How do immune checkpoint-targeted antibodies work? The need for improved pharmacokinetic evaluation in early phase studies
Authors: P.A. Ascierto, A. Marabelle
Journal: Annals of Oncology (2018)

Monoclonal antibodies blocking the Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) pathway have revolutionized treatment across several cancers. In patients with advanced melanoma, 40% long-term overall survival (OS) has been achieved [1.Long G.V. Schachter J. Ribas A. et al.4-year survival and outcomes after cessation of pembrolizumab (pembro) after 2-years in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in KEYNOTE-006.J Clin Oncol. 2018; 36(Suppl 15): 9503Crossref Google Scholar, 2.Hamid O. Robert C. Daud A. et al.5-year survival outcomes in patients (pts) with advanced melanoma treated with pembrolizumab (pembro) in KEYNOTE-001.J Clin Oncol. 2018; 36(Suppl 15): 9516Crossref Google Scholar, 3.Ascierto P.A. Long G.V. Robert C. et al.Three-year survival outcomes in patients with BRAF wild-type melanoma who received nivolumab monotherapy in a randomized phase 3 trial.JAMA Oncol. 2018; PubMed Google Scholar]. In addition, adjuvant use of nivolumab has been associated with a 34% longer recurrence-free survival than ipilimumab in patients with resected stage III–IV melanoma [4.Weber J.S. Mandalà M. Del Vecchio M. et al.Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: updated results from a phase III trial (CheckMate 238).J Clin Oncol. 2018; 36(Suppl 15): 9502Crossref Google Scholar]. Most of the key trials of nivolumab involved the first approved dose of 3 mg/kg every 2 weeks (Q2W) [3.Ascierto P.A. Long G.V. Robert C. et al.Three-year survival outcomes in patients with BRAF wild-type melanoma who received nivolumab monotherapy in a randomized phase 3 trial.JAMA Oncol. 2018; PubMed Google Scholar,5.Wolchok J.D. Chiarion-Sileni V. Gonzalez R. et al.Overall survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med. 2017; 377: 1345-1356Crossref PubMed Scopus (1644) Google Scholar,6.Weber J.S. Hodi F.S. Wolchok J.D. et al.Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma.J Clin Oncol. 2017; 35: 785-792Crossref PubMed Scopus (558) Google Scholar]. Subsequent to this, a flat-dose of 240 mg Q2W was approved for all monotherapy indications. The study reported by Long et al. [7.Long G.V. Tykodi S.S. Schneider J.G. et al.Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer.Ann Oncol. 2018; 29: 2208-2213Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar] provides important information on the use of a new less frequent flat-dose schedule of nivolumab 480 mg/kg every 4 weeks (Q4W), which was approved for some indications by the US Food and Drug Administration (FDA) in March 2018 and by the European Medicines Agency (EMA) in April 2018. The data reported here suggest that the pharmacokinetic (PK) and safety profiles of this new dose schedule are similar to those with the original 3-mg/kg dose schedule. Efficacy across the different anti-PD-1/PD-L1 agents seems to be broadly similar, with the main differences being the administration schedule. Less frequent dosing offers improved convenience and flexibility for patients. In addition, less frequent administration can mean a reduced clinical burden for physicians, especially in major centers that treat large numbers of patients. This is an important consideration, given that the success of PD-1/PD-L1 blocking agents with regard to their high response rates (40%–45% in melanoma) and long duration of response (approximately 3 years) [3.Ascierto P.A. Long G.V. Robert C. et al.Three-year survival outcomes in patients with BRAF wild-type melanoma who received nivolumab monotherapy in a randomized phase 3 trial.JAMA Oncol. 2018; PubMed Google Scholar,5.Wolchok J.D. Chiarion-Sileni V. Gonzalez R. et al.Overall survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med. 2017; 377: 1345-1356Crossref PubMed Scopus (1644) Google Scholar], together with their increasing indications and greater use, has resulted in congested outpatient clinics. As such, the availability of less frequent dosing schedules is to be welcomed. However, as the authors note, most adverse events on anti-PD-1 therapy occur during the first 3 months of treatment. In this study, patients who received nivolumab 480 mg Q4W had transitioned from a prior regimen of 3 mg/kg Q2W which had been well tolerated [6.Weber J.S. Hodi F.S. Wolchok J.D. et al.Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma.J Clin Oncol. 2017; 35: 785-792Crossref PubMed Scopus (558) Google Scholar]. Even though phase I data, including doses up to 10 mg/kg, have shown no clear relationship between dose and toxicity, safety data for this new 480 mg Q4W schedule are required for patients who start therapy on this regimen rather than after switching from a different dose regimen. Whether the toxicity in the first few months differs compared with other dose regimens is a key unanswered question, especially considering that the follow-up from some 61 patients in this trial is relatively short. Another important question that needs to be addressed is how time to response and OS data with this new regimen compare with other schedules. In addition, it has been shown that subsets of patients [e.g. with high C-reactive protein (CRP)] might have a fast clearance of immune checkpoint antibodies with detrimental impact on survival [8.Wang E. Kang D. Bae K. et al.Population pharmacokinetic and pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma.J Clin Pharmacol. 