Research ArticleClinical Studies

Ramucirumab Beyond Disease Progression After Paclitaxel Plus Ramucirumab in Gastric Cancer: A Phase II Trial

YASUYOSHI SATO, HIROHARU YAMASHITA, KOICHI YAGI, SACHIYO NOMURA and YASUYUKI SETO
Anticancer Research July 2024, 44 (7) 3125-3131; DOI: https://doi.org/10.21873/anticanres.17126

Abstract

Background/Aim: Irinotecan monotherapy was the most widely used third-line chemotherapy for unresectable advanced or recurrent gastric cancer in Japan until the approval of nivolumab in September 2017 and trifluridine/tipiracil in August 2019. The benefit of continuing ramucirumab with irinotecan, an anti-VEGFR-2 monoclonal antibody, after the failure of paclitaxel plus ramucirumab (PTX+RAM) as second-line chemotherapy, has been under debate. Patients and Methods: A single-center phase II study was conducted in patients with unresectable advanced or recurrent gastric cancer previously treated with fluoropyrimidines and platinum, who received PTX+RAM as second-line therapy and irinotecan plus ramucirumab (IRI+RAM) as third-line therapy after treatment failure (UMIN000022956). Results: Eleven patients were enrolled from July 2016 to July 2018. Enrolment was discontinued due to difficulties in case ascertainment because of expanded third-line treatment options (originally planned for 53 patients). The median progression-free survival (the primary endpoint) of the IRI+RAM was 3.98 months [95% confidence interval (CI)=1.78-NA]. Among secondary endpoints, the transition rate to IRI+RAM was 45%, the rate of 8-week treatment continuation for IRI+RAM was 100%, the response rate for IRI+RAM was 0%, the median overall survival (OS) for PTX+RAM was 13.53 months (95%CI=1.61-24.36), and the median OS for IRI+RAM was 9.99 months (95CI=4.5-NA). Conclusion: The transition rate from PTX+RAM to IRI+RAM was reasonable. Ramucirumab beyond progressive disease may be beneficial for patients who are able to transition to IRI+RAM.

Key Words:

Ramucirumab is a humanized monoclonal antibody that binds specifically to the human anti-vascular endothelial growth factor receptor-2 (VEGFR-2) and inhibits the binding of vascular endothelial growth factor (VEGF) ligands (VEGF-A, VEGF-C, and VEGF-D) to VEGFR-2, thereby suppressing angiogenesis and exerting antitumor effects. A phase III study (REGARD) comparing ramucirumab alone with placebo in patients with gastric or gastro-esophageal junction cancer who had failed first-line chemotherapy showed an improvement in overall survival (OS) (5.2 months vs. 3.8 months, p=0.047) and progression-free survival (PFS) (2.1 months vs. 1.3 months, p<0.0001) (1). In addition, a Phase III study (RAINBOW) comparing paclitaxel plus ramucirumab (PTX+RAM) versus paclitaxel plus placebo in patients with gastric cancer or gastro-esophageal junction cancer who had failed first-line chemotherapy showed a significant improvement in OS (9.6 months vs. 7.4 months, p=0.017) and PFS (4.4 months vs. 2.9 months, p<0.0001) (2). Based on these results, ramucirumab was approved in Japan in March 2015 for the treatment of unresectable advanced or recurrent gastric cancer, and ramucirumab plus paclitaxel is considered the standard of care for second-line chemotherapy for gastric cancer in Japan (3).

Subsequently, irinotecan monotherapy has become the standard of care for third-line chemotherapy following the failure of PTX+RAM for gastric cancer in Japan. However, there are cases in which the administration of each drug is contraindicated owing to advanced peritoneal seeding, intestinal paralysis, bowel obstruction, gastrointestinal perforation, thrombosis, or other factors.

