Is immunotherapy the way forward for melanoma treatment?

Promising new treatments for advanced melanoma drew considerable attention at ASCO 2013 in Chicago, with investigational immunotherapies taking centre stage.

Three novel strategies that trigger the body’s immune system to attack melanomas were presented during the Melanoma/Skin Cancers Oral Abstract Session, including the first oncolytic (cancer-killing) virus to demonstrate therapeutic benefit against melanoma in a phase III trial. 

Oncolytic virus against melanoma

T-VEC (talimogene laherparepvec) was shown to significantly improve the durable response rate (DRR) in patients with metastatic disease compared with granulocyte-macrophage colony-stimulating factor (GM-CSF). One in six (16.3%) patients who received T-VEC had a complete or partial response lasting at least six months, in contrast with only one in 50 (2.1%) patients given GM-CSF. These interim results from the OPTiM study were presented by Dr Robert Andtbacka, a surgeon and investigator with Intermountain Healthcare and Huntsman Cancer Institute in Salt Lake City, Utah.

termountain Healthcare and Huntsman Cancer Institute, Salt Lake City, Utah, US. Photo by © ASCO/Scott Morgan 2013 (click to enlarge)

“We all know melanoma is a bad disease, particularly for patients with regional and distant metastases. There is currently less than 15% five-year survival for patients with stage IV disease, and less than a third of our patients with stage IIIb and IIIc disease are alive or disease-free after five years,” he said.

Between May 2009 and July 2011, 436 patients with unresectable stage IIIb, IIIc, or IV melanoma were enrolled in OPTiM and randomised 2:1 to receive intratumoural T-VEC or subcutaneous GM-CSF. Patients were required to have at least one cutaneous, subcutaneous, or nodal lesion amenable to injection, as well as to measurable disease. 

“When we looked at the objective overall response rate, once again the patients treated with T-VEC had improved. [The] overall response was 26.4%, with a 10.8% complete response rate, compared to 5.7% [overall response] in the GS-CSF arm.” The complete response was 0.7% in GS-CSF arm.

T-VEC is a modified herpes simplex virus type 1 (HSV-1), designed as a Trojan horse to infiltrate and destroy tumours by wielding a ‘one-two punch’, directly killing tumour cells at the site of injection, while also eliciting host defence mechanisms that indirectly target distant cancer cells for destruction.

Principle investigator, Dr Andtbacka explained that this two-pronged effect is achieved through a number of genetic modifications – deleting its herpes-causing capacity and encoding the virus with the gene required for human GM-CSF production (a protein naturally secreted in the body to initiate an immune response). After injection into a patient’s tumour, T-VEC selectively infects and replicates only in cancer cells, secreting GM-CSF in the process. The cancer cells eventually become overrun with virus and GM-CSF and rupture, expelling new viruses, GM-CSF, and an array of tumour-specific antigens. Newly released GM-CSF acts as a beacon to inflammation-responsive dendritic cells, which process and present the tumour-specific antigens to T cells that then become programmed to seek and destroy antigen-bearing tumour cells throughout the body.

“Ultimately that’s what we want; we want the immune system to be activated against melanoma everywhere. We are teaching the immune system locally how to fight the melanoma at distant sites. I believe this is a very new approach and will change the way we are treating our patients with melanoma,” he told Cancer Professional.

Dr Andtbacka also stressed that T-VEC was an extremely well tolerated treatment. Most common adverse events were fatigue (50.3%), chills (48.6%), fever (42.8%), and nausea (35.6%), while the most common grade 3/4 adverse event observed with T-VEC was cellulitis and occurred at an incidence of only 2.1%. This favourable side-effect profile makes T-VEC a good candidate to combine with other therapies in patients with advanced and metastatic melanoma. To this end, patients are currently being recruited to a study that will evaluate the safety and efficacy of T-VEC in combination with ipilimumab versus ipilimumab alone.

Immune system booster

Results of a phase II study, presented during the ASCO skin cancer session, found that the addition of GM-CSF to an increased dose of ipilimumab not only prolonged overall survival, it also offered reduced toxicity compared with ipilimumab alone.

