Molecular alterations with hyperprogression in lung cancer patients treated with immune checkpoint inhibitors in a large health system.

e15082 Background: Immune checkpoint inhibitor (ICI) therapy has become a mainstay of lung cancer treatment. However, not all NSCLC patients (pts) benefit, a subset paradoxically experience accelerated tumor growth while on immunotherapy. Hyperprogression (HP) refers to accelerated tumor growth on ICI with worsening clinical status. Various molecular alterations may be associated with HP including MDM2/MDM4 amplifications, EGFR aberrations, and STK11/LKB1 mutations. Kato et al. ( http://ow.ly/2n8a30nQpZv ) showed HP in 6/6 pts with MDM2/MDM4 amplification and in 2/10 pts with EGFR alterations. Methods: Lung cancer pts treated with ICI from Jan 2017 to Jan 2019 at Aurora Health Care were reviewed after IRB approved. Pts with NSCLC histology (ICD diagnosis codes and / or manual chart review), ICI treatment, and molecular testing were identified via the real world data (RWD) integrated in the Syapse platform. Additional chart review to ascertain HP was performed, and molecular results obtained via Syapse molecular lab integrations were analyzed. Pts had various forms of real world biomarker testing including oligo NGS panels. HP is defined as: 1) time-to-treatment failure (TTF) < 2 months (time from the start of treatment with ICI to ICI discontinuation for any reason, including progression, patient preference, toxicity, or death), 2) > 50% increase in tumor burden by RECIST, 3) spread of the disease to a new organ between baseline and first radiologic evaluation or clinical deterioration, and 4) ECOG PS ≥2 during the first 2 months of treatment. HP > = 3, Progression 1-2, non-progressor 0 criteria fulfilled.Pts with and without HP were compared using Chi-squared and Fisher Exact tests. T-tests were performed for continuous variables. Results: Out of 1536 lung cancer patients 350 (22.8%) were treated with ICI including: atezolizumab (35), durvalumab (6), nivolumab (177), pembrolizumab (145). Some pts were treated with more than one ICI. 64/350 (18.2%) pts had HP. 79/350 (22.5%) pts had progressive disease without meeting the definition of HP. Biomarker associations with HP are shown in the table. Conclusions: Only the STK11/LKB1 mutation was associated with HP (P = < 0.0001) with 5 of 6 STK11 pts treated with ICI showing HP. Other potential HP biomarkers will be assessed prospectively as larger panels are utilized. [Table: see text]

Download Full-text

Genomic markers associated with hyperprogression in patients with lung cancer treated with immune checkpoint inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9105 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9105-9105

Author(s):

Eyob ale Tadesse ◽

Kayla Heslin ◽

Mohamed Hendawi ◽

Luke Peterson ◽

Frank M. Wolf ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Growth ◽

Immune Checkpoint ◽

Chart Review ◽

Checkpoint Inhibitors ◽

Clinical Status ◽

Molecular Testing ◽

Continuous Variables ◽

Real World Data ◽

Gene Alterations

9105 Background: Immune checkpoint inhibitor (ICI) therapy has become a mainstay of non-small cell lung cancer (NSCLC) treatment. However, not all patients (pts) benefit with a subset paradoxically experiencing accelerated tumor growth while on ICI. Hyperprogression (HP) refers to accelerated tumor growth on ICI with worsening clinical status. Various gene alterations may be associated with HP including MDM2/MDM4 amplifications, EGFR alterations, and STK11/LKB1 mutations. Kato et al. (doi: 10.1158/1078-0432.CCR-16-3133 ) showed HP in 6/6 pts with MDM2/MDM4 amplification and in 2/10 pts with EGFR alterations. This report describes HP in pts with NSCLC treated with ICIs in a large health system. Methods: Pts with NSCLC treated with ICIs from Jan 2012 to Jan 2021 at Advocate Aurora Health were reviewed after IRB approval. Pts with NSCLC histology (ICD diagnosis codes and/or manual chart review), ICI treatment, and molecular testing were identified via the real world data integrated within the Syapse Learning Health Network platform. Additional chart review to ascertain HP was performed, and molecular results were analyzed. HP criteria include: 1) time-to-treatment failure < 2 months (from start to discontinuation of ICI for any reason), 2) > 50% increase in tumor burden by RECIST, 3) spread of the disease to a new organ between baseline and first radiologic evaluation or clinical deterioration, and 4) ECOG PS ≥ 2 during the first 2 months of treatment. Based on the number of criteria fulfilled, HP = > 3, Progression = 1-2, and non-progressor = 0. Pts with and without HP were compared using Chi-squared and Fisher Exact tests. T-tests were performed for continuous variables. Results: Out of 7,078 NSCLC pts, 1,389 (20%) were treated with ICI including atezolizumab (40 pts, 3%), durvalumab (17 pts, 1%), nivolumab (167 pts, 12%), pembrolizumab (190 pts, 14%), and multiple ICIs (12 pts, 1%). Of those pts treated with ICIs, molecular testing was performed in 427 (31%). 98 of 427 pts (23%)had HP and an additional 86 pts (20%) had progressive disease without meeting the definition of HP. Biomarker associations with HP are shown in the table. By tumor gene alterations, HP was seen in pts with: EGFR (20/60), STK11/LKB1 (16/25); and MDM2/4 (4/7). Conclusions: EGFR, STK11/LKB1, and MDM2/4 gene alterations were all statistically significantly associated with HP. Clinical and molecular predictors of HP need to be explored in order to optimize selection of pts for ICI therapy.[Table: see text]