Bevacizumab is a humanized monoclonal antibody that binds specifically to VEGF-A in the blood and inhibits its binding to VEGFR, thereby suppressing angiogenesis and exerting an anti-tumor effect. It has been approved in Japan for the treatment of unresectable advanced or recurrent colorectal cancer in combination with other anti-cancer agents. In a phase III study (ML18147) evaluating the significance of continuing bevacizumab beyond progression in patients with metastatic colorectal cancer that had progressed after first-line treatment using combination chemotherapy with bevacizumab, the median OS in the chemotherapy plus bevacizumab group was significantly longer than that in the chemotherapy group (11.2 months vs. 9.8 months, p=0.0062) (4). In a phase III study (RAISE) evaluating the significance of combining FOLFIRI with ramucirumab in the second-line treatment of patients with unresectable advanced or recurrent colorectal cancer that had progressed after first-line therapy including 5-FU, oxaliplatin, and bevacizumab, the FOLFIRI plus ramucirumab group showed a significant increase in median OS compared with the FOLFIRI group (13.3 months vs. 11.7 months, p=0.0219) (5). These findings demonstrate the significance of continuing treatment with angiogenesis inhibitors that block the VEGF pathway in combination with other chemotherapies after disease progression in colorectal cancer; the same significance is expected in gastric cancer.

Therefore, we conducted a single-center phase II study of ramucirumab beyond disease progression in combination with irinotecan after the failure of weekly paclitaxel plus ramucirumab in patients with advanced gastric cancer previously treated with fluoropyrimidine and platinum to evaluate the value of continuing ramucirumab beyond progression as a third-line treatment.

Patients and Methods

Patients. The inclusion criteria were as follows: histologically proven gastric or esophagogastric junction adenocarcinoma; unresectable or recurrent disease; age over 20 years; Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; previously treated with fluoropyrimidine and platinum; with adequate organ functions (white blood cell count ≥3,000/mm3; neutrophil count ≥1,500/mm3; hemoglobin ≥8.0g/dl; platelet count ≥100,000/mm3; total bilirubin ≤1.5 mg/dl; aspartate aminotransferase concentrations ≤90 U/l; alanine aminotransferase (ALT) concentrations ≤126 U/l; creatinine (Cre) concentration ≤1.5 mg/dl or eGFR≥30 ml/min/1.73 m2). The presence of measurable lesions, according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (6), is not mandatory. We excluded patients with pleural fluid, ascites, and pericardial effusion requiring drainage, ileus, or constipation. All eligible patients provided written informed consent for participation. This study was approved by the University Hospital Medical Information Clinical Trials Registry and registered as UMIN000022956.

Treatments. All eligible patients underwent first registration and received second-line treatment with PTX+RAM: paclitaxel at 80 mg/m2, day 1, 8, and 15 drip intravenous infusion (DIV), and ramucirumab at 8 mg/kg on day 1 and 15 DIV, every 28 days. They progressed after second-line treatment, were evaluated for eligibility for the subsequent therapy, underwent a second registration, and received irinotecan and ramucirumab (IRI+RAM); irinotecan of 150 mg/m2, day 1 DIV, and ramucirumab of 8 mg/kg, on day 1 and 15 DIV, every 14 days). The study treatment was continued until progressive disease (PD), or intolerable adverse events occurred.

Assessments. The primary endpoint was PFS for IRI+RAM as third-line therapy. Secondary endpoints were transition rate, 8-week treatment continuation rate, overall response rate, OS, and adverse events for IRI+RAM, and OS from PTX+RAM as second-line therapies (Figure 1). PFS and OS were estimated using the Kaplan-Meier method and the log-rank test. Patients who were lost to follow-up were censored at the date of their last contact or follow-up. OS was calculated from the date of registration for therapy initiation to the date of death from any cause. Patients who were alive on the last follow-up day were censored for the OS analysis. PFS was calculated from the date of registration for therapy initiation to the date of disease progression, recurrence, or death from any cause. Tumor response was evaluated according to RECIST v1.1 (6) based on computed tomography (CT) findings. The best overall response was defined as a complete response (CR), partial response (PR), stable disease (SD), non-CR/non-PD, or PD. The overall response corresponded to the sum of CR and PR, while disease control corresponded to the sum of CR, PR, SD, and non-CR/non-PD groups. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria), a modified version of R Commander designed to add statistical functions frequently used in biostatistics (7).

