- Email: [email protected]
The effect of proton pump inhibitors on the efficacy of nivolumab monotherapy in different types of cancer
abstracts
Annals of Oncology
MO3 10 1
The effect of proton pump inhibitors on the efficacy of nivolumab monotherapy in different types of cancer
Quy Pham Nguyen, Motoo Nomura, Shigemi Matsumoto, Manabu Muto Department of Medical Oncology, Kyoto University Background: Solid tumors are characterized by a highly acidic microenvironment that might hamper anti-cancer immunity. Several studies have shown that proton pump inhibitors (PPIs) can neutralize the pH of the tumor microenvironment and indirectly affect the function of cytotoxic T lymphocytes, suggesting a possible impact on clinical outcomes of immunotherapies. The aim of this analysis to explore the relationship between the use of PPIs and the efficacy of nivolumab monotherapy in 4 different types of cancer: malignant melanoma (MM), renal cell carcinoma (RCC), gastric cancer (GC), and head and neck cancer (HN). Methods: A retrospective chart review was performed on 95 consecutive patients treated with nivolumab monotherapy between October 2014 and December 2018 at our hospital. Co-medication of PPIs was defined if the patient was prescribed any types of PPIs for more than 2 weeks during the administration of nivolumab. Response rates (RR), progression-free survival (PFS) and overall survival (OS) were compared between PPI users and non-users. Results: The majority of patients were males (65.3%). The median age was 68 years. MM was the most common diagnosis (47.4%) followed by HN (24.2%) and GC (17.8%). PPIs were prescribed in 42% of the cases. There was no statistically significant difference in RR, OS or PFS between PPI users and non-users in GC and HN. However, co-medication of PPIs was associated with lower RR in MM, but higher RR in RCC. Although these results did not translate into significant changes in the PFS or OS, differences were observed in the Kaplan-Meyer curves of these two types of cancer. Conclusion: Our analysis shows that PPIs could have different impact on the benefit of nivolumab monotherapy. These results suggest that unnecessary prescription of PPIs should be avoided in patients who are receiving PD1-based immunotherapy for the treatment of MM, and the effect of PPIs should be considered in interpreting the results from clinical trials.
MO3 10 2
Association of gastric acid suppression with efficacy of immune checkpoint inhibitors (ICIs) in advanced cancer patients
Naoki Izawa1, Hisae Shiokawa2, Risa Onuki2, Koki Hamaji2, Naoki Furuya3, Hiroyuki Ohashi4, Tomohiro Nishi5, Shigeru Kasugai6, Hiroyuki Arai1, Ayako Doi1, Yoshiki Horie1, Mami Hirakawa1, Takuro Mizukami1, Takashi Ogura1, Takashi Tsuda1, Yu Sunakawa1, Takako Nakajima1 1 St. Marianna University School of Medicine, Department of Clinical Oncology, 2St. Marianna University School of Medicine, Department of pharmacy, 3St. Marianna University School of Medicine, Division of Respiratory and Infectious Diseases,Department of Internal Medicine, 4St. Marianna University School of Medicine, Department of Dermatology, 5St. Marianna University School of Medicine, Department of Urology, 6St. Marianna University School of Medicine, Department of Otolaryngology Background: Recent studies have shown that proton pump inhibitor (PPI) negatively impacts on the clinical benefit from ICIs. Gut microbiome modulated by PPI may contribute to decreased efficacy. It has been also reported that H2 blocker (H2B) or gastrectomy affected gut microbiome. We assessed in this study the association of GAS including PPI, H2B and gastrectomy with clinical outcome from ICI. Methods: We retrospectively investigated advanced cancers pts treated with ICIs as the 1st- to the 3rd-line treatment at our institution between July 2014 and September 2018.
