Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate

Abstract

Purpose: Checkpoint inhibitors demonstrate salutary anticancer effects, including long-term remissions. PD-L1 expression/amplification, high mutational burden, and mismatch repair deficiency correlate with response. We have, however, observed a subset of patients who appear to be "hyperprogressors," with a greatly accelerated rate of tumor growth and clinical deterioration compared with pretherapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with "hyperprogression" after immunotherapy.Experimental Design: Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing were analyzed (N = 155). We defined hyperprogression as time-to-treatment failure (TTF) <2 months, >50% increase in tumor burden compared with preimmunotherapy imaging, and >2-fold increase in progression pace.Results: Amongst 155 patients, TTF <2 months was seen in all six individuals with MDM2/MDM4 amplification. After anti-PD1/PDL1 monotherapy, four of these patients showed remarkable increases in existing tumor size (55% to 258%), new large masses, and significantly accelerated progression pace (2.3-, 7.1-, 7.2- and 42.3-fold compared with the 2 months before immunotherapy). In multivariate analysis, MDM2/MDM4 and EGFR alterations correlated with TTF <2 months. Two of 10 patients with EGFR alterations were also hyperprogressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase).Conclusions: Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD-1/PD-L1) inhibitors. Genomic profiles may help to identify patients at risk for hyperprogression on immunotherapy. Further investigation is urgently needed. Clin Cancer Res; 23(15); 4242-50. ©2017 AACR.

Figure 1

Serial imaging before and after immunotherapy among patients with MDM2/4 amplifications (N=6). Baseline imaging refers to images about 2 months before immunotherapy. Pre-immunotherapy imaging refers to imaging immediately before immunotherapy. A. Case #1: Patient with bladder carcinoma. Tumor showed gradual progression over several months prior to atezolizumab. Restaging 1.9 months after atezolizumab showed a 258% increase in tumor size compared to pre-immunotherapy accompanied by a dramatic increase in PET FDG avidity and new liver masses. Follow up imaging 2.8 months after the initiation of atezolizumab confirmed the progression (imaging not shown) and the patient died soon afterwards. B. Case #2: Patient with triple-negative breast cancer. While receiving local therapy against brain metastases, left lung metastasis was overall stable. However 1.5 months after the initiation of pembrolizumab, a CT scan revealed a 55% increase of the left lung mass as well as new chest wall masses and lymphadenopathy. C. Case #3: Patient with endometrial stromal sarcoma. Patient had shown increase in tumor size and CA125 (11 to 33 U/mL) over six months. On 1.5 months of nivolumab, CT imaging demonstrated rapid progression of liver metastases and new bulky abdominal masses (overall 242% increase from pre-immunotherapy imaging) (upper panel). CA125 also increased from 33 to 1040 (U/mL) (lower panel). D. Case #4: Patient with adenocarcinoma of lung. Patient had gradual progression on Abraxane. Soon after starting pembrolizumab, patient noted severe fatigue/malaise, which prompted the physician to obtain repeat CT imaging. The scan showed rapid progression of known lung metastases (135% increase from pre-immunotherapy). E. Case #5: Patient with adenocarcinoma of lung. After first-line chemotherapy, imaging detected new lung disease. Patient was then started on pembrolizumab. However, patient noticed rapidly worsening shortness of breath and severe generalized fatigue. Although CT of the chest showed stable disease, patient was taken off therapy for clinical progression about 1.5 months after the initiation of pembrolizumab. Subsequent MRI of the brain showed multiple new brain metastases. F. Case #6: Patient with squamous cell carcinoma of the hypopharynx was treated with an OX40 agonist (third-line therapy). Within 1.4 months, patient was taken off study due to progressive altered mental status secondary to worsening hyponatremia attributed to tumor-associated SIADH. Imaging at the time was stable. The patient died three months later.

