The new agents demonstrating activity in metastatic melanoma fall into two broad categories: i) immunotherapy, and in particular immune checkpoint modulating antibodies, and ii) oncogene-targeted therapies. The lead compounds for each approach (ipilimumab and vemurafenib, respectively) are being followed by other agents with effects on the same or similar pathways, which are likely to provide similar patient benefits. The immune modulating antibodies (anti-CTLA4, anti-PD1, anti-PDL1, anti-CD40, anti-CD137, anti-OX40) all aim to stimulate long-lasting antitumor immune responses. The antitumor benefits are noted clinically in a variable fraction (arguably small) of the patient population. For example, with the anti-CTLA4 antibody ipilimumab, the objective tumor response rate is on the order of 10–15%, but the reduction in the likelihood of death compared to a vaccine or dacarbazine was 34% and 28% respectively, with the prospect of cure in some of these patients (4
). The long term benefit is noted by a consistent absolute increase of approximately 10% of patients alive in the ipilimumab-containing study arms compared to the control therapy in the two pivotal clinical trials at the end of the study follow up period (4
). This late plateau (or “tail”) in the survival curve is highly reminiscent of that seen with high dose IL-2 (11
), representing long term responders who remain relapse-free for years (). With ipilimumab having demonstrated overall survival benefit in two randomized phase III trials, the development of other agents in this category of immunotherapy agents may involve direct comparison with this agent, perhaps with a focus on decreasing side effects while retaining survival benefits (non-inferiority clinical trials). Alternatively, trials of new immunotherapy agents (or combinations of new agents with ipilimumab) may seek to demonstrate higher objective response rates while preserving or even extending the survival benefits, which will be a higher hurdle to overcome, or test concurrent or sequential therapy schemes that may improve on the tail of the survival curves obtained with ipilimumab alone.
Effects of immunotherapy and targeted therapy on melanoma survival curves
On the opposite side of the spectrum are the dramatic initial results achieved with targeted therapies that block signaling from oncogenic driver mutations in melanoma (inhibitors of c-kit and BRAF) or downstream effectors (MEK inhibitors). The antitumor effects of these agents are restricted to subsets of melanomas that are dependent on a particular mutated oncogene or activated pathway, with minimal to no activity observed using these agents against tumors that do not have that oncogene or pathway “addiction.” In properly selected patients, initial response rates are very high with oncogene-targeted inhibitors (7
), but in a matter of months, tumors frequently find a way to escape these drugs’ antitumor effects via a variety of molecular mechanisms of acquired resistance (13
). The benefit of oncogene-targeted agents is noted in early improvements in the progression free and overall survival curves, since the majority of patients derive a rapid anti-tumor response (). However, the limited duration of these responses is less likely to change the slope of the tail of the survival curve than is seen with immunotherapy, based on the available data. Mature survival data are not yet available from the BRAF targeted therapy phase III trials (6
), and even once available their interpretation will likely be complicated by crossover of control arm patients to agents inhibiting the same oncogenic signaling. Therefore, it is possible that we will not have reliable overall survival curves compared to a control arm to evaluate the long term effects of BRAF-targeted inhibitors in melanoma.