- Email: [email protected]
A retrospective study of immune-related adverse events in various solid tumors
abstracts
Annals of Oncology
P2 189
The therapeutic effect and immune-related adverse event of nivolmab in Anjo Kosei Hospital
Yuichiro Inagaki1, Hirofumi Yokota1, Yuki Takeuchi1, Hitomi Sawa1, Takashi Seki2, Hidetoshi Akita3, Mamiko Takeuchi4, Shoji Mitsuya5, Junko Arima6, Eiji Yoneyama7, Masashi Sawa1 1 Department of Hematology and Oncology, Anjo Kosei Hospital, 2Department of Surgery, Anjo Kosei Hospital, 3Department of Urology, Anjo Kosei Hospital, 4Department of Gastroenterology, Anjo Kosei Hospital, 5Department of Otorhinolaryngology, Anjo Kosei Hospital, 6Division of Nursing, Anjo Kosei Hospital, 7Division of Pharmacology, Anjo Kosei Hospital Background: Nivolmab is approved as a novel immunocheckpoint inhibitor and peculiar immune-related adverse events (irAE) including interstitial lung disease (ILD), endocrinological disorder, and immunological colitis are reported. The rapid diagnosis and treatment are indispensable for the irAE of nivolmab. Cases and Methods: We examined the therapeutic effect and irAE of the 116 cases administrated nivolmab from February 2016 to January 2019 in Anjo Kosei Hospital. Result: The cases included 52 cases of non-squamous cell lung carcinoma (NSCLC), 20 cases of squamous cell lung carcinoma (SCLC), 12 cases of renal cell carcinoma (RCC) and adenocarcinoma of stomach, 5 cases of squamous carcinoma of head and neck region, and 3 cases of malignant melanoma and hodgkin lymphoma. The median observation period was 9.53 months in total. The median overall survival period was 26.8 months in the cases of NSCLC, 27.2 months in SCLC, 14.2 months in RCC, 11.0 months in adenocarcinoma of stomach, respectively. The 12 cases of hyper and hypothyroidism, 7 cases of colitis, 5 cases of ILD and endocrinological disorder, and other 15 cases of irAE were diagnosed. No case of novel diabetes mellitus was developed. The cumulative incidence rate of irAE reached 69.3% through all over the cases. The Brinkman Index over 700 was recognized as clinical factor for development of total irAE with significant p-value 0.039. No clinical factor for specific irAE including ILD, thyroid disorder, endocrinological disorder, colitis and diabetes mellitus respectively. Conclusion: We examined 116 cases administrated nivolmab and recognized equivalent effect with clinical trial and significant relation of Brinkman Index to development of irAE.
P2 195
L-Arginine metabolism alteration by L-Lysine intervention increased cell death in triple negative breast cancer cell
Reza Yarani1,2, Mozhgan Jahani1, Hadis Tahmasebi1, Javad Chehri3, Kamran Mansouri1 Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran, Denmark, 2Department of Clinical Research, Type 1 Diabetes Biology, Steno Diabetes Center, Copenhagen, Denmark, 3Moscow State Academy of Veterinary Medicine, Biotechnology (K.I. Skryabin), Russia
1
Background: L-Arginine effectiveness cancer therapy is a matter of controversy. LArginine is a substrate for different metabolites influencing cancer cells. Arginase and nitric oxide synthase (NOS) are two important enzymes in the L-Arginine metabolic pathway. Nitric oxide (NO) is produced by NOS and the main products of arginase activity are polyamines. NO can decrease cancer cells viability dependent on its concentration but, polyamines shown to promote cancer cell growth/metastasis. Due to Arginase and NOS competition over L-Arginine binding, inhibition of arginase activity seems to increase NOS activity as well as NO production. Thus, the aim of the present study is to affect L-Arginine metabolic pathway through L-Lysine induced arginase inhibition in MDA-MB-231 and MDA-MB-468 Methods: MDA-MB-231 and MDA-MB-468 were used as triple negative breast cancer cells with different arginase activity. Both cell lines were treated with different
Volume 30 | Supplement 6 | October 2019
concentrations of L-Arginine and L-Lysine. Cell viability was assessed by MTT assay 24 and 48h after treatment. Arginase activity, ROS level and NO concentration was examined. Cell cycle was assessed using flowcytometry. Real-time PCR was performed to assess apoptotic and metabolic genes expression Results: Our results indicated that cell viability and arginase activity were decreased in MDA-MB-468 with high arginase level more than MDA-MB-231 and studying the cell cycle also showed G2/M arrest in both cell lines following combination treatment with L-Lysine with L-Arginine. L-Lysine treatment resulted in increased apoptotic genes and decreased metabolic related genes expression in both cell lines Conclusion: Altogether, our findings indicated that alternation in L-Arginine metabolic pathway using L-Lysine causes higher NO concentration which consequently increases cell death in triple negative breast cancer cells with different arginase level, which in turn can increase L-Arginine effect on cell lines with higher arginase activity
P2 198
Antitumor effect of immune checkpoint inhibitor for subsequent therapy