Figure 1

Serial imaging before and after immunotherapy among patients with MDM2/4 amplifications (N=6). Baseline imaging refers to images about 2 months before immunotherapy. Pre-immunotherapy imaging refers to imaging immediately before immunotherapy. A. Case #1: Patient with bladder carcinoma. Tumor showed gradual progression over several months prior to atezolizumab. Restaging 1.9 months after atezolizumab showed a 258% increase in tumor size compared to pre-immunotherapy accompanied by a dramatic increase in PET FDG avidity and new liver masses. Follow up imaging 2.8 months after the initiation of atezolizumab confirmed the progression (imaging not shown) and the patient died soon afterwards. B. Case #2: Patient with triple-negative breast cancer. While receiving local therapy against brain metastases, left lung metastasis was overall stable. However 1.5 months after the initiation of pembrolizumab, a CT scan revealed a 55% increase of the left lung mass as well as new chest wall masses and lymphadenopathy. C. Case #3: Patient with endometrial stromal sarcoma. Patient had shown increase in tumor size and CA125 (11 to 33 U/mL) over six months. On 1.5 months of nivolumab, CT imaging demonstrated rapid progression of liver metastases and new bulky abdominal masses (overall 242% increase from pre-immunotherapy imaging) (upper panel). CA125 also increased from 33 to 1040 (U/mL) (lower panel). D. Case #4: Patient with adenocarcinoma of lung. Patient had gradual progression on Abraxane. Soon after starting pembrolizumab, patient noted severe fatigue/malaise, which prompted the physician to obtain repeat CT imaging. The scan showed rapid progression of known lung metastases (135% increase from pre-immunotherapy). E. Case #5: Patient with adenocarcinoma of lung. After first-line chemotherapy, imaging detected new lung disease. Patient was then started on pembrolizumab. However, patient noticed rapidly worsening shortness of breath and severe generalized fatigue. Although CT of the chest showed stable disease, patient was taken off therapy for clinical progression about 1.5 months after the initiation of pembrolizumab. Subsequent MRI of the brain showed multiple new brain metastases. F. Case #6: Patient with squamous cell carcinoma of the hypopharynx was treated with an OX40 agonist (third-line therapy). Within 1.4 months, patient was taken off study due to progressive altered mental status secondary to worsening hyponatremia attributed to tumor-associated SIADH. Imaging at the time was stable. The patient died three months later.

Figure 1

Serial imaging before and after immunotherapy among patients with MDM2/4 amplifications (N=6). Baseline imaging refers to images about 2 months before immunotherapy. Pre-immunotherapy imaging refers to imaging immediately before immunotherapy. A. Case #1: Patient with bladder carcinoma. Tumor showed gradual progression over several months prior to atezolizumab. Restaging 1.9 months after atezolizumab showed a 258% increase in tumor size compared to pre-immunotherapy accompanied by a dramatic increase in PET FDG avidity and new liver masses. Follow up imaging 2.8 months after the initiation of atezolizumab confirmed the progression (imaging not shown) and the patient died soon afterwards. B. Case #2: Patient with triple-negative breast cancer. While receiving local therapy against brain metastases, left lung metastasis was overall stable. However 1.5 months after the initiation of pembrolizumab, a CT scan revealed a 55% increase of the left lung mass as well as new chest wall masses and lymphadenopathy. C. Case #3: Patient with endometrial stromal sarcoma. Patient had shown increase in tumor size and CA125 (11 to 33 U/mL) over six months. On 1.5 months of nivolumab, CT imaging demonstrated rapid progression of liver metastases and new bulky abdominal masses (overall 242% increase from pre-immunotherapy imaging) (upper panel). CA125 also increased from 33 to 1040 (U/mL) (lower panel). D. Case #4: Patient with adenocarcinoma of lung. Patient had gradual progression on Abraxane. Soon after starting pembrolizumab, patient noted severe fatigue/malaise, which prompted the physician to obtain repeat CT imaging. The scan showed rapid progression of known lung metastases (135% increase from pre-immunotherapy). E. Case #5: Patient with adenocarcinoma of lung. After first-line chemotherapy, imaging detected new lung disease. Patient was then started on pembrolizumab. However, patient noticed rapidly worsening shortness of breath and severe generalized fatigue. Although CT of the chest showed stable disease, patient was taken off therapy for clinical progression about 1.5 months after the initiation of pembrolizumab. Subsequent MRI of the brain showed multiple new brain metastases. F. Case #6: Patient with squamous cell carcinoma of the hypopharynx was treated with an OX40 agonist (third-line therapy). Within 1.4 months, patient was taken off study due to progressive altered mental status secondary to worsening hyponatremia attributed to tumor-associated SIADH. Imaging at the time was stable. The patient died three months later.

