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Irreversible severe cardiotoxicities except for QTc interval prolongation associated with Osimertinib
abstracts
Annals of Oncology
MO2 16 1
Differential efficacy of Osimertinib in EGFR T790M positive non-small cell lung cancer by metastatic site
Shinya Uematsu Division of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation For Cancer Research Background: Osimertinib is a standard treatment for non-small cell lung cancer(NSCLC) with common and T790M EGFR mutation and efficacy for brain metastasis is reported. However there are only a few reports regarding efficacy or other metastatic sites such as pleural effusion, bone metastasis, and pulmonary metastasis. Methods: We retrospectively analyzed efficacy of osimertinib in 84 patients who had NSCLC with common and T790M EGFR mutation and received osimertinib at our hospital between March 2016 to December 2018. Results: Baseline characteristics of the 84 patients is as follows. There were 33 males and 51 females. The median age was 64 years. ECOG PS was 0, 1 or 2 in 19 (22.6%), 56 (66.7%) and 9 (10.7%) patients, respectively. Twenty three patients (27.4%) had pleural effusions, 32 patients (38.1%) had brain metastasis, 42 patients (50%) had bone metastasis, and 58 patients (69.0%) had pulmonary metastasis. For all patients, the response of osimertinib were 48 PR (57.1%), 24 SD (28.6%), 6 PD (7.1%), 6 NE (7.1%). Median time to treatment failure (TTF) was significantly shorter in patients with pleural effusions than those without (9.5 vs 11.1 months, respectively, p ¼ 0.01). Regarding bone metastasis, brain metastasis, or lung metastasis, there was no significant difference in TTF (p ¼ 0.52, p ¼ 0.11, p ¼ 0.88, respectively). Conclusion: Osimertinib might be less potent for pleural effusion.
MO2 16 2
Irreversible severe cardiotoxicities except for QTc interval prolongation associated with Osimertinib
Kei Kunimasa1, Madoka Kimura1, Makiko Oboshi2, Takako Inoue1, Motohiro Tamiya1, Hanako Kuhara1, Kazumi Nishino1, Taku Yasui2, Wataru Shioyama2, Masashi Fujita2, Fumio Imamura3, Toru Kumagai1 1 Department of Thoracic Oncology, Osaka International Cancer Institute, 2Department of Onco-Cardiolody, Osaka International Cancer Institute, 3Department of Clinical Oncology, Osaka International Cancer Institute Background; QTc interval prolongation is a known and warning cardiotoxicity associated with Osimertinib. The final summary on the safety profile of Osimertinib (AstraZeneca plc) reports that severe cardiotoxicities except for QTc interval prolongation are 0.8% (29/3578 patients) and alerts us to such adverse events. Here, we report irreversible severe cardiotoxicities associated with Osimertinib except for QTc interval prolongation. Methods; We reviewed the medical records of EGFR-mutated Non-Small Cell Lung cancer patients who were treated with Osimertinib at Osaka International Cancer Institute between March 2016 and January 2019. We checked cardiotoxicities associated with Osimertinib based on the medical records. Results; We enrolled 123 patients treated with Osimertinib into this study. The median age was 69 (range: 33-86) years. Of 123 patients, 40 (32.5%) were male, all cases except one were adenocarcinoma, EGFR mutation profile was Ex. 19 del/L858R/de novo T790M/others(G719S, L861Q); 62 (50.4%)/56 (45.5%)/3/2. Osimertinib treatment line was 1st; 23 (18.7%), 2nd; 30 (24.4%), 3rd; 18 (14.6%), 4th; 41 (33.3%), 11 pts; switching from other EGFR-TKI during 1st line. Severe cardiotoxicities (CTC-AE Gr.3) were observed in 5 pts (4.1%); acute myocardinal infarction (1), irreversible congestive heart failure due to systolic dysfunction (1), exacerbation of tricupid regurgitation (1), decreasing ejection fraction (EF) (2). Histopathological analysis of a myocardial biopsy from one patient with decreased EF (Gr.2) revealed inflammatory cells infiltration into cardiomyocytes. Conclusion; We experienced severe cardiotoxicities associated with Osimertinib at a higher frequency (4.1%) than reported before. Considering some patients were forced to quit their chemotherapy due to severe cardiotoxicities. We should pay attention to not only QTc interval prolongation but also other cardiotoxicities in administrating Osimertinib in the clinical setting.