2014; 54: 1108-1116Crossref PubMed Scopus (20) Google Scholar]. More data in patients with low body weight are also needed, since few data were available for this group in the overall safety analysis of this trial. Ongoing clinical trials, including CheckMate 384 (NCT02713867) in patients with non-small-cell lung cancer (NSCLC) and the phase III CheckMate 511 study (NCT02714218) in patient with melanoma, will hopefully provide answers to such questions. Within the anti-PD-1 agents, pembrolizumab dosing schedules of 2 mg/kg Q3W, 10 mg/kg Q2W and 10 mg/kg Q3W have all been evaluated [9.Robert C. Ribas A. Wolchok J.D. et al.Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial.Lancet. 2014; 384: 1109-1117Abstract Full Text Full Text PDF PubMed Scopus (1277) Google Scholar]. Pembrolizumab 2 mg/kg Q3W showed the same response rate as higher dosages with a better safety profile, so was selected for further development. However, there has been a trend toward superior efficacy with the higher 10 mg/kg Q3W dosage, with a greater improvement in OS versus chemotherapy observed with pembrolizumab 10 mg/kg Q3W compared with 2 mg/kg Q3W, although neither dose resulted in a statistically significant difference [10.Hamid O. Puzanov I. Dummer R. et al.Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma.Eur J Cancer. 2017; 86: 37-45Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar]. As suggested byFigure 1, similar results have been found during the development of anti-PD-L1 antibodies, although a 10-fold higher dose is needed to saturate PD-L1 because of a ‘sink effect’ (higher expression of PD-L1 than PD-1 in the body). With this data, it is now broadly accepted that anti-PD(L)-1 antibodies act as antagonistic molecules and that there is no relationship between dose, efficacy and toxicity beyond doses saturating the target. With nivolumab, the main question appears to be why a Q4W schedule was not included during phase I development. A phase I dose-finding trial showed no difference in terms of toxicity among different doses, even at the higher dosage of 10 mg/kg, when given Q2W, with 3 mg/kg chosen for further evaluation on the basis of the highest response rate [11.Topalian S.L. Hodi F.S. Brahmer J.R. et al.Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med. 2012; 366: 2443-2454Crossref PubMed Scopus (8025) Google Scholar]. Most interestingly, the first in human trial of nivolumab showed that saturation of PD-1 starts at very low doses of nivolumab (0.3 mg/kg) and that a single infusion of nivolumab at 10 mg/kg was sufficient to saturate PD-1 for at least 3 months [12.Brahmer J.R. Drake C.G. Wollner I. et al.Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.J Clin Oncol. 2010; 28: 3167-3175Crossref PubMed Scopus (2010) Google Scholar]. Therefore, if the rationale for achieving antitumor activity with anti-PD(L)-1 antibodies is to saturate targets, it is possible that a single high-dose infusion every 3 months would be sufficient to obtain optimal clinical benefits. Because most tumor responses are observed before 3 months, and because most tumor responses are durable even when patients stop immunotherapy, this again raises the question of the optimal duration of anti-PD(L)-1 therapy. However, response rate may not be the most appropriate end point to assess such checkpoint inhibitors [13.Ascierto P.A. Long GV. Progression-free survival landmark analysis: a critical endpoint in melanoma clinical trials.Lancet Oncol. 2016; 17: 1037-1039Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar]. On a broader level, the results of this study raise important questions on how phase I PK and pharmacodynamic (PD) studies of immune checkpoint-targeted antibodies are designed. At the beginning of the development of the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibody tremelimumab, the drug was administered using a dose schedule of 15 mg/kg every 3 months [14.Ascierto PA. Is there still a role for tremelimumab in the treatment of cancer?.Transl Cancer Res. 2013; 2: 48-50Google Scholar]. This extended dosing interval, which was selected based on the results of a phase I/II study [15.Camacho L.H. Antonia S. Sosman J. et al.Phase I/II trial of tremelimumab in patients with metastatic melanoma.J Clin Oncol. 2009; 27: 1075-1081Crossref PubMed Scopus (253) Google Scholar], was considered ambitious by many clinicians at the time and failed to show a significant survival benefit over standard of care chemotherapy in a phase III trial in patients with advanced melanoma [16.Ribas A. Kefford R. Marshall M.A. et al.Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.J Clin Oncol. 