Figure 1

Serial imaging before and after immunotherapy among patients with MDM2/4 amplifications (N=6). Baseline imaging refers to images about 2 months before immunotherapy. Pre-immunotherapy imaging refers to imaging immediately before immunotherapy. A. Case #1: Patient with bladder carcinoma. Tumor showed gradual progression over several months prior to atezolizumab. Restaging 1.9 months after atezolizumab showed a 258% increase in tumor size compared to pre-immunotherapy accompanied by a dramatic increase in PET FDG avidity and new liver masses. Follow up imaging 2.8 months after the initiation of atezolizumab confirmed the progression (imaging not shown) and the patient died soon afterwards. B. Case #2: Patient with triple-negative breast cancer. While receiving local therapy against brain metastases, left lung metastasis was overall stable. However 1.5 months after the initiation of pembrolizumab, a CT scan revealed a 55% increase of the left lung mass as well as new chest wall masses and lymphadenopathy. C. Case #3: Patient with endometrial stromal sarcoma. Patient had shown increase in tumor size and CA125 (11 to 33 U/mL) over six months. On 1.5 months of nivolumab, CT imaging demonstrated rapid progression of liver metastases and new bulky abdominal masses (overall 242% increase from pre-immunotherapy imaging) (upper panel). CA125 also increased from 33 to 1040 (U/mL) (lower panel). D. Case #4: Patient with adenocarcinoma of lung. Patient had gradual progression on Abraxane. Soon after starting pembrolizumab, patient noted severe fatigue/malaise, which prompted the physician to obtain repeat CT imaging. The scan showed rapid progression of known lung metastases (135% increase from pre-immunotherapy). E. Case #5: Patient with adenocarcinoma of lung. After first-line chemotherapy, imaging detected new lung disease. Patient was then started on pembrolizumab. However, patient noticed rapidly worsening shortness of breath and severe generalized fatigue. Although CT of the chest showed stable disease, patient was taken off therapy for clinical progression about 1.5 months after the initiation of pembrolizumab. Subsequent MRI of the brain showed multiple new brain metastases. F. Case #6: Patient with squamous cell carcinoma of the hypopharynx was treated with an OX40 agonist (third-line therapy). Within 1.4 months, patient was taken off study due to progressive altered mental status secondary to worsening hyponatremia attributed to tumor-associated SIADH. Imaging at the time was stable. The patient died three months later.

