Flawed trials for cancer
Authors: I.F. Tannock, A.J. Templeton
Journal: Annals of Oncology (2020)

Despite impressive advances in cancer treatment demonstrated in phase III randomized controlled trials (RCTs), some recent RCTs have been reported with flaws in their design and/or analysis, and describe treatments that provide doubtful benefit for patients. Here, we outline problems relating to some recent high-profile trials. A phase III RCT should compare an experimental treatment with the current standard: the new therapy can be tested alone or combined with the current standard, with dose adjustment as appropriate. First-line treatment of metastatic renal cell cancer (RCC) since 2007 had been with a tyrosine kinase inhibitor (TKI), usually sunitinib.1Motzer R.J. Hutson T.E. Tomczak P. et al.Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.N Engl J Med. 2007; 356: 115-124Crossref PubMed Scopus (4750) Google Scholar When an RCT showed improvement in overall survival (OS) using second-line treatment with nivolumab compared with everolimus,2Motzer R.J. Escudier B. McDermott D.F. et al.Nivolumab versus everolimus in advanced renal-cell carcinoma.N Engl J Med. 2015; 373: 1803-1813Crossref PubMed Scopus (3374) Google Scholar it was logical to determine whether outcomes would be improved with anti- programmed cell death 1 (PD1) therapy compared with sunitinib, or by adding anti-PD1 treatment to sunitinib. However, two RCTs have compared sunitinib with immunotherapy combined with the TKI, axitinib,3Motzer R.J. Penkov K. Haanen J. et al.Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med. 2019; 380: 1103-1115Crossref PubMed Scopus (775) Google Scholar,4Rini B.I. Plimack E.R. Stus V. et al.Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med. 2019; 380: 1116-1127Crossref PubMed Scopus (946) Google Scholar which has never been standard first-line treatment of RCC. Sunitinib and axitinib are marketed by Pfizer: sunitinib will lose patent protection in 2021, but axitinib has patent protection until 2028. The trial using pembrolizumab showed improved OS4Rini B.I. Plimack E.R. Stus V. et al.Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med. 2019; 380: 1116-1127Crossref PubMed Scopus (946) Google Scholar and an anti-PD1 drug plus a TKI is appropriate first-line therapy for metastatic RCC. Access to treatment depends on price; there is no evidence that axitinib has greater efficacy or less toxicity than sunitinib, and the partner TKI should be sunitinib. Olaparib, an inhibitor of poly-ADP ribose polymerase, has shown promising efficacy for men with metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair gene alterations.5Mateo J. Carreira S. Sandhu S. et al.DNA-repair defects and olaparib in metastatic prostate cancer.N Engl J Med. 2015; 373: 1697-1708Crossref PubMed Scopus (1224) Google Scholar The PROFound RCT compared olaparib with 'physician's choice' treatment (enzalutamide or abiraterone, whichever not received previously) in men with mCRPC and homologous recombination repair (HRR) mutations.6Hussain M. Mateo J. Fizazi K. et al.PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations.Ann Oncol. 2019; 30 (mdz394.039)PubMed Google Scholar Responses to abiraterone after enzalutamide, or vice versa, are rare,7Khalaf D. Annala M. Finch D.L. et al.Phase 2 randomized cross-over trial of abiraterone + prednisone (ABI+P) vs enzalutamide (ENZ) for patients (pts) with metastatic castration resistant prostate cancer (mCPRC): Results for 2nd-line therapy.J Clin Oncol. 2018; 36Google Scholar, 8Attard G. Borre M. Gurney H. et al.Abiraterone alone or in combination with enzalutamide in metastatic castration-resistant prostate cancer with rising prostate-specific antigen during enzalutamide treatment.J Clin Oncol. 2018; 36: 2639-2646Crossref PubMed Scopus (60) Google Scholar, 9de Bono J.S. Chowdhury S. Feyerabend S. et al.Antitumour activity and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with abiraterone acetate plus prednisone for ≥24 weeks in Europe.Eur Urol. 2018; 74: 37-45Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar and the response rate in the control arm of PROFound was 2.3%. The 'physician's choice' control treatment should have included docetaxel (∼35% of participants had not received it) or cabazitaxel (∼20% had received it), or carboplatin.10Pomerantz M.M. Spisak S. Jia L. et al.The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer.Cancer. 2017; 123: 3532-3539Crossref PubMed Scopus (123) Google Scholar,11Zafeiriou Z. Bianchini D. Chandler R. et al.Genomic analysis of three metastatic prostate cancer patients with exceptional responses to carboplatin indicating different types of DNA repair deficiency.Eur Urol. 2019; 75: 184-192Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Olaparib led to better radiographic progression-free survival (PFS) than the control,6Hussain M. Mateo J. Fizazi K. et al.PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations.Ann Oncol. 2019; 30 (mdz394.039)PubMed Google Scholar but PROFound does not establish olaparib as standard treatment. The KEYNOTE-024 trial for non-small-cell lung cancer (NSCLC) showed improved OS for patients with programmed death ligand 1 (PD-L1) ≥50% on tumour cells who received pembrolizumab compared with platinum-based chemotherapy.12Reck M. Rodriguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (4661) Google Scholar The KEYNOTE-042 trial determined OS for pembrolizumab or chemotherapy above different thresholds for the PD-L1 score.13Mok T.S.K. Wu Y.L. Kudaba I. et al.Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non- small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.Lancet. 