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Incidence of Pneumonitis in Metastatic Lung Cancer Patients Receiving Immune Checkpoint Inhibitors With or Without Thoracic Radiation Therapy
S150
International Journal of Radiation Oncology Biology Physics
available, the future of individualized treatment planning will require integration of genomic data and tissue-specific information. In preparation for this, we set out to establish methods to integrate tissue specific expression with genomic datasets and define the role of tissue specificity in cancer. We hypothesized that genome-wide association studies (GWAS) cancer variants affect genes that are specific to the tissue of the respective cancer type through gene expression regulation. In addition, we aimed to leverage this tissue-specificity to identify genes with prognostic utility for specific cancers. Materials/Methods: We used the Genotype-Tissue Expression (GTEx) dataset to identify tissue-specific genes for 13 tissues with associated cancers. We then assessed whether these tissue-specific genes were in closer proximity to GWAS variants of the respective tissue-associated cancer, obtained from the NIH GRASP database. We calculated significance using a permutation approach accounting for linkage disequilibrium. To evaluate whether the GWAS variants associated with tissue-specific genes via gene expression regulation, we analyzed the association between alleles and expression levels in non-cancer individuals using the GTEx dataset. Finally, we identified examples of tissue-specific genes that associate with survival in TCGA datasets using univariate and multivariate Cox regression. P-values were two-tailed with adjustment for multiple testing. Results: We identified a ranked list of tissue-specific genes for 13 tissues with solid tumor cancers. Highly significant GWAS variants (P 8) lie in closer proximity to the top 500 expressed tissue-specific genes compared to a randomly permuted set (P < 0.001). We found that several of these GWAS variants also associate with the expression of a tissue-specific gene, including a variant that is w117k base pairs away from gene HLA-V in lung cancer (P Z 0.0003). Finally, using a TCGA lung adenocarcinoma dataset (LUAD), we found that the expression of tissue-specific genes associates with survival, and created an indicator that predicted a median survival difference of 41 months (P < 0.0001). Conclusion: We identified that GWAS variants of specific cancer types are enriched near tissue-specific genes and are likely to be driving their gene expression regulation. We also found that tissue-specific genes may be used to prognosticate lung cancer survival, and with further clinical validation, these identified genes may serve to individualize cancer treatments. Author Disclosure: M.S. Binkley: None. R. Kita: None.
Results: The distribution of lung cancer histology in this study was 95% NSCLC and 5% SCLC. Baseline characteristics, including median age (65 vs 63 years), gender (58 vs 56% male), smoking status (88 vs 86%), supplemental oxygen requirement (12% vs 10%), median number of chemotherapy lines prior to ICI (1 vs 1), median number of ICI cycles (5 vs 3), and median follow-up after ICI initiation (8 vs 7 months), were comparable in the +TRT (73 patients) and -TRT (91 patients) groups. The +TRT cohort featured significantly less adenocarcinomas (49 vs 75%, P Z 0.001) and targetable mutations (4 vs 17%, P Z 0.012) than the -TRT group. Rates of all-grade pneumonitis (8.2 vs 5.5%, P Z 0.54) and grade 2 pneumonitis (4.1 vs 3.3%, P Z 1) were not significantly different between the +TRT and -TRT cohorts. Four patients (2.4%) suffered grade 4-5 pneumonitis, with one grade 5 case in the +TRT group compared to two grade 4 cases and one grade 5 case in the -TRT cohort. Mean TRT dose was similar between those patients who developed pneumonitis (56 Gy, range 36-63 Gy) and those who did not (56 Gy, range 18-79 Gy). In the +TRT group, 62 patients received TRT before ICI, 7 patients received concurrent TRT and ICI, 10 patients underwent TRT after ICI, and 6 patients had a combination of pre-, concurrent, and/or post-ICI TRT. For the 62 patients who received TRT before ICI, the median time interval between the end of TRT and start of ICI was 8.6 months (range Z 0.10-69 months). Of the 7 patients who received concurrent ICI and TRT (mean dose Z 37 Gy, range Z 8-48 Gy), none developed grade 2 pneumonitis. Conclusion: Thoracic radiotherapy to a mean dose of w56 Gy in lung cancer patients who received immune checkpoint inhibitors was not associated with an increased risk of pneumonitis. Further study with larger prospective cohorts is needed to validate these findings. Author Disclosure: W. Hwang: None. A. Niemierko: None. H. Willers: Employee; Boston Medical Center. Research Grant; NIH, American Cancer Society, American Lung Association; Radiation Research Society. J. Gainor: Consultant; Boehringer Ingelheim, Jounce Therapeutics, Kyowa Hakko Kirin Pharma. F.K. Keane: None.
