Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC)

Abstract

Immunotherapy is among the most rapidly evolving treatment strategies in oncology. The therapeutic potential of immune-checkpoint inhibitors is exemplified by the recent hail of Food and Drug Administration (FDA) approvals for their use in various malignancies. Continued efforts to enhance outcomes with immunotherapy agents have led to the formulation of advanced treatment strategies. Recent evidence from pre-clinical studies evaluating immune-checkpoint inhibitors in various cancer cell-lines has suggested that combinatorial approaches may have superior survival outcomes compared to single-agent immunotherapy regimens. Preliminary trials assessing combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 immune-checkpoint inhibitors have documented considerable advantages in survival indices over single-agent immunotherapy. The therapeutic potential of combinatorial approaches is highlighted by the recent FDA approval of nivolumab plus ipilimumab for patients with advanced melanoma. Presently, dual-immune checkpoint inhibition with anti-programmed death receptor-1/programmed cell death receptor- ligand-1 (anti-PD-1/PD-L1) plus anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) monoclonal antibodies (MoAbs) is being evaluated for a wide range of tumor histologies. Furthermore, several ongoing clinical trials are investigating combination checkpoint inhibition in association with traditional treatment modalities such as chemotherapy, surgery, and radiation. In this review, we summarize the current landscape of combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 MoAbs for patients with melanoma and non-small cell lung cancer (NSCLC). We present a synopsis of the prospects for expanding the indications of dual immune-checkpoint inhibition therapy to a more diverse set of tumor histologies.

Fig. 1

Mechanism of CTLA 4 and PD-1/PD-L1 inhibition. The activation of T cells is mediated by the interaction of T cell receptor and the CD28 receptor with class II major histocompatibility complex and B7 co-stimulatory molecule located on the antigen presenting cells. The interaction of CTLA-4 with the B7 molecule delivers an inhibitory signal, effectively checked by CTLA-4 inhibitors. On the other hand, the negative regulation of T cells resulting from PD-1/PD-L1 interaction between T cells and tumor cells is prevented by PD-1/PD-L1 inhibitors. Abbreviations: APC, antigen presenting cell; PD-1, programmed death receptor-1; PD-L1, programmed cell death receptor ligand-1; TCR, T cell receptor; MHC I, major histocompatibility complex class I; MHC II, major histocompatibility complex class II

Fig. 2

Current landscape of combination immunotherapy trials for various tumor histologies. a Number of combination checkpoint inhibition trials for various tumor histologies. Abbreviations: NSCLC, non-small cell lung carcinoma; RCC, renal cell carcinoma; GEJ, gastro-esophageal junction; MDS, myelodysplastic syndrome. b Landscape of combination checkpoint inhibition agents. Legend: The figure elaborates relative number of trials for four combinations of immunotherapy agents. Nivolumab plus ipilimumab: 62% (101 trials), pembrolizumab plus ipilimumab 4% (6 trials), tremelimumab plus durvalumab 34% (55 trials) and atezolizumab plus ipilimumab < 1% (1 trial)

Fig. 3

Comparison of objective response in select trials. Legend: Figure presenting a comparison of objective response in study participants, expressed in percent individuals, with different treatment regimens in CheckMate 012, NCT02000947 and CheckMate 067 trials. Abbreviations: NIVO, nivolumab; IPI, ipilimumab; DURVA, durvalumab; TREME, tremelimumab; Q(x)W, every (x) weeks; NSCLC, non-small cell lung cancer

Fig. 4

Comparison of treatment related adverse events for different regimens in CheckMate 012 and CheckMate 067. Legend: The figure elaborates percent patients documented to have adverse events with different treatment regimens assessed in the CheckMate 012 and CheckMate 067 trials. Please note that some participants had more than one adverse event. No treatment associated deaths were reported till point of assessment in CheckMate 012 while 2 treatment related deaths in CheckMate 067 nivolumab group were reported > 100 days after discontinuation of therapy. Abbreviations: NIVO, nivolumab; IPI, ipilimumab; n, number of patients; X axis: treatment regimens, Y axis: percent patients relative to cohort size