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Progression-Free Survival: Helpful Biomarker or Clinically Meaningless End Point? Alan P. Venook, University of California, San Francisco, San Francisco, CA Josep Tabernero, Vall d’Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain See accompanying articles on pages 22 and 36

It seems obvious that patients with cancer would be better off when the burden of malignancy is less rather than more. Yet serial studies have failed to show that tumor shrinkage— objective response rate (ORR)—is predictive of patient outcomes. If tumor shrinkage is not prognostic, perhaps control of tumor growth would be more informative, given that cancer progression represents an ominous march toward death from malignancy. This is the basis for the use of progression-free survival (PFS) as an end point for determining whether a therapeutic intervention is likely, or unlikely, to make a meaningful impact in a patient’s survival. By extension, it also would seem true that the longer it takes for cancer to progress, the longer a patient will live. With this belief, cancer intervention trials of past decades used tumor progression as a surrogate end point of overall survival (OS). And in fact this may well have been valid in the early decades of cancer research, because the absence of cross-sectional or positron emission technology imaging usually meant that progressive disease was determined by declining performance status and worsening symptoms, signaling clinically relevant cancer progression. Given that the most effective therapies were generally employed upfront, survival beyond progression was likely to be shorter than the first-line PFS. The search for surrogate end points, of course, is critical if we are to determine the ultimate effectiveness of therapy without following patients until death. As an example, the end point of disease-free survival (DFS) was shown a decade ago to predict for OS in patients treated with adjuvant therapy for stage III colon cancer and enabled the oncology field to embrace the current standard chemotherapy regimen of infusional fluorouracil, leucovorin, and oxaliplatin without having to wait several years for the data of the MOSAIC trial (Multicenter International Study of Oxaliplatin/5-Fluorouracil/ Leucovorin in the Adjuvant Treatment of Colon Cancer) to mature (and a decade later, the findings were confirmed). If PFS was valid in the past, can it be trusted today? It is not valid with the pseudoprogression that is described in immune-based therapies, where tumors may enlarge before shrinking. Even for conventional treatments, the meaning of PFS has changed. The rigorous assessment of end points in contemporary clinical trials include frequent quantitative imaging, so PFS is almost always determined by strict radiographic tumor measurement, or in the case of positron emission technology, the assessment of FDG avidity by the radiologist, 4

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rather than by the clinical status of the patient. Because patients are typically enrolled on studies with much lower volume metastatic disease compared with years ago—tumor burden migration (Will Roger’s phenomena)—not only are most patients asymptomatic when given the news that the cancer is progressing, but most will live much longer postprogression than before. This is a tribute both to advances in treatment beyond first line and to the lead-time bias resulting from more sensitive imaging techniques. If not ORR or PFS, then what? New measurements, such as time to maximal response and depth of response and image reconstruction to compute volume rather than RECIST measurements, remind us how out of favor response rate has become. Similarly, the energy and money spent to collect data on tumor behavior beyond progression reflect a growing concern that as tumors evolve under the pressure of treatment, early gains may be negated by later losses. For example, the downstream effect of the withdrawal of an agent such as bevacizumab has been recently reported in a randomized study.1 In other words, improved PFS may not always correspond with longer survival. As more agents become available to treat the common cancers, the meaning of the results of the initial treatment is more difficult to assess. In considering the optimization of resources for the successful development of better treatment options in metastatic colorectal cancer (mCRC), we are faced with different challenges. On the one hand, we continuously question as above if PFS correlates with OS and quality of life, the ultimate goals of treating our patients. On the other hand, we strive to develop and validate better efficacy end points that, besides PFS, could provide guidance as to whether it is fair to continue developing a new drug or treatment based on the data generated in small proof-of-efficacy randomized phase II studies (Fig 1). In this issue of Journal of Clinical Oncology, two different approaches that further inform the debate regarding surrogate end points for mCRC trials are reported. Shi et al2 analyzed the raw data of conventional outcomes from the Analysis and Research in Cancers of the Digestive System (ARCAD) database of mCRC patients included in 22 clinical trials conducted between 1997 and 2006. In contrast, Sharma et al3 worked with the original data set from the historical N9741 clinical trial and explored dynamic end points that were not considered a decade ago, such as time to tumor growth (TTG) and log Journal of Clinical Oncology, Vol 33, No 1 (January 1), 2015: pp 4-6