Figure 1

Serial imaging before and after immunotherapy among patients with MDM2/4 amplifications (N=6). Baseline imaging refers to images about 2 months before immunotherapy. Pre-immunotherapy imaging refers to imaging immediately before immunotherapy. A. Case #1: Patient with bladder carcinoma. Tumor showed gradual progression over several months prior to atezolizumab. Restaging 1.9 months after atezolizumab showed a 258% increase in tumor size compared to pre-immunotherapy accompanied by a dramatic increase in PET FDG avidity and new liver masses. Follow up imaging 2.8 months after the initiation of atezolizumab confirmed the progression (imaging not shown) and the patient died soon afterwards. B. Case #2: Patient with triple-negative breast cancer. While receiving local therapy against brain metastases, left lung metastasis was overall stable. However 1.5 months after the initiation of pembrolizumab, a CT scan revealed a 55% increase of the left lung mass as well as new chest wall masses and lymphadenopathy. C. Case #3: Patient with endometrial stromal sarcoma. Patient had shown increase in tumor size and CA125 (11 to 33 U/mL) over six months. On 1.5 months of nivolumab, CT imaging demonstrated rapid progression of liver metastases and new bulky abdominal masses (overall 242% increase from pre-immunotherapy imaging) (upper panel). CA125 also increased from 33 to 1040 (U/mL) (lower panel). D. Case #4: Patient with adenocarcinoma of lung. Patient had gradual progression on Abraxane. Soon after starting pembrolizumab, patient noted severe fatigue/malaise, which prompted the physician to obtain repeat CT imaging. The scan showed rapid progression of known lung metastases (135% increase from pre-immunotherapy). E. Case #5: Patient with adenocarcinoma of lung. After first-line chemotherapy, imaging detected new lung disease. Patient was then started on pembrolizumab. However, patient noticed rapidly worsening shortness of breath and severe generalized fatigue. Although CT of the chest showed stable disease, patient was taken off therapy for clinical progression about 1.5 months after the initiation of pembrolizumab. Subsequent MRI of the brain showed multiple new brain metastases. F. Case #6: Patient with squamous cell carcinoma of the hypopharynx was treated with an OX40 agonist (third-line therapy). Within 1.4 months, patient was taken off study due to progressive altered mental status secondary to worsening hyponatremia attributed to tumor-associated SIADH. Imaging at the time was stable. The patient died three months later.

Figure 1

Serial imaging before and after immunotherapy among patients with MDM2/4 amplifications (N=6). Baseline imaging refers to images about 2 months before immunotherapy. Pre-immunotherapy imaging refers to imaging immediately before immunotherapy. A. Case #1: Patient with bladder carcinoma. Tumor showed gradual progression over several months prior to atezolizumab. Restaging 1.9 months after atezolizumab showed a 258% increase in tumor size compared to pre-immunotherapy accompanied by a dramatic increase in PET FDG avidity and new liver masses. Follow up imaging 2.8 months after the initiation of atezolizumab confirmed the progression (imaging not shown) and the patient died soon afterwards. B. Case #2: Patient with triple-negative breast cancer. While receiving local therapy against brain metastases, left lung metastasis was overall stable. However 1.5 months after the initiation of pembrolizumab, a CT scan revealed a 55% increase of the left lung mass as well as new chest wall masses and lymphadenopathy. C. Case #3: Patient with endometrial stromal sarcoma. Patient had shown increase in tumor size and CA125 (11 to 33 U/mL) over six months. On 1.5 months of nivolumab, CT imaging demonstrated rapid progression of liver metastases and new bulky abdominal masses (overall 242% increase from pre-immunotherapy imaging) (upper panel). CA125 also increased from 33 to 1040 (U/mL) (lower panel). D. Case #4: Patient with adenocarcinoma of lung. Patient had gradual progression on Abraxane. Soon after starting pembrolizumab, patient noted severe fatigue/malaise, which prompted the physician to obtain repeat CT imaging. The scan showed rapid progression of known lung metastases (135% increase from pre-immunotherapy). E. Case #5: Patient with adenocarcinoma of lung. After first-line chemotherapy, imaging detected new lung disease. Patient was then started on pembrolizumab. However, patient noticed rapidly worsening shortness of breath and severe generalized fatigue. Although CT of the chest showed stable disease, patient was taken off therapy for clinical progression about 1.5 months after the initiation of pembrolizumab. Subsequent MRI of the brain showed multiple new brain metastases. F. Case #6: Patient with squamous cell carcinoma of the hypopharynx was treated with an OX40 agonist (third-line therapy). Within 1.4 months, patient was taken off study due to progressive altered mental status secondary to worsening hyponatremia attributed to tumor-associated SIADH. Imaging at the time was stable. The patient died three months later.

