Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?
Authors: Jacob J. Adashek, Ishwaria M. Subbiah, Ignacio Matos, Elena Garralda, Arjun K. Menta, Dhakshina Moorthy Ganeshan, Vivek Subbiah
Journal: Trends in cancer (2020)

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; mdy303.011Google Scholar], again supporting the hypothesis that ICIs have a crucial role in the development of HPD. A retrospective study analyzing patients with non-small-cell lung cancer (NSCLC) receiving ICI reviewed imaging from 220 patients and found 17% (37/220) to have HPD based on volume-based growth kinetics. This study also found that patients with HPD had both significantly lower median PFS and median OS. Compared with patients without HPD, the PFS of patients with HPD was 1.2 months versus 4.1 months (P<0.000) [7.Kim Y. et al.Hyperprogression after immunotherapy: clinical implication and genomic alterations in advanced non-small cell lung cancer patients (NSCLC).J. Clin. Oncol. 2018; 36: 9075Crossref Google Scholar]. This study further implicates the role of ICIs in developing HPD and an association with poorer outcomes. In the largest retrospective study to date, which included 406 patients with NSCLC, the authors mandated in their inclusion criteria that patients had to have had a minimum of two computerized tomography (CT) scans before ICI treatment and one CT scan during ICI. The authors calculated TGR by using the percentage increase in tumor volume, based on summing the largest diameters of the target lesion, per month [8.Ferté C. et al.Tumor growth rate is an early indicator of antitumor drug activity in phase I clinical trials.Clin. Cancer Res. 2014; 20: 246-252Crossref PubMed Scopus (94) Google Scholar]. They subsequently reported the difference between TGR pre- and post-ICI to validate their findings. Furthermore, HPD was defined as a difference in TGR >50% and PD on first evaluation. With these criteria, 13.8% (56/406) of patients treated with ICIs were identified to have HPD compared with only 5.1% of those treated with chemotherapy. This study additionally found a significant positive association between developing HPD and having more than two metastatic sites before the initiation of ICI (P=0.006) [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 importance of the presence of pre-ICI CT scans is noteworthy because an objective analysis of TGR before the initiation of ICI is not possible. Thus, this study further supports the relationship between ICI and HPD. In another large retrospective study of 155 patients with a variety of tumor types [melanoma, NSCLC, HNSCC, cutaneous SCC, renal cell carcinoma (RCC), and colorectal carcinoma (CRC)], specific genomic aberrations were identified in association with HPD. This study defined HPD as >50% increase in tumor burden compared with pre-ICI with a <2-month TTF and doubling of pace progression. The study reported that 4% (6/155) of patients were found to have HPD. In the six patients with MDM2/4 amplifications, four met the criteria for HPD and had increases in progression rate (range 2.3–42.3-fold). In the ten patients with mutations in EGFR, two had HPD and subsequent progression rate increased (range, 35.7–41.7-fold). The authors conducted a bootstrap analysis and found significant correlations between MDM2/4 and EGFR alterations in patients with HPD (P=0.001 and P=0.014, respectively) [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 offers new insights into the role of specific genomic alterations that may drive or predispose certain individuals to developing HPD. Further validating these data, a review of a molecular database including 696 patients analyzed the pre-ICI next-generation sequencing (NGS) of tumors from patients who had HPD defined as a >50% increase in tumor size compared with pre-ICI, progression on first evaluation, and greater than a twofold increase in TGR. Although infrequently found, five (0.72%) patients (NSCLC, esophageal adenocarcinoma and SCC, and RCC) had HPD and, of these five, four had NGS results with the most common amplifications in MDM2/4 (50%) and EGFR (25%). In the entire database, MDM2/4 amplifications were present in 4% of patients (N=26), and EGFR amplifications were seen in 4% of patients (N=26) as well as 11q13 amplifications in 4% of patients (N=25). In total, ten patients with these alterations received ICIs; the subsequent incidence of HPD was 66%, 50%, and 43% in patients with MDM2/4, EGFR, and 11q13 amplifications, respectively [9.Alqwasmi A. et al.1140PDPredictive biomarkers for hyper–progression (HP) in response to immune checkpoint inhibitors (ICI) – analysis of somatic alterations (SAs).Ann. Oncol. 