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Editorial

A Tumor Size

OS

Tumor Shrinkage

Baseline Degree of early tumor shrinkage Depth of response (nadir) PFS TTG First-Line Treatment

Tumor Size

Death

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First-line treatment

Tumor Shrinkage Difference Tumor Shrinkage

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Treatment A Treatment B

TTG Difference

PFS Difference

OS Difference Time

C Tumor Size

Death

Tumor Shrinkage Difference Tumor Shrinkage

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First-line treatment Treatment A Treatment B

TTG Difference

PFS Difference

OS Difference

Time

Fig 1. Correlation models between tumor response, time to tumor growth (TTG), progression-free survival (PFS), and overall survival (OS). (A) Response to treatment cannot only be measured by the well-established parameter objective response rate (ORR) but also with other innovative parameters addressing tumor shrinkage, like early tumor shrinkage and depth of response (nadir). (B) The differential effect of two first-line therapies can translate into differences in tumor shrinkage at nadir, in PFS, and in OS. The correlation between PFS and OS may be more or less apparent depending on multiple factors, including availability of postprogression treatment options. (C) Recent studies have raised the possibility of differential effects between first-line treatments in ORR, tumor shrinkage, and OS, without differences in PFS.

ratio of tumor size at selected time points, and compared their performance in predicting OS with PFS. The ARCAD4 database reflects a collaborative effort among dozens of investigators around the world who have solicited and incorpowww.jco.org

rated the actual patient data from contemporary trials in mCRC. With the power of more than 16,000 patients and well-documented outcomes, the statisticians demonstrated a modest but significant relationship between PFS and OS that persisted over the decade during which the trials were conducted.2 Survival beyond PFS was about 10 months on average in those trials, and the median OS was less than 20 months; in fact, in no study was a statistically significant difference in OS seen without a difference in PFS having been demonstrated. Although the data included in ARCAD reflects studies closed in 2006, these results do reflect the use of biologic agents, which were administered to 44% of the patients studied. Although no biomarker enrichment (such as RAS mutation status) was incorporated in the design of any of these trials, the retrospective data that was available included those analyses. In the field of mCRC, perhaps no study has generated as much informative data (or publications) as N9741.5 An intergroup trial that compared oxaliplatin and irinotecan-containing regimens, it contained no biologics nor biomarkers, but the reanalysis of N9741 validates TTG as perhaps a better end point than PFS, which was employed in the original analysis of the data.3 It also performs equally or better to tumor size log ratio in the different treatment arm comparisons and consistently shows robustness when modeled in simulations of small randomized phase II clinical trials. In contrast to PFS, TTG better captures the change in the tumor growth curve produced by a particular drug or treatment and therefore allows differentiating the real effect of the treatment while avoiding the potential bias of a more favorable prognosis an individual tumor may have. Actually, there are some other studies that have suggested that TTG is a valid end point, especially in mCRC.6,7 In this regard, the study validates the consideration of TTG to be considered as an important end point in new clinical studies, although its absolute infallibility is still questionable. Indeed, some other continuous efficacy end points like log ratio or change in tumor size have not provided better accuracy than PFS in the prediction of OS.8-10 These exercises are particularly timely given the findings of two recently reported studies. FIRE-3 is a phase III study that has compared the addition of bevacizumab or cetuximab to first-line irinotecan-based chemotherapy in the KRAS exon 2 wild-type mCRC population, with a primary end point to demonstrate a difference in ORR based on the investigator assessment. The initial presentation of this study showed no differences either in ORR, the primary end point, or in PFS but did show a clinically meaningful difference in OS.11 Although several factors may have contributed to this survival difference, including the cross-over at progression and the availability of later treatment options, an independent review of response has suggested that there may be significant differences in tumor response parameters, like early tumor shrinkage (ETS) and depth of response.12 With the ARCAD experience in mind, FIRE-3 would be the first of its kind to find a difference in OS but not in PFS, although another independent review of response between the two arms may in part explain the differences in OS. In contrast, recently presented data from the large phase III CALGB/SWOG 80405 study comparing cetuximab or bevacizumab added to standard first-line chemotherapy—infusional fluorouracil, leucovorin, and oxaliplatin or fluorouracil, leucovorin, and irinotecan—in the same mCRC population showed no statistically significant differences in either PFS or OS but a slight trend for a © 2014 by American Society of Clinical Oncology

