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Association of survival and blood-based genomic signature with atezolizumab for patients with second-line and third-line EGFR wild-type non-small cell lung cancer: Pooled analysis of individual patient data from the POPLAR and OAK trials
Annals of Oncology 30 (Supplement 9): ix107–ix114, 2019 doi:10.1093/annonc/mdz438
IMMUNOTHERAPY OF CANCER Association of survival and blood-based genomic signature with atezolizumab for patients with second-line and third-line EGFR wildtype non-small cell lung cancer: Pooled analysis of individual patient data from the POPLAR and OAK trials
Y. Yu1, A. Li1,2, Y. Chen1,3, Q. Li1, Q. Ou1, D. Lin1,4, W. Zhang1,2, Z. Li1, H. Hu1, H. Yao1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Oncology, Phase I Clinical Trial Centre, Breast Tumor Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China, 2Guangdong Medical University, Zhanjiang, Guangdong, China, 3Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, 4State key laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
1
Background: Individual patient data from two multicentre, randomised trials comparing atezolizumab with docetaxel in previously treated advanced non-small-cell lung cancer (NSCLC) were analyzed to identify any preferable therapeutic approaches for patient subsets stratified by EGFR mutation status. Methods: We pooled 1,137 patients from the phase II POPLAR trial (NCT01903993) and the phase III OAK trial (NCT02008227). Patients were randomly assigned to receive either atezolizumab or docetaxel and were analyzed based on stratification of EGFR mutation status. We built a novel algorithm integrating the blood-based tumor mutation burden and the ctDNA maximum somatic allele frequency (bTMB-MSAF score) and developed a novel clinicopathologic-genomic nomogram to predict individual survival. Results: In the whole intention-to-treat population, OS was significantly longer with atezolizumab than with docetaxel (hazard ratio [HR] 0.72, P < 0.001). Among patients without EGFR or ALK mutations, overall survival (OS) was significantly longer with atezolizumab than with docetaxel (HR 0.67; P < 0.001); patients with a bTMB-MSAF score<20 showed improvement in OS (HR 0.56; P < 0.001) and progression-free survival (PFS) (HR 0.74; P ¼ 0.0023), and these patients who concurrently had programmed death ligand 1 (PD-L1) expressing on over 50% tumor cells or over 10% of tumor-infiltrating immune cells (TC3 or IC3) had the greatest OS improvements (HR 0.44; P ¼ 0.007) and promising PFS benefits (HR 0.54; P ¼ 0.019). EGFR mutant patients could not gain significant OS or PFS benefits from atezolizumab over docetaxel, irrespective of PD-L1 expression and bTMB-MSAF score. Patients with low-risk scores had longer OS (HR 0.17; P < 0.001; AUC¼0.912 for 3-year OS) than patients with high-risk scores classified by the nomogram. Conclusions: Atezolizumab showed better OS and PFS than docetaxel in previously treated EGFR wild-type NSCLC patients with a bTMB-MSAF score < 20, especially in those with PD-L1 expression of TC3 or IC3. Our clinicopathologic-genomic nomogram is effective in predicting survival of NSCLC patients undergoing atezolizumab. Clinical trial identification: NCT01903993 and NCT02008227. Legal entity responsible for the study: Herui Yao. Funding: Herui Yao is funded by the National Science and Technology Major Project under Grant [2020ZX09201021]; National Natural Science Foundation of China under Grant [81372819, 81572596, U1601223]; Natural Science Foundation of Guangdong Province under Grant [2017A030313828]; and Guangzhou Science and Technology Program under Grant [201704020131]. Disclosure: All authors have declared no conflicts of interest.
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Both low and high blood tumour mutational burden are favourable predictors with atezolizumab
W. Nie, B. Han Department of respiration, Shanghai Chest Hospital, Shanghai, China Background: A recent study has demonstrated that high blood tumor mutational burden (bTMB) was associated with significant improvements in PFS from atezolizumab in NSCLC. However, a prospective, phase II, B-F1RST study did not confirm the result. Multiple genetic mutations may result in resistance to therapy, including immunetherapy. Therefore, we speculated that low bTMB might be a favorable prognostic biomarker for immunetherapy and both high and low bTMB patients could derive benefit from atezolizumab. We thus investigated the non-linear association between bTMB and PFS, and tried to find new cut-off values. Methods: This study used the clinical and bTMB data from POPLAR (n ¼ 105, training set) and OAK (n ¼ 324, validation set) studies. The non-linear association between bTMB and PFS was assessed using restricted cubic spline (RCS). The cut-off values for bTMB were calculated by using X-tile software.