Figure 1.
Figure 1.

Study design (single-center, single-arm phase 2 study). PTX: Paclitaxel; IRI: irinotecan; RAM: ramucirumab; OS: overall survival; AEs: adverse events; PFS: progression-free survival; ORR: overall response rate.

Results

Patient characteristics. Eleven patients were enrolled between July 2016 and July 2018. Enrolment was discontinued owing to difficulties in case ascertainment due to expanded third-line treatment options (8), although 53 patients were originally planned for enrolment. Patient characteristics are shown in Table I. Data were censored on March 31, 2019 [for the intention to treat (ITT) analysis] and August 31, 2023 (for the post hoc long-term analysis).

View this table:
Table I.

Baseline characteristics of the study patients (n=11).

Efficacy and safety. The median progression-free survival (primary endpoint) of the IRI+RAM was 3.98 months (95%CI=1.78-NA) (Figure 2). The transition rate to IRI+RAM was 45% (5 out of 11). The reasons for no transition were as follows: severe ascites in two patients; PS decline in one; brain metastases with herniation in one; colorectal stenting in one; and conversion to endoscopic submucosal dissection (ESD) in one. The 8-week treatment continuation rate in the IRI+RAM group was 100%. For the five patients who received IRI+RAM, the best overall responses were as follows: CR 0 (0%), PR 0 (0%), SD 3 (60%), and PD 2 (40%), which calculated the response rate for IRI+RAM as 0% (Table II). The median OS for IRI+RAM was 9.99 (95%CI=4.5-NA) (Figure 3A), and the median OS for PTX+RAM was 13.1 (95%CI=3.8-NA) (ITT analysis) (Figure 3B). In addition, the post hoc long-term analysis showed that the median OS for IRI+RAM was 9.99 (95%CI=4.5-NA) (Figure 4A), while the median OS from PTX+RAM was 13.1 (95%CI=3.8-24.3) (the ITT analysis) (Figure 4B). The adverse events associated with IRI+RAM are listed in Table III. No severe adverse events were reported. A summary of these results is shown in Figure 5.

Figure 2.
Figure 2.

Kaplan-Meier curves for progression-free survival (the primary endpoint) upon treatment with irinotecan plus ramucirumab (IRI+RAM).

View this table:
Table II.

Efficacy of irinotecan plus ramucirumab (IRI+RAM) as third line (n=5).

Figure 3.
Figure 3.

Kaplan-Meier curves for overall survival (A) upon treatment with irinotecan plus ramucirumab (IRI+RAM) (n=5) and (B) with paclitaxel (PTX)+RAM (n=11) (ITT analysis).

Figure 4.
Figure 4.

Kaplan-Meier curves for overall survival (A) upon treatment with irinotecan plus ramucirumab (IRI+RAM) (n=5) and (B) with paclitaxel (PTX)+RAM (n=11) (post hoc long-term analysis).

View this table:
Table III.

Adverse events for irinotecan plus ramucirumab (IRI+RAM) (n=5).

Figure 5.
Figure 5.

A summary of the results. PTX: Paclitaxel; IRI: irinotecan; RAM: ramucirumab; OS: overall survival; AEs: adverse events; PFS: progression-free survival; ORR: overall response rate.

Discussion

In this study, we investigated the efficacy and safety of ramucirumab beyond disease progression in combination with irinotecan after the failure of weekly PTX+RAM in patients with advanced gastric cancer who were previously treated with fluoropyrimidine and platinum, including the transition rate. We found that the transition rate from PTX+RAM to IRI+RAM was reasonable. However, beyond progression, ramucirumab may be beneficial in patients who can transition to IRI+RAM.

Irinotecan monotherapy was the most widely used third-line chemotherapy for unresectable advanced or recurrent gastric cancer until the approval of nivolumab (9) in September 2017 and trifluridine/tipiracil (10) in August 2019 for third or subsequent lines of therapy in Japan (8). The benefit of continuing ramucirumab with irinotecan, an anti-VEGFR-2 monoclonal antibody, after the failure of PTX+RAM as second-line chemotherapy, has been debated. Moreover, nivolumab has proven to be beneficial in addition to first-line chemotherapy (11, 12). Furthermore, nivolumab plus chemotherapy has become the standard of care for the first-line treatment of HER2-negative unresectable advanced or recurrent gastric cancer. Accordingly, third-line treatment options after second-line PTX+RAM therapy have become a more controversial issue.

