2 e-Letters

  • Response to the E-letter by Kopp et al.

    We thank Kopp and colleagues for their thorough analysis of our work. We agree
    with their assessment that the modified progression-free survival ratio (mPFSr),
    which was modeled based on publicly available data from the MOSCATO 01
    trial, may have limitations when applied to different clinical settings. While the
    two-month PFS1 cut-off for the pre-PFS time was motivated by the shortest
    meaningful staging interval irrespective of tumor entity and line of treatment,
    setting the post-PFS time to 24 months if the PFS2 time exceeds six months was
    considered in the first place for the population of advanced-stage, heavily
    pretreated cancer patients currently enrolled in precision oncology trials.
    However, as molecular stratification and precision oncology moves toward earlier
    treatment lines, the cut-off for the post-PFS time might be too liberal and
    subsequently adapted in future iterations of the mPFSr.
    As we were aware of the need for a validation cohort, we applied the mPFSr to
    the data from the WINTHER trial. In this second, independent patient cohort, the
    mPFSr provided the same result as in the training cohort from the MOSCATO 01
    trial (Figure 3D). In addition, we plan to include and evaluate the mPFSr in a
    retrospective analysis of more than 1300 patients with advanced cancers
    enrolled in the MASTER trial of NCT Heidelberg/Dresden and the German
    Cancer Consortium....

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  • The modified PFS ratio is not ready for prime time

    We agree with the starting points underlying Mock et al. [1]:

    1. In molecularly guided tumor therapies, an intra-patient assessment of response to therapy is an attractive approach in attempt to reduce between-patient heterogeneity.

    2. Defining the success of a therapy purely based on patient’s progression-free time on the molecularly guided therapy (PFS2) exceeding e.g. 1.3 times their progression-free time on the previous line of therapy (PFS1) may be problematic, especially for small values of PFS1.

    Their proposed solution, the modified PFS ratio (mPFSr), is derived from the majority decision of a sample of 100 oncologists classifying data from 194 patients as "success" or "failure" based on their PFS1 and PFS2 times. In Fig. 1 (https://tinyurl.com/ubbvorg), we illustrate this by plotting PFS1 vs. PFS2 times and adding the cutoff curves (separating therapeutic success from failure) defined by the mPFSr and PFSr criteria.

    Fig. 1 here
    Legend: Points above the dashed line (PFSr = 1.3) or the solid line (mPFSr definition) are successes.

    The mPFSr defines a cutoff curve with sharp changes in direction. This curve entails difficulties in interpretation. Particularly, changing all PFS2 times exceeding 6 months to 24 months seems overly liberal as a general rule (although in the studied data sets the effect is balanced by the more strict requirement on small PFS1 times).

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