Shigeru Tanaka1, Masaru Kondou1, Norihiro Takahara2, Eiichi Maruyama2, Shuuhei Hayashi2, Nobuaki Mukouyama3, Hidehito Tanaka3, Shouei You3, Shin Yamada4, Satoshi Katsuno4, Yuuta Kashiwagi4, Masataka Tamura4, Gyo Asai1 1 Department of Clinical Oncology, Okazaki City Hospital, 2Department of Respiratory Medicine, Okazaki City Hospital, 3Department of Otorhinolaryngology, Okazaki City Hospital, 4Department of Urology, Okazaki City Hospital Background: The pathway consisting of the receptor programmed cell death 1 (PD-1) and its ligands plays a crucial role to escape T cell-mediated immunity. Antibodies targeting PD-1 and its ligands have beneficial antitumor effects on many cancers, and some cases show long-time survival. Methods: We retrospectively reviewed medical records of non-small cell lung cancer (NSCLC), head and neck cancer, and renal cancer patients who received subsequent therapy (chemotherapy or targeted therapy) after the administration of anti PD-1 or PD-L1 antibody between January 2016 and December 2018 at Okazaki City Hospital. Subsequent therapy included S-1, Pemetrexed (PEM), Cisplatin (CDDP) þPEM þBevacizumab (BV) and PEM þBV maintenance, Carboplatin (CBDCA) þPEM and PEM maintenance, weekly Paclitaxel (wPTX), Docetaxel (DTX), Everolimus and Pazopanib. The latest analysis was performed in June 2019. Results: Of the 13 patients who had received anti PD-1 antibody (NSCLC/head and neck cancer/renal cancer, 7/3/3; Nivolumab/Pembrolizumab, 10/3), 2 had partial response and 7 had stable disease for the 1st line subsequent therapy (overall response rate, 15%; disease control rate, 69%). Duration of median progression free survival (PFS) at the therapy was 10.9 m (S-1 in NSCLC), 16.0 m (CDDPþPEMþBV and PEMþBV maintenance), NE (PEM), 6.2 m (CBDCAþ PEM and PEM maintenance), 5.0 m (wPTX), 0.5 m (DTX), 6.0 m (Everolimus) and 14.1 m (Pazopanib) each. Median overall survival was 14.0 m, and 7 of the 13 patients were still alive. Two patients with Grade 2 interstitial lung disease due to Everolimus and PEM were successfully treated. Conclusion: PFS of S-1 in NSCLC after the administration of anti PD-1 antibody was longer than that of the East Asia S-1 Trial in Lung Cancer. Interstitial lung disease due to targeted therapy was successfully managed.
P2 199
A retrospective study of immune-related adverse events in various solid tumors
Keitaro Shimozaki1, Yasutaka Sukawa1, Noriko Beppu3, Isao Kurihara4, Shigeaki Suzuki5, Seiji Asoda6, Hiroyuki Ozawa7, Ryuichi Mizuno8, Takeru Funakoshi9, Shinnosuke Ikemura2,10, Kai Tsugaru1, Kazuhiro Togasaki1, Kenta Kawasaki1, Kenro Hirata1, Hideyuki Hayashi2, Yasuo Hamamoto2, Takanori Kanai1, Hiromasa Takaishi2 1 Divison of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 2Keio Cancer Center, Keio University School of Meicine, 3 Department of Pharmacy, Keio University Hospital, 4Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, Keio University School of Medicine, 5Department of Neurology, Keio University School of Medicine, 6 Department of Dentistry and Oral surgery, Keio University School of Medicine, 7 Department of Otorhinolaryngology, Head and Neck Surgery,, Keio University School of Medicine, 8Department of Urology, Keio University School of Medicine, 9Department of Dermatology, Keio University School of Medicine, 10Division of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine Background: Immune checkpoint inhibitors (ICIs) have been approved in various type of cancers. Although ICIs are less toxic than cytotoxic chemotherapy, they cause various immune-related adverse events (irAEs). A cooperation with experts is needed to diagnose and treat irAEs properly. The aim of this study was to evaluate frequency and management of irAEs in a real-world practice. Methods: We conducted a retrospective study of patients(pts) who received ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab or avelumab) at Keio university hospital between September 2014 and January 2019. Treatment-related AEs were
doi:10.1093/annonc/mdz343 | vi135
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companion diagnostics has increased the need for the use of high-quality specimens for the diagnosis. Methods: From August 2015 to May 2018, 82 patients who were enrolled in a nationwide genome screening, LC-SCRUM-Japan, from our institution were examined for the success rates of genetic analysis according to sample types. A NGS analysis, Oncomine Comprehensive Assay, was performed using DNA and RNA extracted from lung cancer specimens. Results: The success rates of DNA and RNA analyses were 100% (82/82 cases) and 78% (64/82), respectively. Of the 82 samples analyzed, 80 (98%) were tissues and two (2%) were pleural effusions. The success rates of RNA analysis in the 80 tissue samples were 45/60 (73%) in bronchoscopic byopsy, 10/10(100%) in operation, 5/6(83%) in Percutaneous biopsy and 3/4(75%) in others. Of the 60 bronchoscopic samples, the success rates were 72% (18/25) in EBUS-TBNA, 88% (7/8) in EBUS-GS (large diameter), 69% (11/16) in EBUS-GS (small diameter) and 82% (9/11) in direct vision biopsy. In the 82 cases analyzed, a total of 52 actionable gene alterations (18 KRAS mut, 6 EGFR mut, 6 MET amp/fus, 5 RET fus, 5 ALK fus, 4 PIK3CA mut, 2 ERBB2 mut, 2 ROS1 fus, 2 FGFR1 amp, 1 BRAF mut, 1 FGFR3 fus) were detected in 48 cases (59%). Twelve of the 48 (15%) were registered in ongoing clinical trials of targeted drugs. Conclusions: All the samples were available for DNA analysis of the NGS. The success rates of RNA analysis were lower in samples obtained from EBUS-TBNA and EBUS-GS (small diameter), suggesting that the success rates depend on the sample size.
