An article by John Haanen released in occasion of ESMO Immuno-Oncology Congress 2017, 7-10 December, Geneva, Switzerland.
Immunotherapy Combinations and Sequencing
Cancer immunotherapy, in particular, blockade of the immune checkpoint pathway PD-1/PD-L1, has substantially altered the treatment paradigm for a broad spectrum of tumour types (1). Although five drugs that block the PD-1/PD-L1 pathway are approved for treatment across multiple cancer types, a substantial proportion of patients do not respond to single-agent anti-PD-1/PD-L1 blockade. Tumour responses, although often profound, are limited to a subset of patients and a proportion of responders to immune checkpoint inhibitor therapy develop resistance (1). This has precipitated a search for predictive biomarkers to allow enrichment for treatment-responsive patients, and extensive clinical trial activity involving combination or sequenced therapies that might overcome resistance, either primary or acquired. This short review describes current attempts to overcome the mechanisms of intrinsic and secondary resistance to PD-1/PD-L1 blockade using synergistic treatment combinations and regimens.
PD-1/PD-L1 blockade in combination therapies
Based on the hypothesis derived from preclinical studies that a combined blockade of two distinct T-cell immune checkpoints (CTLA-4 and PD-1) may produce greater antitumor activity than either single agent, a phase II trial found that the PD-1 inhibitor nivolumab in combination with the CTLA-4 inhibitor ipilimumab given concurrently gave superior objective response rates than ipilimumab alone in BRAF V600 wild-type melanoma (objective response rates (ORR) 61% with the combination and 11% with monotherapy, with complete responses in 22% and 0% of patients, respectively) (2). However, there was a sharp rise in grade 3 or 4 adverse events related to combination therapy—54% in the combination regimen group compared to 24% of the patients who received ipilimumab monotherapy. Subsequent phase III randomised data (3) led to the approval of nivolumab in combination with ipilimumab for the treatment of patients with unresectable or metastatic melanoma, corroborating the results from the phase II study, but adding insight in the differences in ORR, progression-free survival (PFS) and overall survival (OS) between the ipilimumab/nivolumab combination and nivolumab single agent, although the study was not powered for that comparison. Numerically, in terms of ORR and PFS, the combination was superior, and for OS rates at 2 and 3 years as well. Differences in PFS and OS were not apparent in patients with PD-L1 positive (>1%) tumours, suggesting that PD-L1 expression by tumour cells could be a predictive biomarker when choosing single agent or combination therapy, especially since the difference in immune-related toxicity between the two treatments remained substantial. This in turn has opened the door to huge clinical research activity investigating combination immunotherapy in advanced cancer.
Many hundreds of ongoing clinical trials are now exploring combinations of anti–CTLA-4, anti-PD-1/PD-L1 with standard therapies of surgery, radiotherapy, and chemical therapies (both chemotherapy and kinase inhibitors) and experimental immune modulators (1). These include immunomodulatory monoclonal antibodies (such as anti-LAG3, -TIM-3, -GITR, -OX40, -CD137, -CD27), oncolytic viruses, cancer vaccines, epigenetic drugs, and metabolic drugs (1). Here, we discuss briefly some of the most promising combination therapies so far.
Anti-PD-1 in combination with anti-LAG3
A complex series of receptor-ligand interactions modulate immune cell function (4). LAG3 is one of many immune checkpoint or inhibitory receptors expressed on tumour-antigen specific CD8+ T-cells. Preclinical models show that LAG3 and PD-1 physically interact, and are trafficked to the immunological synapse with synergistic inhibition of T-cell signalling (5). In a murine model, synergistic anti-tumour effects have been shown with dual blockade of PD-1 and LAG3 (6). Anti-LAG3 monoclonal antibodies have now entered clinical trials. A recent phase I/IIa trial of anti-LAG3 (BMS-986016 or relatlimab) in combination with nivolumab showed promising activity in patients with melanoma who were relapsed or refractory to anti-PD-1/PD-L1 therapy (7). The ORR was 12.5% in 48 evaluable patients. It was also shown that LAG3 expression by immunohistochemistry enriched for response (7).