Volume 30 | Supplement 6 | October 2019
GAS was defined as using PPI or H2B within 30 days before start of ICI, or having past history of gastrectomy. Response to ICIs was assessed by RECIST v1.1. Performance status (PS), body mass index, antibiotics, steroid, LDH level, albumin level, CPR and neutrophil-lymphocyte ratio (NLR) were compared between the GAS and non-GAS arms. Associations of nominal variables with the response were evaluated. Results: Total of 115 pts (lung 69.9%, skin 11.3%, head and neck 7.8%, renal cell 6.9%, stomach 4.2%, and urothelium 2.5%) were evaluated. The types of ICIs were nivolumab of 72.2%, pembrolizumab of 22.6%, and atezolizumab of 5.2%. Sixty of 115 pts recieved GAS (PPI 83.3%, H2B 11.6%, and gastorectomy 5%) before start of ICI. Patients’ characteristics between the GAS and non-GAS arms was almost well balanced. However, pts with lower PS (>2) or high NLR were more frequently observed in the GAS arm (20% vs. 0%, 40% vs. 16%, respectively). The response rate (RR) was almost significantly lower in the GAS arm than the non-GAS arm (12% vs. 25%, P ¼ 0.055). GAS did not remain statistically significant in a multivariate analysis (P ¼ 0.091), while LDH was significant in both uni- and multivariate analyses. Conclusion: Pts with GAS and pts without GAS have different patients’ background such as PS and NLR, and the RR in pts with GAS was numerically lower compared to that without GAS in advanced cancer treated with ICI.
MO3 10 3
Sustained fever associated with immune checkpoint inhibitors may be a poor prognostic factor
Hiroki Ueda, Eriko Murakami, Yuka Okuda, Eri Takase, Takahiro Kaki, Yuhei Harutani, Nao Yamagata, Katsuyuki Furuta, Chigusa Shimono, Nobuyuki Yamamoto Wakayama Medical University,Department of Pulmonary Medicine and Oncology Immune-checkpoint inhibitors (ICIs) have been established as novel standard treatment for various types of malignancies, and immune-related adverse events (irAEs) are frequently observed with ICIs. This study aimed to evaluate whether fever associated with ICIs correlates with treatment response or prognosis. We conducted a retrospective study of patients who received anti PD-1antibody monotherapy at Wakayama Medical University hospital (n ¼ 188). Fever was classified as transient fever related to irAE and infection and sustained fever from onset of ICI administration. Sustained fever was observed in 10 out of 188 people (5.3%), and all cases were controlled with Acetaminophen or Naproxen. All patients with sustained fever and had high tumor burden and Performance Status 1 or 2. In 7 of 10 patients, PS decreased rapidly after ICI administration and the second cycle was discontinued and died within 3 months. Three out of ten cases were able to continue, three patients were both effective, fever disappeared and antipyretics were also stopped. Our data suggest that Sustained fever after ICI administration was considered to be a poor prognostic factor unless response.
MO3 10 5
Safety of PD-1/PD-L1 blockade in patients with preexisting positive antinuclear antibodies and autoimmune disease
Tomoki Sakakida1, Takeshi Ishikawa1,2, Yusuke Chihara2,3, Sachi Harita3, Junji Uchino3, Yusuke Tabuchi2,10, Satoshi Komori4, Jun Asai4, Tsukasa Narukawa5, Tomoki Takata1, Akihito Arai6, Hiroaki Tsunezuka7, Toshiyuki Kosuga8, Hirotaka Konishi8, Fumiya Hongo5, Masayoshi Inoue7, Shigeru Hirano6, Osamu Ukimura5, Yoshito Itoh1, Tetsuya Taguchi2,9, Koichi Takayama3 1 Dept of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 2 Outpatient Oncology Unit, University Hospital, Kyoto Prefectural University of Medicine, 3Dept. of Pulmonary Medicine, Kyoto Prefectural University of Medicine, 4 Dept. of Dermatology, Kyoto Prefectural University of Medicine, 5Dept. of Urology, Kyoto Prefectural University of Medicine, 6Dept. of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, 7Division of Thoracic Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 8Division of Digestive Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 9Dept. of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, 10Departments of Hospital Pharmacy, Kyoto Prefectural University of Medicine Introduction: Anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) monotherapies have shown promising clinical activity in advanced cancers. Many studies of immune-related adverse events (irAEs) have been reported. Although, the safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting positive antinuclear antibodies (ANA) and autoimmune disease (AD) remains unclear. Methods: 216 patients who received nivolumab, pembrolizumab, atezolizumab or durvalumab for unresectable