323 Incidence of Pneumonitis in Metastatic Lung Cancer Patients Receiving Immune Checkpoint Inhibitors With or Without Thoracic Radiation Therapy W. Hwang,1 A. Niemierko,2 H. Willers,3 J. Gainor,2 and F.K. Keane4; 1 Harvard Radiation Oncology Program, Massachusetts General Hospital, Boston, MA, 2Massachusetts General Hospital, Boston, MA, 3Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, 4 Harvard Radiation Oncology Program, Harvard Medical School, Boston, MA Purpose/Objective(s): Immune checkpoint inhibitors (ICIs) have transformed the management of advanced lung cancer. However, ICIs are also associated with a unique spectrum of immune-related toxicities. In particular, autoimmune pneumonitis is an uncommon, but potentially fatal complication of ICIs. Thoracic radiotherapy (TRT) can also cause pneumonitis, but it is not known whether patients who receive both TRT and ICI are at increased risk of developing pneumonitis. Materials/Methods: We retrospectively reviewed 164 patients with metastatic lung cancer consecutively treated with PD-1/PD-L1 inhibitors at our institution from 2013-2016. Included patients had a minimum of one month follow-up, except in cases of rapid death from an adverse event (n Z 4). Patients were grouped based on receipt of TRT (+ vs -), with TRT defined as RT to the lung, mediastinum, or thoracic spine. Pneumonitis grades were assigned based on the NCI Common Terminology Criteria for Adverse Events v4.0. Outcomes were compared using the two-sided Student’s t-test and Fisher’s exact test.
324 CNS Radiation-Related Adverse Events in Lung Cancer Patients Treated With PD-1/PD-L1 Inhibitors H. Hubbeling, E. Schapira, A. Shaw, K.S. Oh, J. Gainor, and H.A. Shih; Massachusetts General Hospital, Boston, MA Purpose/Objective(s): Reports of symptomatic radiation necrosis after CNS radiation (RT) in patients on immune checkpoint blockers (ICB) fit with preclinical data showing synergistic immunogenic activity with RT and ICB. However, the toxicity profile of this combination is understudied in lung cancer. Here, we investigate CNS RT-related adverse events (AEs) in a cohort of lung cancer patients treated with PD-1/PD-L1 inhibitors to determine whether RT volume and/or the relative timing of ICB and CNS RT influence the frequency or severity of these events. Materials/Methods: We performed a single institution retrospective review of all lung cancer patients treated with a PD-1 or PD-L1 inhibitor between 2013 and 2017, identifying patients with a history of 1 CNS RT and 1 mo follow-up from RT start. ICB was defined as “concurrent” with RT if administered 4 weeks before or after RT. Medical records were reviewed and RT toxicity was classified using CTCAE version 4.0. Pseudoprogression (PP) and radiation necrosis (RN) were defined as MRI findings consistent with inflammation seen within 3 months of or >3 months after RT, respectively, with subsequent resolution without intervention. Significance was assessed with the Kruskal-Wallis test. Results: We identified 52 lung cancer patients (48 non-small cell, 4 small cell, 32 female, median age 60 at diagnosis) treated with ICB and CNS RT. Patients received a total of 140 CNS RT treatments: 99 SRS (median Z 18 Gy, range Z 10-30 Gy), 33 whole brain radiotherapy (median Z 30 Gy, range Z 30-37.5 Gy) and 8 partial brain irradiation (median Z 33 Gy, range Z 25-36 Gy). PD-1/PD-L1 inhibitors included nivolumab (n Z 42), pembrolizumab (n Z 8), and atezolizumab (n Z 4), median 8.5 doses. Median follow-up post-RT was 17 months. Significantly more RT-related AEs occurred after concurrent RT/ICB [35 AE/39 RT (90%)] as compared
International Journal of Radiation Oncology Biology Physics