abstracts
P2 200
Management of Liver Dysfunction Developing as an ImmuneRelated Adverse Event
Makoto Arai1, Akinobu Tawada1, Chiaki Imai2, Yuichi Takiguchi1 Department of Medical Oncology, Chiba University, 2Division of Pharmacy, Chiba University Hospital
1
Background: The side effects of the immune checkpoint inhibitors are designated as immune-related adverse events (irAEs). Liver dysfunction is one of the well-known irAEs. According to the irAE guideline (JSMO), steroid treatment is definitely indicated for liver dysfunction developing as an irAE, however, there is no mention of evaluation of the prothrombin time, which is one of the most important parameters in the management of acute liver failure. In addition, the role of image evaluation is not documented. In this study, we retrospectively evaluated the severity of liver dysfunction and the most suitable treatment in cases of liver dysfunction occurring as an irAE. Methods: From August 2015 to June 2018, 224 cases were treated with immune checkpoint inhibitors (nivolumab, 153; pembrolizumab, 62; ipilimumab, 9 cases) at our hospital. We conducted a retrospective evaluation of the incidence rate, severity, examination findings, treatment, and imaging findings of liver dysfunction occurring as an irAE. Results: Twenty-three patients (10.2%) developed liver dysfunction as an irAE (nivolumab, 14; pembrolizumab, 7; ipilimumab, 2 cases). In one patient, HCV infection was detected and treated with direct-acting antiviral agents. Liver biopsy was performed in two patients. One patient with liver dysfunction who showed wall thickening of the common bile duct on CT and cholangitis on liver biopsy received steroid therapy. Four patients received treatment with Stronger Neo-Minophagen C (glycyrrhizin, SNMC) and four patients received treatment with ursodeoxycholic acid (UDCA). Conclusions: It appears that most cases of liver dysfunction developing in patients receiving checkpoint inhibitors are not treated with a steroid, and that UDCA and SNMC are used more widely for the treatment. Liver biopsy and imaging findings (US and CT) could be useful for evaluating the pathophysiology of liver dysfunction occurring as an irAE.
P2 205
To establish the procedures of microsatellite instability testing for the solid cancer in our hospital
Akihiro Shinji1, Kuniyuki Gomi2, Yuko Hasebe3, Motohiro Mihara2, Toshitugu Nakamura4, Shinya Houkibara4 1 Department of Medical Oncology, Suwa red cross hospital, 2Department of Gastroenterological Surgery, Suwa red cross hospital, 3Nursing unit, Suwa red cross hospital, 4Department of Diagnostic Pathology, Suwa red cross hospital Background: In December 2018, we can have microsatellite instability testing for the solid tumors in clinical practice in Japan. The microsatellite instability testing was used to check out familial tumors called Lynch syndrome, for which we must care patients with genetic counseling. Purpose: To make the rule of the microsatellite instability testing in our hospital, conducting the testing smoothly. Method: We discussed with the pathological examination section and listed out several problems suspected with MSI testing. One thing was considering genetic counseling, others were increasing of the burden of each doctors to explain the MSI testing, increasing tasks of the pathological examination section. To resolve these problems, the MSI testing was ordered only by the Doctor of Medical oncology department using the consent form based on the Japanese society for Familial Tumors and arranged by us. If patients needed to genetic counseling, we would consult to Center for Medical
vi136 | Poster Session
Genetics, Shinshu University. With the formal process we decided to make the rule of the MSI testing. Results: From December 2018 to the end of February 2019, for 29 patients we had the MSI testing under the rule, which were 9 colorectal carcinoma, 5 soft tissue sarcoma, 3 pancreatic carcinoma, 3 ovarian carcinoma, 3 cervical carcinoma, 3 bile duct carcinoma, 2 endometrial carcinoma, and 1 head and neck carcinoma. Only 1 case among 27 cases whose results were found was MSI-H for the testing. It took 13 days on average to find the test results. There are no problems with the testing. Conclusion: To make the MSI testing smoothly, Medical oncologist can play a role of it
P2 206
Companion diagnosis by BRACAnalysis CDxTM and therapeutic experience of Olaparib for HER2-negative breast cancer
