• Users Online: 128
  • Print this page
  • Email this page


 
 
Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 36-39

Should we design clinical trials differently in the era of cancer immunotherapy?


Department of Oncology, National Taiwan University Hospital; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

Date of Web Publication01-Apr-2019

Correspondence Address:
Prof. Chia-Chi Lin
Department of Oncology, National Taiwan University Hospital, 7 Chung Shan South Road, Taipei 10002
Taiwan
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JIPO.JIPO_5_19

Get Permissions

  Abstract 


The oncology clinical trials are evolving in the era of cancer immunotherapy. In Phase I trials, some severe immune-related adverse events occur beyond the first cycle. This is important to determine the recommended Phase II dose if the treatment duration is long. If there is no dose–response/toxicity relationship, it will not be necessary to push to the maximum tolerated dose. In Phase II trials, companion predictive biomarkers are valuable in cancers with intermediate response rates. Randomized (comparison, selection, or discontinuation) Phase II trials are needed in cancer immunotherapy combination. In Phase III trials, milestone analysis and restricted mean survival time could serve as the alternatives to hazard ratio to fit the survival kinetics of cancer immunotherapy.

Keywords: Clinical trials, drug development, immuno-oncology


How to cite this article:
Lin CC. Should we design clinical trials differently in the era of cancer immunotherapy?. J Immunother Precis Oncol 2019;2:36-9

How to cite this URL:
Lin CC. Should we design clinical trials differently in the era of cancer immunotherapy?. J Immunother Precis Oncol [serial online] 2019 [cited 2019 Apr 25];2:36-9. Available from: http://www.jipoonline.org/text.asp?2019/2/2/36/255340




  Introduction Top


The designs of Phase I–III clinical trials were established in the era of cancer chemotherapy. To fit the unique feature (dose–response/toxicity relationship) of chemotherapy, the primary endpoints of Phase I trial were to find dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and hence recommended Phase II dose. The primary endpoints of Phase II and III trials were objective response rate (RR) and overall survival (OS), respectively. It implied that a high objective RR can translate to improve OS. Since the beginning of targeted therapy era in 2000, the relevance of traditional primary endpoints had been debated. For example, MTD without chronic toxicity taken into consideration may not define the recommended Phase II dose. Patients with stable disease sometimes derived benefit from targeted therapy. Therefore, objective RRs might not be a surrogate of survival. From the beginning of immunotherapy era in 2010, this issue has become even more complicated as immunotherapy is distinct from chemotherapy and targeted therapy. In this article, I discuss the important aspects of designs of Phase I, II, and III trials under the context of cancer immunotherapy.


  Phase I Trials Top


The objective of a Phase I trial is to determine the appropriate dosage of an agent or combination to be taken into further study and to provide initial pharmacologic and pharmacokinetic studies. It is generally assumed, at this stage of testing, that increased dose is associated with an increased chance of clinical efficacy. Therefore, the Phase I trial is designed as a dose-escalation study to determine the MTD, that is, the maximum dose associated with an acceptable level of DLT (usually defined to be Grade 4 or above hematologic toxicity and Grade 3 or above nonhematologic toxicity). The recommended Phase II dose will take MTD, together with pharmacodynamics, pharmacokinetics, and preliminary antitumor activity into consideration.

Dose-limiting toxicity

In cancer immunotherapy, especially anti-CTLA4 (cytotoxic T lymphocyte antigen 4) antibodies and anti-PD-1 (programmed cell death 1) / PD-L1 (programmed cell death 1 ligand 1) antibodies, the major toxicity is immune-related adverse events (irAEs). The major categories of the irAEs are cutaneous (pruritus, rash, vitiligo [in malignant melanoma]), gastrointestinal (diarrhea and colitis), hepatic (transaminitis), endocrine (hypophysitis [in anti-CTLA4 antibodies] and thyroiditis), and pulmonary (pneumonitis [in anti-PD-1/PD-L1 antibodies]).[1],[2] There are variations in time to onset of irAEs. For example, rash could occur as early as the first cycle and hypophysitis tends to appear beyond Cycle 1 in patients with ipilimumab (anti-CTLA4 antibody).[1] The one cycle (3–4 weeks) of the traditional DLT-observing period is not adequate to capture all toxicities severe enough to limit the dose.[3] One practical way is to enroll more patients at each dose level and to take DLTs beyond Cycle 1 and intolerable Grade 2 AEs into consideration, similar to the proposal in the era of targeted therapies.[4]

