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Drug of the year: Programmed Death-1 receptor/Programmed Death-1 Ligand-1 receptor monoclonal antibodies
European Journal of Cancer, 14, 49, pages 2968 - 2971
Programmed death-1 receptor (PD-1)/its ligand (PD-L1) antibodies have changed the landscape in oncology in 2013. The most mature results have been obtained in advanced melanoma patients. They indicate important response rates and high quality responses or prolonged duration. Also in renal cancer and in lung cancer remarkable activity has been demonstrated. Thus it is clear that these antibodies have a very broad potential and trials in many tumour types are being initiated. Breaking tolerance at the tumour site is a potent phenomenon and the potential for synergy with other checkpoint inhibitors such as ipilimumab have also been demonstrated in 2013. Long term tumour control now seems achievable and thus the concept of a clinical cure is emerging by modulation of the immune system. These antibodies bring immunotherapy to the forefront and indicate that immune-modulation will be a key component of therapeutic strategies from now on. Because of all these reasons PD-1/PD-L1 antibodies are considered ‘drug of the year’.
Keywords: PD-1/PD-L1, Checkpoint inhibitors, Immunotherapy, Drug development.
What makes a drug the ‘drug of the year’? Any drug that is widely regarded as a break-through treatment, in terms of clinical impact on one or more tumours, on the basis of clinical evidence sufficiently mature to allow the accolade of ‘drug of the year’.
The European Journal of Cancer launches this annual article and the winner in 2013 is: Programmed death-1 receptor (PD-1)/its ligand (PD-L1) antibodies. A multitude of clinical studies were reported at this year’s American Society of Clinical Oncology (ASCO) annual meeting. They changed the mind of oncologists and researchers alike, regarding their potential and the prospects of success of immunotherapy in many tumour types.
2. Checkpoint inhibitors breaking tolerance
Immunotherapy of cancer has entered a new and exciting phase because of the discovery of checkpoint receptor inhibitors such as Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and more recently Programmed death-1 receptor (PD1) and its ligand (PD-L1).
The emerging paradigm consists of activating the immune system or to re-awaken silenced immune responses by ‘inhibiting inhibitors’ that are responsible for paralysing T-cells and creating a state of immune tolerance. 1 An effective immune signal depends on both an antigen being presented by an MHC molecule and a co-stimulatory molecule, B7.1 or B7.2, binding to CD28 for T-cell activation. Downregulation of this process is simultaneously initiated by B7-CTLA4 binding, and thus, monoclonal antibodies that bind to CTLA-4 prevent the inhibition of this negative switch and break tolerance to self-tissues and induce anti-tumour responses.2, 3, and 4
Two such antibodies, tremelimumab and ipilimumab had similar effects in phase I–II studies.3 and 4 In melanoma the development of tremelimumab failed to yield superior results compared to dacarbazine in phase III, probably because of dose-scheduling and cross over problems. 5 In contrast, more intensive schedules of ipilimumab succeeded in patients with advanced melanoma both in second line and in first line and lead to its approval by Federal Drug Agency (FDA) and European Medicine Agency (EMA).6 and 7 In view of its similar performance in advanced renal cell cancer 8 and its capacity to break tolerance, which has broad implications in oncology in general, ipilimumab has been considered by many as the drug of the year in 2010–2011. 9
Here we focus on Programmed death-1 receptor (PD1) and its ligand (PD-L1). These targets have been rapidly established as the currently most important breakthrough targets in the development of effective immunotherapy.
3. PD-1 and PD-L1 antibodies: immune-control of solid tumours becoming a reality
PD1 and PD-L1 are highly promising new targets in immunotherapy. PD1 protein is another immune checkpoint expressed in many tumours in response to inflammation. It has two ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC). The engagement of PD1 on the lymphocyte surface by PD-L1 on melanoma cells downregulates T cell function. 10 Recent data have indicated that this downregulation of T cells can already be present in pre-malignant lesions. 11 Phase I results were published in 2012 indicating clear activity in melanoma, renal cell cancer and lung cancer patients. 12 Remarkable results of extended phase I trials evaluating two anti-PD1 antibodies (nivolumab and lambrolizumab) were presented at the 2013 ASCO annual meeting, indicating objective response rates of 30% to 50% in melanoma, with long term benefit in the majority of the responding patients.13 and 14
Furthermore, the expression of PD-L1 on the surface of melanoma cells appears to be a predictive biomarker. Anti-PD-L1 antibody also gave an encouraging long term response rate of 17.3% in melanoma patients in a recent phase I study. 15 New reports regarding their use in various tumours have been presented in 2013. Importantly, the safety profile of these new agents is far more favourable than that of ipilimumab.
The fact that the PD1/PDL-1 checkpoint interaction takes place peripherally, i.e. at the tumour site, whereas CTLA4/B7 interaction occurs mostly centrally, i.e. in the lymphoid organs, may explain the higher response rates and more rapid tumour responses associated with PD1/PD-L1 antibodies as well as the clearly lower incidence of immune related adverse events (irAE).
We will provide an overview of the results in two sections: one on melanoma, where the most voluminous and mature data are available, and one on other tumours, with a particular emphasis on results in lung cancer and renal cell cancer.