Yuri Kimura, Tomoko Itagaki, Masahiro Ohara Department of Breast surgery, Hiroshima General Hospital Background: Olaparib has been approved for patients with germline BRCA1/2 mutations who have HER2 negative advanced / recurrent breast cancer, and BRACAnalysis diagnostic systemTM was started as a companion diagnostics, greatly advancing breast cancer treatment based on genetic diagnosis. We report the current status of companion diagnostics and the therapeutic experience of Olaparib. Methods: Between July 2018 and February 2019, information on BRACAnalysis diagnostic systemTM and hereditary breast and ovarian cancer was provided to patients with HER2 negative advanced / recurrent breast cancer. Results: Median age was 52 years. Twelve patients with breast cancer received companion diagnostics (5 advanced and 7 recurrent). Median treatment line at the time of the examination was 3, 8 cases were under chemotherapy. Deleterious mutations were detected in 1 case of BRCA1 (1651insG), 1 case of BRCA2 (4081insG) and 1 case of VUS (Q84E 478 C>G). A 53 - year - old female patient received Olaparib, with a strong family history of breast cancer (elder sister, maternal cousin and 2 maternal aunt). The pathological diagnosis was invasive ductal carcinoma, cT1cN3cM1 (OSS, LYM), Stage IV, ER (þ), PgR (-), HER2 (-), and Ki-67 50 %. In 6th line chemotherapy, companion diagnostics revealed a germ line BRCA1 mutations. Subsequently, consciousness disturbance due to meningeal dissemination appeared, and commenced Olaparib on 7th line. Improvement of consciousness disturbance, decrease of tumor marker was observed, therapeutic effect was obtained, but her general condition deteriorated and died 3 months after meningeal dissemination diagnosis. Conclusion: We experienced a patient in which Olaparib was effective for late line. While further development of precision medicine is expected, active companion diagnostics for eligible patients should be considered.
P2 208
Current progress and issues of cancer genomic medicine in Kyushu University Hospital
Mamoru Ito1, Hitomi Kawaji2, Makoto Kubo2, Eiji Oki3, Eiji Iwama4, Takahiro Maeda5, Masanobu Ogawa6, Masayuki Ochiai7, Sawako Shikada8, Hidetaka Yamamoto9, Maya Suzuki10, Koji Todaka10, Naoki Nakashima11, Minako Yoshihara12, Mikita Suyama12, Eishi Baba4, Koichi Akashi1, Yoichi Nakanishi13 1 Department of Hematology, Oncology & Cardiovascular medicine, Kyushu University, 2 Department of Surgery and Oncology, Kyushu University, 3Department of Surgery and Science, Kyushu University, 4Department of Comprehensive Clinical Oncology, Kyushu University, 5Center for Cellular & Molecular Medicine, Kyushu University Hospital, 6 Research Center for Environment and Developmental Medical Science, Kyushu University, 7Department of Pediatrics, Kyushu University, 8Clinical Genetics, Kyushu University Hospital, 9Department of Anatomic Pathology, Pathological Science, Kyushu University, 10Center for Clinical and Translational Research, Kyushu University Hospital, 11 Medical Information Center, Kyushu University Hospital, 12Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, 13Research Institute for Diseases of the Chest, Kyushu University Kyushu University Hospital has been designated as a Core Hospital for Cancer Genomic Medicine since February 2018. Our institution promotes cancer genomic medicine collaborating with 16 Cooperative Hospitals for Cancer Genomic Medicine among Kyushu, Chugoku, and Shikoku region. From November 2018 to March 2019, a total of 120 solid tumor cases has been examined by clinical sequencing tests and the results have been intensively evaluated and discussed in the expert panel meetings. One of the features of our institution is an employment of multiple clinical sequencing tests for different purposes and that the concordance of each test is assessed. In our institution, a cancer genomic outpatient, which enhanced genetic counseling division, has been started and a new hospital information system for cancer genomic medicine was developed. This hospital information system integrates the result of a cancer genome sequence report and physicians can refer to the progress and results of clinical sequencing test in real time. Current progress and issues of cancer genomic medicine in Kyushu University Hospital will be presented.
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retrospectively evaluated from medical records and graded using Common Terminology Criteria for Adverse Events version 4. Results: ICIs were administered in 299 pts with lung cancer (n ¼ 123), malignant melanoma (n ¼ 63), renal cell carcinoma (n ¼ 37), gastric cancer (n ¼ 29), head and neck cancer (n ¼ 26), urothelial cancer (n ¼ 19), Merkel cell carcinoma and microsatellite instability-high ovary cancer (n ¼ 1). A total of 209 pts experienced any grade of AEs. In 60 pts experienced grade 3 AEs, pneumonitis and ALT increased (5.3%) were most frequently identified, followed by adrenal insufficiency (3.0%) and diarrhoea (2.7%). No cancer-type specific tendency was observed. Pts who were treated with ipilimumab experienced 3 AEs more frequently than those with anti-PD1 antibodies (p ¼ 0.0003). Regarding the treatment to grade 3 AEs, all pts with pneumonitis received therapeutic intervention by respiratory physicians. Although only 63% of diarrhoea and 50% of ALT increased pts had an examination by gastroenterologists or hepatologists, those who needed immunosuppressive treatment were supported by experts appropriately. Conclusions: The incidence of ICI-related AEs in our hospital was comparable to previous reports. The cooperation with experts for irAEs would be important for proper management of irAEs.