People tend to think that immune checkpoint modulators, because of monoclonal antibody in nature, are relatively safe. There were no DLTs in the Phase I trials of agonistic antibodies against OX40 (CD134, MORX0916[5] and PF04518600[6]); 4-1BB (CD137, BMS663513 [urelumab][7] and PF05082566 [utomilumab][8]); and GITR (CD357, BMS986156[9] and TRX518[10]). We should not forget the tragic lesson we learned from the Phase I trial of TGN1412, an anti-CD28 agonistic antibody.[11],[12]

Maximum tolerated dose and recommended Phase II dose

The assumption behind the MTD is that the dose–response (toxicity) relationship exists. The higher dose of ipilimumab, anti-CLTA4 antibody, confers the higher OS and irAE rate in patients with malignant melanoma.[13] However, the dose–response relationship does not exist in anti-PD-1/PD-L1 antibodies.[14],[15],[16] To push the dose of cancer immunotherapy to the highest tolerable (or administered) needs to reconsider.

Pharmacokinetics and pharmacodynamics

The main aspects of pharmacodynamics are the tissue, the assay, and the level of target modulation. All of these are closely related to the appropriate sample size for the pharmacodynamic endpoint. In cancer immunotherapy, tumor biopsies repeated before treatment and on treatment are a better tissue source to study pharmacodynamics. We need more preclinical effort to develop the best assay and the right level of target modulation given that the dose–response (toxicity) relationship might not exist in certain cancer immunotherapy. If we do not have other means to determine the recommended Phase II dose, pharmacodynamics will be the primary endpoint rather than just a proof-of-principle study.

Preliminary antitumor activity – Cohort expansion

Because antitumor activities were observed in malignant melanoma and non-small cell lung cancer (and led to the Food and Drug Administration approval of these two indications) in the Phase I trial of pembrolizumab (KEYNOTE-001), people were optimistic that we will see promising preliminary antitumor activities in each and every Phase I trial in the era of cancer immunotherapy.[17] The sample sizes of the cohort expansion still need to be justified with respect to their primary aim (dose seeking based on dose-limiting toxicities, ineffectiveness, or target modulation) and include interim analyses to allow for early stopping.


  Phase II Trials Top


The objective of Phase II trials is to determine if the drug has antitumor activity against the tumor type in question. For this objective, RR is an appropriate endpoint for evaluating the question posed by the trial. However, it is important to recognize that tumor response is not a direct measure of patient benefit.

Objective response rate

The highest RRs (50%–90% except for microsatellite instability–high colorectal cancer) of single-agent anti-PD-1/PD-L1 antibody are in Hodgkin's lymphoma, Merkel cell carcinoma of the skin, squamous cell carcinoma of the skin, and microsatellite instability–high colorectal cancer (40%). A second group of cancers with intermediate RRs (15%–25% except for cutaneous melanoma) are in cutaneous melanoma (40%), nonsmall cell lung cancer, head-and-neck cancer, gastric cancer, urothelial carcinoma, renal cell carcinoma, and hepatocellular carcinoma. In microsatellite-stable colorectal cancer, pancreatic cancer, prostate cancer, and triple-negative breast cancer, the RRs of single-agent anti-PD-1/PD-L1 antibody are lowest (<10%).[18],[19] One practical way is to develop biomarkers (e.g., tumor PD-L1, tumor mutational burden, mismatch repair, and T-cell-inflamed gene signature) predictive of higher RR in the intermediate group. This topic is beyond the scope of this review.[20],[21]


  Phase III Trials Top


Progression-free survival

Progression-free survival (PFS) curves, although commonly used for conventional treatment modalities, are not an ideal endpoint for cancer immunotherapy clinical trials. First, on initiation of anti-PD-1/PD-L1 therapy and the subsequent promotion of T-cell recruitment/expansion, preexisting tumor lesions may initially increase and new radiological lesions may transiently appear before obtaining a stable disease or partial/complete response. These pseudo-progressions are classified as progressive diseases per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.[22] Therefore, it seems necessary to use dedicated radiological criteria, such as immune RECIST (iRECIST), to assess these atypical tumor responses, and to capture the spectrum of clinical benefits of cancer immunotherapies.[23] Second, PFS curves do not correlate with the OS benefits of cancer immunotherapies that are explained by long-term responses and by possible sensitization of the tumor to the next line of chemotherapy.