available, the future of individualized treatment planning will require integration of genomic data and tissue-specific information. In preparation for this, we set out to establish methods to integrate tissue specific expression with genomic datasets and define the role of tissue specificity in cancer. We hypothesized that genome-wide association studies (GWAS) cancer variants affect genes that are specific to the tissue of the respective cancer type through gene expression regulation. In addition, we aimed to leverage this tissue-specificity to identify genes with prognostic utility for specific cancers. Materials/Methods: We used the Genotype-Tissue Expression (GTEx) dataset to identify tissue-specific genes for 13 tissues with associated cancers. We then assessed whether these tissue-specific genes were in closer proximity to GWAS variants of the respective tissue-associated cancer, obtained from the NIH GRASP database. We calculated significance using a permutation approach accounting for linkage disequilibrium. To evaluate whether the GWAS variants associated with tissue-specific genes via gene expression regulation, we analyzed the association between alleles and expression levels in non-cancer individuals using the GTEx dataset. Finally, we identified examples of tissue-specific genes that associate with survival in TCGA datasets using univariate and multivariate Cox regression. P-values were two-tailed with adjustment for multiple testing. Results: We identified a ranked list of tissue-specific genes for 13 tissues with solid tumor cancers. Highly significant GWAS variants (P 8) lie in closer proximity to the top 500 expressed tissue-specific genes compared to a randomly permuted set (P < 0.001). We found that several of these GWAS variants also associate with the expression of a tissue-specific gene, including a variant that is w117k base pairs away from gene HLA-V in lung cancer (P Z 0.0003). Finally, using a TCGA lung adenocarcinoma dataset (LUAD), we found that the expression of tissue-specific genes associates with survival, and created an indicator that predicted a median survival difference of 41 months (P < 0.0001). Conclusion: We identified that GWAS variants of specific cancer types are enriched near tissue-specific genes and are likely to be driving their gene expression regulation. We also found that tissue-specific genes may be used to prognosticate lung cancer survival, and with further clinical validation, these identified genes may serve to individualize cancer treatments. Author Disclosure: M.S. Binkley: None. R. Kita: None.
Results: The distribution of lung cancer histology in this study was 95% NSCLC and 5% SCLC. Baseline characteristics, including median age (65 vs 63 years), gender (58 vs 56% male), smoking status (88 vs 86%), supplemental oxygen requirement (12% vs 10%), median number of chemotherapy lines prior to ICI (1 vs 1), median number of ICI cycles (5 vs 3), and median follow-up after ICI initiation (8 vs 7 months), were comparable in the +TRT (73 patients) and -TRT (91 patients) groups. The +TRT cohort featured significantly less adenocarcinomas (49 vs 75%, P Z 0.001) and targetable mutations (4 vs 17%, P Z 0.012) than the -TRT group. Rates of all-grade pneumonitis (8.2 vs 5.5%, P Z 0.54) and grade 2 pneumonitis (4.1 vs 3.3%, P Z 1) were not significantly different between the +TRT and -TRT cohorts. Four patients (2.4%) suffered grade 4-5 pneumonitis, with one grade 5 case in the +TRT group compared to two grade 4 cases and one grade 5 case in the -TRT cohort. Mean TRT dose was similar between those patients who developed pneumonitis (56 Gy, range 36-63 Gy) and those who did not (56 Gy, range 18-79 Gy). In the +TRT group, 62 patients received TRT before ICI, 7 patients received concurrent TRT and ICI, 10 patients underwent TRT after ICI, and 6 patients had a combination of pre-, concurrent, and/or post-ICI TRT. For the 62 patients who received TRT before ICI, the median time interval between the end of TRT and start of ICI was 8.6 months (range Z 0.10-69 months). Of the 7 patients who received concurrent ICI and TRT (mean dose Z 37 Gy, range Z 8-48 Gy), none developed grade 2 pneumonitis. Conclusion: Thoracic radiotherapy to a mean dose of w56 Gy in lung cancer patients who received immune checkpoint inhibitors was not associated with an increased risk of pneumonitis. Further study with larger prospective cohorts is needed to validate these findings. Author Disclosure: W. Hwang: None. A. Niemierko: None. H. Willers: Employee; Boston Medical Center. Research Grant; NIH, American Cancer Society, American Lung Association; Radiation Research Society. J. Gainor: Consultant; Boehringer Ingelheim, Jounce Therapeutics, Kyowa Hakko Kirin Pharma. F.K. Keane: None.