Results: In training set, bTMB showed an upside down J shape curve with PFS in RCS plot, suggesting a non-linear relationship between bTMB and PFS (P for non-linear < 0.001). The cut-off values of bTMB for predicting PFS were 7 and 14 mutations/Mb, and all patients were claasified into low ( 7 mutations/Mb), medium (8 bTMB 13 mutations/Mb), and high bTMB ( 14 mutations/Mb) groups according to the cutoff values. The median PFS and OS of patients with low and high bTMB were significantly longer than those of patients with medium bTMB in multivariate analysis. Similar results were shown in the validation set and the combined set (Table).
Table: 318O Prognostic value of bTMB for PFS and OS in the training, validation, and combined data sets PFS HR
95% CI
Training data set (n ¼ 105) Low bTMB 0.367 0.212-0.637 Medium bTMB 1 Reference High bTMB 0.207 0.105-0.410 Validation data set (n ¼ 324) Low bTMB 0.689 0.502-0.945 Medium bTMB 1 Reference High bTMB 0.644 0.457-0.909 Combined data set (n ¼ 429) Low bTMB 0.596 0.456-0.779 Medium bTMB 1 Reference High bTMB 0.558 0.415-0.750
OS P value HR
P value
<0.001 0.441 0.239-0.814 0.009 1 Reference <0.001 0.336 0.161-0.704 0.004 0.021 0.012
0.644 0.441-0.939 0.022 1 Reference 0.637 0.431-0.943 0.024
<0.001 0.649 0.476-0.884 0.006 1 Reference <0.001 0.689 0.496-0.958 0.027
Conclusions: There was a non-linear association between bTMB and survival in NSCLC patients receiving atezolizumab. Both high and low bTMB were associated with better clinical benefit with atezolizumab. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
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Combined model of frameshift mutations and TMB in predicting response to immunotherapy in NSCLC
H. Zhou, J. Liu, Y. Zhang, W. Fang, L. Zhang Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China Background: Immune checkpoint inhibitors (ICIs) therapy has been a pivotal treatment for NSCLC. However, additional biomarkers should be found out to cover more patients who may derive the greatest benefit from ICIs. Frameshift mutation by insertion or deletion (fsindel) has come to prominence due to its higher immunogenicity. Previous study has identified a positive correlation between fsindel and favorable clinical benefit in NSCLC. But it still requires validation. Therefore, we conducted a study to further assess the predictive role of fsindel. Methods: A publicly available cohort of 385 ICIs-treated NSCLC patients from MSKCC were analyzed. We categorized patients into two groups; 0 fsindel (FS-) and more than 1 fsindel (FSþ). The OS, PFS and response to ICIs therapy (ORR, DCR and DCB) were evaluated. We also developed a combined model of TMB and fsindel to further clarify the role of fsindel. Results: 214 patients (55.58%) were found to be fsindel present (FSþ). 189 patients (88.32%) were treated with PD-1/PD-L1 inhibitor monotherapy. Among the 356 patients with OS data, the OS of the FSþ patients was similar with that of FS- patients (median OS: 11 months vs. 12 months, P ¼ 0.615). 240 patients (131 FSþ, 109 FS-) were able to be evaluated for response to ICIs therapy. The median PFS was similar between FSþ and FS- group (median PFS, 3.43 months vs. 3.17 months, P ¼ 0.114). The presence of fsindel was correlated with higher ORR (24.43% vs 15.60%, P ¼ 0.091), DCR (56.49% vs 53.21%, P ¼ 0.611) and DCB (35.77% vs. 24.04%, P ¼ 0.055). TMBH patients show significant difference in OS (median OS: 15 months vs. 10 months, P ¼ 0.017) and marginally-significant difference in PFS (median PFS, 4.73 months vs. 2.60 months, P ¼ 0.051). Moreover, TMB-H and FSþ patients had significantly better
C European Society for Medical Oncology 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V
All rights reserved. For permissions, please email: [email protected].