Overall survival

For the design of randomized Phase III trials using OS as the primary endpoint, the paradigm has shifted from the conventional approach based on a proportional hazards model to those that account for the unique survival kinetics observed in immuno-oncology trials. The results of the Phase III trial of ipilimumab in metastatic melanoma demonstrated a 4-month delay (overlapping of the survival curves) and long-term OS of approximately 20%.[24] In Phase III trials comparing chemotherapies with anti-PD-1/PD-L1 antibodies, a “crossing of survival curves” can be observed at about 3 months after starting treatment whereby the survival rate is lower in the immunotherapy arm in the early stages of the study.[25],[26],[27],[28],[29] One of the explanations of a “crossing of the survival curves” is hyperprogression which means that a subset of patients might present with accelerated progressive disease on treatment with anti-PD-1/PD-L1 antibodies.[30] At least two randomized Phase III trial designs were proposed based on milestone analysis (e.g., 2-year milestone survival)[31] and restricted mean survival time (e.g., the area under the Kaplan–Meier curves within the window of 36–72 months)[32] to simplify the process of sample size determination while keeping OS as the primary endpoint. The new designs are unaffected by the uncertainty of the survival kinetics demonstrated by cancer immunotherapies.

This is even more complicated when we design the Phase III trials of immunotherapy combination, including immunotherapy plus immunotherapy (e.g., nivolumab + ipilimumab in malignant melanoma), immunotherapy plus chemotherapy (e.g., pembrolizumab + platinum-based doublets in nonsmall cell lung cancer), and immunotherapy plus targeted therapy (e.g., avelumab + axitinib in renal cell carcinoma) versus standard therapy. First, single-agent control arm should be available to show synergism, for example, avelumab + axitinib versus avelumab versus sunitinib in renal cell carcinoma. Second, the “long-term” survival benefit needs to be demonstrated. Third, predictive biomarkers of immunotherapy combination might not be the same as those of immunotherapy single agent.


  Summary Top


In the era of cancer immunotherapy, the designs of clinical trials should be adjusted to find the best dose and schedule of the new drugs and to demonstrate the efficacy in the most precise and efficient way [Table 1].
Table 1: Comparison of clinical trial design among chemotherapy, targeted therapy, and immunotherapy, as well as immunotherapy combination

Click here to view


Financial support and sponsorship

The author disclosed no funding related to this article.

Conflicts of interest

The author disclosed no conflicts of interest related to this article.



 
  References Top

1.
Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012;30:2691-7.  Back to cited text no. 1
    
2.
Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: A pooled analysis of patients with advanced melanoma. J Clin Oncol 2017;35:785-92.  Back to cited text no. 2
    
3.
Kanjanapan Y, Day D, Butler MO, et al. Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials. Eur J Cancer 2019;107:1-7.  Back to cited text no. 3
    
4.
Postel-Vinay S, Collette L, Paoletti X, et al. Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents – Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted Therapies, an European Organisation for Research and Treatment of Cancer-led study. Eur J Cancer 2014;50:2040-9.  Back to cited text no. 4
    
5.
Infante JR, Hansen AR, Pishvaian MJ, et al. A phase Ib dose escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumors. J Clin Oncol 2016;34:101.  Back to cited text no. 5
    
6.
Hamid O, Thompson JA, Diab A, et al. First in human (FIH) study of an OX40 agonist monoclonal antibody (mAb) PF-04518600 (PF-8600) in adult patients (pts) with select advanced solid tumors: Preliminary safety and pharmacokinetic (PK)/pharmacodynamic results. J Clin Oncol 2016;34:3079.  Back to cited text no. 6
    
7.
Segal NH, Logan TF, Hodi FS, et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res 2017;23:1929-36.  Back to cited text no. 7
    
