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K. Hotta

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    MS25 - Translating Research into Practice (Applied Statistics) (ID 42)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Statistics
    • Presentations: 1
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      MS25.1 - Defining the Gold Standard: PFS v OS (ID 579)

      14:00 - 15:30  |  Author(s): K. Hotta

      • Abstract
      • Presentation
      • Slides

      Approval of most new agents for advanced non-small-cell lung cancer (NSCLC) has been based on prolongation of OS, representing a direct measure of clinical benefit, in randomized clinical trials. Recently, however, as we have more opportunity to obtain trial results showing “significant improvement in PFS without any OS benefit”, most investigators feel that the assessment of OS may become of limited use and that PFS must be surrogate endpoint for assessing the efficacy of an experimental agent in NSCLC. Originally, PFS is quite different from OS since it is subjective, but not a direct measure of clinical benefit. Progression is often asymptomatic, and it is not always clinically relevant. To use PFS as surrogate endpoint, its validity should be statistically evaluated. In the pooled analysis using individual patient data of randomized trials comparing first-line docetaxel with vinca-alkaloids, Buyse et al. showed relatively weak PFS-OS correlation [BMJ open 2013;3:e001802]. So far, there seem no other large-scaled validation studies investigating the surrogacy of PFS for OS endpoint with formal statistical approach. Thus, PFS has not yet been a statistically acceptable surrogate endpoint for OS in patients with metastatic NSCLC. Now, what could we interpret “significant improvement in PFS without any OS benefit”? Also, what would be the clinically meaningful endpoint in advanced NSCLC? The literature-based study was conducted to assess the PFS-OS relationship with the data of the phase III trials investigating molecular-targeted agents in advanced NSCLC [Lung Cancer 2013;79:20]. It showed a strong PFS-OS correlation only in trials where subsequent therapy was conducted less frequently, whilst trials with a higher proportion of use of subsequent therapy had weaker association. The study concluded that 1) the relationship between PFS and OS is originally strong enough to support potential surrogacy of PFS, but that 2) given the observation that increasing use of effective salvage therapies could affect the PFS-OS association, improvement in PFS without any OS benefit does not mean the experimental agent fails to have a true clinical benefit. That is, a potentially true OS benefit by an experimental agent would have been seen without any confounding if no subsequent therapy had been given. This theory is called “explanatory approach”, supporting the use of PFS as a clinically meaningful outcome. Rather, there is an opposite opinion, suggesting the observed difference in OS would be considered the measure of clinical benefit, regardless of subsequent therapies, provided that they follow the current standard of care. This is the pragmatic approach [JCO 2011;29:2439]. The observed difference in OS, of course, will be expected smaller by the subsequent therapy than one would see if it was not available, leading to the need of a large sample size to detect such differences. But, according to the pragmatic approach, such potentially attenuated but actually observed OS difference should be used for assessing the true clinical benefit of the experimental agent in the given clinical setting under reflecting the clinical reality of available subsequent treatments. Recently, ASCO discussed what would be clinical meaningful outcome in advanced NSCLC without EGFR or EML4-ALK mutations, and provided draft recommendations as follows: 1) survival after first line therapy is relatively short, and OS is a feasible endpoint although the effects of the experimental agent on OS can be clouded by treatments administered after the period of therapy, and 2) clinical trials should aim to improve OS by a minimum of 25% as compared with standard therapy. ASCO seems to support the importance of measuring OS rather PFS, in favor of the pragmatic approach. Even in the first-line metastatic colorectal cancer, though PFS has already been established as a surrogate for OS in the 90’s, its surrogacy was reappraised using individual patient data between 1997 and 2006 because of the advance in the treatment during the last decade and recent improvement of OS [JCO 2013 (suppl;abstr 3533)]. Surprisingly, the PFS-OS relationship was not as strong as was seen in the 90’s. The study concluded that in modern metastatic colorectal cancer trials where SPP exceeds time to first progression, the treatment effects on PFS do not reliably predict those on OS. It seems that even though PFS was once accepted as a suitable surrogate for OS, its validity should be assessed repeatedly along with the advances especially in the post-progression treatment, which also supports the concept of the pragmatic approach. Regarding the regulatory considerations, the FDA stated OS should be considered the standard clinical benefit endpoint and that it should be used to establish the efficacy of a treatment in metastatic NSCLC, although it can also consider PFS for regulatory decision of drug approval based on the population. Some of the abovementioned findings potentially support the rationale of the pragmatic approach, stressing the importance of a possibly attenuated, but actually observed OS difference. However, this theory is unlikely to be applied in more recent trials investigating specific targeted therapies including EGFR-TKIs or ALK inhibitors, because no OS difference would be arguably obtained due to a quite high level of crossover inevitably for the ethical reason. Thus, under the special situation where i) an experimental agent has theoretically been considered to target specific molecules, and ii) the earlier trials showed dramatic effect, this possibly high proportion of crossover can compromise the ability to assess clinical benefit, and also lead to the unrealistic sample size to detect significant OS difference. Rather, in this condition, whether both large magnitude of PFS advantage and great OS advantage compared with historical control can be obtained would be more important than the conventional assessment of OS difference between the arms. In conclusion, the goals of any new cancer treatment are to offer patients a true clinical benefit. PFS has not yet been formally accepted as a valid surrogate for the OS endpoint in advanced NSCLC, and its surrogacy will be addressed by each drug mechanism of action and patient population. Finally, OS remains the primary endpoint of clinical trials, except in a situation where agents targeting specifically driver oncogenes are being evaluated with anticipation of high level of crossover.