95% CI
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_9/mdz438/5638720 by University Library Utrecht user on 09 December 2019
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IMMUNOTHERAPY OF CANCER Association of survival and blood-based genomic signature with atezolizumab for patients with second-line and third-line EGFR wildtype non-small cell lung cancer: Pooled analysis of individual patient data from the POPLAR and OAK trials
Y. Yu1, A. Li1,2, Y. Chen1,3, Q. Li1, Q. Ou1, D. Lin1,4, W. Zhang1,2, Z. Li1, H. Hu1, H. Yao1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Oncology, Phase I Clinical Trial Centre, Breast Tumor Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China, 2Guangdong Medical University, Zhanjiang, Guangdong, China, 3Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, 4State key laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
1
Background: Individual patient data from two multicentre, randomised trials comparing atezolizumab with docetaxel in previously treated advanced non-small-cell lung cancer (NSCLC) were analyzed to identify any preferable therapeutic approaches for patient subsets stratified by EGFR mutation status. Methods: We pooled 1,137 patients from the phase II POPLAR trial (NCT01903993) and the phase III OAK trial (NCT02008227). Patients were randomly assigned to receive either atezolizumab or docetaxel and were analyzed based on stratification of EGFR mutation status. We built a novel algorithm integrating the blood-based tumor mutation burden and the ctDNA maximum somatic allele frequency (bTMB-MSAF score) and developed a novel clinicopathologic-genomic nomogram to predict individual survival. Results: In the whole intention-to-treat population, OS was significantly longer with atezolizumab than with docetaxel (hazard ratio [HR] 0.72, P < 0.001). Among patients without EGFR or ALK mutations, overall survival (OS) was significantly longer with atezolizumab than with docetaxel (HR 0.67; P < 0.001); patients with a bTMB-MSAF score<20 showed improvement in OS (HR 0.56; P < 0.001) and progression-free survival (PFS) (HR 0.74; P ¼ 0.0023), and these patients who concurrently had programmed death ligand 1 (PD-L1) expressing on over 50% tumor cells or over 10% of tumor-infiltrating immune cells (TC3 or IC3) had the greatest OS improvements (HR 0.44; P ¼ 0.007) and promising PFS benefits (HR 0.54; P ¼ 0.019). EGFR mutant patients could not gain significant OS or PFS benefits from atezolizumab over docetaxel, irrespective of PD-L1 expression and bTMB-MSAF score. Patients with low-risk scores had longer OS (HR 0.17; P < 0.001; AUC¼0.912 for 3-year OS) than patients with high-risk scores classified by the nomogram. Conclusions: Atezolizumab showed better OS and PFS than docetaxel in previously treated EGFR wild-type NSCLC patients with a bTMB-MSAF score < 20, especially in those with PD-L1 expression of TC3 or IC3. Our clinicopathologic-genomic nomogram is effective in predicting survival of NSCLC patients undergoing atezolizumab. Clinical trial identification: NCT01903993 and NCT02008227. Legal entity responsible for the study: Herui Yao. Funding: Herui Yao is funded by the National Science and Technology Major Project under Grant [2020ZX09201021]; National Natural Science Foundation of China under Grant [81372819, 81572596, U1601223]; Natural Science Foundation of Guangdong Province under Grant [2017A030313828]; and Guangzhou Science and Technology Program under Grant [201704020131]. Disclosure: All authors have declared no conflicts of interest.
318O
Both low and high blood tumour mutational burden are favourable predictors with atezolizumab
W. Nie, B. Han Department of respiration, Shanghai Chest Hospital, Shanghai, China Background: A recent study has demonstrated that high blood tumor mutational burden (bTMB) was associated with significant improvements in PFS from atezolizumab in NSCLC. However, a prospective, phase II, B-F1RST study did not confirm the result. Multiple genetic mutations may result in resistance to therapy, including immunetherapy. Therefore, we speculated that low bTMB might be a favorable prognostic biomarker for immunetherapy and both high and low bTMB patients could derive benefit from atezolizumab. We thus investigated the non-linear association between bTMB and PFS, and tried to find new cut-off values. Methods: This study used the clinical and bTMB data from POPLAR (n ¼ 105, training set) and OAK (n ¼ 324, validation set) studies. The non-linear association between bTMB and PFS was assessed using restricted cubic spline (RCS). The cut-off values for bTMB were calculated by using X-tile software.