Volume 30 | Supplement 6 | October 2019
MO2 16 3
Population PK/PD Analysis of Necitumumab: Dose justification for Squamous Cell Lung Cancer (SqCLC) Patients in Japan
Hanaka Mimura1, Amanda Long2, Emmanuel Chigutsa2, Johan Wallin3, Sotaro Enatsu1, Kazuhiko Nakagawa4, Tomohide Tamura5 1 Eli Lilly Japan K.K, 2Eli Lilly and Company, 3Lilly Sweden, 4Department of Medical Oncology, Kindai University Faculty of Medicine, 5Thoracic Center, St.Luke’s International Hospital Background: Necitumumab (NEC) in combination with gemcitabineþcisplatin (GC) demonstrated significant improvement in overall survival (OS) compared to GC in advanced SqCLC patients (pts) in Global Ph3 study JFCC. In Study JFCM Ph2 part, NEC in combination with GC improved OS compared to GC in SqCLC pts in Japan. Population PK/PD analysis including Study JFCM was conducted to determine the adequacy of the dose in pts in Japan based on NEC PK, and relationship between exposure and efficacy and safety. Methods: Two studies, one of which Study JFCM, were added into the analysis previously performed with five Ph 1, 2, and 3 studies. The effect of Japan/non-Japan origin on NEC PK was assessed. Simulations were performed to compare predicted NEC serum concentrations after flat 800 mg and body weight based dosing. The relationship between exposure and OS in Studies JFCC and JFCM Ph2 part was explored. The relationship between exposure and safety measurements (hypomagnesemia, rash and thromboembolic events) in Studies JFCC and JFCM Ph2 part was explored. Results: Population PK analysis included blood samples collected from 967 pts (including 114 pts in Japan) treated with NEC. PK parameters were similar between Japanese and non-Japanese pts. NEC PK is dependent on body weight; however, simulations indicated weight-based dosing would not significantly decrease PK variability. Exposure-response analysis included 1195 pts, including 181 pts in Japan. Exposureefficacy analysis suggested that pts with higher NEC concentration had longer OS, however, majority of pts in both studies had steady state exposure greater than EC80. No correlation was observed between NEC serum exposure and severity of hypomagnesemia or rash. No correlation was observed between NEC serum exposure and risk of treatment emergent thromboembolic events. Conclusion: Population PK/PD analysis supports the administration of 800 mg NEC on Day 1 and 8 of a 21-day cycle as an appropriate dose in SqCLC pts in Japan.
MO2 16 4
Exploratory analysis of JFCM: Predictive value of rash, EGFR expression, and EGFR copy for necitumumab in squamous NSCLC
Yasushi Goto1, Makoto Nishio2, Nobuyuki Yamamoto3, Yuichiro Ohe1, Ami Kamada4, Kazumi Suzukawa4, Sotaro Enatsu4, Kazuhiko Nakagawa5, Tomohide Tamura6 1 Department of Thoracic Oncology, National Cancer Center Hospital, 2Department of Thoracic Medical Oncology, The Cancer Institute Hospital of JFCR, 3Third Department of Internal Medicine, Wakayama Medical University, 4Eli Lilly Japan K.K, 5Department of Medical Oncology, Kindai University Faculty of Medicine, 6Thoracic Center, St. Luke’s International Hospital Background: JFCM, an open-label, multicenter, phase 1b/2 study (n ¼ 181), demonstrated that addition of necitumumab (N) to gemcitabine and cisplatin (GC) resulted in significant improvement in overall survival (OS; hazard ratio [HR] ¼ 0.66) in the first-line treatment of advanced squamous non-small cell lung cancer (NSCLC) patients in Japan. Previous studies have suggested that rash, EGFR expression, and EGFR copy number gain might be associated with the efficacy of EGFR-targeting drugs in the treatment of squamous NSCLC. Methods: Our analysis assessed: development of acne-like rash in the first cycle; EGFR expression (evaluated by H-score of immunohistochemistry, H 200 vs H < 200); and EGFR copy number gain of tumor cells (evaluated by fluorescence in situ hybridization [FISH]; positive vs negative) for association with clinical outcome in JFCM study. Results: Of the 90 patients in the GCþN arm, 80 (88.9%) had first-cycle