8.
Segal NH, He AR, Doi T, et al. Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res 2018;24:1816-23.  Back to cited text no. 8
    
9.
Siu LL, Steeghs N, Meniawy T, et al. Preliminary results of a phase I/IIa study of BMS-986156 (glucocorticoid-induced tumor necrosis factor receptor – related gene [GITR] agonist), alone and in combination with nivolumab in pts with advanced solid tumors. J Clin Oncol 2017;35:104.  Back to cited text no. 9
    
10.
Koon HB, Shepard DR, Merghoub T, et al. First-in-human phase 1 single-dose study of TRX-518, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) monoclonal antibody in adults with advanced solid tumors. J Clin Oncol 2016;34:3017.  Back to cited text no. 10
    
11.
Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006;355:1018-28.  Back to cited text no. 11
    
12.
Kenter MJ, Cohen AF. Establishing risk of human experimentation with drugs: Lessons from TGN1412. Lancet 2006;368:1387-91.  Back to cited text no. 12
    
13.
Ascierto PA, 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;18:611-22.  Back to cited text no. 13
    
14.
Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: Results of a randomized phase II trial. J Clin Oncol 2015;33:1430-7.  Back to cited text no. 14
    
15.
Robert C, Ribas A, Wolchok JD, 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;384:1109-17.  Back to cited text no. 15
    
16.
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016;387:1540-50.  Back to cited text no. 16
    
17.
Kang SP, Gergich K, Lubiniecki GM, et al. Pembrolizumab KEYNOTE-001: An adaptive study leading to accelerated approval for two indications and a companion diagnostic. Ann Oncol 2017;28:1388-98.  Back to cited text no. 17
    
18.
Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018;359:1350-5.  Back to cited text no. 18
    
19.
Hirsch L, Zitvogel L, Eggermont A, et al. PD-loma: A cancer entity with a shared sensitivity to the PD-1/PD-L1 pathway blockade. Br J Cancer 2019;120:3-5.  Back to cited text no. 19
    
20.
Tray N, Weber JS, Adams S. Predictive biomarkers for checkpoint immunotherapy: Current status and challenges for clinical application. Cancer Immunol Res 2018;6:1122-8.  Back to cited text no. 20
    
21.
Fujii T, Naing A, Rolfo C, et al. Biomarkers of response to immune checkpoint blockade in cancer treatment. Crit Rev Oncol Hematol 2018;130:108-20.  Back to cited text no. 21
    
22.
Hodi FS, Hwu WJ, Kefford R, et al. Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol 2016;34:1510-7.  Back to cited text no. 22
    
23.
Seymour L, Bogaerts J, Perrone A, et al. IRECIST: Guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017;18:e143-52.  Back to cited text no. 23
    
24.
Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23.  Back to cited text no. 24
    
25.
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-39.  Back to cited text no. 25
    
26.
Ferris RL, Blumenschein G Jr., Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856-67.  Back to cited text no. 26
    
27.
Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:1015-26.  Back to cited text no. 27
    
28.
Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): A multicentre, open-label, phase 3 randomised controlled trial. Lancet 2018;391:748-57.  Back to cited text no. 28
    
29.
Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018;378:2093-104.  Back to cited text no. 29
    
30.
Champiat S, Ferrara R, Massard C, et al. Hyperprogressive disease: Recognizing a novel pattern to improve patient management. Nat Rev Clin Oncol 2018;15:748-62.  Back to cited text no. 30
    
31.
Chen TT. Designing late-stage randomized clinical trials with cancer immunotherapy: Can we make it simpler? Cancer Immunol Res 2018;6:250-4.  Back to cited text no. 31
    
32.
Pak K, Uno H, Kim DH, et al. Interpretability of cancer clinical trial results using restricted mean survival time as an alternative to the hazard ratio. JAMA Oncol 2017;3:1692-6.  Back to cited text no. 32
    



 
 
    Tables

  [Table 1]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
   Abstract
  Introduction
  Phase I Trials
  Phase II Trials
  Phase III Trials
  Summary
   References
   Article Tables

 Article Access Statistics
    Viewed219    
    Printed16    
    Emailed0    
    PDF Downloaded34    
    Comments [Add]    

Recommend this journal