Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?

Abstract

The phenomenon of hyperprogressive disease (HPD) is a provocative phenomenon in the era of immune checkpoint inhibitors (ICI).Multiple groups report HPD in a variety of cancers treated with ICI and it to be associated with shorter progression free survival and overall survival.The tumor microenvironment along with varying T cell subtypes have been postulated to have an intricate role in HPD, as well as different proteomic domains within the antibody complex [Fc-F(ab)2]. An increase in the ILC3 subset of the innate lymphocyte system has also been implicated.Universal criteria, along with predictive likelihood factors, are needed to define HPD to identify patients, prospectively or otherwise. Immunotherapy (IO) has altered the therapeutic landscape for multiple cancers. There are emerging data from retrospective studies on a subset of patients who do not benefit from IO, instead experiencing rapid progression with dramatic acceleration of disease trajectory, termed ‘hyperprogressive disease’ (HPD). The incidence of HPD ranges from 4% to 29% from the studies reported. Biological basis and mechanisms of HPD are currently being elucidated, with one theory involving the Fc region of antibodies. Another group has shown EGFR and MDM2/MDM4 amplifications in patients with HPD. This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease. Thus, prospective studies are urgently needed to confirm the underlying biology, predict patients who are susceptible to HPD, and determine the modality of therapy post progression. Immunotherapy (IO) has altered the therapeutic landscape for multiple cancers. There are emerging data from retrospective studies on a subset of patients who do not benefit from IO, instead experiencing rapid progression with dramatic acceleration of disease trajectory, termed ‘hyperprogressive disease’ (HPD). The incidence of HPD ranges from 4% to 29% from the studies reported. Biological basis and mechanisms of HPD are currently being elucidated, with one theory involving the Fc region of antibodies. Another group has shown EGFR and MDM2/MDM4 amplifications in patients with HPD. This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease. Thus, prospective studies are urgently needed to confirm the underlying biology, predict patients who are susceptible to HPD, and determine the modality of therapy post progression. The treatment landscape for patients with cancer continues to evolve at a rapid pace. The latest addition to the clinical artillery is the revamping of IO with the advent of immune checkpoint inhibitors (ICI) (see Glossary). As an increasing number of patients are treated with these agents, there are emerging data that a subset of patients do not benefit from IO, instead experiencing rapid progression with dramatic acceleration of disease trajectory, termed HPD) (Figure 1). One research group defined HPD as a tumor growth rate (TGR) that was at least twofold greater during ICI therapy than immediately before IO during traditional chemotherapy [1.Champiat S. et al.Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1.Clin. Cancer Res. 2017; 23: 1920-1928Crossref PubMed Scopus (633) Google Scholar]. Others define HPD as a >50% increase in tumor burden with a <2-month ‘time to treatment failure’ (TTF) and doubling of pace progression [2.Kato S. et al.Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate.Clin. Cancer Res. 2017; 23: 4242-4250Crossref PubMed Scopus (458) Google Scholar]. Still other groups have defined HPD as disease progression of >50% at the time of the first evaluation from before treatment [3.Ferrara R. et al.Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy.JAMA Oncol. 2018; 4: 1543-1552Crossref PubMed Scopus (334) Google Scholar]. Although these definitions differ slightly, the underpinnings are all the same: expansive growth or change in the rate of tumor progression that is grossly different from baseline causing a detrimental effect on the patient. Several preclinical studies have hypothesized mechanisms, but a clearcut biological underpinning of this phenomenon remains elusive. Thus, prospective studies are needed to recognize this phenomenon, and to predict patients who are susceptible to HPD. Herein, we review the concept of HPD based on currently available evidence. The correlation between HPD and ICI has been shown across multiple tumor types at multiple centers worldwide. Multiple studies have shown the impact HPD has on progression-free survival (PFS) and overall survival (OS) as well as change in rate of tumor progression. The clinical impact of HPD is well described and important for patient care. In a retrospective study of 218 patients enrolled in Phase I clinical trials, the authors used TGR before ICI treatment and compared it with TGR while on ICI therapy to better understand the relationship between TGR, anatomical variables, and OS outcomes. This study defined HPD as a twofold or more increase in TGR from pre-ICI to on-ICI scans and progressive disease (PD) on the first evaluation by Response Evaluation Criteria In Solid Tumors (RECIST). In this cohort, 9% of patients were found to have HPD with a median increase in TGR of 20.7-fold (range, 2.0–141.3). Interestingly, the patients who were determined to have HPD had fewer new lesions at the first evaluation than their non-HPD counterparts (33% vs 84%, P=0.0019). This result should not be overinterpreted in the context of a retrospective study because: (i) TGR was calculated based on the target lesions only and patients who showed a rapid growth rate in new lesions were not evaluated for HPD; and (ii) the authors did not include 18 patients who had clinical progression before being evaluated. A significant difference was noted in patients aged over 65 years having more HPD (19% vs 5%, P=0.018) but the authors caution the effect of a limited sample size although the difference was significant. The association between HPD status and OS was also alarming when compared with the cohorts who were defined to have complete or partial responses (CR-PR), stable disease (SD), or PD. Inevitably patients with SD, PD, or HPD fared worse than their CR-PR counterparts, but those with HPD had a markedly higher likelihood of death [hazard ratio (HR) 25.94; 95% confidence limits (CI) 5.57–120.74; P=0.000033) [1.Champiat S. et al.Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1.Clin. Cancer Res. 2017; 23: 1920-1928Crossref PubMed Scopus (633) Google Scholar]. These findings suggest not only that HPD is a serious adverse effect of ICI, but also that it confers a poorer outcome and is significantly detrimental to survival. In 182 patients who were enrolled in early-phase clinical trials across a breadth of tumor types [head and neck squamous cell carcinoma (HNSCC), gynecological, lung, gastrointestinal (GI), genitourinary (GU), melanoma, sarcoma, endocrine, and breast], there was a subset of patients found to have HPD. This study also defined HPD as a twofold or more increase in TGR from pre-ICI to on-ICI scans and PD on the first evaluation by RECIST 1.1 criteria. Of these patients, 80% had received single-agent ICI. In this cohort of various tumor types, 7% of patients were identified as having HPD and it was more likely in females than in males (P=0.01). Having HPD was also significantly associated with a shorter PFS of 1.6 months versus 2.8 months (HR 3.7; 95% CI, 2.0–7.1; P<0.001) [4.Kanjanapan Y. et al.Hyperprogressive disease (HPD) in early-phase immunotherapy (IO) trials.J. Clin. Oncol. 2018; 36: 3063Crossref Google Scholar]. Thus, this is another example of HPD resulting from ICI use and, importantly, shows that it is not tumor type specific and may occur across a variety of histologies. Further analysis of 214 patients in Phase I trials with multiple tumor types found 15% (33/214) of patients to be considered to have HPD based on the criteria used (TTF <2 months and a minimum increase in target lesions of 10 mm plus either an increase of ≥40% in the target tumor burden or of ≥20% with additional new lesions being present). However, pretreatment scans were not necessary for inclusion in this study. The study found that the median OS for patients with HPD was 4.8 months (95% CI, 3.4–7.3) versus 8.7 months (95% CI, 6.3–10.2) in patients without HPD (HR 1.87; 95% CI, 1.1–3.3; P=0.03) [5.Matos I. et al.Incidence and clinical implications of a new definition of hyperprogression (HPD) with immune checkpoint inhibitors (ICIs) in patients treated in phase 1 (Ph1) trials.J. Clin. Oncol. 2018; 36: 3032Crossref Google Scholar]. The conclusion of this study, which was validated in multiple other studies, was that patients with HPD have poorer outcomes. In a piggyback study, the authors further found no difference between the TGR pre-ICI between patients with HPD and patients with non-HPD (P=0.15), but found that TGR on-ICI was significantly higher in patients with HPD (P<0.001) [6.Matos I. et al.Refining criteria of hyperprogression (HPD) with immune checkpoint inhibitors (ICIs) to improve clinical applicability.Ann. Oncol. 2018; the that have a role in the of HPD. A retrospective study patients with lung cancer ICI from patients and found to have HPD based on growth This study also found that patients with HPD had significantly median PFS and median with patients without HPD, the PFS of patients with HPD was months versus months Y. et after immunotherapy: clinical and genomic alterations in advanced non-small cell lung cancer patients Clin. Oncol. 2018; 36: Google Scholar]. This study further the role of in HPD and an association with poorer outcomes. In the retrospective study to which patients with the authors in their inclusion criteria that patients had to have had a minimum of scans before ICI treatment and one during ICI. The authors calculated TGR by the increase in tumor based on the of the target et growth rate is an of in phase I clinical Cancer Res. PubMed Scopus Google Scholar]. the difference between TGR and to their HPD was defined as a difference in TGR >50% and PD on first these criteria, of patients treated with were identified to have HPD compared with only of those treated with This study found a significant association between HPD and having more than before the of ICI [3.Ferrara R. et al.Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy.JAMA Oncol. 2018; 4: 1543-1552Crossref PubMed Scopus (334) Google Scholar]. The of the of pre-ICI scans is an analysis of TGR before the of ICI is not Thus, this study further the relationship between ICI and HPD. In another retrospective study of patients with a variety of tumor types cell carcinoma and carcinoma specific genomic were identified in association with HPD. This study defined HPD as >50% increase in tumor burden compared with pre-ICI with a <2-month and doubling of pace progression. The study that 4% of patients were found to have HPD. In the patients with the criteria for HPD and had in progression rate In the patients with in had HPD and progression rate (range, The authors a analysis and found significant between and EGFR alterations in patients with HPD and [2.Kato S. et al.Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate.Clin. Cancer Res. 2017; 23: 4242-4250Crossref PubMed Scopus (458) Google Scholar]. This study new the role of specific genomic alterations that may or to HPD. Further these a review of a patients the pre-ICI of from patients who had HPD defined as a >50% increase in tumor size compared with progression on first and greater than a twofold increase in Although patients and and had HPD and, of these had with the amplifications in and EGFR In the amplifications were in 4% of patients and EGFR amplifications were in 4% of patients as well as amplifications in 4% of patients In patients with these alterations received the incidence of HPD was and in patients with and et for in to immune checkpoint inhibitors (ICI) analysis of alterations Oncol. 2017; Scholar]. The that these findings were to those from other studies from other should to their to identify to better identify which patients may HPD. A study of patients with or treated with ICI used a ratio of the rate of tumor growth pre-ICI compared with the rate on-ICI to define HPD. The study found patients to have HPD and showed that was significantly associated with HPD This study also found that HPD was associated with a PFS of months months et during therapy in patients with and neck squamous cell Oncol. 2017; PubMed Scopus Google Scholar]. Although the of HPD was higher than that for other tumor types, this not the findings or of the study. The number of patients with HPD is likely to as the and the of criteria to define HPD. this study as the of in the of HPD and that HPD confers poorer for patients to the of HPD in patients with advanced treated with cell death This study used TGR, and to HPD and, based on these and of patients in the cohort to have HPD. who the criteria for and TGR of HPD had a significantly PFS 95% CI, and OS 95% CI, compared with patients without HPD et al.Hyperprogressive disease during PD-1/PD-L1 in patients with lung Oncol. PubMed Scopus Google Scholar]. the authors found a ratio of T to T and higher of T to T in patients with HPD and poorer survival et al.Hyperprogressive disease during PD-1/PD-L1 in patients with lung Oncol. PubMed Scopus Google Scholar]. The findings of all of the studies are in of associated cell death or target of of patients inclusion of patient found to have HPD lung, melanoma, sarcoma, endocrine, increase in TGR from pre-ICI to on-ICI scans and PFS significantly shorter in phenomenon vs natural history of Oncol. PubMed Scopus Google I tumor increase in TGR from pre-ICI to on-ICI scans and increase in TGR of S. et al.Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1.Clin. Cancer Res. 2017; 23: 1920-1928Crossref PubMed Scopus (633) Google I tumor <2 minimum increase in 10 mm either increase ≥40% in burden or increase ≥20% with additional new OS significantly shorter in I. et al.Incidence and clinical implications of a new definition of hyperprogression (HPD) with immune checkpoint inhibitors (ICIs) in patients treated in phase 1 (Ph1) trials.J. Clin. Oncol. 2018; 36: 3032Crossref Google T cell and et by the of 2017; PubMed Scopus Google growth PFS significantly shorter in Y. et after immunotherapy: clinical and genomic alterations in advanced non-small cell lung cancer patients Clin. Oncol. 2018; 36: Google in TGR >50% and PD on first at baseline significantly associated with R. et al.Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy.JAMA Oncol. 2018; 4: 1543-1552Crossref PubMed Scopus (334) Google increase in tumor burden compared with pre-ICI with <2 twofold increase progression and EGFR significantly associated with HPD S. et al.Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate.Clin. Cancer Res. 2017; 23: 4242-4250Crossref PubMed Scopus (458) Google and increase in TGR, >50% increase in tumor size compared with PD on first and amplifications in patients with et for in to immune checkpoint inhibitors (ICI) analysis of alterations Oncol. 