rash. Median OS was 14.52 vs 15.93 months (HR ¼ 1.39) in patients experiencing first-cycle rash vs those without rash in the GCþN arm. For EGFR expression, the majority of patients had H < 200 in both arms (H < 200: GCþN¼74, GC ¼ 65; H 200: GCþN¼13, GC ¼ 23). The efficacy outcome did not vary significantly with EGFR expression with median OS of 14.92 and 10.28 months (HR ¼ 0.643) in the H < 200 subgroup, and 14.00 and 10.28 months (HR ¼ 0.580) in H 200 subgroup, for GCþN and GC arms respectively. For EGFR copy number, 29 vs 37 cases were FISH positive while 38 vs 32 cases were FISH negative in the GCþN vs GC arms, respectively. In FISH positive patients, median OS was 14.00 and 9.43 months (HR ¼ 0.73) while median OS in FISH negative patients was 15.70 and 12.02 months (HR ¼ 0.65) in GCþN vs GC arms, respectively. Conclusion: Our analysis did not identify first-cycle rash, EGFR expression, and EGFR copy number gain as predictive markers of survival in JFCM study. (Trial Registration Number: NCT01763788)
doi:10.1093/annonc/mdz338 | vi109
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz338.081/5582955 by Stockholm University Library user on 09 November 2019
Results: To date, 90 pts are enrolled, 15 are from Japan. At data cut-off (16/10/2018), in 35 evaluable LBx pts ORR (95% CI) was 51.4% (34.0, 68.6) by IRC with a median duration of response (mDoR) (range) of 9.8 months (1.1, 18.0) and 63.9% (46.2, 79.2) by INV with a mDOR of 17.1 months (1.3, 21.5). In 41 evaluable TBx pts, ORR was 41.5% (26.3, 57.9) by IRC and 58.5% (42.1, 73.7) by INV; mDoR was 12.4 months (1.1, 18.0; IRC) and 14.3 months (1.3, 21.5; INV). Of 11 evaluable Japanese pts, 6 were METex14 positive by LBx and 9 by TBx (overlap occurred). Confirmed responses were reported in 4/6 LBx pts and 3/9 TBx pts by IRC and in 4/6 LBx pts and 4/9 TBx pts by INV. Safety was evaluable in 69 pts. Main treatment-related adverse events (TRAEs; 15%) of any grade were peripheral edema (47.8%), diarrhea (18.8%), nausea (15.9%). The safety profile was similar in Japanese pts. TRAEs led to permanent discontinuation in 2 (2.9%) pts (1 ILD, 1 diarrhea & nausea). No TRAEs led to death. Conclusion: In NSCLC pts with METex14 mutations, tepotinib had promising clinical efficacy. Similar activity was observed in Japanese pts. The safety profile was favorable. Recruitment, including a MET amplification cohort, is ongoing.
Annals of Oncology
MO2 16 1
Differential efficacy of Osimertinib in EGFR T790M positive non-small cell lung cancer by metastatic site
Shinya Uematsu Division of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation For Cancer Research Background: Osimertinib is a standard treatment for non-small cell lung cancer(NSCLC) with common and T790M EGFR mutation and efficacy for brain metastasis is reported. However there are only a few reports regarding efficacy or other metastatic sites such as pleural effusion, bone metastasis, and pulmonary metastasis. Methods: We retrospectively analyzed efficacy of osimertinib in 84 patients who had NSCLC with common and T790M EGFR mutation and received osimertinib at our hospital between March 2016 to December 2018. Results: Baseline characteristics of the 84 patients is as follows. There were 33 males and 51 females. The median age was 64 years. ECOG PS was 0, 1 or 2 in 19 (22.6%), 56 (66.7%) and 9 (10.7%) patients, respectively. Twenty three patients (27.4%) had pleural effusions, 32 patients (38.1%) had brain metastasis, 42 patients (50%) had bone metastasis, and 58 patients (69.0%) had pulmonary metastasis. For all patients, the response of osimertinib were 48 PR (57.1%), 24 SD (28.6%), 6 PD (7.1%), 6 NE (7.1%). Median time to treatment failure (TTF) was significantly shorter in patients with pleural effusions than those without (9.5 vs 11.1 months, respectively, p ¼ 0.01). Regarding bone metastasis, brain metastasis, or lung metastasis, there was no significant difference in TTF (p ¼ 0.52, p ¼ 0.11, p ¼ 0.88, respectively). Conclusion: Osimertinib might be less potent for pleural effusion.