2017; 28mdx376.006Google Scholar]. The fact that these findings were similar to those from other studies from other institutions should prompt researchers to continue their efforts to identify prognostic biomarkers to better identify which patients may develop HPD. A study of 34 patients with recurrent or metastatic HNSCC treated with ICI used a ratio ≥2 of the rate of tumor growth pre-ICI compared with the rate on-ICI (TGKR) to define HPD. The study found ten patients (29%) to have HPD and showed that regional recurrence was significantly associated with HPD (P=0.008). This study also found that HPD was associated with a lower PFS of 2.5 months vs. 3.4 months (P=0.003) [10.Saada-Bouzid E. et al.Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.Ann. Oncol. 2017; 28: 1605-1611Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar]. Although the finding of HPD was higher than that reported for other tumor types, this does not negate the findings or significance of the study. The reported number of patients with HPD is most likely due to using TGKR as the criterion and supports the importance of identifying universal criteria to define HPD. Additionally, this study serves as evidence supporting the function of ICIs in the evolution of HPD and that HPD confers poorer outcomes for patients. Researchers analyzed 263 patients to evaluate the occurrence of HPD in patients with recurrent and/or advanced NSCLC treated with programmed cell death (ligand)-1 [PD-(L)1] inhibitors. This study used TGK, TGR, and TTF to categorize HPD and, based on these definitions, reported 20.9% (N=55), 20.5% (N=54), and 37.3% (N=98), respectively of patients in the cohort to have HPD. Patients who met the criteria for TGK and TGR of HPD had a significantly lower PFS (HR, 4.619; 95% CI, 2.868–7.440) and OS (HR, 5.079; 95% CI, 3.136-8.226) compared with patients without HPD [11.Kim C.G. et al.Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.Ann. Oncol. 2019; 30: 1104-1113Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar]. Additionally, the authors found a lower ratio of CCR7-negative CD45RA-negative T cells to total CD8+ T cells and higher proportion of TIGIT-negative T cells to PD-1-positive CD8+ T cells in patients with HPD and poorer survival [11.Kim C.G. et al.Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.Ann. Oncol. 2019; 30: 1104-1113Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar]. The findings of all of the discussed studies are detailed in Table 1.Table 1Hyperprogressive Disease (HPD): Results of Published StudiesaAbbreviations: CTLA-4, cytotoxic T-lymphocyte associated protein-4; gyn, gynecologic; mets, metastatic sites; mo, months; PD-(L)1, programmed cell death (ligand) 1; R/M, recurrent or metastatic; RR, regional recurrence; TL, target lesion.Setting of studyNumber of patients includedTumor typeHPD inclusion criteriaICI usedTotal no. of patient found to have HPD (%)Significant associationsSurvival outcomesRefsEarly-phase trials182HNSCC, gyn, lung, GI, GU, melanoma, sarcoma, endocrine, breast≥Twofold increase in TGR from pre-ICI to on-ICI scans and PDNot reported7%Not reportedMedian PFS significantly shorter in HPD[24.Pearson A.T. Sweis R.F. Hyperprogression-immunotherapy-related phenomenon vs intrinsic natural history of cancer.JAMA Oncol. 2019; 5: 743Crossref PubMed Scopus (5) Google Scholar]Phase I trials218Various tumor typesTwo-fold increase in TGR from pre-ICI to on-ICI scans and PDPD-(L)1 inhibitors9%Median increase in TGR of 20.7-foldNot reported[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]Phase I trials214Various tumor typesTTF <2 mo + minimum increase in TL 10 mm + either increase ≥40% in TL burden or increase ≥20% with additional new lesionsNot reported15%Not reportedMedian OS significantly shorter in HPD[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]Phase II trial (case series)3Adult T cell leukemia-lymphomaNot reportedNivolumab100%HTLV-1 levels increased 63.0- and 2.4-foldNot reported[21.Kinosada H. et al.HTLV-1 bZIP factor enhances T-cell proliferation by impeding the suppressive signaling of co-inhibitory receptors.PLoS Pathog. 2017; 13e1006120Crossref PubMed Scopus (31) Google Scholar]Retrospective220NSCLCVolume-based growth kineticsNot reported17%Not reportedMedian PFS significantly shorter in HPD[7.Kim Y. et al.Hyperprogression after immunotherapy: clinical implication and genomic alterations in advanced non-small cell lung cancer patients (NSCLC).J. Clin. Oncol. 