2017; PFS significantly significantly associated with et during therapy in patients with and neck squamous cell Oncol. 2017; PubMed Scopus Google defined as change in of of target lesions to RECIST 1.1 criteria TGR defined as change in of of target lesions to RECIST 1.1 criteria <2 T T cell higher T T cell survival rate in patients with et al.Hyperprogressive disease during PD-1/PD-L1 in patients with lung Oncol. PubMed Scopus Google associated cell death or target in a new TGR and et growth to RECIST in cancer patients treated with PubMed Scopus Google were years with the advent of The first of TGR was based on a Phase I by et et growth and RECIST criteria in PubMed Scopus Google Scholar]. patients treated in Phase I clinical trials were evaluated with this An in TGR was in of the patients considered as at to and of patients were as progressive to RECIST with a in The authors the use of growth rate during the when it was significantly with the evaluation of to RECIST criteria. However, the not to the used for HPD. The first to TGR and RECIST was by et et growth rate is an of in phase I clinical Cancer Res. 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PubMed Scopus Google there were at least patients with PD and TGR Thus, it be to determine the for HPD in this TGR was evaluated in patients with cell carcinoma treated in the in Cancer Evaluation vs and cancer treatment with vs Phase TGR was associated with worse PFS (HR 95% and worse OS (HR 95% from the and from the treatment in the cohort et growth rate to and treatment in cell carcinoma an analysis of the and phase PubMed Scopus Google Scholar]. in a cohort with patients with treated with et described a HPD rate of of in patients with PD as [3.Ferrara R. et al.Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy.JAMA Oncol. 2018; 4: 1543-1552Crossref PubMed Scopus (334) Google Scholar]. et patients treated in Phase I clinical trials with for HPD TGR and RECIST I. et and disease (HPD) in patients to in phase I trials from immune checkpoint inhibitors (ICIs) be to other Oncol. 2018; Scholar]. patients had PD as the and were for criteria. The authors an HPD rate of of patients and of with no difference in overall survival between the HPD group versus non-HPD I. et and disease (HPD) in patients to in phase I trials from immune checkpoint inhibitors (ICIs) be to other Oncol. 2018; Scholar]. Although HPD criteria be in patients on agents, the of survival impact from and cohorts to that it is not a clinical groups have hypothesized mechanisms for HPD, of of and responses to antibody There has also been involving These mechanisms may in or may be A study of patients with found patients to have HPD by the inclusion (i) <2 (ii) increase of of target at least new lesions in of disease to a different and clinical with a in status on the within the first months of treatment et on as a for hyperprogressive disease in non-small cell lung cancer to PD-1/PD-L1 Cancer Res. PubMed Scopus Google Scholar]. this study only patients who had at least of IO and HPD. of the patients with HPD were found to have tumor by tumor from patients was in or that were treated with or the the Fc region of the antibodies. The authors found that of treated with had a increase in the number of and, HPD. this study found that have the to and it the effect et on as a for hyperprogressive disease in non-small cell lung cancer to PD-1/PD-L1 Cancer Res. PubMed Scopus Google R. et the of the PD-1/PD-L1 PubMed Scopus Google Scholar]. However, in treated with there was no tumor growth or HPD. Another by these authors the role of EGFR on HPD in In to with EGFR that to those with of EGFR had significant in TGR and cancer cell further the that the Fc of the antibody HPD, that had EGFR were treated with but showed no of HPD or of cancer cell et on as a for hyperprogressive disease in non-small cell lung cancer to PD-1/PD-L1 Cancer Res. PubMed Scopus Google Scholar]. Thus, this study the of the tumor microenvironment and the between various Another for HPD is the impact of the relationship between T and In a study of patients with treated with either or who had baseline of a significant increase in TGR after the of an ICI was who an increase in of (95% CI, also had HPD. patients who a in of (95% CI, tumor with ICI et T identify and of hyperprogression to immune checkpoint in lung 2018; Scholar]. Although the role of is not this study that have a significant role in tumor Another study in the of T in patients with advanced cancer who on to HPD compared with the cohort that did not HPD. This study in patients with HPD, the T T cell ratio did not significantly change after treatment with an by this ratio significantly in patients without HPD. the authors found that the of T in significantly compared with patient without HPD, in these were post treatment et T by hyperprogression of S. PubMed Scopus Google Scholar]. from a T cell showed that or T to In when the of T are with a is and as a et in and PubMed Scopus Google Scholar]. This study found in as a tumor this in significant tumor The authors used which