Real-World Pseudoprogression: an Uncommon Phenomenon
Authors: Karen L. Reckamp
Journal: Journal of Thoracic Oncology (2018)

In NSCLC, treatment with programmed cell death 1 (PD-1) and programmed death ligand 1 inhibitors has demonstrated improved survival over standard chemotherapy.1Reck M. Rodriguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (6211) Google Scholar, 2Herbst R.S. Baas P. Kim D.W. et al.Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.Lancet. 2016; 387: 1540-1550Abstract Full Text Full Text PDF PubMed Scopus (4546) Google Scholar, 3Brahmer J. Reckamp K.L. Baas P. et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.N Engl J Med. 2015; 373: 123-135Crossref PubMed Scopus (6233) Google Scholar, 4Borghaei H. Paz-Ares L. Horn L. et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med. 2015; 373: 1627-1639Crossref PubMed Scopus (6769) Google Scholar, 5Rittmeyer A. Barlesi F. Waterkamp D. et al.Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.Lancet. 2017; 389: 255-265Abstract Full Text Full Text PDF PubMed Scopus (3163) Google Scholar When single-agent checkpoint inhibition is used for advanced NSCLC and patients are selected for high (≥50%) expression of programmed death ligand 1, response rates remain less than 50% (44.8%) by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 (RECIST 1.1).1Reck M. Rodriguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (6211) Google Scholar It is also important to note that in the first-line trial, the median time to response was the same for pembrolizumab and chemotherapy at 2.2 months. Therefore, most patients do not experience tumor response according to RECIST and are likely to discontinue therapy early in the course of treatment. Unconventional responses, including pseudoprogression, hyperprogression, and clinical benefit without tumor response, are seen. Because of the nature of immune checkpoint inhibition, activation of the immune system and tumor response may be delayed. This delay has led to challenges for clinicians in understanding when to discontinue therapy that may have future benefit. Pseudoprogression has been described as an initial increase in a tumor (either the primary lesion or new lesions), with a subsequent response with possible immune cell infiltrates within the growing lesion. Pseudoprogression associated with checkpoint inhibitor therapy was first described in melanoma with the use of cytotoxic T-lymphocyte associated protein 4 inhibitors, leading to the use of immune-related response criteria (iRRC).6Wolchok J.D. Hoos A. O'Day S. et al.Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.Clin Cancer Res. 2009; 15: 7412-7420Crossref PubMed Scopus (2502) Google Scholar, 7Hodi F.S. Hwu W.J. Kefford R. et al.Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab.J Clin Oncol. 2016; 34: 1510-1517Crossref PubMed Scopus (519) Google Scholar Four response patterns associated with survival benefit were described: (1) shrinkage of baseline tumors without new lesions, (2) durable stable disease, (3) an increase in tumor burden followed by response, and (4) a response in the presence of new lesions.6Wolchok J.D. Hoos A. O'Day S. et al.Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.Clin Cancer Res. 2009; 15: 7412-7420Crossref PubMed Scopus (2502) Google Scholar Additional immune-based criteria to account for immune-specific patterns of response have been described and refined.8Nishino M. Giobbie-Hurder A. Gargano M. Suda M. Ramaiya N.H. Hodi F.S. Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements.Clin Cancer Res. 2013; 19: 3936-3943Crossref PubMed Scopus (360) Google Scholar, 9Seymour L. Bogaerts J. Perrone A. et al.iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.Lancet Oncol. 2017; 18: e143-e152Abstract Full Text Full Text PDF PubMed Scopus (1171) Google Scholar The consistent requirement across immune-based response criteria includes reevaluation of new lesions and confirmation of progressive disease (Table 16Wolchok J.D. Hoos A. O'Day S. et al.Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.Clin Cancer Res. 2009; 15: 7412-7420Crossref PubMed Scopus (2502) Google Scholar, 9Seymour L. Bogaerts J. Perrone A. et al.iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.Lancet Oncol. 2017; 18: e143-e152Abstract Full Text Full Text PDF PubMed Scopus (1171) Google Scholar, 10Eisenhauer E.A. Therasse P. Bogaerts J. et al.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer. 2009; 45: 228-247Abstract Full Text Full Text PDF PubMed Scopus (18111) Google Scholar). Pseudoprogression has been described across tumor types treated with immune checkpoint inhibitor therapy, with lower rates in solid tumors than those seen in melanoma.11Chiou V.L. Burotto M. Pseudoprogression and immune-related response in solid tumors.J Clin Oncol. 2015; 33: 3541-3543Crossref PubMed Scopus (584) Google ScholarTable 1Immune-based Response Criteria Compared with RECIST 1.1CriteriaCRPRStable DiseasePDRECIST 1.110Eisenhauer E.A. Therasse P. Bogaerts J. et al.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer. 2009; 45: 228-247Abstract Full Text Full Text PDF PubMed Scopus (18111) Google ScholarDisappearance of all target lesionsDecrease in target lesions of ≥30%Not meeting criteria for CR, PR, or PDIncrease in target lesions of ≥20%. Nontarget lesions require unequivocal progression if target lesion growth is <20%iRRC6Wolchok J.D. Hoos A. O'Day S. et al.Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.Clin Cancer Res. 2009; 15: 7412-7420Crossref PubMed Scopus (2502) Google ScholarDisappearance of all lesions (measurable and nonmeasurable) with consecutive assessment ≥4 wk from first documented CRDecrease in tumor burden of ≥50% relative to baseline that is confirmed with consecutive assessment ≥4 wk from first documented PRNot meeting the criteria for irCR or irPR in the absence of irPDIncrease in tumor burden of ≥25% relative to nadirDifference from RECIST 1.1 regardless of new lesionsDifference from RECIST 1.1 regardless of new lesionsDifference from RECIST 1.1 requires confirmation with consecutive assessment ≥4 wk from first documented PD; not considered irPD if new lesions are present and increase in baseline is <25%iRECIST9Seymour L. Bogaerts J. Perrone A. et al.iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.Lancet Oncol. 2017; 18: e143-e152Abstract Full Text Full Text PDF PubMed Scopus (1171) Google ScholarAs per RECIST 1.1, but patient may have had iUPD and new lesions must be confirmedAs per RECIST 1.1, but patients may have had iUPD and new lesions must be confirmedAs per RECIST 1.1, but patient may have had iUPD and new lesions must be confirmedAs per RECIST 1.1, except that confirmation is required ≥4 wk from first documented iUPD to determine iCPDRECIST 1.1, Response Evaluation Criteria in Solid Tumors version 1.1; CR, complete response; PR, partial response; PD, progressive disease; iRRC, immune-related response criteria; irCR, immune-related complete response; irPR, immune-related partial response; irPD, immune-related progressive disease; iRECICST, immune RECIST; iUPD, immune-unconfirmed progressive disease; iCPD, immune-confirmed progressive disease. Open table in a new tab RECIST 1.1, Response Evaluation Criteria in Solid Tumors version 1.1; CR, complete response; PR, partial response; PD, progressive disease; iRRC, immune-related response criteria; irCR, immune-related complete response; irPR, immune-related partial response; irPD, immune-related progressive disease; iRECICST, immune RECIST; iUPD, immune-unconfirmed progressive disease; iCPD, immune-confirmed progressive disease. In this issue of the Journal of Thoracic Oncology, Katz et al.12Katz S.I. Hammer M. Bagley S.J. et al.Radiologic pseudoprogression during anti–PD-1 therapy for advanced non-small cell lung cancer.J Thorac Oncol. 2018; 13: 978-986Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar offer an assessment of pseudoprogression in patients treated with anti–PD-1 therapy for NSCLC by RECIST 1.1,10Eisenhauer E.A. Therasse P. Bogaerts J. et al.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer. 2009; 45: 228-247Abstract Full Text Full Text PDF PubMed Scopus (18111) Google Scholar unidimensional iRRC,8Nishino M. Giobbie-Hurder A. Gargano M. Suda M. Ramaiya N.H. Hodi F.S. Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements.Clin Cancer Res. 2013; 19: 3936-3943Crossref PubMed Scopus (360) Google Scholar and immune RECIST (iRECIST)9Seymour L. Bogaerts J. Perrone A. et al.iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.Lancet Oncol. 2017; 18: e143-e152Abstract Full Text Full Text PDF PubMed Scopus (1171) Google Scholar to provide observations about real-world clinical practice. This retrospective analysis included patients who received nivolumab or pembrolizumab monotherapy as second-line or later therapy. In the analysis, 15 patients (9%) were clinically suspected to have pseudoprogression on the basis of radiographic findings of tumor enlargement or new lesions on first computed tomography imaging during therapy and they continued to receive anti–programmed cell death 1 therapy. Each of these patients had imaging evaluated by RECIST 1.1, unidimensional iRRC, and iRECIST. Notably, the patients were initially assessed clinically, and upon radiologic review, only three patients (2%) had evidence of radiologic pseudoprogression. This discrepancy in numbers highlights the experience in clinical practice, in which many patients are not assessed by RECIST, and the phenomenon of pseudoprogression in the general population may be inflated. The group performed a RECIST 1.1 assessment on 166 patients who were treated with immunotherapy and met the eligibility criteria; thus, the numbers represent a detailed investigation of pseudoprogression in NSCLC and provide insights into the uncommon event. The results are consistent with those of other retrospective studies in NSCLC. An assessment of 56 patients with NSCLC who were treated with nivolumab did not identify any cases of pseudoprogression when the patients were evaluated by RECIST 1.1 and immune-related RECIST.13Nishino M. Pseudoprogression and measurement variability.J Clin Oncol. 2016; 34: 3480-3481Crossref PubMed Scopus (10) Google Scholar In a study that compared RECIST 1.1 with iRRC in 41 patients with NSCLC who received immune checkpoint inhibition, two patients exhibited pseudoprogression.14Kim H.K. Heo M.H. Lee H.S. et al.Comparison of RECIST to immune-related response criteria in patients with non-small cell lung cancer treated with immune-checkpoint inhibitors.Cancer Chemother Pharmacol. 2017; 80: 591-598Crossref PubMed Scopus (41) Google Scholar Some limitations of this retrospective study include the relatively small sample size owing to the rarity of pseudoprogression. The method used to identify patients within the medical record and lack of information about patients who may have discontinued therapy because of toxicity and may have experienced a response at a later time decreased the ability to generalize the results. Furthermore, the analysis is largely based on patients who received second-line or later therapy with nivolumab and a small proportion who received second-line or later therapy with pembrolizumab. Similar to what occurred with the use of pembrolizumab in the first-line setting, the median time to response in the second-line and beyond was approximately 2 months in the phase 3 trials, with lower response rates of 18% to 20%.2Herbst R.S. Baas P. Kim D.W. et al.Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.Lancet. 2016; 387: 1540-1550Abstract Full Text Full Text PDF PubMed Scopus (4546) Google Scholar, 3Brahmer J. Reckamp K.L. Baas P. et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.N Engl J Med. 2015; 373: 123-135Crossref PubMed Scopus (6233) Google Scholar, 4Borghaei H. Paz-Ares L. Horn L. et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med. 2015; 373: 1627-1639Crossref PubMed Scopus (6769) Google Scholar This confirms that most patients will experience development of true progression and anti–PD-1 therapy will be appropriately discontinued. The field is rapidly evolving to include PD-1 inhibition in the frontline setting alone or as part of combination therapy, which is not considered in the cohort of Katz et al.12Katz S.I. Hammer M. Bagley S.J. et al.Radiologic pseudoprogression during anti–PD-1 therapy for advanced non-small cell lung cancer.J Thorac Oncol. 2018; 13: 978-986Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Despite its limitations, the study by Katz et al.12Katz S.I. Hammer M. Bagley S.J. et al.Radiologic pseudoprogression during anti–PD-1 therapy for advanced non-small cell lung cancer.J Thorac Oncol. 2018; 13: 978-986Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar reminds clinicians that pseudoprogression is a rare event and true progression is most likely when new and growing lesions are seen on imaging. Clinical assessment and toxicity evaluation are also required when a patient experiences an atypical response to immunotherapy. Much of the research on pseudoprogression after immune checkpoint inhibitor therapy describes pseudoprogression in advanced melanoma, and application of iRRC and iRECIST criteria can identify patients who are likely to benefit from continuing therapy but requires repeat, confirmatory imaging. Increased use of liquid biopsies may also assist in identifying pseudoprogression, allowing patients who may benefit from immunotherapy to continue receiving treatment. A recent study assessed circulating tumor DNA (ctDNA) from 29 patients with melanoma with BRAF or NRAS mutation and progressive disease during checkpoint inhibitor therapy.15Lee J.H. Long G.V. Menzies A.M. et al.Association between circulating tumor DNA and pseudoprogression in patients with metastatic melanoma treated with anti-programmed cell death 1 antibodies.JAMA Oncol. 2018; : e175332Google Scholar The study found that nine patients had pseudoprogression as defined by iRRC and all had an undetectable or reduced ctDNA level by week 12. In all, 20 patients experienced true progression and 90% had a ctDNA level that remained stable or increased. These data provide evidence that determination of ctDNA may be a method to assist in early evaluation of unconventional responses to immunotherapy. Prospective studies are needed to understand the significance of pseudoprogression in NSCLC and solid tumors. A small subset of patients will experience development of a response to therapy that is not accurately assessed by RECIST 1.1, and the various immune-related response criteria can be helpful in identifying these patients. Furthermore, when response assessments are made in the clinic, pseudoprogression may appear more common despite actual tumor progression, leading to continuation of therapy without benefit. Confirmation imaging is currently recommended to assess for pseudoprogression, but in clinical practice, delaying the first assessment to week12 may mitigate against seeing the phenomenon. Immune-related toxicities or genomic alterations may provide insight into unconventional responses to immune checkpoint inhibitor therapy. Additional insight into tumor response has been demonstrated with neoadjuvant nivolumab in patients with resectable NSCLC.16Forde P.M. Chaft J.E. Smith K.N. et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med. 2018; 378: 1976-1986Crossref PubMed Scopus (1024) Google Scholar Despite tumor growth that was evident on imaging, immune infiltrate was seen in the resected tumor with a major pathologic response. Furthermore, a higher tumor mutational burden was seen in those with a major pathologic response, and neoantigen-specific T-cell clones could be expanded in a patient with a complete pathologic response. As immunotherapy moves into the frontline setting for NSCLC and combination therapies are explored, understanding surrogates for clinical benefit should lead to more appropriate therapy for all patients. Work supported by the National Cancer Institute of the National Institutes of Health under award number P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Massey/Clark Lung Cancer Research Fund, and the STOP Cancer Carrie Scott Seed Grant. Radiologic Pseudoprogression during Anti–PD-1 Therapy for Advanced Non–Small Cell Lung CancerJournal of Thoracic OncologyVol. 13Issue 7PreviewAnti–programmed cell death protein 1 (PD-1) therapy can lead to unconventional tumor responses, including radiologic pseudoprogression. Here we have determined the real-world incidence of radiologic pseudoprogression in advanced NSCLC and compared radiologic response criteria for assessment of disease response. Full-Text PDF Open Archive