The number of cancer patients who benefit from immunotherapy has increased due to a better understanding of the immune response to cancer along with recent advances in biomarker development. In particular, an interesting component of immunotherapy is the long-lasting tumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit from immunotherapy, and efforts should focus on improving the efficacy of immunotherapy through the use of both combination or sequential approaches and predictive biomarkers of response and resistance 17. The goal of combination approaches, targeting several steps of the cancer-immunity cycle, is to expand the spectrum of patients who respond to cancer immunotherapy (increased number of responding patients in tumors that are sensitive to single agent therapy and the identification of new sensitive tumor types that do not respond to monotherapy alone) and to improve the quality of clinical responses (i.e., time span of response, PFS and OS) beyond what can be achieved with monotherapy alone. 18The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combination. In our analysis, we found that combination therapy was superior to monotherapy. This may have several explanations: (1) the efficacy of monotherapy is limited by low response rates, with only a small proportion of patients responding to treatment; (2) combining anti-CTLA-4 and anti-PD-1 therapies may activate the antitumor immune response synergistically, thus increasing response rates; (3) combining anti-CTLA-4 and anti-PD-1 therapies significantly increases the ratios of both CD8+/regulatory T cells and CD4 + effector/regulatory T cells within the tumor, so that CD8 + and CD4 + T cells continue to survive, proliferate and carry out effector functions in the tumor; (4) combining anti-CTLA-4 and anti-PD-1 therapies induces the accumulation of active T cells that express CTLA-4 and PD-1 and would otherwise be energized ; and (5) combining anti-CTLA-4 and anti-PD-1 therapies increases the production of inflammatory cytokines (such as IFN-γ and TNF-α) in the tumor itself and in its draining lymph nodes.
The scientific rationale of the combination is linked to the evidence that each immunotherapy checkpoint blockade leads to a distinct and non-overlapping signature of changes in T cells and the immune compartment. In particular, several investigators have demonstrated that PD-1 blockade mainly leads to changes in genes implicated in cytolysis and NK cell function, differently from CTLA-4 blockade that induces a proliferative signature in a subset of memory T cells. This activity of ipilimumab on the memory cell compartment may be responsible for the prolonged responses observed in patients treated with this drug. Indeed, although objective antitumor response rates were low (~ 10%), approximately 20% of patients had a long-lasting response up to 10 years and this sustained benefit may represent the potential of anti-CTLA4 immunotherapy in raising the tail of the survival curve. This effect on immunologic memory can be further demonstrated by the observation that less than 4 doses of ipilimumab can be sufficient to induce the long term effect on the survival curve.
In intermediate/poor risk metastatic renal cell carcinoma, first-line therapy with the combination ipilimumab plus nivolumab showed that 60% of patients were alive at 30 months, with a 42% ORR and 11% CR. In untreated advanced melanoma nivolumab plus ipilimumab versus nivolumab alone results in higher 5-yr OS ([52% versus 46%] with HR of 0.83 [95% CI, 0.67–1.03]), and PFS (37% versus, 31% with HR 0.79 [95% CI, 0.64–0.96]). These differences were consistent across many clinically relevant subgroups, including BRAF-mutant patients and poor prognostic subgroups, such as patients with elevated LDH levels and M1c disease. First-line therapy for non small-cell lung cancer using combination nivolumab plus ipilimumab in patients with a PD-L1 expression level of 1% or more, shows a median overall survival of 17.1 months and 15.7 months with nivolumab alone [HR 0.90 (0.76–1.07)] and a 2-year overall survival rate of 40.0% and 36%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 15.5 months with nivolumab. Overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab. Preliminary but very encouraging results derive from the combination of ipilimumab plus nivolumab in melanoma patients treated in the neoadjuvant setting, achieving 78% of pathological response. 19
In this analysis, we confirmed, in a larger population with several cancer subtypes, the results of Yang and colleagues 20. In particular we demonstrate that the addition of ipilimumab to nivolumab increases ORR to approximately 68% (range 8–95) and reduces the risk of progression and death of about 20% (range 10–28) and 13% (range 1–24), respectively, regardless of tumor type.
Additional evidences of the improved outcome by adding ipilimumab to nivolumab (“boost” cycles) in metastatic RCC patients, with early significant progressive disease (PD ) at week 8 or stable disease (SD) or PD at week 16 during nivolumab induction, has been reported in the Titan trial 21. Of the 207 patients enrolled in the study, 64.3% (133/207) received at least one “boost” cycle. Overall 29.8% (14/47) of RCC patients in first line treatment and 38.6% (22/57) of patients in second line treatment with SD/PD after nivolumab monotherapy had improvement in best overall response (BOR) with the “boost” cycles, respectively.
From a safety point of view, no new signals have been observed with the combination compared to monotherapy and, despite the higher level of immune relate adverse events (irAE) observed with the combination therapy, it is worth noting that: 1) patients who were required to come off treatment due to irAE had an overall benefit when compared to the entire population and 2) toxicity of the combination appears to be as manageable as single agent immunotherapy and it has been demonstrated that the need to treat irAE with corticosteroids does not impact on outcome.
However, the added benefit of each additional drug must be properly evaluated against the added toxicities, even if no new signals have been observed with the combination compared to the monotherapy.