Scientific Integrity and Data Accuracy
Authors: Mary L. (Nora) Disis, Lee M. Ellis
Journal: JAMA Oncology (2019)

In Reply We would like to thank Pearson and Sweis for their insightful comments on our article. 1To evaluate the occurrence of hyperprogression (HPD) in patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs), we studied 3 CT scans, 2 scans performed before (CT scans A and B) and 1 scan performed after ICI therapy (CT scan C). 1 The speed of growth is reflected by the tumor growth rate (TGR) evaluated before (A vs B) and during ICI therapy (B vs C).Our definition of HPD was very stringent: if the tumor growth was 10% per month before ICI therapy, it must exceed 60% after therapy and more than 80% per month if tumor growth was 30% before ICI therapy.We believe that such a change in tumor growth cannot be explained by the natural history of NSCLC, but reflects an intrinsic negative effect of ICI therapy.To support that belief, we performed the same measurements among patients receiving single-agent chemotherapy.Pearson and Sweis question the validity of the singleagent chemotherapy cohort and argue for a cohort treated with a placebo or agents from phase 1 studies that were found to be ineffective.None of the randomized prospective studies that evaluated a single-agent ICI used a placebo, which seems ethically appropriate, and used docetaxel instead.Moreover, significant clinical benefit for patients with NSCLC treated in phase 1 trials 2 has been reported, and experimental agents in early phase studies might also have a detrimental effect, so we considered a chemotherapy cohort the most appropriate.The "disease-stabilizing effect" of late lines of chemotherapy treatment seems uncertain.Treatments were administered in the third or later lines in 2 of 3 patients with HPD in the chemotherapy cohort vs 24 (43%) of 56 patients with HPD in the ICI cohort.The overall survival (OS) data in these small samples are challenging to compare; our cohorts reflect the outcomes of pretreated patients with chemotherapy resistance.We agree with Pearson and Sweis that fewer patients with more than 2 metastatic sites in the chemotherapy cohort may have lowered the HPD rate.However, the assessment of the tumor burden in our study is unperfected; TGR computation requires the measurement of the same lesions before baseline and during ICI therapy and does not take into account the possible lesions that appeared at baseline.Our retrospective analysis can only generate a hypothesis on risk factors for HPD.Finally, although the crossing of OS curves is not directly indicative of HPD, it reflects a higher initial mortality rate with a single-agent ICI or combination of ICIs, such as in the Checkmate 057 3 and MYSTIC 4 trials.Some studies have described patients with an increase of more than 50% in the sum of long diameters of target lesions 6 weeks after baseline as "fast progressors." 5However, fast progression is not a surrogate of HPD, and HPD cannot be assessed in these trials owing to the absence of a prebaseline CT scan.To conclude, our work was aimed at evaluating the possibility of faster tumor growth speed associated with ICI therapy compared with chemotherapy.This possibility is now supported by preclinical evidence, highlighting the role of innate immune cells in driving HPD.