Late divergence of survival curves in cancer immunotherapy trials: interpretation and implications

Abstract

Late divergence of survival curves of treated patients and controls is commonly seen in successful cancer immunotherapy trials. Although late survival curve divergence may be caused by a delayed action of therapy, it may also be related to early effects of the treatment.We suggest that late survival divergence most often reflects a specific benefit of therapy for patients who suffer from a more slowly progressing disease. The occurrence of delayed survival curve divergence has important implications for the statistical analysis of immunotherapy trials. Thus, it leads to non-proportional hazard ratios that make commonly used statistical tests, e.g. the logrank test, suboptimal. It is therefore suggested that the statistical analysis of immunotherapy trials primarily should be based on a test that compares the survival curves at or after a pre-specified, fixed, late time point. PrécisLate survival curve divergence in immunotherapy trials has important implications for the statistical analysis and is commonly misinterpreted to be a consequence of delayed therapeutic effects.3

Effectiveness of Nivolumab versus Docetaxel as Second-Line Treatment in Non-Small Cell Lung Cancer Patients in Clinical Practice

“…Accordingly, immunotherapy trials have shown a delayed separation of survival curves when comparing chemotherapy and immunotherapy. The clinical effects of classical chemotherapy are achieved early [16]. On the other hand, immunotherapy response profiles have shown that some patients progress rapidly and other exhibit a longer response, as previously described in this study.…”

“…Similarly, the OS of nivolumab-treated patients at 8 months was 58%, while the OS of docetaxel-treated patients was 16%. The survival rates at partial times for the nivolumab-treated group evidenced a characteristic response profile for an immunotherapeutic treatment [16]. Among the study population, some patients were nonresponders with a fast-progressing disease, and another subgroup of patients maintained the response for a longer time.…”

Opposing effects of immunotherapy in melanoma using multisubtype interferon-alpha – can tumor immune escape after immunotherapy accelerate disease progression?

“… 11-16 However, as we have described earlier, late divergence of survival curves is in fact more likely to reflect early elimination of tumor cells. 17 The explanation for this is essentially that late divergence results from the presence of late events only in the control arm of the study. An event that appears late indicates that the disease is slowly progressive, and thus late curve divergence is a consequence of prevention of late events, which means that the immune system preferentially inhibits a slowly progressing tumor.…”

Differential effects of two therapeutic cancer vaccines on short- and long-term survival populations among patients with advanced lung cancer

“…[17,18] The phenomena of antigen spreading adds further complexity to the process, because for immunotherapy trials in which it is known that delayed clinical effects may occur. [20,21,3] An alternative approach would be to use two mixture distribution models, where one can interpret the two components as defining two groups with different intrinsic mortality patterns. These models allow separate interpretation of the effect of the therapy on the mixing proportion and on the failure time distribution of the short-and long-term survival populations via two sets of regression coefficients.…”