Data suggest that immunotherapies can produce durable responses, especially after treatment completion or discontinuation, albeit at the expense of taking a longer time to achieve clinical benefit and the risk of potentially serious immune-related adverse effects. This idea of a durable, off-treatment response is highlighted by a study that followed 105 patients who had achieved a complete response (CR) and found that 24-month disease-free survival from the time of CR was 90.9% in all patients and 89.9% in the 67 patients who had discontinued pembrolizumab after attaining CR.15 BRAF/MEK inhibition has the potential for rapid clinical responses, though concerns exist about the development of resistance to therapy. The following sections explore the evidence supporting the use of these therapies.
Immunotherapy with Immune Checkpoint Inhibitors
Immunotherapy via immune checkpoint blockade has revolutionized the treatment of many solid tumors over the past decade. The promise of immunotherapy revolves around the potential for achieving a dynamic and durable systemic response against cancer by augmenting the antitumor effects of the immune system. T-cells are central to mounting a systemic antitumor response, and, in addition to antigen recognition, their function depends heavily on fine tuning between co-stimulatory and co-inhibitory signaling. The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expressed on T-cells was the first discovered co-inhibitory receptor of T-cell activation.16 Later, it was discovered that the programmed cell death 1 receptor (PD-1), expressed on T-cells, and its ligands PD-L1 and PD-L2, expressed on antigen presenting cells, tumor cells, or other cells in the tumor microenvironment, also served as a potent negative regulator of T-cell function.17
Together, these 2 signaling pathways help to maintain peripheral immune tolerance, whereby autoreactive T-cells that have escaped from the thymus are silenced to prevent autoimmunity. However, these pathways can also be utilized by cancer cells to escape immune surveillance. Monoclonal antibodies that inhibit the aforementioned co-inhibitory signaling pathways, and thus augment the immune response, have proven to be an effective anticancer therapy capable of producing profound and durable responses in certain malignancies.16,17
Ipilimumab is a monoclonal antibody that inhibits the function of the CTLA-4 co-inhibitory immune checkpoint. In a phase 3 randomized controlled trial of 676 patients with previously treated metastatic melanoma, ipilimumab at a dose of 3 mg/kg every 3 weeks for 4 cycles, with or without a gp100 peptide vaccine, resulted in an improved median OS of 10.0 and 10.1 months, respectively, compared to 6.4 months in those receiving the peptide vaccine alone, meeting the primary endpoint.4 Subsequently, a phase 3 trial of 502 patients with untreated metastatic melanoma compared ipilimumab at a dose of 10 mg/kg every 3 weeks for 4 cycles plus dacarbazine to dacarbazine plus placebo and found a significant increase in median OS (11.2 months vs 9.1 months), with no additive benefit of chemotherapy. There was a higher reported rate of grade 3 or 4 adverse events in this trial with ipilimumab dosed at 10 mg/kg, which was felt to be dose-related.18 These trials were the first to show improved OS with any systemic therapy in metastatic melanoma and led to US Food and Drug Administration approval of ipilimumab for this indication in 2011.
PD-1 Inhibitor Monotherapy
The PD-1 inhibitors nivolumab and pembrolizumab were initially approved for metastatic melanoma after progression on ipilimumab. In the phase 1 trial of patients with previously treated metastatic melanoma, nivolumab therapy resulted in an ORR of 28%.19 The subsequent phase 2 trial conducted in pretreated patients, including patients who had progressed on ipilimumab, confirmed a similar ORR of 31%, as well as a median PFS of 3.7 months and a median OS of 16.8 months. The estimated response duration in patients who did achieve a response to therapy was 2 years.20 A phase 3 trial (CheckMate 037) comparing nivolumab (n = 120) to investigator’s choice chemotherapy (n = 47) in those with melanoma refractory to ipilimumab demonstrated that nivolumab was superior for the primary endpoint of ORR (31.7% vs 10.6%), had less toxicity (5% rate of grade 3 or 4 adverse events versus 9%), and increased median duration of response (32 months vs 13 months).21