Annals of Oncology
Annals of Oncology
P2 189
The therapeutic effect and immune-related adverse event of nivolmab in Anjo Kosei Hospital
Yuichiro Inagaki1, Hirofumi Yokota1, Yuki Takeuchi1, Hitomi Sawa1, Takashi Seki2, Hidetoshi Akita3, Mamiko Takeuchi4, Shoji Mitsuya5, Junko Arima6, Eiji Yoneyama7, Masashi Sawa1 1 Department of Hematology and Oncology, Anjo Kosei Hospital, 2Department of Surgery, Anjo Kosei Hospital, 3Department of Urology, Anjo Kosei Hospital, 4Department of Gastroenterology, Anjo Kosei Hospital, 5Department of Otorhinolaryngology, Anjo Kosei Hospital, 6Division of Nursing, Anjo Kosei Hospital, 7Division of Pharmacology, Anjo Kosei Hospital Background: Nivolmab is approved as a novel immunocheckpoint inhibitor and peculiar immune-related adverse events (irAE) including interstitial lung disease (ILD), endocrinological disorder, and immunological colitis are reported. The rapid diagnosis and treatment are indispensable for the irAE of nivolmab. Cases and Methods: We examined the therapeutic effect and irAE of the 116 cases administrated nivolmab from February 2016 to January 2019 in Anjo Kosei Hospital. Result: The cases included 52 cases of non-squamous cell lung carcinoma (NSCLC), 20 cases of squamous cell lung carcinoma (SCLC), 12 cases of renal cell carcinoma (RCC) and adenocarcinoma of stomach, 5 cases of squamous carcinoma of head and neck region, and 3 cases of malignant melanoma and hodgkin lymphoma. The median observation period was 9.53 months in total. The median overall survival period was 26.8 months in the cases of NSCLC, 27.2 months in SCLC, 14.2 months in RCC, 11.0 months in adenocarcinoma of stomach, respectively. The 12 cases of hyper and hypothyroidism, 7 cases of colitis, 5 cases of ILD and endocrinological disorder, and other 15 cases of irAE were diagnosed. No case of novel diabetes mellitus was developed. The cumulative incidence rate of irAE reached 69.3% through all over the cases. The Brinkman Index over 700 was recognized as clinical factor for development of total irAE with significant p-value 0.039. No clinical factor for specific irAE including ILD, thyroid disorder, endocrinological disorder, colitis and diabetes mellitus respectively. Conclusion: We examined 116 cases administrated nivolmab and recognized equivalent effect with clinical trial and significant relation of Brinkman Index to development of irAE.
P2 195
L-Arginine metabolism alteration by L-Lysine intervention increased cell death in triple negative breast cancer cell
Reza Yarani1,2, Mozhgan Jahani1, Hadis Tahmasebi1, Javad Chehri3, Kamran Mansouri1 Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran, Denmark, 2Department of Clinical Research, Type 1 Diabetes Biology, Steno Diabetes Center, Copenhagen, Denmark, 3Moscow State Academy of Veterinary Medicine, Biotechnology (K.I. Skryabin), Russia
1
Background: L-Arginine effectiveness cancer therapy is a matter of controversy. LArginine is a substrate for different metabolites influencing cancer cells. Arginase and nitric oxide synthase (NOS) are two important enzymes in the L-Arginine metabolic pathway. Nitric oxide (NO) is produced by NOS and the main products of arginase activity are polyamines. NO can decrease cancer cells viability dependent on its concentration but, polyamines shown to promote cancer cell growth/metastasis. Due to Arginase and NOS competition over L-Arginine binding, inhibition of arginase activity seems to increase NOS activity as well as NO production. Thus, the aim of the present study is to affect L-Arginine metabolic pathway through L-Lysine induced arginase inhibition in MDA-MB-231 and MDA-MB-468 Methods: MDA-MB-231 and MDA-MB-468 were used as triple negative breast cancer cells with different arginase activity. Both cell lines were treated with different
Volume 30 | Supplement 6 | October 2019
concentrations of L-Arginine and L-Lysine. Cell viability was assessed by MTT assay 24 and 48h after treatment. Arginase activity, ROS level and NO concentration was examined. Cell cycle was assessed using flowcytometry. Real-time PCR was performed to assess apoptotic and metabolic genes expression Results: Our results indicated that cell viability and arginase activity were decreased in MDA-MB-468 with high arginase level more than MDA-MB-231 and studying the cell cycle also showed G2/M arrest in both cell lines following combination treatment with L-Lysine with L-Arginine. L-Lysine treatment resulted in increased apoptotic genes and decreased metabolic related genes expression in both cell lines Conclusion: Altogether, our findings indicated that alternation in L-Arginine metabolic pathway using L-Lysine causes higher NO concentration which consequently increases cell death in triple negative breast cancer cells with different arginase level, which in turn can increase L-Arginine effect on cell lines with higher arginase activity
P2 198
Antitumor effect of immune checkpoint inhibitor for subsequent therapy