Dr Stephen Hodi explained that ipilimumab has been shown to improve survival in patients with metastatic melanoma, “albeit with a 10-25% high-grade rate of adverse events.”

Dr Stephen Hodi, director, Melanoma Center, Dana-Farber/Brigham and Women’s Cancer Center, Boston, US. Photo by © ASCO/Scott Morgan 2013 (click to enlarge)

Whereas ipilimumab functions to knocks out the activity of CTLA-4, a protein that dampens T cell activation, GM-CSF promotes white blood cell production and recruits immune cells to sites of inflammation. Dr Hodi said that the combination of CTLA-4 blockade and GM-CSF secreting tumour cell vaccines has demonstrated therapeutic synergies in pre-clinical and early clinical trials where this combination has greater efficacy than either modality alone. 

Based on this background, he and colleagues embarked on a phase II trial (E1608) in which a total of 245 patients with unresectable stage III melanoma (who had received up to one prior therapy) were randomly assigned to get ipilimumab induction and maintenance at a dose of 10mg/kg either with or without the addition of GM-CSF. Dr Hodi explained that, due to the known inflammatory effects produced by immunotherapies that may appear as disease progression, patients were permitted to continue therapy even if their target lesions doubled in size and up to four new lesions appeared, so long as their general wellbeing held steady.

Given that the ipilimumab/GM-CSF arm showed no difference from the ipilimumab-alone arm in overall response (15.5% versus 14.8%) or median progression-free survival (3.1 versus 3.1 months), the improvement in overall survival with the combination regimen was rather surprising. 

Based on a median follow-up of 13.3 months, median overall survival stretched to 17.5 months with ipilimumab and GM-CSF compared with 12.7 months with ipilimumab. Data are still being collected for the final overall survival analysis.

Another important finding was that the addition of GM-CSF to ipilimumab decreased the incidence of high-grade adverse events. Overall grade 3 to 5 toxicities fell from 58.3% with ipilimumab alone to 44.9% with combination therapy, driven largely by decreases in grade 3 to 5 gastrointestinal events (26.7% versus 16.1%) and pulmonary events (7.5% versus. 0%).

PD-1 blockade

A new group of checkpoint inhibitors that block the programmed death 1 (PD-1) and PD-1 ligand (PD-L1) are also demonstrating remarkable potential in the treatment of advanced melanoma. 

Long-term data from an expanded phase I trial of the PD-1 inhibitor nivolumab in heavily pretreated patients with advanced melanoma was presented by Dr Mario Sznol, professor of oncology at the Yale Cancer Center in New Haven, Connecticut. These demonstrated a striking median overall survival duration of nearly 17 months, complemented by a favourable safety profile.

Dr Mario Sznol, professor of oncology, Yale Cancer Center, New Haven, Connecticut, US. Photo by © ASCO/Scott Morgan 2013 (click to enlarge)

Similar to CTLA-4, upregulated PD-1 expression on the surface of tumour-infiltrating lymphocytes puts the brakes on T cell activation, in turn preventing these immune cells from fighting off cancer. Nivolumab is a fully human anti-body that binds to the PD-1 receptor, thereby keeping T cells primed and ready for tumour attack.

More than 100 patients with advanced melanoma received up to 12 eight-week cycles in which intravenous nivolumab was administered every two weeks at five different doses. All patients had disease that progressed despite one to five prior lines of systemic therapy. Two-thirds of patients had received at least two prior therapies, and one-quarter had received three or more.

Dr Sznol reported that the response to nivolumab treatment was “both rapid and durable”. The subjective response rate across the different doses was 31%, which is a high number for previously treated patients, but reached 41% among patients treated with 3mg/kg of nivolumab – the dose being pursued in further clinical development.

Responses occurred rapidly in most patients (45% of responding patients showed at least 30% tumour shrinkage at the first tumour assessment eight weeks following the start of treatment) and median duration of response was two years. Sixty-two percent of patients survived to one year and 43% to two years.

Dr Sznol also pointed out, “Of 17 patients who went off drug for reasons other than disease progression, 12 [71%] continued to respond for 16 or more weeks since the end of therapy.” Nivolumab is currently being evaluated in three ongoing phase III trials in advanced melanoma.