The addition of nivolumab (anti–PD-1) to ipilimumab (anti–CTLA-4) did not further improve response rate or progression-free survival among patients with PD-L1–positive tumors. The combination was ...much more effective in patients with PD-L1–negative tumors.
Considerable progress in the treatment of metastatic melanoma has been made in the past 5 years, with the approval of immune checkpoint–blocking antibodies and, in parallel, agents targeting aberrant signaling in the 40 to 50% of melanomas with
BRAF
mutations.
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–
6
Ipilimumab, an anti–cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody, acts to up-regulate antitumor immunity and was the first agent to be associated with an improvement in overall survival in a phase 3 study involving patients with metastatic melanoma.
5
,
6
Ipilimumab was associated with responses in 10% and 15% of patients
5
,
6
; approximately 20% of treated patients had long-term survival. . . .
The addition of a MEK inhibitor to a BRAF inhibitor improved response rates by nearly 16 percentage points (from 51% to 67%) and improved progression-free survival by 0.5 months (from 8.8 to 9.3 ...months).
Targeted inhibition of the RAF–MEK–ERK (MAPK) pathway with BRAF inhibitors dabrafenib or vemurafenib, as compared with chemotherapy, improves the progression-free and overall survival of patients who have metastatic melanoma with
BRAF
V600 mutations.
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,
2
However, resistance develops in a majority of patients, resulting in a median progression-free survival of 6 to 7 months.
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,
4
Most reported resistance mechanisms reactivate the MAPK pathway.
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–
7
In addition, BRAF-inhibitor–induced paradoxical activation of the MAPK pathway
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10
can result in secondary cancers, including cutaneous squamous-cell carcinoma, and may reactivate RAS-mutant tumors.
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Independently, single-agent trametinib, a MEK inhibitor, improves the overall survival of patients . . .
In patients with surgically resected melanoma, those with
BRAF
mutations who received 1 year of oral adjuvant therapy with dabrafenib and trametinib had a 53% lower risk of 3-year recurrence than ...those who received placebo.
To provide a more precise estimate of long-term survival observed for ipilimumab-treated patients with advanced melanoma, we performed a pooled analysis of overall survival (OS) data from multiple ...studies.
The primary analysis pooled OS data for 1,861 patients from 10 prospective and two retrospective studies of ipilimumab, including two phase III trials. Patients were previously treated (n = 1,257) or treatment naive (n = 604), and the majority of patients received ipilimumab 3 mg/kg (n = 965) or 10 mg/kg (n = 706). We also conducted a secondary analysis of OS data (n = 4,846) with an additional 2,985 patients from an expanded access program. OS rates were estimated using the Kaplan-Meier method.
Among 1,861 patients, median OS was 11.4 months (95% CI, 10.7 to 12.1 months), which included 254 patients with at least 3 years of survival follow-up. The survival curve began to plateau around year 3, with follow-up of up to 10 years. Three-year survival rates were 22%, 26%, and 20% for all patients, treatment-naive patients, and previously treated patients, respectively. Including data from the expanded access program, median OS was 9.5 months (95% CI, 9.0 to 10.0 months), with a plateau at 21% in the survival curve beginning around year 3.
To our knowledge, this is the largest analysis of OS to date for ipilimumab-treated patients with advanced melanoma. We observed a plateau in the survival curve, beginning at approximately 3 years, which was independent of prior therapy or ipilimumab dose. These data add to the evidence supporting the durability of long-term survival in ipilimumab-treated patients with advanced melanoma.
With a 5-year minimum follow-up in patients with metastatic melanoma, overall survival at 5 years was 52% with a combination of nivolumab plus ipilimumab, as compared with 44% with nivolumab alone ...and 26% with ipilimumab alone. Programmed cell death ligand 1 expression did not influence the response rate or progression-free survival.
In long-term follow-up of more than 500 patients with melanoma containing a
BRAF
V600E or V600K mutation, a combination of dabrafenib plus trametinib was associated with progression-free survival in ...19% of the patients and overall survival in 34% at 5 years. A complete response to dabrafenib plus trametinib was the strongest predictor of long-term survival.
At 5 years of follow-up, the 12-month use of adjuvant therapy with dabrafenib (a BRAF inhibitor) plus trametinib (a MEK inhibitor) in patients with stage III melanoma with
BRAF
V600 mutations ...resulted in relapse-free survival of 52%, as compared with 36% with placebo.
Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers
. Current predictive ...biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota
. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8
T cells and CD20
B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8
CD20
tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7
naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
Both nivolumab alone and nivolumab plus ipilimumab resulted in longer overall survival among patients with previously untreated advanced melanoma than ipilimumab alone. The combination was associated ...with a higher rate of toxic effects.
Metastasis requires cancer cells to undergo metabolic changes that are poorly understood
. Here we show that metabolic differences among melanoma cells confer differences in metastatic potential as a ...result of differences in the function of the MCT1 transporter. In vivo isotope tracing analysis in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumour lactate in efficient metastasizers. Efficient metastasizers had higher levels of MCT1, and inhibition of MCT1 reduced lactate uptake. MCT1 inhibition had little effect on the growth of primary subcutaneous tumours, but resulted in depletion of circulating melanoma cells and reduced the metastatic disease burden in patient-derived xenografts and in mouse melanomas. In addition, inhibition of MCT1 suppressed the oxidative pentose phosphate pathway and increased levels of reactive oxygen species. Antioxidants blocked the effects of MCT1 inhibition on metastasis. MCT1
and MCT1
cells from the same melanomas had similar capacities to form subcutaneous tumours, but MCT1
cells formed more metastases after intravenous injection. Metabolic differences among cancer cells thus confer differences in metastatic potential as metastasizing cells depend on MCT1 to manage oxidative stress.
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