Shigeru Tanaka1, Masaru Kondou1, Norihiro Takahara2, Eiichi Maruyama2, Shuuhei Hayashi2, Nobuaki Mukouyama3, Hidehito Tanaka3, Shouei You3, Shin Yamada4, Satoshi Katsuno4, Yuuta Kashiwagi4, Masataka Tamura4, Gyo Asai1 1 Department of Clinical Oncology, Okazaki City Hospital, 2Department of Respiratory Medicine, Okazaki City Hospital, 3Department of Otorhinolaryngology, Okazaki City Hospital, 4Department of Urology, Okazaki City Hospital Background: The pathway consisting of the receptor programmed cell death 1 (PD-1) and its ligands plays a crucial role to escape T cell-mediated immunity. Antibodies targeting PD-1 and its ligands have beneficial antitumor effects on many cancers, and some cases show long-time survival. Methods: We retrospectively reviewed medical records of non-small cell lung cancer (NSCLC), head and neck cancer, and renal cancer patients who received subsequent therapy (chemotherapy or targeted therapy) after the administration of anti PD-1 or PD-L1 antibody between January 2016 and December 2018 at Okazaki City Hospital. Subsequent therapy included S-1, Pemetrexed (PEM), Cisplatin (CDDP) þPEM þBevacizumab (BV) and PEM þBV maintenance, Carboplatin (CBDCA) þPEM and PEM maintenance, weekly Paclitaxel (wPTX), Docetaxel (DTX), Everolimus and Pazopanib. The latest analysis was performed in June 2019. Results: Of the 13 patients who had received anti PD-1 antibody (NSCLC/head and neck cancer/renal cancer, 7/3/3; Nivolumab/Pembrolizumab, 10/3), 2 had partial response and 7 had stable disease for the 1st line subsequent therapy (overall response rate, 15%; disease control rate, 69%). Duration of median progression free survival (PFS) at the therapy was 10.9 m (S-1 in NSCLC), 16.0 m (CDDPþPEMþBV and PEMþBV maintenance), NE (PEM), 6.2 m (CBDCAþ PEM and PEM maintenance), 5.0 m (wPTX), 0.5 m (DTX), 6.0 m (Everolimus) and 14.1 m (Pazopanib) each. Median overall survival was 14.0 m, and 7 of the 13 patients were still alive. Two patients with Grade 2 interstitial lung disease due to Everolimus and PEM were successfully treated. Conclusion: PFS of S-1 in NSCLC after the administration of anti PD-1 antibody was longer than that of the East Asia S-1 Trial in Lung Cancer. Interstitial lung disease due to targeted therapy was successfully managed.
P2 199
A retrospective study of immune-related adverse events in various solid tumors
Keitaro Shimozaki1, Yasutaka Sukawa1, Noriko Beppu3, Isao Kurihara4, Shigeaki Suzuki5, Seiji Asoda6, Hiroyuki Ozawa7, Ryuichi Mizuno8, Takeru Funakoshi9, Shinnosuke Ikemura2,10, Kai Tsugaru1, Kazuhiro Togasaki1, Kenta Kawasaki1, Kenro Hirata1, Hideyuki Hayashi2, Yasuo Hamamoto2, Takanori Kanai1, Hiromasa Takaishi2 1 Divison of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 2Keio Cancer Center, Keio University School of Meicine, 3 Department of Pharmacy, Keio University Hospital, 4Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, Keio University School of Medicine, 5Department of Neurology, Keio University School of Medicine, 6 Department of Dentistry and Oral surgery, Keio University School of Medicine, 7 Department of Otorhinolaryngology, Head and Neck Surgery,, Keio University School of Medicine, 8Department of Urology, Keio University School of Medicine, 9Department of Dermatology, Keio University School of Medicine, 10Division of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine Background: Immune checkpoint inhibitors (ICIs) have been approved in various type of cancers. Although ICIs are less toxic than cytotoxic chemotherapy, they cause various immune-related adverse events (irAEs). A cooperation with experts is needed to diagnose and treat irAEs properly. The aim of this study was to evaluate frequency and management of irAEs in a real-world practice. Methods: We conducted a retrospective study of patients(pts) who received ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab or avelumab) at Keio university hospital between September 2014 and January 2019. Treatment-related AEs were
doi:10.1093/annonc/mdz343 | vi135
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companion diagnostics has increased the need for the use of high-quality specimens for the diagnosis. Methods: From August 2015 to May 2018, 82 patients who were enrolled in a nationwide genome screening, LC-SCRUM-Japan, from our institution were examined for the success rates of genetic analysis according to sample types. A NGS analysis, Oncomine Comprehensive Assay, was performed using DNA and RNA extracted from lung cancer specimens. Results: The success rates of DNA and RNA analyses were 100% (82/82 cases) and 78% (64/82), respectively. Of the 82 samples analyzed, 80 (98%) were tissues and two (2%) were pleural effusions. The success rates of RNA analysis in the 80 tissue samples were 45/60 (73%) in bronchoscopic byopsy, 10/10(100%) in operation, 5/6(83%) in Percutaneous biopsy and 3/4(75%) in others. Of the 60 bronchoscopic samples, the success rates were 72% (18/25) in EBUS-TBNA, 88% (7/8) in EBUS-GS (large diameter), 69% (11/16) in EBUS-GS (small diameter) and 82% (9/11) in direct vision biopsy. In the 82 cases analyzed, a total of 52 actionable gene alterations (18 KRAS mut, 6 EGFR mut, 6 MET amp/fus, 5 RET fus, 5 ALK fus, 4 PIK3CA mut, 2 ERBB2 mut, 2 ROS1 fus, 2 FGFR1 amp, 1 BRAF mut, 1 FGFR3 fus) were detected in 48 cases (59%). Twelve of the 48 (15%) were registered in ongoing clinical trials of targeted drugs. Conclusions: All the samples were available for DNA analysis of the NGS. The success rates of RNA analysis were lower in samples obtained from EBUS-TBNA and EBUS-GS (small diameter), suggesting that the success rates depend on the sample size.
