You are here
Society for Melanoma Research 2014
The Society for Melanoma Research annual congress hosted more than 900 researchers and clinicians in Zurich, Switzerland, from November 13 to 16. Notable sessions covered an oncolytic immunotherapy, combined BRAF/MEK inhibition, and a programmed death-1 (PD-1) inhibitor, all in advanced melanoma.
Talimogene Immunotherapy—Clinical Data In Local, Regional, and Distantly Metastatic Melanoma
- Robert Andtbacka, Associate Professor, University of Utah School of Medicine; and Merrick Ross, MD, Professor, University of Texas MD Anderson Cancer Center, Houston, Texas
In a subanalysis of results among patients with advanced unresected cutaneous head and neck melanoma (CHNM) in the OPTiM trial and in a phase 1b/2 multicenter, open-label trial in previously untreated advanced melanoma patients, talimogene laherparepvec (T-VEC) demonstrated significant benefits. T-VEC is a herpes simplex virus-1–derived oncolytic immunotherapy.
Compared with other tumor locations, Dr. Andtbacka said, CHNM has a higher risk for recurrence, a worse prognosis, and limited treatment options. “The in-transit and nodal recurrences and visceral disease can be very challenging to treat. Lesions can become symptomatic and cosmetically disfiguring,” he said.
The OPTiM trial included 436 patients with injectable, unresectable stage IIIB–IV melanoma who were randomized 2:1 to T-VEC or granulocyte-macrophage colony-stimulating factor (GM-CSF). Dr. Andtbacka reported on 61 of 295 patients (20.7%) in the T-VEC arm and 26 of 141 patients (18.4%) in the GM-CSF arm with CHNM.
Durable responses were defined as a complete or partial response that began at any point within 12 months of initiation of therapy and lasted continuously for six months or longer. T-VEC durable response rates were higher in the CHNM patients than in the OPTiM general population (36.1% compared with 16%). The durable response rate for GM-CSF in CHNM patients was 3.9% (P = 0.003 versus T-VEC in CHNM). Among responders, Dr. Andtbacka emphasized, 73% had responses lasting 15 months or longer.
The objective overall response rate for T-VEC in CHNM was 47.5% versus 7.7% for GM-CSF (P = 0.0004). Complete and partial response rates with T-VEC were 29.5% and 18.0% versus 0.0% and 7.7% with GM-CSF, respectively.
“In patients with cutaneous head or neck melanoma, T-VEC as a monotherapy or likely in a combination will be an important treatment modality,” Dr. Andtbacka concluded. “If you have head or neck melanoma and you had a durable response to T-VEC, you were likely to have a very long-lasting response.”
In earlier phase 1 reporting (American Society of Clinical Oncology, 2014) of the phase 1b/2 trial of T-VEC plus ipilimumab versus T-VEC alone in 18 patients with previously untreated or unresected advanced melanoma, there were no dose-limiting toxicities and a 56% response rate with complete responses (CRs) in 33%—results Dr. Andtbacka called “very encouraging.” Because T-VEC promotes the release and presentation of tumor-derived antigens and ipilimumab, an immune checkpoint inhibitor, improves T-cell responses, there is potential for enhanced efficacy beyond that of either therapy alone, he said.
Dr. Ross elaborated on the rationale for combining systemic immunotherapies with ablative intralesional treatments in an interview. “I am actually very enthusiastic about the combination of these oncolytic immunotherapies with the other targeted immunotherapies like the anti-CTLA-4 or anti-PD-1 agents,” he said. The anti-PD-1 and anti-CTLA-4 agents affect precise targets: for example, blocking a specific receptor to activate T cells and make the immune system function, he said. They differ from “classic” immunotherapies that elicit very specific T-cell responses through antigen presentation.
The oncolytic immunotherapies, including an oncolytic virus such as T-VEC or the chemical ablator PV-10, rupture the tumor in a manner similar to a multivalent vaccine, releasing antigens potentially specific to the tumor. This may include antigens that were “hidden” to the immune system when the tumor was intact, Dr. Ross said. Chemotherapies and BRAF inhibitors, he continued, probably cause oncolysis by inducing apoptosis. This programmed cell death may not cause the tumor to express antigens in a way that is useful to the immune system. “So the type of oncolysis may be very relevant. The tumor ablative agents could be synergistic with ipilimumab. It would make sense because they act at different places in the immune system.”