2018; 36: 9075Crossref Google Scholar]Retrospective406NSCLCDifference in TGR >50% and PD on first evaluationNivolumab, pembrolizumab, atezolizumab, durvalumab13.8%>Two mets at baseline significantly associated with HPDNot reported[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]Retrospective155Melanoma, NSCLC, HNSCC, cutaneous SCC, RCC, CRC>50% increase in tumor burden compared with pre-ICI with <2 mo TTF, twofold increase progression rateCTLA-4, PD-(L)1, investigational agents4%MDM2/4 and EGFR significantly associated with HPD developmentNot reported[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]Retrospective (case series)5NSCLC, esophageal adenocarcinoma and SCC, RCC>Twofold increase in TGR, >50% increase in tumor size compared with pre-ICI, PD on first evaluationPembrolizumab, nivolumab100%MDM2/4, EGFR, and 11q13 amplifications detected in patients with HPDNot reported[9.Alqwasmi A. et al.1140PDPredictive biomarkers for hyper–progression (HP) in response to immune checkpoint inhibitors (ICI) – analysis of somatic alterations (SAs).Ann. Oncol. 2017; 28mdx376.006Google Scholar]Retrospective34R/M HNSCCTGKR ≥2PD-(L)1 inhibitors29%Not reportedMedian PFS significantly shorter, RR significantly associated with HPD[10.Saada-Bouzid E. et al.Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.Ann. Oncol. 2017; 28: 1605-1611Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar]Retrospective263R/M NSCLCTGK defined as change in sum of longest diameters (SLD) of target lesions according to RECIST 1.1 criteria per month; TGR defined as log-scale calibrated change in sum of volumes of target lesions according to RECIST 1.1 criteria per month; TTF <2 moPD-(L)1 inhibitorsTGK: 20.9%; TGR: 20.5%; TTF: 37.3%Lower CCR7-CD45RA– T cell:CD8+ T cell ratio; higher TIGIT+ T cell:PD-1+CD8+ T cell ratioPoorer survival rate in patients with HPD[11.Kim C.G. et al.Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.Ann. Oncol. 2019; 30: 1104-1113Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar]a Abbreviations: CTLA-4, cytotoxic T-lymphocyte associated protein-4; gyn, gynecologic; mets, metastatic sites; mo, months; PD-(L)1, programmed cell death (ligand) 1; R/M, recurrent or metastatic; RR, regional recurrence; TL, target lesion. Open table in a new tab TGR and TGKR [12.Le Tourneau C. et al.Tumour growth kinetics assessment: added value to RECIST in cancer patients treated with molecularly targeted agents.Br. J. Cancer. 2012; 106: 854-857Crossref PubMed Scopus (26) Google Scholar] were developed many years ago with the advent of targeted therapies. The first description of TGR was made based on a Phase I population by Gomez-Roca et al. [13.Gomez-Roca C. et al.Tumour growth rates and RECIST criteria in early drug development.Eur. J. Cancer. 2011; 47: 2512-2516Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar]. Here, 73 patients treated in Phase I clinical trials were evaluated with this method. An increased in TGR was observed in 20 (38%) of the 53 patients considered as nonprogressive at week 12 according to RECIST, and 12 out of 23 (53%) patients were classified as progressive according to RECIST with a decrease in TGR. The authors discussed the use of growth rate measured during the experimental period when it was significantly correlated with the evaluation of response according to RECIST criteria. However, the paper does not refer to the cut-off points used for HPD. The first attempt to combine TGR and RECIST was made by Ferté et al. [8.Ferté C. et al.Tumor growth rate is an early indicator of antitumor drug activity in phase I clinical trials.Clin. Cancer Res. 2014; 20: 246-252Crossref PubMed Scopus (94) Google Scholar], again in patients treated in Phase I clinical trials: 201 patients were assessed for TGR and RECIST, and 26% (N=51) were classified as PD, of which 35% showed an increase in TGR. In this cohort, an increase in the TGR did not correlate with the appearance of new lesions; in fact, 20 out of the 28 patients (71%) progressing with new lesions at the first tumor evaluation experienced simultaneously a decrease in TGR. Although the authors did not specify the TGR of each patient, in Figure 2 of [8.Ferté C. et al.Tumor growth rate is an early indicator of antitumor drug activity in phase I clinical trials.Clin. Cancer Res. 2014; 20: 246-252Crossref PubMed Scopus (94) Google Scholar] there were at least five patients with PD and TGR >2. Thus, it would be interesting to determine the cut-off point for HPD in this population. TGR was evaluated in patients with metastatic renal cell carcinoma treated in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) (sorafenib vs placebo) and Renal Cell cancer treatment with Oral RAD001 given Daily (RECORD) (everolimus vs placebo) Phase III trials. Higher TGR (first cycle) was associated with worse PFS (HR 3.61; 95% CI 2.45–5.34) and worse OS (HR 4.69; 95% CI 1.54–14.39), independently from the Motzer score and from the