2013; 31: 616-622Crossref PubMed Scopus (567) Google Scholar]. However, despite the use of an every 3-month infusion schedule, as well as the fact that about 60% of patients received just a single cycle of tremelimumab, the OS curve for tremelimumab was similar to OS curves seen with ipilimumab in pivotal trials [17.Eroglu Z. Kim D.W. Wang X. et al.Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab.Eur J Cancer. 2015; 51: 2689-2697Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 18.Hodi F.S. O' Day S.J. McDermott D.F. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (9848) Google Scholar, 19.Robert C. Thomas L. Bondarenko I. et al.Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N Engl J Med. 2011; 364 (2256): 2517Crossref PubMed Scopus (3263) Google Scholar]. Subsequently, the schedule was revised to tremelimumab 10 mg/kg Q4W. With ipilimumab, 10 mg/kg was the chosen dose for clinical development on the basis of higher responses rates in phase I/II studies. However, a phase III study also showed that ipilimumab 3 mg/kg Q3W was effective, with improved OS in patients with previously treated metastatic melanoma with or without a gp100 peptide vaccine, compared with gp100 alone [18.Hodi F.S. O' Day S.J. McDermott D.F. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (9848) Google Scholar]. In a more recent phase III study that compared ipilimumab 3 mg/kg versus 10 mg/kg in patients with advanced melanoma, the higher dose resulted in significantly longer OS, although with increased treatment-related adverse events [20.Ascierto P.A. Del Vecchio M. Robert C. et al.Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial.Lancet Oncol. 2017; 18: 611-622Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar]. Importantly, this study showed that there is a relationship between dose, efficacy and toxicity with anti-CTLA-4 (ipilimumab), as opposed to with anti-PD(L)-1 antibodies. Because linear PK is seen with both regimens, these data challenge the notion that ipilimumab works as an antagonistic ‘checkpoint inhibitor’ antibodyin vivo and illustrates the potential impact of the antibody isotype that is chosen for clinical development (i.e. ADCC-prone isotypes IgG1 or IgG2 versus pure antagonistic antibodies IgG4 or Fc-mutated IgG1). Both doses have been approved by the FDA and EMA. The history of anti-CTLA-4 clinical development in metastatic melanoma is also insightful for the current developments of anti-PD(L)-1 antibodies in other tumor indications. Indeed, the idea of combining immune checkpoint-targeted monoclonal antibodies together with chemotherapy was tested in melanoma before than in NSCLC or Triple Negative Breast Cancer. Ipilimumab in combination with dacarbazine (DTIC) showed higher response rates than ipilimumab alone in a phase II trial (14.3% versus 5.4%) [21.Hersh E.M. O'Day S.J. Powderly J. et al.A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naive patients with advanced melanoma.Invest New Drugs. 2011; 29: 489-498Crossref PubMed Scopus (229) Google Scholar]. This result led to a phase III randomized study which showed that the addition of dacarbazine was detrimental to the activity of ipilimumab (same OS of approximately 20% with a shorter median duration of response of 19.3 months with ipilimumab 10 mg/kg + DTIC versus not reached with ipilimumab 3 mg/kg) [18.Hodi F.S. O' Day S.J. McDermott D.F. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (9848) Google Scholar,19.Robert C. Thomas L. Bondarenko I. et al.Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N Engl J Med. 2011; 364 (2256): 2517Crossref PubMed Scopus (3263) Google Scholar]. This speaks to the potential detrimental impact of chemotherapy on the quality of the antitumor response generated by immunotherapy and the current enthusiasm for anti-PD(L)-1 plus chemotherapy combinations currently developed in several indications where the objective response rate is higher but the durability of response seems worse than with immunotherapy alone combinations [22.Gandhi L. Rodríguez-Abreu D. Gadgee S. et al.Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer.N Engl J Med. 2018; 378: 2078-2092Crossref PubMed Scopus (2222) Google Scholar]. Here again, the potential impact of chemotherapies on anti-PD(L)-1 antibodies PK/PD remains to be determined. Across the various checkpoint inhibitors, identifying the optimal dosing schedule appears to be a process of trial-and-error, with the most effective regimens still not known even several years after agents have first been approved and after several phase III studies. One factor in this may be the choice of ORR as a primary end point in phase I/II studies, with dosing schedules selected for further development having been largely chosen based on response rates. Looking at the history of checkpoint inhibitor development, it is clear that better PK data with improved evaluation of dosing schedule at phase I/II are needed in order to avoid potentially misleading data and to more readily allow the best dose and schedule for use in clinical practice to be identified at an earlier stage. None declared.