In Zurich, Dr. Andtbacka reported that analysis of biomarkers in the phase 1b/2 trial showed increases from baseline after treatment with T-VEC and further increases after ipilimumab treatment in total and activated CD8 T cells in peripheral blood. Increases in CD4 T cells expressing inducible T-cell costimulator also followed ipilimumab treatment, indicating upregulated CTLA-4 blockade. Importantly, patients with disease control after T-VEC had more than 1.4 times as many activated CD8 T cells, while four out of five patients with tumor growth did not have such increases. The phase 2 study comparing T-VEC plus ipilimumab to T-VEC is going forward and adding patients based on these findings.
Combined BRAF/MEK Inhibitor Therapy in BRAF-Mutant Melanoma
- Keith Flaherty, MD, Director of the Henri and Belinda Termeer Center for Targeted Therapies, Massachusetts General Hospital Cancer Center
The call to explore two-pathway solutions went out even before phase 3 data were available on BRAF monotherapy inhibition, Dr. Flaherty said in an interview. “When translational research suggested reactivation of the MAP kinase pathway for BRAF and MEK, that immediately pointed to the concept of BRAF/MEK combination therapy as a strategy, given the ready availability of numerous MEK inhibitors that were already reasonably far along in clinical development.”
Recent clinical trial data showing unequivocal improvements in overall survival (OS) for regimens joining BRAF and MEK inhibition in BRAF-mutant melanoma effectively “close the book” on defining clinical benefit, Dr. Flaherty said in his presentation. Increases in CR rates suggest that with longer-term follow-up, increases in durable responses will be demonstrated as well.
Preclinical evidence suggested that BRAF/MEK inhibition could be safe and better tolerated than either monotherapy—taking advantage of the fact that BRAF inhibitors have a very different effect on signaling in the MAP kinase pathway in tumor tissue versus normal tissue that lacks BRAF mutations. This separates the BRAF/MEK combination, Dr. Flaherty said, from other two-drug pairings in other cancers.
Combined BRAF/MEK inhibition improved response rates, progression-free survival (PFS), and OS, based on data accrued in the last year and presented at the European Society of Medical Oncology. In the phase 3 BRIM trial of vemurafenib (n = 336) versus DTIC (n = 336), the hazard ratio for OS favoring vemurafenib was 0.37 (95% confidence interval [CI], 0.26–0.55; P < 0.001). It is the OS finding that “closes the book,” Dr. Flaherty said.
Dr. Flaherty’s research comparing BRAF/MEK to single-agent BRAF inhibition (dabrafenib) showed delayed resistance for the combination, with respective PFS of 9.4 months and 5.9 months (hazard ratio [HR], 0.39; P < 0.001). With dabrafenib monotherapy, rates of cutaneous squamous-cell carcinoma, skin papilloma, and hyperkeratosis were 19%, 15%, and 30% versus 7%, 4%, and 9%, respectively, for patients receiving dabrafenib/trametinib.1
Dr. Flaherty added that in a recent study by Long et al2 in stage IIIC or IV BRAF-mutant melanoma, six-month HRs for PFS and OS in those treated with dabrafenib/trametinib versus dabrafenib were significantly superior. Similarly, in a dabrafenib/trametinib combination trial by Robert et al,3 with vemurafenib as the comparator, HRs favored the combination for PFS and OS.
In a BRAF/MEK inhibition trial by Larkin et al4 favoring the combination of vemurafenib/cobimetininb versus vemurafenib, the HRs were 0.51 for PFS (95% CI, 0.39–0.68; P < 0.0001) and 0.65 for OS (95% CI, 0.42–1.00; P = 0.046).
The best evidence for BRAF/MEK synergy, aside from these findings, Dr. Flaherty said, is the near-doubling of CR rates. In the phase 2 trial data that supported the Food and Drug Administration’s accelerated approval of dabrafenib/trametinib in BRAF-mutant unresectable or metastatic melanoma, the respective CR rates for dabrafenib/trametinib and dabrafenib monotherapy were 9% and 4%. In Roberts et al, the CR rates with dabrafenib/trametinib and vemurafenib were 13% and 8%, respectively.