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    P2.09 - Poster Session 2 - Combined Modality (ID 213)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P2.09-005 - Cisplatin, S-1 and concurrent thoracic radiotherapy for locally advanced non-small-cell lung cancer: A phase II study of Okayama Lung Cancer Study Group 0501 (ID 1202)

      09:30 - 16:30  |  Author(s): K. Hotta

      • Abstract

      Concurrent chemoradiotherapy is the standard treatment for locally advanced non-small-cell lung cancer (LA-NSCLC). However, its cure rate remains unsatisfied, and further improvement in the treatment outcome is strongly warranted. S-1 (S), an oral fluoropyrimidine, is a new active agent possessing a radio-sensitizing effect. Additionally, combining S and cisplatin (P) offered an active and safe regimen for metastatic non-small-cell lung cancer. The objective of this study was to assess the efficacy and safety of S plus P with concurrent thoracic radiotherapy (TRT) for LA-NSCLC.

      Patients with stage IIIA/IIIB, aged ≤75 years and PS 0-1, and without any prior chemotherapy were eligible for this study. Patients were treated with P (40 mg/m² on day 1, 8, 29 and 36) and S (40 mg/m²/dose b.i.d. on days 1-14 and 29-42) and TRT (60 Gy/30 fr over 6 weeks starting on day 1). Primary endpoint was respsonse rate, and required sample size was 48 patients.

      Between 2006 and 2009, 48 patients were enrolled (37 men; median age, 66 years; PS 0/1, 36/14; IIIA/IIIB, 23/25; sq/non-sq, 22/26). Partial response was observed in 37 patients (77%; 95% confidence interval: 63-88%). At a median follow-up of 54 months for the surviving patients, median progression-free survival and median survival time were 9.3 months and 31.3 months, respectively. No difference in efficacy (response and survivals) was observed stratified by histology (sq vs. non-sq). Toxicities were generally mild, including G3/4 neutropenia (44%), G3/4 thrombocytopenia (13%), G3 febrile neutropenia (8%) and G3 pneumonitis (4%). No one developed Gr3/4 esophagitis. No toxic deaths have occurred.

      This chemoradiotherapy regimen yielded a favorable overall survival data. Also, it was well-tolerated in patients with LA-NSCLC as compared with concurrent docetaxel plus P with TRT therapy especially in term of TRT-related toxicities.