advanced cancers between September 2014 and December 2018 were retrospectively identified. The patients were divided into the positive (ANA titers1:80) and negative (titers1:40) ANA groups. Development and characteristics of irAEs, the response rate (RR) and disease control rate (DCR) were estimated. We also focused on the patients with preexisting AD and assessed their clinical courses. Results: 17 out of 190 patients had positive ANA. 8 patients developed irAEs of any grade in the positive ANA group while 65 developed in the negative group, which showed no significant difference among the two groups. No significant differences were shown in the development of endocrine, pulmonary and cutaneous irAEs, while the presence of positive ANA was significantly higher in patients who developed colitis (3/ 17) than in patients who did not (2/173, P < 0.0001). No statistically significant
doi:10.1093/annonc/mdz338 | vi115
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz338.107/5582836 by Serials Processing Library University of Canberra user on 15 December 2019
Lung Cancer (ES-SCLC). We assessed its efficacy and safety in Japanese patients through subgroup analyses of the phase 3 IMpower133 trial (NCT02763579). Methods: IMpower133 is a Phase I/III, multicenter, double-blinded, placebo-controlled randomized trial evaluating atezolizumab plus carboplatin and etoposide in chemotherapy-naı¨ve ES-SCLC patients. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo until they had unacceptable toxicity, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. Results: Of the 403 patients randomized in the IMpower133 trial, 42 patients were enrolled from Japanese centers. In Japanese patients from the ITT population, median PFS in the atezolizumab group (n ¼ 20) was longer than the placebo group (n ¼ 22; 4.5 months [95% CI, 4.2-8.1] vs 4.0 months [95% CI, 2.9-5.6], respectively; HR 0.47 [95% CI, 0.23-0.96]), and median OS in the atezolizumab group was longer than the placebo group (14.6 months [95% CI, 11.8-17.8] vs 11.9 months [95% CI, 8.4-15.8], respectively; HR 0.72 [95% CI, 0.31-1.67]). The atezolizumab regimen was generally well tolerated, with no treatment-related deaths. Conclusion: The addition of atezolizumab to carboplatin and etoposide was effective and well tolerated in Japanese patients with ES-SCLC. Results are consistent with the primary analysis of IMpower133 trial.
Annals of Oncology
MO3 10 1
The effect of proton pump inhibitors on the efficacy of nivolumab monotherapy in different types of cancer
Quy Pham Nguyen, Motoo Nomura, Shigemi Matsumoto, Manabu Muto Department of Medical Oncology, Kyoto University Background: Solid tumors are characterized by a highly acidic microenvironment that might hamper anti-cancer immunity. Several studies have shown that proton pump inhibitors (PPIs) can neutralize the pH of the tumor microenvironment and indirectly affect the function of cytotoxic T lymphocytes, suggesting a possible impact on clinical outcomes of immunotherapies. The aim of this analysis to explore the relationship between the use of PPIs and the efficacy of nivolumab monotherapy in 4 different types of cancer: malignant melanoma (MM), renal cell carcinoma (RCC), gastric cancer (GC), and head and neck cancer (HN). Methods: A retrospective chart review was performed on 95 consecutive patients treated with nivolumab monotherapy between October 2014 and December 2018 at our hospital. Co-medication of PPIs was defined if the patient was prescribed any types of PPIs for more than 2 weeks during the administration of nivolumab. Response rates (RR), progression-free survival (PFS) and overall survival (OS) were compared between PPI users and non-users. Results: The majority of patients were males (65.3%). The median age was 68 years. MM was the most common diagnosis (47.4%) followed by HN (24.2%) and GC (17.8%). PPIs were prescribed in 42% of the cases. There was no statistically significant difference in RR, OS or PFS between PPI users and non-users in GC and HN. However, co-medication of PPIs was associated with lower RR in MM, but higher RR in RCC. Although these results did not translate into significant changes in the PFS or OS, differences were observed in the Kaplan-Meyer curves of these two types of cancer. Conclusion: Our analysis shows that PPIs could have different impact on the benefit of nivolumab monotherapy. These results suggest that unnecessary prescription of PPIs should be avoided in patients who are receiving PD1-based immunotherapy for the treatment of MM, and the effect of PPIs should be considered in interpreting the results from clinical trials.