2019; 393: 1819-1830Abstract Full Text Full Text PDF PubMed Scopus (921) Google Scholar An appropriate design would have partitioned patients by their PD-L1 score: e.g. 1%–19%, 20%–49%, ≥50%. Instead, the trial first evaluated patients with tumour PD-L1 scores ≥50%, then if they benefitted, all patients with PD-L1 scores ≥20%, and if that was also positive, then patients with PD-L1 scores ≥1%. The study confirmed better survival with pembrolizumab in the 47% of participants with PD-L1 ≥50%, and pembrolizumab is appropriate for such patients. It was predictable that including this group together with smaller groups with PD-L1 scores of 20%–50% or 1%–50% might show a better outcome, but the question of interest was whether pembrolizumab improves outcomes compared to chemotherapy in patients with PD-L1 <50%.14Smit E.F. de Langen A.J. Pembrolizumab for all PD-L1-positive NSCLC.Lancet. 2019; 393: 1776-1778Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar It does not: 'exploratory analysis' revealed no survival benefit for those with intermediate PDL-1 scores of 1%–49%.13Mok T.S.K. Wu Y.L. Kudaba I. et al.Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non- small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.Lancet. 2019; 393: 1819-1830Abstract Full Text Full Text PDF PubMed Scopus (921) Google Scholar,14Smit E.F. de Langen A.J. Pembrolizumab for all PD-L1-positive NSCLC.Lancet. 2019; 393: 1776-1778Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar This study was specifically designed to extend the registration of pembrolizumab, regardless of benefit compared with standard chemotherapy—and it succeeded: the US Food and Drug Administration (FDA) approved pembrolizumab for treatment of NSCLC and tumour PD-L1 scores ≥1%. Pembrolizumab might be less toxic than chemotherapy, but for those with PD-L1 scores <50%, it is not more effective and hugely more expensive. Much is written about PFS as a primary end point in phase III trials. A reasonable conclusion is that PFS is appropriate if (and only if) it is a true surrogate for either OS or quality of life (QoL), and this has been shown rarely. Patients like to be told that their cancer is not progressing, but effects on QoL depend on the balance between the lack of tumour progression and added toxicity. PFS is inappropriate as a primary end point when expected survival is short. Publication of the POLO trial (and approval by the FDA) of maintenance olaparib for BRCA-mutated pancreatic cancer is an example. The trial showed improved PFS with olaparib in patients without progression during platinum-based chemotherapy, with a median OS of ∼18 months in both groups.15Golan T. Hammel P. Reni M. et al.Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.N Engl J Med. 2019; 381: 317-327Crossref PubMed Scopus (506) Google Scholar Olaparib has anti-tumour activity, but added toxicity, and did not improve QoL. The cost per life-year gained is infinite. When PFS is used as the primary end point of an RCT, there are two ways in which a drug should be regarded as 'failing': either it is not halting disease progression, or it is not tolerated and the patient stops taking it. Most analyses of PFS consider only the former; if patients stop treatment or withdraw consent or start a different therapy, they are censored if their disease has not met the criteria for tumour progression. Censoring of patients before disease progression disturbs the principle of randomization, since only some patients can be followed to their primary end point. Greater dropout on the experimental arm due to toxicity can give a false impression of benefit from treatment.16Templeton A.J. Ace O. Amir E. et al.Influence of censoring on conclusions of trials for women with metastatic breast cancer.Eur J Cancer. 2015; 51: 721-724Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Informative censoring occurred in the BOLERO-2 trial, where exemestane plus everolimus was compared with exemestane plus placebo for postmenopausal women with hormone receptor-positive advanced breast cancer.17Baselga J. Campone M. Piccart M. et al.Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.N Engl J Med. 2012; 366: 520-529Crossref PubMed Scopus (1982) Google Scholar Dropout and censoring occurred in 24% and 6% in experimental and control groups, respectively, and subsequent analysis showed no significant difference in OS.18Piccart M. Hortobagyi G.N. Campone M. et al.Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2.Ann Oncol. 2014; 25: 2357-2362Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar A recent example is the SOLAR-1 trial of fulvestrant plus alpelisib or placebo for postmenopausal women with PIK3CA-mutated hormone receptor-positive advanced breast cancer.19André F. Ciruelos E. Rubovszky G. et al.Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer.N Engl J Med. 2019; 380: 1929-1940Crossref PubMed Scopus (577) Google Scholar Alpelisib targets PIK3CA, and previous attempts to target this mutation were unsuccessful because of toxicity. The SOLAR-1 trial showed improved PFS for alpelisib, but censoring occurred in 39% and 25% of the alpelisib and placebo groups, respectively. The median duration of exposure to alpelisib and placebo differed by <1 month. SOLAR-1 will not show a difference in OS, and because of toxicity, the overall effects of alpelisib (despite having anti-tumour effects) will likely be harmful. There is no mention of informative censoring in the trial report19André F. Ciruelos E. Rubovszky G. et al.Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer.N Engl J Med. 2019; 380: 1929-1940Crossref PubMed Scopus (577) Google Scholar and alpelisib has been approved by the FDA and is being marketed. Substantial advances in treatment for many cancers have been disclosed by well-designed RCTs, but some recent RCTs have inherent problems in design and/or analysis, such that the apparent benefit does not stand up to rigorous review. Sometimes having a commercial success and helping patients live longer and have better lives are congruent, but sometimes they are not. PFS may be valuable when it indicates long-term 'Progression-Free Survival' in people with prolonged survival; at other times PFS might indicate a 'Planned Flawed Study' that leads to 'Profit For Sponsor'.