REVIEWS Developing biomarker-specific end points in lung cancer clinical trials Joel W. Neal, Justin F. Gainor and Alice T. Shaw Abstract | In cancer-drug development, a number of different end points have been used to establish efficacy and support regulatory approval, such as overall survival, progression-free survival (PFS), and radiographic response rate. However, these traditional end points have important limitations. For example, in lung cancer clinical trials, evaluating overall survival end points is a protracted process and these end points are most reliable when crossover to the investigational therapy is not permitted. Furthermore, although radiographic surrogate end points, such as PFS and response rate, generally correlate with clinical benefit in the setting of cytotoxic chemotherapy and molecular targeted therapies, novel immunotherapies might have atypical response kinetics, which confounds radiographic interpretation. In this Review, we discuss the need to develop alternative or surrogate end points for lung cancer clinical trials, and focus on several new biomarkers that could serve as surrogate end points, including functional imaging biomarkers, circulating factors (tumour proteins, DNA, and cells), and pharmacodynamic tumour markers. By enabling the size, duration, and complexity of cancer trials to be reduced, biomarker end points hold the promise to accelerate drug development and improve patient outcomes. Neal, J. W. et al. Nat. Rev. Clin. Oncol. advance online publication 23 December 2014; doi:10.1038/nrclinonc.2014.222
Introduction
Department of Medicine, Division of Oncology, Stanford Cancer Institute and Stanford University School of Medicine, Stanford University, 875 Blake Wilbur Drive, Stanford, CA 94305, USA (J.W.N.). Division of Hematology–Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02114, USA (J.F.G., A.T.S.). Correspondence to: A.T.S. ashaw1@ mgh.harvard.edu
Since the inception of anticancer systemic chemotherapy by Louis Goodman and Sidney Farber in the 1940s,1,2 the optimal design of clinical trials in oncology has presented a persistent challenge to drug development. The ultimate goal is clear: for a life-threatening disease such as cancer, a new therapy should provide clinically significant reductions in morbidity and mortality compared with the established standard of care. As the biology of human cancers has been unravelled, the tradition of performing large, double-blinded, placebo-controlled, randomized trials in unselected patient cohorts and with overall survival as the primary end point has come under scrutiny. Indeed, historically, clinical trials incorporating overall survival as a primary end point have been both large and prolonged—involving hundreds to thousands of participants and taking years to decades, depending on the frequency of predicted events. As a result, clinical research has become increasingly expensive to conduct, slowing drug development and regulatory approvals of potentially effective therapies. Other end points of efficacy have been used as alternatives to overall survival, including progression-free survival (PFS) and response rate, but even these end points have inherent limitations. Competing interests J.W.N. has received grants for research support from ArQule, Boehringer–Ingelheim, Merck and Roche/Genentech, and has acted as a consultant for Clovis Oncology. J.F.G. has acted as a consultant for Boehringer–Ingelheim, Jounce Therapeutics and Kyowa Hakko Kirin. A.T.S. has acted as a consultant for Ariad, Chugai, Genentech, Ignyta, Novartis and Pfizer, and has received honouraria for speaking for Novartis, Pfizer and Roche.
Thus, surrogate biomarker end points that correlate strongly with clinical benefit and can substitute for a clinical end point—survival or response rates—are of immediate interest. The term ‘biomarker’ refers to a characteristic that can be evaluated objectively, and that reflects normal biological or pathological processes, or pharmacological responses to therapeutic intervention. Prognostic biomarkers generally provide insights into the disease course and, therefore, the probable outcome, independent of treatment. Predictive biomarkers, on the other hand, offer information on the likelihood of response to a given therapy. Cancer biomarkers are typically evaluated in blood, body fluids or tumour specimens ex vivo, or in tumours in situ. To date, biomarkers of response have not served as primary end points for therapeutic trials that supported the approval of cancer therapies, although in select cases they have been used as components of composite end points. In this Review, using clinical trials in non-small-cell lung cancer (NSCLC) as examples, we describe the limitations in current efficacy end points used in clinical trials, such as overall survival, PFS, and response rate. We also explore the potential use of biomarkers as surrogate end points, including functional imaging techniques, bloodbased assays for circulating tumour markers, and direct molecular tumour assessments. Incorporation of such biomarker-based end points into clinical trials might help accelerate drug development and regulatory approval, thus enabling the benefit of new therapies on the lives of patients with cancer to be realized more rapidly.