Download Full-text

804 Real-world incidence and impact of pneumonitis in lung cancer patients treated with immune checkpoint inhibitors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.804 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A841-A841

Author(s):

Bruce Tiu ◽

Leyre Zubiri ◽

James Iheke ◽

Vartan Pahalyants ◽

Nicholas Theodosakis ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Clinical Oncology ◽

Healthcare Utilization ◽

Real World ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Drug Induced ◽

Lung Cancer Patients

BackgroundImmune checkpoint inhibitors (ICI) generate T-cell mediated anti-tumor responses that are effective across numerous malignancies, but their use is frequently complicated by immune-related adverse events (irAEs). irAEs may lead to treatment delays, need for immunosuppression, morbidity, and even mortality.1–3Checkpoint inhibitor pneumonitis (CIP) is the most common cause of fatality related to anti-programmed cell death receptor/ligand 1 (PD-1/PD-L1) agents, and can be difficult to diagnose.3 We aimed to characterize the real-world incidence and management of CIP, as well as its impact on clinical course and healthcare utilization, in a large cohort of ICI patients using a multi-institutional database.MethodsPropensity score-matched cohorts of 14,461 lung cancer patients who did or did not receive PD-1/PD-L1 inhibitors between 2014 to 2021 were identified from TriNetX Dataworks, a database of health records and claims data from over 40 institutions. Incidence of pneumonia/pneumonitis was estimated using billing codes. A subgroup of 158 patients was selected by the most specific code group and confirmed to have features consistent with suspected CIP, permitting analysis of management practices and outcomes. To describe differences in healthcare utilization and survival, a second propensity score-matched cohort was generated for the subgroup.ResultsThe attributable risk of pneumonitis to PD-1/PD-L1 inhibitors in lung cancer at 1 year after ICI initiation was 6.88% (95% CI 6.01–7.75%). Median time to onset of drug-induced pneumonitis in the subgroup was 4.4 months (IQR 2.1–7.8 months). Of 158 patients, 21 (13.3%) underwent bronchoscopy within 30 days after diagnosis. Prednisone (130/158, 82.3%), methylprednisolone (80/158, 50.6%), and antibiotics (135/158, 85.4%) were frequently prescribed. ICI was discontinued in 69.5% of patients within 90 days of drug-induced pneumonitis. Within the first year of PD-1/PD-L1 therapy, patients with pneumonitis had more hospitalizations (83.5% vs 49.4%, RR 1.69, p<0.0001) and ICU requirements than controls (28.5% vs 8.9%, RR 3.21, p<0.0001). Landmark analysis at 6 months demonstrated that CIP associated with reduced overall survival, with a mortality HR of 1.43 (95% CI 1.03–1.97, p=0.03).ConclusionsTo our knowledge, this is the largest study of CIP to date. Importantly, the study found that the incidence of PD-1/PD-L1-induced pneumonitis, 6.88%, is higher than clinical trial estimates (2–5%), but lower than reported in uncontrolled real-world studies (17–19%).4–8 CIP had significant negative impacts on therapy continuation, healthcare utilization, and overall survival in lung cancer. This work demonstrates proof of concept that studies of irAE incidences and patient outcomes are feasible using large claims and electronic health record databases.ReferencesBrahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline. Journal of Clinical Oncology 2018;36(17):1714–1768. doi:10.1200/JCO.2017.77.6385.Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. Journal for ImmunoTherapy of Cancer 2017;5(1):95. doi:10.1186/s40425-017-0300-z.Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncology 2018;4(12):1721–1728. doi:10.1001/jamaoncol.2018.3923.Nishino M, Giobbie-Hurder A, Hatabu H, Ramaiya NH, Hodi FS. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer a systematic review and meta-analysis. JAMA Oncology 2016;2(12):1607–1616. doi:10.1001/jamaoncol.2016.2453.Naidoo J, Wang X, Woo KM, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. Journal of Clinical Oncology 2017;35(7):709–717. doi:10.1200/JCO.2016.68.2005.Delaunay M, Cadranel J, Lusque A, et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. European Respiratory Journal 2017;50(2). doi:10.1183/13993003.00050-2017.Suresh K, Voong KR, Shankar B, et al. Pneumonitis in non–small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors. Journal of Thoracic Oncology 2018;13(12):1930–1939. doi:10.1016/j.jtho.2018.08.2035.Cathcart-Rake EJ, Sangaralingham LR, Henk HJ, Shah ND, Riaz I bin, Mansfield AS. A population-based study of immunotherapy-related toxicities in lung cancer. Clinical Lung Cancer 2020;21(5):421–427.e2. doi:10.1016/j.cllc.2020.04.003Ethics ApprovalAs described on TriNetX's website (https://trinetx.com/trinetx-publication-guidelines/), all data available on the network is de-identified and in-line with HIPAA Privacy Rule standards.