abstracts
P2 200
Management of Liver Dysfunction Developing as an ImmuneRelated Adverse Event
Makoto Arai1, Akinobu Tawada1, Chiaki Imai2, Yuichi Takiguchi1 Department of Medical Oncology, Chiba University, 2Division of Pharmacy, Chiba University Hospital
1
Background: The side effects of the immune checkpoint inhibitors are designated as immune-related adverse events (irAEs). Liver dysfunction is one of the well-known irAEs. According to the irAE guideline (JSMO), steroid treatment is definitely indicated for liver dysfunction developing as an irAE, however, there is no mention of evaluation of the prothrombin time, which is one of the most important parameters in the management of acute liver failure. In addition, the role of image evaluation is not documented. In this study, we retrospectively evaluated the severity of liver dysfunction and the most suitable treatment in cases of liver dysfunction occurring as an irAE. Methods: From August 2015 to June 2018, 224 cases were treated with immune checkpoint inhibitors (nivolumab, 153; pembrolizumab, 62; ipilimumab, 9 cases) at our hospital. We conducted a retrospective evaluation of the incidence rate, severity, examination findings, treatment, and imaging findings of liver dysfunction occurring as an irAE. Results: Twenty-three patients (10.2%) developed liver dysfunction as an irAE (nivolumab, 14; pembrolizumab, 7; ipilimumab, 2 cases). In one patient, HCV infection was detected and treated with direct-acting antiviral agents. Liver biopsy was performed in two patients. One patient with liver dysfunction who showed wall thickening of the common bile duct on CT and cholangitis on liver biopsy received steroid therapy. Four patients received treatment with Stronger Neo-Minophagen C (glycyrrhizin, SNMC) and four patients received treatment with ursodeoxycholic acid (UDCA). Conclusions: It appears that most cases of liver dysfunction developing in patients receiving checkpoint inhibitors are not treated with a steroid, and that UDCA and SNMC are used more widely for the treatment. Liver biopsy and imaging findings (US and CT) could be useful for evaluating the pathophysiology of liver dysfunction occurring as an irAE.
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To establish the procedures of microsatellite instability testing for the solid cancer in our hospital
Akihiro Shinji1, Kuniyuki Gomi2, Yuko Hasebe3, Motohiro Mihara2, Toshitugu Nakamura4, Shinya Houkibara4 1 Department of Medical Oncology, Suwa red cross hospital, 2Department of Gastroenterological Surgery, Suwa red cross hospital, 3Nursing unit, Suwa red cross hospital, 4Department of Diagnostic Pathology, Suwa red cross hospital Background: In December 2018, we can have microsatellite instability testing for the solid tumors in clinical practice in Japan. The microsatellite instability testing was used to check out familial tumors called Lynch syndrome, for which we must care patients with genetic counseling. Purpose: To make the rule of the microsatellite instability testing in our hospital, conducting the testing smoothly. Method: We discussed with the pathological examination section and listed out several problems suspected with MSI testing. One thing was considering genetic counseling, others were increasing of the burden of each doctors to explain the MSI testing, increasing tasks of the pathological examination section. To resolve these problems, the MSI testing was ordered only by the Doctor of Medical oncology department using the consent form based on the Japanese society for Familial Tumors and arranged by us. If patients needed to genetic counseling, we would consult to Center for Medical
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Genetics, Shinshu University. With the formal process we decided to make the rule of the MSI testing. Results: From December 2018 to the end of February 2019, for 29 patients we had the MSI testing under the rule, which were 9 colorectal carcinoma, 5 soft tissue sarcoma, 3 pancreatic carcinoma, 3 ovarian carcinoma, 3 cervical carcinoma, 3 bile duct carcinoma, 2 endometrial carcinoma, and 1 head and neck carcinoma. Only 1 case among 27 cases whose results were found was MSI-H for the testing. It took 13 days on average to find the test results. There are no problems with the testing. Conclusion: To make the MSI testing smoothly, Medical oncologist can play a role of it
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Companion diagnosis by BRACAnalysis CDxTM and therapeutic experience of Olaparib for HER2-negative breast cancer
Yuri Kimura, Tomoko Itagaki, Masahiro Ohara Department of Breast surgery, Hiroshima General Hospital Background: Olaparib has been approved for patients with germline BRCA1/2 mutations who have HER2 negative advanced / recurrent breast cancer, and BRACAnalysis diagnostic systemTM was started as a companion diagnostics, greatly advancing breast cancer treatment based on genetic diagnosis. We report the current status of companion diagnostics and the therapeutic experience of Olaparib. Methods: Between July 2018 and February 2019, information on BRACAnalysis diagnostic systemTM and hereditary breast and ovarian cancer was provided to patients with HER2 negative advanced / recurrent breast cancer. Results: Median age was 52 years. Twelve patients with breast cancer received companion diagnostics (5 advanced and 7 recurrent). Median treatment line at the time of the examination was 3, 8 cases were under chemotherapy. Deleterious mutations were detected in 1 case of BRCA1 (1651insG), 1 case of BRCA2 (4081insG) and 1 case of VUS (Q84E 478 C>G). A 53 - year - old female patient received Olaparib, with a strong family history of breast cancer (elder sister, maternal cousin and 2 maternal aunt). The pathological diagnosis was invasive ductal carcinoma, cT1cN3cM1 (OSS, LYM), Stage IV, ER (þ), PgR (-), HER2 (-), and Ki-67 50 %. In 6th line chemotherapy, companion diagnostics revealed a germ line BRCA1 mutations. Subsequently, consciousness disturbance due to meningeal dissemination appeared, and commenced Olaparib on 7th line. Improvement of consciousness disturbance, decrease of tumor marker was observed, therapeutic effect was obtained, but her general condition deteriorated and died 3 months after meningeal dissemination diagnosis. Conclusion: We experienced a patient in which Olaparib was effective for late line. While further development of precision medicine is expected, active companion diagnostics for eligible patients should be considered.
