Hyperprogression with immunotherapy: Is it real?

The advent of immune checkpoint inhibitor (CPI) therapy has revolutionized systemic therapy for cancer, with unprecedented long-term survival now identified for subsets of patients with advanced cancer and with a step-change increase in the cure rate when it is used in the radical setting, especially for diseases considered relatively refractory to conventional therapies such as non–small cell lung cancer (NSCLC) and melanoma. Nevertheless, challenges, including the identification of those patients most likely to benefit and those at greatest risk for serious or life-threatening immune-related adverse events and the definition of the kinetics of benefit, remain in the routine use of CPIs. A number of different radiological patterns of clinical benefit from CPI therapy have been identified, initially in melanoma; they include a response with no new lesions, durable stable disease, a response after an increase in the tumor burden, and a response in the presence of new lesions (the latter two combined are termed pseudoprogression). Such response patterns have been similarly identified in other tumor subtypes, albeit with differing incidences. Indeed, the unprecedented duration of response observed with CPIs in comparison with standard-of-care drugs has resulted in the marked survival gains observed. In addition, the advent of neoadjuvant CPI trials has clearly demonstrated a dissociation between radiological findings and tumor status, with several data sets now demonstrating radiologically stable changes but increasing necrosis associated with complete or nearly complete pathological responses on resection. Importantly, another pattern of progression with CPIs has also been reported; termed hyperprogressive disease (HPD), it is characterized by a rapid and unexpected rate and volume of progression and is often associated with early fatality. This, therefore, represents a potential major problem in CPI use, particularly with respect to being able to predict its occurrence. Such HPD was initially proposed to account for the early crossing over of progression-free survival and overall survival curves with the initially inferior outcomes observed in some of the early registration trials of CPIs versus docetaxel for relapsed NSCLC, and it was further explored and defined by Champiat et al as a ≥2-fold increase in the tumor growth rate during experimental therapy in comparison with the period immediately before that. Nevertheless, considerable debate still exists about whether HPD is a true phenomenon, is specifically CPI-related, or is simply a normal function of tumor growth kinetics. It is, therefore, against this background that in this issue of Cancer, Kanjanapan et al report outcomes of 182 patients treated in phase 1 trials of CPIs at the Princess Margaret Cancer Centre (Toronto, Ontario, Canada) and explore the rate of HPD and associated patient characteristics. Here, HPD was similarly defined according to Champiat et al and was identified in 7% of patients across different tumor types, regardless of age, sex, prognostic score, or cancer subtype, but it was observed more frequently in females; the prevalence and the tumor distribution were similar to those identified previously. So, does HPD exist? If so, is it limited to CPI-directed therapy, or is it simply a factor of individual tumor growth kinetics in a progressing tumor that may be preferentially noted by investigators because of a recall bias? Several factors must be considered. First, our current knowledge of tumor growth kinetics dates back many years and forms the cornerstone of chemotherapeutic delivery schedules and radiation fractionation. Based on isolates and cell models, direct measures of tumor doubling times have demonstrated that, in general, tumor kinetics tend to follow simple patterns such as exponential, log-logistic, or Gompertz distributions. Although the proliferation rate is generally higher in metastatic lesions than primaries, major changes in doubling times are usually not observed outside the well-recognized accelerated repopulation rates observed with the selection pressures of traditional chemotherapy and radiotherapy, where growth acceleration is characterized by the ratio of the doubling time before treatment to that during the repopulation phase, which has been previously reported as 2.5 to 5.0. Second, as Kanjanapan et al have observed, definitions of HPD have differed between series and have likely affected the differences in HPD prevalence reported, albeit not markedly. Tumor