MO3 10 2
Association of gastric acid suppression with efficacy of immune checkpoint inhibitors (ICIs) in advanced cancer patients
Naoki Izawa1, Hisae Shiokawa2, Risa Onuki2, Koki Hamaji2, Naoki Furuya3, Hiroyuki Ohashi4, Tomohiro Nishi5, Shigeru Kasugai6, Hiroyuki Arai1, Ayako Doi1, Yoshiki Horie1, Mami Hirakawa1, Takuro Mizukami1, Takashi Ogura1, Takashi Tsuda1, Yu Sunakawa1, Takako Nakajima1 1 St. Marianna University School of Medicine, Department of Clinical Oncology, 2St. Marianna University School of Medicine, Department of pharmacy, 3St. Marianna University School of Medicine, Division of Respiratory and Infectious Diseases,Department of Internal Medicine, 4St. Marianna University School of Medicine, Department of Dermatology, 5St. Marianna University School of Medicine, Department of Urology, 6St. Marianna University School of Medicine, Department of Otolaryngology Background: Recent studies have shown that proton pump inhibitor (PPI) negatively impacts on the clinical benefit from ICIs. Gut microbiome modulated by PPI may contribute to decreased efficacy. It has been also reported that H2 blocker (H2B) or gastrectomy affected gut microbiome. We assessed in this study the association of GAS including PPI, H2B and gastrectomy with clinical outcome from ICI. Methods: We retrospectively investigated advanced cancers pts treated with ICIs as the 1st- to the 3rd-line treatment at our institution between July 2014 and September 2018.
Volume 30 | Supplement 6 | October 2019
GAS was defined as using PPI or H2B within 30 days before start of ICI, or having past history of gastrectomy. Response to ICIs was assessed by RECIST v1.1. Performance status (PS), body mass index, antibiotics, steroid, LDH level, albumin level, CPR and neutrophil-lymphocyte ratio (NLR) were compared between the GAS and non-GAS arms. Associations of nominal variables with the response were evaluated. Results: Total of 115 pts (lung 69.9%, skin 11.3%, head and neck 7.8%, renal cell 6.9%, stomach 4.2%, and urothelium 2.5%) were evaluated. The types of ICIs were nivolumab of 72.2%, pembrolizumab of 22.6%, and atezolizumab of 5.2%. Sixty of 115 pts recieved GAS (PPI 83.3%, H2B 11.6%, and gastorectomy 5%) before start of ICI. Patients’ characteristics between the GAS and non-GAS arms was almost well balanced. However, pts with lower PS (>2) or high NLR were more frequently observed in the GAS arm (20% vs. 0%, 40% vs. 16%, respectively). The response rate (RR) was almost significantly lower in the GAS arm than the non-GAS arm (12% vs. 25%, P ¼ 0.055). GAS did not remain statistically significant in a multivariate analysis (P ¼ 0.091), while LDH was significant in both uni- and multivariate analyses. Conclusion: Pts with GAS and pts without GAS have different patients’ background such as PS and NLR, and the RR in pts with GAS was numerically lower compared to that without GAS in advanced cancer treated with ICI.
MO3 10 3
Sustained fever associated with immune checkpoint inhibitors may be a poor prognostic factor
Hiroki Ueda, Eriko Murakami, Yuka Okuda, Eri Takase, Takahiro Kaki, Yuhei Harutani, Nao Yamagata, Katsuyuki Furuta, Chigusa Shimono, Nobuyuki Yamamoto Wakayama Medical University,Department of Pulmonary Medicine and Oncology Immune-checkpoint inhibitors (ICIs) have been established as novel standard treatment for various types of malignancies, and immune-related adverse events (irAEs) are frequently observed with ICIs. This study aimed to evaluate whether fever associated with ICIs correlates with treatment response or prognosis. We conducted a retrospective study of patients who received anti PD-1antibody monotherapy at Wakayama Medical University hospital (n ¼ 188). Fever was classified as transient fever related to irAE and infection and sustained fever from onset of ICI administration. Sustained fever was observed in 10 out of 188 people (5.3%), and all cases were controlled with Acetaminophen or Naproxen. All patients with sustained fever and had high tumor burden and Performance Status 1 or 2. In 7 of 10 patients, PS decreased rapidly after ICI administration and the second cycle was discontinued and died within 3 months. Three out of ten cases were able to continue, three patients were both effective, fever disappeared and antipyretics were also stopped. Our data suggest that Sustained fever after ICI administration was considered to be a poor prognostic factor unless response.