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Current progress and issues of cancer genomic medicine in Kyushu University Hospital
Mamoru Ito1, Hitomi Kawaji2, Makoto Kubo2, Eiji Oki3, Eiji Iwama4, Takahiro Maeda5, Masanobu Ogawa6, Masayuki Ochiai7, Sawako Shikada8, Hidetaka Yamamoto9, Maya Suzuki10, Koji Todaka10, Naoki Nakashima11, Minako Yoshihara12, Mikita Suyama12, Eishi Baba4, Koichi Akashi1, Yoichi Nakanishi13 1 Department of Hematology, Oncology & Cardiovascular medicine, Kyushu University, 2 Department of Surgery and Oncology, Kyushu University, 3Department of Surgery and Science, Kyushu University, 4Department of Comprehensive Clinical Oncology, Kyushu University, 5Center for Cellular & Molecular Medicine, Kyushu University Hospital, 6 Research Center for Environment and Developmental Medical Science, Kyushu University, 7Department of Pediatrics, Kyushu University, 8Clinical Genetics, Kyushu University Hospital, 9Department of Anatomic Pathology, Pathological Science, Kyushu University, 10Center for Clinical and Translational Research, Kyushu University Hospital, 11 Medical Information Center, Kyushu University Hospital, 12Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, 13Research Institute for Diseases of the Chest, Kyushu University Kyushu University Hospital has been designated as a Core Hospital for Cancer Genomic Medicine since February 2018. Our institution promotes cancer genomic medicine collaborating with 16 Cooperative Hospitals for Cancer Genomic Medicine among Kyushu, Chugoku, and Shikoku region. From November 2018 to March 2019, a total of 120 solid tumor cases has been examined by clinical sequencing tests and the results have been intensively evaluated and discussed in the expert panel meetings. One of the features of our institution is an employment of multiple clinical sequencing tests for different purposes and that the concordance of each test is assessed. In our institution, a cancer genomic outpatient, which enhanced genetic counseling division, has been started and a new hospital information system for cancer genomic medicine was developed. This hospital information system integrates the result of a cancer genome sequence report and physicians can refer to the progress and results of clinical sequencing test in real time. Current progress and issues of cancer genomic medicine in Kyushu University Hospital will be presented.
Volume 30 | Supplement 6 | October 2019
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retrospectively evaluated from medical records and graded using Common Terminology Criteria for Adverse Events version 4. Results: ICIs were administered in 299 pts with lung cancer (n ¼ 123), malignant melanoma (n ¼ 63), renal cell carcinoma (n ¼ 37), gastric cancer (n ¼ 29), head and neck cancer (n ¼ 26), urothelial cancer (n ¼ 19), Merkel cell carcinoma and microsatellite instability-high ovary cancer (n ¼ 1). A total of 209 pts experienced any grade of AEs. In 60 pts experienced grade 3 AEs, pneumonitis and ALT increased (5.3%) were most frequently identified, followed by adrenal insufficiency (3.0%) and diarrhoea (2.7%). No cancer-type specific tendency was observed. Pts who were treated with ipilimumab experienced 3 AEs more frequently than those with anti-PD1 antibodies (p ¼ 0.0003). Regarding the treatment to grade 3 AEs, all pts with pneumonitis received therapeutic intervention by respiratory physicians. Although only 63% of diarrhoea and 50% of ALT increased pts had an examination by gastroenterologists or hepatologists, those who needed immunosuppressive treatment were supported by experts appropriately. Conclusions: The incidence of ICI-related AEs in our hospital was comparable to previous reports. The cooperation with experts for irAEs would be important for proper management of irAEs.
Annals of Oncology