MO2 16 2
Irreversible severe cardiotoxicities except for QTc interval prolongation associated with Osimertinib
Kei Kunimasa1, Madoka Kimura1, Makiko Oboshi2, Takako Inoue1, Motohiro Tamiya1, Hanako Kuhara1, Kazumi Nishino1, Taku Yasui2, Wataru Shioyama2, Masashi Fujita2, Fumio Imamura3, Toru Kumagai1 1 Department of Thoracic Oncology, Osaka International Cancer Institute, 2Department of Onco-Cardiolody, Osaka International Cancer Institute, 3Department of Clinical Oncology, Osaka International Cancer Institute Background; QTc interval prolongation is a known and warning cardiotoxicity associated with Osimertinib. The final summary on the safety profile of Osimertinib (AstraZeneca plc) reports that severe cardiotoxicities except for QTc interval prolongation are 0.8% (29/3578 patients) and alerts us to such adverse events. Here, we report irreversible severe cardiotoxicities associated with Osimertinib except for QTc interval prolongation. Methods; We reviewed the medical records of EGFR-mutated Non-Small Cell Lung cancer patients who were treated with Osimertinib at Osaka International Cancer Institute between March 2016 and January 2019. We checked cardiotoxicities associated with Osimertinib based on the medical records. Results; We enrolled 123 patients treated with Osimertinib into this study. The median age was 69 (range: 33-86) years. Of 123 patients, 40 (32.5%) were male, all cases except one were adenocarcinoma, EGFR mutation profile was Ex. 19 del/L858R/de novo T790M/others(G719S, L861Q); 62 (50.4%)/56 (45.5%)/3/2. Osimertinib treatment line was 1st; 23 (18.7%), 2nd; 30 (24.4%), 3rd; 18 (14.6%), 4th; 41 (33.3%), 11 pts; switching from other EGFR-TKI during 1st line. Severe cardiotoxicities (CTC-AE Gr.3) were observed in 5 pts (4.1%); acute myocardinal infarction (1), irreversible congestive heart failure due to systolic dysfunction (1), exacerbation of tricupid regurgitation (1), decreasing ejection fraction (EF) (2). Histopathological analysis of a myocardial biopsy from one patient with decreased EF (Gr.2) revealed inflammatory cells infiltration into cardiomyocytes. Conclusion; We experienced severe cardiotoxicities associated with Osimertinib at a higher frequency (4.1%) than reported before. Considering some patients were forced to quit their chemotherapy due to severe cardiotoxicities. We should pay attention to not only QTc interval prolongation but also other cardiotoxicities in administrating Osimertinib in the clinical setting.
Volume 30 | Supplement 6 | October 2019
MO2 16 3
Population PK/PD Analysis of Necitumumab: Dose justification for Squamous Cell Lung Cancer (SqCLC) Patients in Japan
Hanaka Mimura1, Amanda Long2, Emmanuel Chigutsa2, Johan Wallin3, Sotaro Enatsu1, Kazuhiko Nakagawa4, Tomohide Tamura5 1 Eli Lilly Japan K.K, 2Eli Lilly and Company, 3Lilly Sweden, 4Department of Medical Oncology, Kindai University Faculty of Medicine, 5Thoracic Center, St.Luke’s International Hospital Background: Necitumumab (NEC) in combination with gemcitabineþcisplatin (GC) demonstrated significant improvement in overall survival (OS) compared to GC in advanced SqCLC patients (pts) in Global Ph3 study JFCC. In Study JFCM Ph2 part, NEC in combination with GC improved OS compared to GC in SqCLC pts in Japan. Population PK/PD analysis including Study JFCM was conducted to determine the adequacy of the dose in pts in Japan based on NEC PK, and relationship between exposure and efficacy and safety. Methods: Two studies, one of which Study JFCM, were added into the analysis previously performed with five Ph 1, 2, and 3 studies. The effect of Japan/non-Japan origin on NEC PK was assessed. Simulations were performed to compare predicted NEC serum concentrations after flat 800 mg and body weight based dosing. The relationship between exposure and OS in Studies JFCC and JFCM Ph2 part was explored. The relationship between exposure and safety measurements (hypomagnesemia, rash and thromboembolic events) in Studies JFCC and JFCM Ph2 part was explored. Results: Population PK analysis included blood samples collected from 967 pts (including 114 pts in Japan) treated with NEC. PK parameters were similar between Japanese and non-Japanese pts. NEC PK is dependent on body weight; however, simulations indicated weight-based dosing would not significantly decrease PK variability. Exposure-response analysis included 1195 pts, including 181 pts in Japan. Exposureefficacy analysis suggested that pts with higher NEC concentration had longer OS, however, majority of pts in both studies had steady state exposure greater than EC80. No correlation was observed between NEC serum exposure and severity of hypomagnesemia or rash. No correlation was observed between NEC serum exposure and risk of treatment emergent thromboembolic events. Conclusion: Population PK/PD analysis supports the administration of 800 mg NEC on Day 1 and 8 of a 21-day cycle as an appropriate dose in SqCLC pts in Japan.