323 Incidence of Pneumonitis in Metastatic Lung Cancer Patients Receiving Immune Checkpoint Inhibitors With or Without Thoracic Radiation Therapy W. Hwang,1 A. Niemierko,2 H. Willers,3 J. Gainor,2 and F.K. Keane4; 1 Harvard Radiation Oncology Program, Massachusetts General Hospital, Boston, MA, 2Massachusetts General Hospital, Boston, MA, 3Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, 4 Harvard Radiation Oncology Program, Harvard Medical School, Boston, MA Purpose/Objective(s): Immune checkpoint inhibitors (ICIs) have transformed the management of advanced lung cancer. However, ICIs are also associated with a unique spectrum of immune-related toxicities. In particular, autoimmune pneumonitis is an uncommon, but potentially fatal complication of ICIs. Thoracic radiotherapy (TRT) can also cause pneumonitis, but it is not known whether patients who receive both TRT and ICI are at increased risk of developing pneumonitis. Materials/Methods: We retrospectively reviewed 164 patients with metastatic lung cancer consecutively treated with PD-1/PD-L1 inhibitors at our institution from 2013-2016. Included patients had a minimum of one month follow-up, except in cases of rapid death from an adverse event (n Z 4). Patients were grouped based on receipt of TRT (+ vs -), with TRT defined as RT to the lung, mediastinum, or thoracic spine. Pneumonitis grades were assigned based on the NCI Common Terminology Criteria for Adverse Events v4.0. Outcomes were compared using the two-sided Student’s t-test and Fisher’s exact test.
324 CNS Radiation-Related Adverse Events in Lung Cancer Patients Treated With PD-1/PD-L1 Inhibitors H. Hubbeling, E. Schapira, A. Shaw, K.S. Oh, J. Gainor, and H.A. Shih; Massachusetts General Hospital, Boston, MA Purpose/Objective(s): Reports of symptomatic radiation necrosis after CNS radiation (RT) in patients on immune checkpoint blockers (ICB) fit with preclinical data showing synergistic immunogenic activity with RT and ICB. However, the toxicity profile of this combination is understudied in lung cancer. Here, we investigate CNS RT-related adverse events (AEs) in a cohort of lung cancer patients treated with PD-1/PD-L1 inhibitors to determine whether RT volume and/or the relative timing of ICB and CNS RT influence the frequency or severity of these events. Materials/Methods: We performed a single institution retrospective review of all lung cancer patients treated with a PD-1 or PD-L1 inhibitor between 2013 and 2017, identifying patients with a history of 1 CNS RT and 1 mo follow-up from RT start. ICB was defined as “concurrent” with RT if administered 4 weeks before or after RT. Medical records were reviewed and RT toxicity was classified using CTCAE version 4.0. Pseudoprogression (PP) and radiation necrosis (RN) were defined as MRI findings consistent with inflammation seen within 3 months of or >3 months after RT, respectively, with subsequent resolution without intervention. Significance was assessed with the Kruskal-Wallis test. Results: We identified 52 lung cancer patients (48 non-small cell, 4 small cell, 32 female, median age 60 at diagnosis) treated with ICB and CNS RT. Patients received a total of 140 CNS RT treatments: 99 SRS (median Z 18 Gy, range Z 10-30 Gy), 33 whole brain radiotherapy (median Z 30 Gy, range Z 30-37.5 Gy) and 8 partial brain irradiation (median Z 33 Gy, range Z 25-36 Gy). PD-1/PD-L1 inhibitors included nivolumab (n Z 42), pembrolizumab (n Z 8), and atezolizumab (n Z 4), median 8.5 doses. Median follow-up post-RT was 17 months. Significantly more RT-related AEs occurred after concurrent RT/ICB [35 AE/39 RT (90%)] as compared