As a counter-argument to skeptics who suggest that combination therapy may merely be a “temporizing strategy” that fails to create more durable responses, Dr. Flaherty said, “We know that complete responders to BRAF-inhibitor monotherapy have the most durable responses. So it’s reasonable to expect, based on dabrafenib/trametinib data showing that complete responders shine through as the patients not only who maintain response the longest, but clearly also who survive the longest, that another year of follow-up data will likely assuage this concern.”
Long-term Survival of Ipilimumab-Naïve Patients With Advanced Melanoma Treated With Nivolumab
- F. Stephen Hodi, Director of the Melanoma Center and the Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Long-term survival in previously treated patients with advanced melanoma receiving single-agent nivolumab (a PD-1 inhibitor) in the phase 1 CA209-003 study was comparable to that seen with current standard-of-care agents. Responses occurred early and were durable.
The 107 advanced melanoma patients enrolled had received between one and five prior lines of systemic therapy. Their mean age was 61 years (range, 29–58); 67% were male. Most patients (62%) had received two or more systemic regimens, of which 65% were immunotherapies (but not CTLA-4 or PD-1 inhibitors). At baseline, visceral metastases were present in 78% of patients, and elevated lactate dehydrogenase levels were found in 36%. Dr. Hodi emphasized that the median follow-up of 55 months in this study is longer than that of any other study of an anti-PD-1 agent.
Patients received up to 96 weeks of nivolumab at doses between 0.1 mg/kg and 10 mg/kg intravenously every two weeks. While safety and tolerability were the study’s primary objectives, preliminary efficacy was a secondary objective, and the protocol was amended to collect OS and retreatment outcomes data as well, Dr. Hodi said.
The overall response rate for all doses was 32% (34 of 107), with a median response duration of 23 months (range, 4–32). For the 3-mg/kg dose ultimately selected for phase 3 studies, the overall response rate was 41% (7 of 17), and the median duration of response was 22 months (range, 9–27).
Among responding patients, 44% (15 of 34) showed a response at the week 8 first tumor assessment. In addition, among responders who discontinued for reasons other than disease progression, responses lasted for 16 months or longer in 21 patients. Responses are ongoing in 14 patients.
OS rates with the 3-mg/kg dose (n = 17) in years 1 to 4 are 65%, 47%, 41%, and 35%, respectively, and for all the cohorts are 63%, 48%, 42%, and 32%, respectively. Dr. Hodi noted, “There is a suggestion of a plateau in the curve at this point … but further confirmation will obviously be needed in continued follow-up.”
For all cohorts, median OS was 17.3 months (95% CI, 12.5–37.8). For the 3-mg/kg dose, it was 20.3 months (7.2, NE). Median PFS was longest in the 3-mg/kg group (10 months; CI, 2–16). Median OS in this cohort was 20 months (CI, 7, NE).
Investigators also conducted an exploratory analysis of patients who entered the follow-up period with ongoing disease control (CR, partial response, or stable disease). Retreatment was permitted in these patients after confirmed disease progression at the same dose assigned for up to a total of three years. Prolonged response or stabilization of disease was observed among five patients who were retreated; an increased adrenal mass was successfully excised in one patient. “We need prospective analyses to evaluate the efficacy and safety of nivolumab retreatment,” Dr. Hodi said.
Treatment-related immune-mediated adverse events were reported in 58% of patients, with 5% of grade 3 or 4. They included skin (38%), gastrointestinal (19%), endocrine (14%), and infusion reactions (6%). Dr. Hodi noted that immune-mediated adverse events with potential immunological etiologies require more frequent monitoring and/or unique interventions. In general, Dr. Hodi said, nivolumab treatment was well tolerated, with no new safety signals after a year of follow-up.
Three ongoing phase 3 trials are evaluating nivolumab 3 mg/kg in patients with advanced melanoma.
- Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367(18):1694–1703.
- Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014;371(20):1877–1888.
- Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2014. doi:10.1056/NEJMoa1412690.
- Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014;371(20):1867–1876.
- Cassese S, Byrne RA, Tada T, et al. Clinical impact of extended dual antiplatelet therapy after percutaneous coronary interventions in the drug-eluting stent era: a meta-analysis of randomized trials. Eur Heart J 2012;33(24):3078–3087.
- Dayer MJ, Jones S, Prendergast B, et al. Incidence of infective endocarditis in England, 2000–13: a secular trend, interrupted time-series analysis. Lancet 2014. doi:10.1016/S0140-6736(14)62007-9.