treatment arm in the entire TARGET cohort [14.Ferté C. et al.Tumor growth rate provides useful information to evaluate sorafenib and everolimus treatment in metastatic renal cell carcinoma patients: an integrated analysis of the TARGET and RECORD phase 3 trial data.Eur. Urol. 2014; 65: 713-720Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. Recently, in a control cohort with patients with NSCLC treated with chemotherapy, Ferrara et al. described a HPD rate of 14.2% (three of 21) (TGR >50%) in patients with PD as best response [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]. Finally, Matos et al. analyzed 180 patients treated in Phase I clinical trials with targeted agents for HPD using TGR (>2) and RECIST [15.Matos I. et al.Immune prognostic index (IPI) and hyper-progressive disease (HPD) in patients (pts) exposed to targeted agents (TAs) in phase I trials (Ph1T): Can lessons from immune checkpoint inhibitors (ICIs) be translated to other scenarios?.Ann. Oncol. 2018; 29mdy269.108Google Scholar]. Overall, 48 patients had PD as the best response and were evaluable for both criteria. The authors observed an HPD rate of 33% (12 out of 48 patients ) and 26% (ten out of 48 patients), respectively, with no difference in overall survival between the HPD group versus non-HPD progressors [15.Matos I. et al.Immune prognostic index (IPI) and hyper-progressive disease (HPD) in patients (pts) exposed to targeted agents (TAs) in phase I trials (Ph1T): Can lessons from immune checkpoint inhibitors (ICIs) be translated to other scenarios?.Ann. Oncol. 2018; 29mdy269.108Google Scholar]. Although HPD criteria can be met in patients on targeted agents, the lack of survival impact (which differs from internal and external cohorts exposed to ICIs) suggests that it is not a relevant clinical finding. Various groups have hypothesized mechanisms for HPD, including modulation of subpopulations of immunosuppressive cells and differing responses to antibody domains. There has also been evidence involving deleterious transcription factors. These mechanisms may act independently, in concert, or may be complementary. A study of 187 patients with NSCLC found 39 patients to have HPD by meeting the following inclusion criteria: (i) TTF <2 months; (ii) increase of ≥50% of target lesions; (iii) at least two new lesions in any previously involved organ; (iv) spread of disease to a different organ; and (v) clinical deterioration with a decline in performance status ≥2 points on the Eastern Cooperative Oncology Group scale within the first 2 months of treatment [16.Lo Russo G. et al.Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade.Clin. Cancer Res. 2019; 25: 989-999Crossref PubMed Scopus (174) Google Scholar]. Additionally, this study only included patients who had at least two cycles of IO and consequent HPD. All of the patients with HPD were found to have tumor infiltration by M2-like epithelioid macrophages. NSCLC tumor tissue from patients was transplanted in athymic nude or severe combined immunodeficient (SCID) mice [patient-derived xenografts (PDX)] that were subsequently treated with nivolumab or nivolumab F(ab)2 fragments, the latter lacking the Fc region of the antibodies. The authors found that both subsets of mice treated with nivolumab had a massive increase in the number of intratumoral macrophages and, consequently, HPD. Furthermore, this study found that tumor-associated macrophages (TAM) have the ability to express PD-1 and blocking it maintains the TAM anticancer effect [16.Lo Russo G. et al.Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade.Clin. Cancer Res. 2019; 25: 989-999Crossref PubMed Scopus (174) Google Scholar,17.Dahan R. et al.FcgammaRs modulate the anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis.Cancer Cell. 2015; 28: 285-295Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar]. However, in mice treated with nivolumab F(ab)2 fragments, there was no substantial tumor growth or HPD. Another experiment carried out by these authors assessed the role of EGFR on HPD in PDX SCID mice. In contrast to control mice with wild-type EGFR that responded to nivolumab, those mice with mutated versions of EGFR had significant increases in TGR and cancer cell dissemination (P=0.0286). To further support the hypothesis that the Fc portion of the antibody causes HPD, mice that had mutated EGFR PDX were treated with nivolumab F(ab)2 fragments, but showed no evidence of HPD or of cancer cell dissemination [16.Lo Russo G. et al.Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade.Clin. Cancer Res. 2019; 25: 989-999Crossref PubMed Scopus (174) Google Scholar]. Thus, this study provides insight into the complexity of the tum