The therapeutic advances by targeting PD-1 in melanoma have revolutionised therapeutic prospects in this disease like no other and like never before. At the 2013 ASCO annual meeting the long-term follow-up data of patients treated with nivolumab were presented. The results confirmed excellent durability of nivolumab-induced responses and showed unprecedented 61% 1-year and 44% 2-year survival rates. 13 Moreover the large experience with lambrolizumab was presented, reporting response rates close to 50% and again excellent durability. 14 So it is now clear that the efficacy indicators of the anti-PD-1 molecules nivolumab and lambrolizumab appear quite superior to those of ipilimumab. Anti-PD1 monoclonal antibodies seem to combine the best of both worlds, i.e. high response rates and durable responses. Importantly the vast experience in hundreds of patients also confirm that the toxicity profile is favourable compared to ipilimumab.
In addition the first data on the combination of anti-PD1 and anti-CTLA4 were presented: in 53 patients it was demonstrated that ipilimumab and nivolumab can be used in combination, that the combination may improve response rates even further, and that the combination does not enhance the toxicity profile of ipilimumab significantly. 16 Also the quality of the responses obtained by the combination of ipilimumab and nivolumab seem to be superior. In 36 patients, who were treated with ipilimumab and nivolumab, 26 showed a tumour regression, but most importantly 22 patients had a >80% reduction of indicator lesions. 16
The optimal dose, schedule and duration of nivolumab or lambrolizumab therapy in melanoma have not been established thus far. It is of importance that a relapse after stopping treatment with nivolumab has been successfully treated by re-induction with nivolumab. 17 It may indicate that schedules with a long maintenance period may not be necessary.
MPDL3280A is a human monoclonal antibody (containing an engineered Fc designed to avoid Antibody Dependend Cellular Cytotoxicity (ADCC)) that targets programmed death-ligand 1 (PD-L1). In a phase I trial expansion melanoma cohort, 38 melanoma patients were exposed to this compound. An overall response rate (ORR) of 29% was reported with a 43% 24-week progression-free survival (PFS) rate. 18
5. Lung cancer and renal cell carcinoma
Remarkable activity in lung cancer has been reported with various molecules. In the phase I trial testing nivolumab, 122 non-small cell lung cancer (NSCLC) patients were enrolled. Objective responses were observed in 33% of Squamous Cell Cancer (SCC) (n = 6/18) and 12% of non-SCC (n = 7/56). 12
BMS-936559 is a monoclonal antibody that binds to PD-L1. The expansion cohort of its phase I trial enrolled 75 patients with NSCLC. 15 ORR was 8% in SCC (n = 1/13) and 11% in non-SCC (n = 4/36). Data were updated in 2013 and median overall survival (mOS) was 9.2 months for SCC and 9.6 months for non-SCC. Overall survival at 1 and 2 years was 44% and 44% for SCC and 41% and 17% for non-SCC. 19
Fifty-two patients were enrolled in an expansion cohort of the phase I trial of MPDL3280A, 62% of them were heavily pretreated NSCLC (⩾3 lines of systemic therapy) and the ORR was 22%. 20 Analysis of biomarker data from archival tumour samples demonstrated a correlation between PD-L1 status and response and lack of progressive disease. 21
Similarly results in renal cell cancer (RCC) are promising. In renal cell cancer, 55 patients were enrolled in an expansion cohort of the MDPL3280A phase I trial. Out of 47 evaluable patients, overall ORR was 13% (6/47), 20% in PDL1-positive patients (2/10) and 10% in PDL1-negative patients (2/21). 22 Nivolumab results on 34 patients with metastatic renal cell carcinoma (mRCC) were updated at ASCO 2013, with a one-year OS rate of 72% and a 3-year OS of 52%. 23
6. Combinations with PD-1/PD-L1 inhibitors
As indicated in the melanoma section, the combination of nivolumab and ipilimumab seems to further improve response rates. 16 Combinations of various immunomodulating agents are now to be explored.
Interestingly, the combination of ipilimumab and Granulocyte-Macrophage-Colony Stimulating Factor (GM-CSF) was reported to improve survival compared to ipilimumab alone in melanoma patients. These results were associated with a more favourable toxicity profile for the combination in comparison with ipilimumab alone. 24 This is poorly understood and it indicates that we are only beginning to explore and understand combinations in immunotherapy-based approaches and in particular the anti-PD1/PD-L1 molecules.
With anti-PD1/PD-L1 antibodies a new era for immunotherapy has arrived. Tumour control and the concept of a ‘clinical cure’ are emerging possibilities that appear already within reach in melanoma. Most of the patients with durable responses seem to have obtained a state of tumour control rather than one of complete tumour eradications, for which the term ‘clinical cure’ may be appropriate. 25 These goals should be attainable in various solid tumours. Programmes in most tumour types are currently launched and the next 5 years will be enormously informative and exciting.
Finally, there is no doubt that anti-PD1 and anti-PDL-1 warrant being drugs of the year and because of the therapeutic breakthrough they represent, the task will be extremely challenging for next year’s candidates.
Conflict of interest statement
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