NATURE REVIEWS | CLINICAL ONCOLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Evaluating overall survival improvement as a cancer clinical trials end point is time-consuming and costly, but traditional radiographic measurements of tumours might not accurately reflect clinical benefit due to confounding factors ■■ Molecular imaging aims to augment traditional radiographic measurements by differentiating malignant from normal tissues in order to better capture biological or molecular responses to therapy ■■ Circulating tumour factors, such as proteins, DNA, and cells, hold great promise as early predictors of therapeutic response and disease recurrence ■■ Tumour-derived factors present in the circulation might also enable early detection of molecular resistance markers and provide information on tumour heterogeneity ■■ Pharmacodynamic biomarkers evaluate the biological, molecular, and functional effects of a drug on its target, potentially offering insights into mechanisms of action of new compounds and/or validating new targets ■■ Validation of specific biomarkers requires their broad inclusion in clinical trials for assessment of performance
Limitations of current end points
In oncology, the gold standard of clinical benefit for a new therapy is an improvement in overall survival. In the contemporary era of NSCLC treatment, clinically and statistically significant improvements in overall survival have been only infrequently established despite numerous randomized clinical trials. Although a number of drugs are currently used in the treatment of NSCLC, few drugs have been approved based on an ‘additive’, placebo-controlled comparison with a standard therapeutic regimen (that is, with the investigational agent used in combination with standard therapy versus standard therapy plus a placebo).3 Even the widespread use of cisplatin and carboplatin is based on accumulated evidence from many small trials without placebo comparison and subsequent combination trials,4 and pemetrexed was introduced based on comparisons with other chemotherapies.5,6 A summary of supporting evidence for selected FDA approved cytotoxic chemotherapies and targeted therapies in locally advanced and/or metastatic NSCLC based on a positive overall survival end point is provided in Table 1. One of the major limitations with overall survival as an end point is that survival benefit can be confounded
by a number of factors, including non-cancer related causes of mortality, as well as crossover and/or the effects of other therapies received after the study drug. The latter factor might be particularly relevant for diseases in which numerous active therapies are available. As an example, the Iressa Pan-Asia Study 7 (IPASS) was a randomized trial of gefitinib, a small-molecule EGFR tyrosine kinase inhibitor (TKI), versus standard first-line carboplatin and paclitaxel in Asian patients with advanced NSCLC. In those patients with sensitizing EGFR mutations, both response rate and PFS were statistically significantly improved with gefitinib compared with chemotherapy (RR 71.2% versus 47.3%, P
Introduction
Department of Medicine, Division of Oncology, Stanford Cancer Institute and Stanford University School of Medicine, Stanford University, 875 Blake Wilbur Drive, Stanford, CA 94305, USA (J.W.N.). Division of Hematology–Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02114, USA (J.F.G., A.T.S.). Correspondence to: A.T.S. ashaw1@ mgh.harvard.edu
Since the inception of anticancer systemic chemotherapy by Louis Goodman and Sidney Farber in the 1940s,1,2 the optimal design of clinical trials in oncology has presented a persistent challenge to drug development. The ultimate goal is clear: for a life-threatening disease such as cancer, a new therapy should provide clinically significant reductions in morbidity and mortality compared with the established standard of care. As the biology of human cancers has been unravelled, the tradition of performing large, double-blinded, placebo-controlled, randomized trials in unselected patient cohorts and with overall survival as the primary end point has come under scrutiny. Indeed, historically, clinical trials incorporating overall survival as a primary end point have been both large and prolonged—involving hundreds to thousands of participants and taking years to decades, depending on the frequency of predicted events. As a result, clinical research has become increasingly expensive to conduct, slowing drug development and regulatory approvals of potentially effective therapies. Other end points of efficacy have been used as alternatives to overall survival, including progression-free survival (PFS) and response rate, but even these end points have inherent limitations. Competing interests J.W.N. has received grants for research support from ArQule, Boehringer–Ingelheim, Merck and Roche/Genentech, and has acted as a consultant for Clovis Oncology. J.F.G. has acted as a consultant for Boehringer–Ingelheim, Jounce Therapeutics and Kyowa Hakko Kirin. A.T.S. has acted as a consultant for Ariad, Chugai, Genentech, Ignyta, Novartis and Pfizer, and has received honouraria for speaking for Novartis, Pfizer and Roche.