In the present study, the transition rate from PTX+RAM to IRI+RAM was 45%, mainly because of disease progression. This result is consistent with those of the previous studies. A recent retrospective cohort study used a Japanese administrative claims database from June 2014 to September 2019, which included 10,581 patients with gastric cancer, and showed a 52.9% transition rate from second-line therapy (n=4,522) to third-line therapy (n=2,390) (13).

In the present study, PFS and OS with IRI+RAM were 3.98 and 9.99 months, respectively, which appears to be superior than those of nivolumab monotherapy as third-line or subsequent therapy (PFS=1.61 and OS=5.62 months) in the ATTRACTION-2 trial (9) and trifluridine/tipiracil monotherapy as third-line or later therapy (PFS=2.0 and OS=5.7 months) in the TAGS trial (10). The outcome of the IRI+RAM in this study is consistent with previous reports. Moreover, OS after the second line PTX+RAM was 13.1 months, which appears superior to the OS of 9.63 months in the RAINBOW trial (2). In this study, nivolumab was administered to two patients after IRI+RAM, and in three of the six patients who could not receive IRI+RAM, therefore, it is not clear whether the survival benefit was due to IRI+RAM. Considering these results, IRI+RAM could be a promising option for third-line treatment for patients who were able to undergo the transition.

In a phase III WJOG 4007 trial comparing irinotecan with paclitaxel as second-line therapy in 219 patients with advanced gastric cancer without severe peritoneal metastasis, the median PFS and OS of irinotecan monotherapy (n=111) were 2.3 and 8.4 months, respectively (14). A retrospective study of 146 patients with gastric cancer treated with irinotecan monotherapy as the third (n=135) or fourth (n=11) line showed that the median PFS and OS of irinotecan monotherapy were 3.19 and 6.61 months, respectively (15). Compared to these previous reports, IRI+RAM appears to have a survival benefit over irinotecan monotherapy. However, a phase III RINDBeRG trial, comparing IRI+RAM with irinotecan monotherapy in the third or later line beyond progression after ramucirumab for advanced gastric cancer, reported that addition of ramucirumab beyond progression improved PFS (3.8 vs. 2.8 months (HR=0.72, 95%CI=0.59-0.88; p=0.001)) with manageable toxicity, but the primary endpoint of OS was not met [9.4 vs. 8.5 months (HR=0.91, 95%CI=0.74-1.12; p=0.369)] (16). Although this may be because the difference in OS diminished with the introduction of nivolumab and other treatments after the fourth line therapy, the benefits of ramucirumab beyond PD may be limited.

This study has several limitations. First, we were only able to accumulate a significantly smaller number of cases than originally planned (53 cases). Second, selection bias may have resulted from physician subjectivity in determining which patients would be eligible candidates for this study.

Conclusion

The present study highlights the potential efficacy and safety of ramucirumab combined with irinotecan after PTX+RAM failure in advanced gastric cancer patients previously treated with fluoropyrimidine and platinum. The transition rate from PTX+RAM to IRI+RAM was 45%, consistent with prior research. PFS and OS for IRI+RAM were 3.98 and 9.99 months, respectively, suggesting a survival benefit over third-line monotherapies like nivolumab and trifluridine/tipiracil. However, the study’s smaller sample size and potential selection bias limit the findings. While ramucirumab beyond progression improved PFS, the overall survival benefit is uncertain, especially with newer therapies. Therefore, further research with larger cohorts and randomized trials is necessary to confirm these results and refine treatment strategies for advanced gastric cancer.

Acknowledgements

The Authors thank the medical staff of the Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, Japan.