Figure 1

Serial imaging before and after immunotherapy among patients with MDM2/4 amplifications (N=6). Baseline imaging refers to images about 2 months before immunotherapy. Pre-immunotherapy imaging refers to imaging immediately before immunotherapy. A. Case #1: Patient with bladder carcinoma. Tumor showed gradual progression over several months prior to atezolizumab. Restaging 1.9 months after atezolizumab showed a 258% increase in tumor size compared to pre-immunotherapy accompanied by a dramatic increase in PET FDG avidity and new liver masses. Follow up imaging 2.8 months after the initiation of atezolizumab confirmed the progression (imaging not shown) and the patient died soon afterwards. B. Case #2: Patient with triple-negative breast cancer. While receiving local therapy against brain metastases, left lung metastasis was overall stable. However 1.5 months after the initiation of pembrolizumab, a CT scan revealed a 55% increase of the left lung mass as well as new chest wall masses and lymphadenopathy. C. Case #3: Patient with endometrial stromal sarcoma. Patient had shown increase in tumor size and CA125 (11 to 33 U/mL) over six months. On 1.5 months of nivolumab, CT imaging demonstrated rapid progression of liver metastases and new bulky abdominal masses (overall 242% increase from pre-immunotherapy imaging) (upper panel). CA125 also increased from 33 to 1040 (U/mL) (lower panel). D. Case #4: Patient with adenocarcinoma of lung. Patient had gradual progression on Abraxane. Soon after starting pembrolizumab, patient noted severe fatigue/malaise, which prompted the physician to obtain repeat CT imaging. The scan showed rapid progression of known lung metastases (135% increase from pre-immunotherapy). E. Case #5: Patient with adenocarcinoma of lung. After first-line chemotherapy, imaging detected new lung disease. Patient was then started on pembrolizumab. However, patient noticed rapidly worsening shortness of breath and severe generalized fatigue. Although CT of the chest showed stable disease, patient was taken off therapy for clinical progression about 1.5 months after the initiation of pembrolizumab. Subsequent MRI of the brain showed multiple new brain metastases. F. Case #6: Patient with squamous cell carcinoma of the hypopharynx was treated with an OX40 agonist (third-line therapy). Within 1.4 months, patient was taken off study due to progressive altered mental status secondary to worsening hyponatremia attributed to tumor-associated SIADH. Imaging at the time was stable. The patient died three months later.

Figure 2

Rate of change in growth pattern in four cases with MDM2 amplification that progressed rapidly while on immunotherapy. Rate of progression is compared from about 2 months prior to immunotherapy (baseline) to image immediately before immunotherapy (pre-immunotherapy), and then to first imaging after immunotherapy. Percent change was evaluated with immune-related response criteria (18). Case #1: Pre-immunotherapy imaging showed ~36% increase in size of tumors when compared to baseline imaging. After immunotherapy, tumor progressed with 390% increase in lesions when compared to baseline imaging (258% increase from pre-immunotherapy) (7.2-fold increase in progression pace compared to ~2 months before immunotherapy). New liver masses also appeared. Case #2: Pre-immunotherapy imaging showed 1.3% increase in size of tumors when compared to baseline imaging. After immunotherapy, tumor progressed with 56% increase when compared to baseline imaging (55% increase from pre-immunotherapy) (42.3-fold increase in pace of progression compared to the ~2 months before immunotherapy). New masses also appeared. Case #3: Pre-immunotherapy imaging showed 106% increase in size of tumors when compared to baseline imaging. After immunotherapy, patient’s tumor progressed with 563% increase compared to baseline (242% increase compared to pre-immunotherapy) (~2.3 fold increase in rate of progression compared to the 2 months before immunotherapy). Multiple new large masses were seen. Case #4: Pre-immunotherapy imaging showed a 19% increase in size of tumors when compared to baseline imaging. After immunotherapy, patient’s tumor progressed with 181% increase from baseline imaging (135% increase from pre-immunotherapy) (7.1-fold increase in progression pace compared to 2 months before therapy).