MO3 10 5
Safety of PD-1/PD-L1 blockade in patients with preexisting positive antinuclear antibodies and autoimmune disease
Tomoki Sakakida1, Takeshi Ishikawa1,2, Yusuke Chihara2,3, Sachi Harita3, Junji Uchino3, Yusuke Tabuchi2,10, Satoshi Komori4, Jun Asai4, Tsukasa Narukawa5, Tomoki Takata1, Akihito Arai6, Hiroaki Tsunezuka7, Toshiyuki Kosuga8, Hirotaka Konishi8, Fumiya Hongo5, Masayoshi Inoue7, Shigeru Hirano6, Osamu Ukimura5, Yoshito Itoh1, Tetsuya Taguchi2,9, Koichi Takayama3 1 Dept of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 2 Outpatient Oncology Unit, University Hospital, Kyoto Prefectural University of Medicine, 3Dept. of Pulmonary Medicine, Kyoto Prefectural University of Medicine, 4 Dept. of Dermatology, Kyoto Prefectural University of Medicine, 5Dept. of Urology, Kyoto Prefectural University of Medicine, 6Dept. of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, 7Division of Thoracic Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 8Division of Digestive Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 9Dept. of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, 10Departments of Hospital Pharmacy, Kyoto Prefectural University of Medicine Introduction: Anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) monotherapies have shown promising clinical activity in advanced cancers. Many studies of immune-related adverse events (irAEs) have been reported. Although, the safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting positive antinuclear antibodies (ANA) and autoimmune disease (AD) remains unclear. Methods: 216 patients who received nivolumab, pembrolizumab, atezolizumab or durvalumab for unresectable advanced cancers between September 2014 and December 2018 were retrospectively identified. The patients were divided into the positive (ANA titers1:80) and negative (titers1:40) ANA groups. Development and characteristics of irAEs, the response rate (RR) and disease control rate (DCR) were estimated. We also focused on the patients with preexisting AD and assessed their clinical courses. Results: 17 out of 190 patients had positive ANA. 8 patients developed irAEs of any grade in the positive ANA group while 65 developed in the negative group, which showed no significant difference among the two groups. No significant differences were shown in the development of endocrine, pulmonary and cutaneous irAEs, while the presence of positive ANA was significantly higher in patients who developed colitis (3/ 17) than in patients who did not (2/173, P < 0.0001). No statistically significant
doi:10.1093/annonc/mdz338 | vi115
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz338.107/5582836 by Serials Processing Library University of Canberra user on 15 December 2019
Lung Cancer (ES-SCLC). We assessed its efficacy and safety in Japanese patients through subgroup analyses of the phase 3 IMpower133 trial (NCT02763579). Methods: IMpower133 is a Phase I/III, multicenter, double-blinded, placebo-controlled randomized trial evaluating atezolizumab plus carboplatin and etoposide in chemotherapy-naı¨ve ES-SCLC patients. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo until they had unacceptable toxicity, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. Results: Of the 403 patients randomized in the IMpower133 trial, 42 patients were enrolled from Japanese centers. In Japanese patients from the ITT population, median PFS in the atezolizumab group (n ¼ 20) was longer than the placebo group (n ¼ 22; 4.5 months [95% CI, 4.2-8.1] vs 4.0 months [95% CI, 2.9-5.6], respectively; HR 0.47 [95% CI, 0.23-0.96]), and median OS in the atezolizumab group was longer than the placebo group (14.6 months [95% CI, 11.8-17.8] vs 11.9 months [95% CI, 8.4-15.8], respectively; HR 0.72 [95% CI, 0.31-1.67]). The atezolizumab regimen was generally well tolerated, with no treatment-related deaths. Conclusion: The addition of atezolizumab to carboplatin and etoposide was effective and well tolerated in Japanese patients with ES-SCLC. Results are consistent with the primary analysis of IMpower133 trial.