Anti-PD-1 in combination with oncolytic virotherapy
Patients with pre-therapy lack of CD8+ tumour infiltrating lymphocytes have previously been shown less likely to respond to PD-1/PD-L1 blockade across various cancer types. A recent phase Ib clinical trial combined talimogene laherparepvec, a genetically modified herpes simplex virus, with pembrolizumab in patients with metastatic melanoma based on the hypothesis that intra-tumoral viral injection might favourably change the tumour microenvironment, increasing the CD8+ T-cell pool and reactive PD-1 expression (8). Although small, the study was positive, with a confirmed ORR of 62% with the pembrolizumab combination and with increased CD8+ T-cells and elevated PD-L1 protein expression in responders. While these data are highly promising, it is the results of the ongoing randomised phase III trial that will define the synergy between local administration of this viral vaccine and PD-1 blockade (9). Nonetheless, the study confirms our increasing understanding of the requirements for T-cell-mediated control of cancer.
Anti-PD-1 in combination with IDO inhibitor (epacadostat)
Indoleamine 2,3-dioxygenase 1 (IDO) is an immunosuppressive enzyme that modulates T-cell function (10). It catalyses the cleavage of L-tryptophan, with the metabolites promoting regulatory T-cell generation and blocking of effector T-cell activation, which can contribute to immune surveillance avoidance by tumour cells. Epacadostat is a potent and selective inhibitor of IDO which, combined with ipilimumab and pembrolizumab (11) in proof-of-concept studies, has shown strong efficacy with improved response rates compared with prior data for immune checkpoint inhibitors alone, with minimal additional toxicity. Recently, a large programme of trials of epacadostat plus pembrolizumab was initiated in patients across five tumour types: metastatic melanoma, non-small cell lung cancer, bladder cancer, renal cell carcinoma, and squamous cell carcinoma of the head and neck. Combinations of epacadostat plus nivolumab are also in clinical trials.
CTLA-4 and PD-1/PD-L1 blockade in combination with, or sequenced with, BRAF and or MEK inhibition
The elucidation of the activated MAPK pathway in BRAFV600E mutated melanoma resulted in the development and approval of small molecule kinase inhibitors that target BRAF and MEK, which improve patient outcome (12,13). Although a high proportion of patients respond, relapse rates are also high, with long-term survival seen in about 20% for patients treated with combined BRAF plus MEK inhibition. It has been shown that BRAF and MEK inhibition can alter the tumour microenvironment, with an increased expression of melanoma antigens and an increase in CD8+ T-cell infiltrate suggesting possible synergy with PD-1/PD-L1 pathway inhibition (14). Clinical trials are currently underway that combine BRAF with or without MEK inhibition and PD-1/PD-L1 blockade showing very promising efficacy. An important consideration, however is whether to combine or sequence these drug classes. Some ongoing trials include assessing the optimal order in which to administer kinase inhibitors with immune checkpoint blockade to gain maximum clinical benefit. One of the reasons treatment sequencing may be more appropriate than combination treatment is because of safety and toxicity concerns as suggested by previous combination trials (15,16). An ongoing trials in metastatic melanoma is the ‘Sequential Combo Immuno and Target Therapy’ (SECOMBIT) Study, that includes three arms: A. combination BRAF plus MEK inhibition (encorafenib with binimetinib), followed by combination checkpoint inhibition (nivolumab with ipilimumab); B. combination checkpoint inhibition followed by BRAF plus MEK inhibition; and C. sandwich therapy, consisting of BRAF plus MEK inhibition followed by combination checkpoint inhibition followed by BRAF plus MEK inhibition. This study will provide important insights into the optimal sequencing of these drugs based on efficacy safety balance.
The next stage for immunotherapy
The ongoing development of checkpoint immunotherapies that that can potentially be combined with complimentary treatments such as kinase inhibitors, but also classical chemotherapy or other immuno-oncology drugs in rational, biology-driven combinations and sequences, is likely to define the next major paradigm in advanced cancer treatment.
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