Download Full-text

Prognostic impact of primary cancer adjoining emphysematous bullae in non-small cell lung cancer patients treated with immune checkpoint inhibitors

Cancer Immunology Immunotherapy ◽

10.1007/s00262-020-02783-6 ◽

2021 ◽

Author(s):

Shinkichi Takamori ◽

Kazuki Takada ◽

Mototsugu Shimokawa ◽

Mikako Jinnnouchi ◽

Taichi Matsubara ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Prognostic Impact ◽

Primary Cancer ◽

Small Cell Lung ◽

Lung Cancer Patients

Download Full-text

Higher CD4/CD8 ratio of pleural effusion predicts better survival for lung cancer patients receiving immune checkpoint inhibitors

Scientific Reports ◽

10.1038/s41598-021-89043-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Po-Hsin Lee ◽

Tsung-Ying Yang ◽

Kun-Chieh Chen ◽

Yen-Hsiang Huang ◽

Jeng-Sen Tseng ◽

...

Keyword(s):

Lung Cancer ◽

Pleural Effusion ◽

Cancer Patients ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Lung Cancer Patients ◽

Predicting Factor ◽

Type 3

AbstractPleural effusion is a rare immune-related adverse event for lung cancer patients receiving immune checkpoint inhibitors (ICIs). We enrolled 281 lung cancer patients treated with ICIs and 17 were analyzed. We categorized the formation of pleural effusion into 3 patterns: type 1, rapid and massive; type 2, slow and indolent; and type 3, with disease progression. CD4/CD8 ratio of 1.93 was selected as the cutoff threshold to predict survival. Most patients of types 1 and 2 effusions possessed pleural effusion with CD4/CD8 ratios ≥ 1.93. The median OS time in type 1, 2, and 3 patients were not reached, 24.8, and 2.6 months, respectively. The median PFS time in type 1, 2, and 3 patients were 35.5, 30.2, and 1.4 months, respectively. The median OS for the group with pleural effusion CD4/CD8 ≥ 1.93 and < 1.93 were not reached and 2.6 months. The median PFS of those with pleural effusion CD4/CD8 ≥ 1.93 and < 1.93 were 18.4 and 1.2 months. In conclusion, patients with type 1 and 2 effusion patterns had better survival than those with type 3. Type 1 might be interpreted as pseudoprogression of malignant pleural effusion. CD4/CD8 ratio ≥ 1.93 in pleural effusion is a good predicting factor for PFS.

Download Full-text