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Editorial

better response in patients treated with cetuximab, although this investigator-based assessment requires further validation.13 At this point, the definitive metric for assessing treatment is OS. But waiting a decade for results (CALGB/SWOG 80405 was initiated in 2004) paralyzes the research field at a time when biomarker-driven treatments should be gaining traction and need to be assessed early and often, as opposed to waiting a decade for a more traditional end point to mature. The information presented in these studies means we have to pay more attention to tumor response end points and their correlation with survival parameters (PFS and OS) to better understand the behavior of the disease in the continuum of care. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at www.jco.org. AUTHOR CONTRIBUTIONS

Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Bennouna J, Sastre J, Arnold D, et al: Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomised phase 3 trial. Lancet Oncol 14:29-37, 2013 2. Sharma MR, Gray E, Goldberg RM, et al: Resampling the N9741 trial to compare tumor dynamic versus conventional end points in randomized phase II trials. J Clin Oncol 33:36-41, 2015 3. Shi Q, de Gramont A, Grothey A, et al: Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: Findings from the Analysis and Research in Cancers of the Digestive System database. J Clin Oncol 33:22-28, 2015 4. de Gramont A, Haller DG, Sargent DJ, et al: Toward efficient trials in colorectal cancer: The ARCAD Clinical Trials Program. J Clin Oncol 28:527-530, 2010

5. Goldberg RM, Sargent DJ, Morton RF, et al: Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: A North American Intergroup Trial. J Clin Oncol 24:3347-3353, 2006 6. Claret L, Girard P, Hoff PM, et al: Model-based prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor dynamics. J Clin Oncol 27:4103-4108, 2009 7. Claret L, Gupta M, Han K, et al: Evaluation of tumor-size response metrics to predict overall survival in Western and Chinese patients with first-line metastatic colorectal cancer. J Clin Oncol 31:2110-2114, 2013 8. An MW, Mandrekar SJ, Branda ME, et al: Comparison of continuous versus categorical tumor measurement-based metrics to predict overall survival in cancer treatment trials. Clin Cancer Res 17:6592-6599, 2011 9. Heun JM, Grothey A, Branda ME, et al: Tumor status at 12 weeks predicts survival in advanced colorectal cancer: Findings from NCCTG N9741. Oncologist 16:859-867, 2011 10. Kaiser L: Tumor burden modeling versus progression-free survival for phase II decision making. Clin Cancer Res 19:314-319, 2013 11. Heinemann V, Fischer von Weikersthal L, Decker T, et al: Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). J Clin Oncol 31:206s, 2013 (suppl; abstr LBA3506) 12. Heinemann V, Modest DP, Fischer von Weikersthal L, et al: Independent radiological evaluation of objective response, early tumor shrinkage, and depth of response in FIRE-3 (AIO KRK-0306). Ann Oncol 25:ii117, 2014 (suppl 2; abstr LBA O-0030) 13. Venook A, Niedzwiecki D, Lenz HJ, et al: CALGB/SWOG 80405: Phase III trial of irinotecan (FOLFIRI) or oxaliplatin/5FU/leucovorin (mFOLFOX6) with bevacizumab (Bv) or cetuximab (CET) for patients (pts) with KRAS wild type (wt) untreated metastatic adenocarcinoma of the colon. Ann Oncol 25:ii112-ii113, 2014 (suppl 2; abstr LBA O-0019)

DOI: 10.1200/JCO.2014.57.9557; published online ahead of print at www.jco.org on November 3, 2014

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JOURNAL OF CLINICAL ONCOLOGY

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Editorial

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Progression-Free Survival: Helpful Biomarker or Clinically Meaningless End Point? The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Alan P. Venook Research Funding: Bayer Pharmaceuticals (Inst), Onyx Pharmaceuticals (Inst), GlaxoSmithKline (Inst), Genentech/Roche (Inst), BMS (Inst) Patents, Royalties, Other Intellectual Property: Royalties from Now-UptoDate for authoring and maintaining two chapters Travel, Accommodations, Expenses: Halozyme, Genentech, Roche

www.jco.org

Josep Tabernero Consulting or Advisory Role: Amgen, ImClone Systems, Lilly, Merck KGaA, Millennium Takeda, Novartis, Roche/Genentech, Sanofi, Celgene, Chugai Pharma, Taiho Pharmaceutical

© 2014 by American Society of Clinical Oncology

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Progression-free survival: helpful biomarker or clinically meaningless end point?

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