Results: In training set, bTMB showed an upside down J shape curve with PFS in RCS plot, suggesting a non-linear relationship between bTMB and PFS (P for non-linear < 0.001). The cut-off values of bTMB for predicting PFS were 7 and 14 mutations/Mb, and all patients were claasified into low ( 7 mutations/Mb), medium (8 bTMB 13 mutations/Mb), and high bTMB ( 14 mutations/Mb) groups according to the cutoff values. The median PFS and OS of patients with low and high bTMB were significantly longer than those of patients with medium bTMB in multivariate analysis. Similar results were shown in the validation set and the combined set (Table).
Table: 318O Prognostic value of bTMB for PFS and OS in the training, validation, and combined data sets PFS HR
95% CI
Training data set (n ¼ 105) Low bTMB 0.367 0.212-0.637 Medium bTMB 1 Reference High bTMB 0.207 0.105-0.410 Validation data set (n ¼ 324) Low bTMB 0.689 0.502-0.945 Medium bTMB 1 Reference High bTMB 0.644 0.457-0.909 Combined data set (n ¼ 429) Low bTMB 0.596 0.456-0.779 Medium bTMB 1 Reference High bTMB 0.558 0.415-0.750
OS P value HR
P value
<0.001 0.441 0.239-0.814 0.009 1 Reference <0.001 0.336 0.161-0.704 0.004 0.021 0.012
0.644 0.441-0.939 0.022 1 Reference 0.637 0.431-0.943 0.024
<0.001 0.649 0.476-0.884 0.006 1 Reference <0.001 0.689 0.496-0.958 0.027
Conclusions: There was a non-linear association between bTMB and survival in NSCLC patients receiving atezolizumab. Both high and low bTMB were associated with better clinical benefit with atezolizumab. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
319O
Combined model of frameshift mutations and TMB in predicting response to immunotherapy in NSCLC
H. Zhou, J. Liu, Y. Zhang, W. Fang, L. Zhang Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China Background: Immune checkpoint inhibitors (ICIs) therapy has been a pivotal treatment for NSCLC. However, additional biomarkers should be found out to cover more patients who may derive the greatest benefit from ICIs. Frameshift mutation by insertion or deletion (fsindel) has come to prominence due to its higher immunogenicity. Previous study has identified a positive correlation between fsindel and favorable clinical benefit in NSCLC. But it still requires validation. Therefore, we conducted a study to further assess the predictive role of fsindel. Methods: A publicly available cohort of 385 ICIs-treated NSCLC patients from MSKCC were analyzed. We categorized patients into two groups; 0 fsindel (FS-) and more than 1 fsindel (FSþ). The OS, PFS and response to ICIs therapy (ORR, DCR and DCB) were evaluated. We also developed a combined model of TMB and fsindel to further clarify the role of fsindel. Results: 214 patients (55.58%) were found to be fsindel present (FSþ). 189 patients (88.32%) were treated with PD-1/PD-L1 inhibitor monotherapy. Among the 356 patients with OS data, the OS of the FSþ patients was similar with that of FS- patients (median OS: 11 months vs. 12 months, P ¼ 0.615). 240 patients (131 FSþ, 109 FS-) were able to be evaluated for response to ICIs therapy. The median PFS was similar between FSþ and FS- group (median PFS, 3.43 months vs. 3.17 months, P ¼ 0.114). The presence of fsindel was correlated with higher ORR (24.43% vs 15.60%, P ¼ 0.091), DCR (56.49% vs 53.21%, P ¼ 0.611) and DCB (35.77% vs. 24.04%, P ¼ 0.055). TMBH patients show significant difference in OS (median OS: 15 months vs. 10 months, P ¼ 0.017) and marginally-significant difference in PFS (median PFS, 4.73 months vs. 2.60 months, P ¼ 0.051). Moreover, TMB-H and FSþ patients had significantly better
C European Society for Medical Oncology 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V
All rights reserved. For permissions, please email: [email protected].
95% CI
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_9/mdz438/5638720 by University Library Utrecht user on 09 December 2019
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