Thus, surrogate biomarker end points that correlate strongly with clinical benefit and can substitute for a clinical end point—survival or response rates—are of immediate interest. The term ‘biomarker’ refers to a characteristic that can be evaluated objectively, and that reflects normal biological or pathological processes, or pharmacological responses to therapeutic intervention. Prognostic biomarkers generally provide insights into the disease course and, therefore, the probable outcome, independent of treatment. Predictive biomarkers, on the other hand, offer information on the likelihood of response to a given therapy. Cancer biomarkers are typically evaluated in blood, body fluids or tumour specimens ex vivo, or in tumours in situ. To date, biomarkers of response have not served as primary end points for therapeutic trials that supported the approval of cancer therapies, although in select cases they have been used as components of composite end points. In this Review, using clinical trials in non-small-cell lung cancer (NSCLC) as examples, we describe the limitations in current efficacy end points used in clinical trials, such as overall survival, PFS, and response rate. We also explore the potential use of biomarkers as surrogate end points, including functional imaging techniques, bloodbased assays for circulating tumour markers, and direct molecular tumour assessments. Incorporation of such biomarker-based end points into clinical trials might help accelerate drug development and regulatory approval, thus enabling the benefit of new therapies on the lives of patients with cancer to be realized more rapidly.
NATURE REVIEWS | CLINICAL ONCOLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Evaluating overall survival improvement as a cancer clinical trials end point is time-consuming and costly, but traditional radiographic measurements of tumours might not accurately reflect clinical benefit due to confounding factors ■■ Molecular imaging aims to augment traditional radiographic measurements by differentiating malignant from normal tissues in order to better capture biological or molecular responses to therapy ■■ Circulating tumour factors, such as proteins, DNA, and cells, hold great promise as early predictors of therapeutic response and disease recurrence ■■ Tumour-derived factors present in the circulation might also enable early detection of molecular resistance markers and provide information on tumour heterogeneity ■■ Pharmacodynamic biomarkers evaluate the biological, molecular, and functional effects of a drug on its target, potentially offering insights into mechanisms of action of new compounds and/or validating new targets ■■ Validation of specific biomarkers requires their broad inclusion in clinical trials for assessment of performance
Limitations of current end points
In oncology, the gold standard of clinical benefit for a new therapy is an improvement in overall survival. In the contemporary era of NSCLC treatment, clinically and statistically significant improvements in overall survival have been only infrequently established despite numerous randomized clinical trials. Although a number of drugs are currently used in the treatment of NSCLC, few drugs have been approved based on an ‘additive’, placebo-controlled comparison with a standard therapeutic regimen (that is, with the investigational agent used in combination with standard therapy versus standard therapy plus a placebo).3 Even the widespread use of cisplatin and carboplatin is based on accumulated evidence from many small trials without placebo comparison and subsequent combination trials,4 and pemetrexed was introduced based on comparisons with other chemotherapies.5,6 A summary of supporting evidence for selected FDA approved cytotoxic chemotherapies and targeted therapies in locally advanced and/or metastatic NSCLC based on a positive overall survival end point is provided in Table 1. One of the major limitations with overall survival as an end point is that survival benefit can be confounded
by a number of factors, including non-cancer related causes of mortality, as well as crossover and/or the effects of other therapies received after the study drug. The latter factor might be particularly relevant for diseases in which numerous active therapies are available. As an example, the Iressa Pan-Asia Study 7 (IPASS) was a randomized trial of gefitinib, a small-molecule EGFR tyrosine kinase inhibitor (TKI), versus standard first-line carboplatin and paclitaxel in Asian patients with advanced NSCLC. In those patients with sensitizing EGFR mutations, both response rate and PFS were statistically significantly improved with gefitinib compared with chemotherapy (RR 71.2% versus 47.3%, P