MO2 16 4
Exploratory analysis of JFCM: Predictive value of rash, EGFR expression, and EGFR copy for necitumumab in squamous NSCLC
Yasushi Goto1, Makoto Nishio2, Nobuyuki Yamamoto3, Yuichiro Ohe1, Ami Kamada4, Kazumi Suzukawa4, Sotaro Enatsu4, Kazuhiko Nakagawa5, Tomohide Tamura6 1 Department of Thoracic Oncology, National Cancer Center Hospital, 2Department of Thoracic Medical Oncology, The Cancer Institute Hospital of JFCR, 3Third Department of Internal Medicine, Wakayama Medical University, 4Eli Lilly Japan K.K, 5Department of Medical Oncology, Kindai University Faculty of Medicine, 6Thoracic Center, St. Luke’s International Hospital Background: JFCM, an open-label, multicenter, phase 1b/2 study (n ¼ 181), demonstrated that addition of necitumumab (N) to gemcitabine and cisplatin (GC) resulted in significant improvement in overall survival (OS; hazard ratio [HR] ¼ 0.66) in the first-line treatment of advanced squamous non-small cell lung cancer (NSCLC) patients in Japan. Previous studies have suggested that rash, EGFR expression, and EGFR copy number gain might be associated with the efficacy of EGFR-targeting drugs in the treatment of squamous NSCLC. Methods: Our analysis assessed: development of acne-like rash in the first cycle; EGFR expression (evaluated by H-score of immunohistochemistry, H 200 vs H < 200); and EGFR copy number gain of tumor cells (evaluated by fluorescence in situ hybridization [FISH]; positive vs negative) for association with clinical outcome in JFCM study. Results: Of the 90 patients in the GCþN arm, 80 (88.9%) had first-cycle rash. Median OS was 14.52 vs 15.93 months (HR ¼ 1.39) in patients experiencing first-cycle rash vs those without rash in the GCþN arm. For EGFR expression, the majority of patients had H < 200 in both arms (H < 200: GCþN¼74, GC ¼ 65; H 200: GCþN¼13, GC ¼ 23). The efficacy outcome did not vary significantly with EGFR expression with median OS of 14.92 and 10.28 months (HR ¼ 0.643) in the H < 200 subgroup, and 14.00 and 10.28 months (HR ¼ 0.580) in H 200 subgroup, for GCþN and GC arms respectively. For EGFR copy number, 29 vs 37 cases were FISH positive while 38 vs 32 cases were FISH negative in the GCþN vs GC arms, respectively. In FISH positive patients, median OS was 14.00 and 9.43 months (HR ¼ 0.73) while median OS in FISH negative patients was 15.70 and 12.02 months (HR ¼ 0.65) in GCþN vs GC arms, respectively. Conclusion: Our analysis did not identify first-cycle rash, EGFR expression, and EGFR copy number gain as predictive markers of survival in JFCM study. (Trial Registration Number: NCT01763788)
doi:10.1093/annonc/mdz338 | vi109
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz338.081/5582955 by Stockholm University Library user on 09 November 2019
Results: To date, 90 pts are enrolled, 15 are from Japan. At data cut-off (16/10/2018), in 35 evaluable LBx pts ORR (95% CI) was 51.4% (34.0, 68.6) by IRC with a median duration of response (mDoR) (range) of 9.8 months (1.1, 18.0) and 63.9% (46.2, 79.2) by INV with a mDOR of 17.1 months (1.3, 21.5). In 41 evaluable TBx pts, ORR was 41.5% (26.3, 57.9) by IRC and 58.5% (42.1, 73.7) by INV; mDoR was 12.4 months (1.1, 18.0; IRC) and 14.3 months (1.3, 21.5; INV). Of 11 evaluable Japanese pts, 6 were METex14 positive by LBx and 9 by TBx (overlap occurred). Confirmed responses were reported in 4/6 LBx pts and 3/9 TBx pts by IRC and in 4/6 LBx pts and 4/9 TBx pts by INV. Safety was evaluable in 69 pts. Main treatment-related adverse events (TRAEs; 15%) of any grade were peripheral edema (47.8%), diarrhea (18.8%), nausea (15.9%). The safety profile was similar in Japanese pts. TRAEs led to permanent discontinuation in 2 (2.9%) pts (1 ILD, 1 diarrhea & nausea). No TRAEs led to death. Conclusion: In NSCLC pts with METex14 mutations, tepotinib had promising clinical efficacy. Similar activity was observed in Japanese pts. The safety profile was favorable. Recruitment, including a MET amplification cohort, is ongoing.