impressive data on duration of response suggest that there will be significant prolongation of progression-free and overall survival when the analysis of those data is mature,” said Weber.

Commenting on the results, Olivier Michielin, from the University of Lausanne, said:

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.”

The poster session “Melanoma and other skin tumours” on Sunday featured T-VEC oncolytic viral immunotherapy and PV-10, two intralesional therapies for cutaneous melanoma where injections are leading to tumor regression not only in the injected lesions, but also in “bystander” lesions suggesting that the strategy is augmenting the immune response. Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-derived investigational oncolytic immunotherapy; while PV-10 is a 10% solution of the dye Rose Bengal.

Abstract no 1120P provided the latest analysis of a phase 2 study evaluating intralesional injection of PV-10 in 80 patients with stage IIIB-IV melanoma. The rationale for PV-10 is that the agent has a local chemoablative effect where it enters lysosomes causing local necrosis, and then in some patients a systemic effect believed to be immunologically mediated. Studies have demonstrated increases in T cells in peripheral blood, following injection, including CD8+, CD4+, CD3+ and NKT.

For the subgroup of 28 patients who had all their lesions injected with PV-10 (i.e. had no uninjected lesions), the poster showed the overall response rate was 71% (CI 51-87%) with 50% achieving a complete response (CI 31-69%). The abstract furthermore showed a marked difference in progression-free survival according to number of lesions injected.

The 28 patients who had all their lesions injected had a progression-free survival of 9.8 months compared with seven patients with a median of five untreated lesions who had a progression-free survival of 6 months.

“The progression-free survival of 9.8 months compares favorably with historical progression-free survivals of less than 2.5 months for DTIC/TMZ,” said Sanjiv Agarwala, the first author from St. Luke’s Hospital and Health Network, Bethlehem, PA.

Such data, he added, suggests PV-10 will deliver significant progression-free survival effects in the phase 3 study, due to start Q4 2014. “The abstract also shows us that we’re likely to get the highest responses when all lesions are injected.”

Additional data showed that for the 232 lesions that achieved a complete response, 121 required a single injection, 84 required two injections, 22 required three injections and five required four injections. “The few injections needed in this study bode well for patient compliance with PV-10 treatment,” said Eric Wachter, an author of the poster.

Abstract 1102P reported on an extension of the phase 3 OPTiM study in patients with unresected Stage IIIB-IV melanoma, which, at ASCO 2014, showed that median overall survival was 23.3 months in the T-VEC arm versus 18.9 months in the granulocyte macrophage colony-stimulating factor (GM-CSF) arm (HR 0.79, P=0.051).

The extension study was made available to patients who did not have clinically relevant progressive disease or had a complete response and then developed a new lesion within 12 months from the end of last treatment. In total, 31 patients were enrolled into the extension trial, including three from the GM-CSF arm and 28 from the T-VEC arm who continued on randomized treatment for up to 12 months.

Results showed that the best overall responses improved in seven patients in the T-VEC arm, with five patients who had a partial response in the main trial achieving complete responses and two patients who had stable disease in the main trial achieving complete responses.

Furthermore, the adverse events reported were grade 1 or 2 in severity and did not lead to discontinuation, with the only grade 3 adverse events being local cellulitis at the injection site.

“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,” said study author Kevin Harrington, from the Institute of Cancer Research in London, UK.