are specific to T cell to the that In treated with ICI that were in there was an T cell However, when were in with the T were to This is a in the era of of tumor and tumor and also the important of the impact of patient T cell Another study found that T cell type 1 also of the effect of was In these to the effect of and it for T cell in a to by ICI treatment from having effect et by the of 2017; PubMed Scopus Google Scholar]. This study further the in HPD and in patients who may HPD. In a Phase of in patients with T cell with tumor burden and of the first patients in the study showed progression of disease after a of the patients had disease over the of months and the other had stable disease (SD), all with within with the of the patients had and one of all patients and in In of the patients, of the of by a of and and these patients also had and and Thus, these patients were immediately the and received chemotherapy and one received to and lesions et progression of after 2018; PubMed Scopus Google Scholar]. This is an example of the effect that ICI have on HPD and further the described of the effect of in treated with ICI. A study evaluated the genomic and between and of patients showed HPD after ICI treatment et landscape to hyperprogressive disease after immunotherapy for 2018; PubMed Scopus Google Scholar]. Interestingly, were in tumor as and in addition to of and in HPD compared with et landscape to hyperprogressive disease after immunotherapy for 2018; PubMed Scopus Google Scholar]. HPD also showed an increase in the ILC3 subset of the innate lymphocyte system after immunotherapy et landscape to hyperprogressive disease after immunotherapy for 2018; PubMed Scopus Google Scholar]. that all of the for HPD is with no specific that HPD could still be the history of disease’ phenomenon vs natural history of Oncol. PubMed Scopus Google to immunotherapy when patients are to therapy (Figure The genomic and for HPD are from only a patients and could be a tumor or additional of genomic in to Thus, the phenomenon of HPD is than and studies as well as we that HPD is a outcome of ICI et landscape to hyperprogressive disease after immunotherapy for 2018; PubMed Scopus Google Scholar]. Another is one HPD from ICI versus traditional chemotherapy versus This is to There are data to suggest that HPD is associated with worse of the [3.Ferrara R. et al.Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy.JAMA Oncol. 2018; 4: 1543-1552Crossref PubMed Scopus (334) Google I. et al.Incidence and clinical implications of a new definition of hyperprogression (HPD) with immune checkpoint inhibitors (ICIs) in patients treated in phase 1 (Ph1) trials.J. Clin. Oncol. 2018; 36: 3032Crossref Google Y. et after immunotherapy: clinical and genomic alterations in advanced non-small cell lung cancer patients Clin. Oncol. 2018; 36: Google et during therapy in patients with and neck squamous cell Oncol. 2017; PubMed Scopus Google et al.Hyperprogressive disease during PD-1/PD-L1 in patients with lung Oncol. PubMed Scopus Google Y. et al.Hyperprogressive disease in early-phase immunotherapy clinical and association with PubMed Scopus Google Scholar]. A to be to the of ICI versus HPD in the may from trials that patients not for chemotherapy and use ICI in a with HPD from groups who received chemotherapy versus ICI could greater these but with clinical HPD is a provocative phenomenon in the era of ICI (Figure et and immune checkpoint or Scholar]. There continues to be an increasing of retrospective that shows that it is by ICI. HPD has been across multiple tumor The tumor microenvironment along with varying T cell subtypes has been postulated to have an intricate as have different proteomic domains within the antibody complex [Fc-F(ab)2]. to identify which patients may be by HPD after of ICI is The use of ICI in the of various cancers has to clinical for patients, but for it has been Thus, criteria are needed to define HPD to prospective identify patients along with predictive likelihood to identify these patients (see we criteria to define prospective studies or the HPD are the genomic of are the of are the of patients be prospectively identified as being at of it to post disease we criteria to define prospective studies or the HPD are the genomic of are the of are the of patients be prospectively identified as being at of it to post disease has an by has received research from is a or on clinical trials by and has received from from and is on the of and the of research for clinical and Cancer and Cancer has received from and and is on the of and of all target that on tumor and T to for an immune cancer of time from either the of or the of treatment that a patient with the disease remains at least a in the of the of target as the baseline of time during and after the treatment that a patient with the disease but it not at least a increase in the of the of target as the the treatment or the of one or more new T a to for a increase to for PD, as the the treatment

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