Footnotes

  • Authors’ Contributions

    Conceptualization, YSa, HY and YSe; Data curation, YSa; Formal analysis, YSa; Funding acquisition, YSe; Investigation, YSa, HY, KY, SN, and YSe; Methodology, YSa and HY; Project administration, YSa and HY; Resources, HY, KY, SN, and YSe; Software, YSa; Supervision, YSe; Validation, YSa; Visualization, YSa; Roles/Writing – original draft, YSa; Writing – review & editing, HY, KY, SN, and YSe.

  • Funding

    No funding.

  • Conflicts of Interest

    YS reports receiving personal fees from ONO Pharmaceutical Co., Ltd., Bristol-Myers Squibb Company, MSD KK, and TAIHO Pharmaceutical Co., Ltd. outside the submitted work. The other Authors declare no competing interests.

  • Received May 8, 2024.
  • Revision received June 3, 2024.
  • Accepted June 4, 2024.

References

  1. ↵
    1. Fuchs CS,
    2. Tomasek J,
    3. Yong CJ,
    4. Dumitru F,
    5. Passalacqua R,
    6. Goswami C,
    7. Safran H,
    8. Dos Santos LV,
    9. Aprile G,
    10. Ferry DR,
    11. Melichar B,
    12. Tehfe M,
    13. Topuzov E,
    14. Zalcberg JR,
    15. Chau I,
    16. Campbell W,
    17. Sivanandan C,
    18. Pikiel J,
    19. Koshiji M,
    20. Hsu Y,
    21. Liepa AM,
    22. Gao L,
    23. Schwartz JD,
    24. Tabernero J, REGARD Trial Investigators
    : Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383(9911): 31-39, 2014. DOI: 10.1016/S0140-6736(13)61719-5
    OpenUrlCrossRefPubMed
  2. ↵
    1. Wilke H,
    2. Muro K,
    3. Van Cutsem E,
    4. Oh SC,
    5. Bodoky G,
    6. Shimada Y,
    7. Hironaka S,
    8. Sugimoto N,
    9. Lipatov O,
    10. Kim TY,
    11. Cunningham D,
    12. Rougier P,
    13. Komatsu Y,
    14. Ajani J,
    15. Emig M,
    16. Carlesi R,
    17. Ferry D,
    18. Chandrawansa K,
    19. Schwartz JD,
    20. Ohtsu A, RAINBOW Study Group
    : Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15(11): 1224-1235, 2014. DOI: 10.1016/S1470-2045(14)70420-6
    OpenUrlCrossRefPubMed
  3. ↵
    1. Japanese Gastric Cancer Association
    : Japanese gastric cancer treatment guidelines 2018 (5th edition). Gastric Cancer 24(1): 1-21, 2021. DOI: 10.1007/s10120-020-01042-y
    OpenUrlCrossRefPubMed
  4. ↵
    1. Bennouna J,
    2. Sastre J,
    3. Arnold D,
    4. Österlund P,
    5. Greil R,
    6. Van Cutsem E,
    7. von Moos R,
    8. Viéitez JM,
    9. Bouché O,
    10. Borg C,
    11. Steffens CC,
    12. Alonso-Orduña V,
    13. Schlichting C,
    14. Reyes-Rivera I,
    15. Bendahmane B,
    16. André T,
    17. Kubicka S, ML18147 Study Investigators
    : Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 14(1): 29-37, 2013. DOI: 10.1016/S1470-2045(12)70477-1
    OpenUrlCrossRefPubMed
  5. ↵
    1. Tabernero J,
    2. Yoshino T,
    3. Cohn AL,
    4. Obermannova R,
    5. Bodoky G,
    6. Garcia-Carbonero R,
    7. Ciuleanu TE,
    8. Portnoy DC,
    9. Van Cutsem E,
    10. Grothey A,
    11. Prausová J,
    12. Garcia-Alfonso P,
    13. Yamazaki K,
    14. Clingan PR,
    15. Lonardi S,
    16. Kim TW,
    17. Simms L,
    18. Chang SC,
    19. Nasroulah F, RAISE Study Investigators
    : Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16(5): 499-508, 2015. DOI: 10.1016/S1470-2045(15)70127-0
    OpenUrlCrossRefPubMed
  6. ↵
    1. Eisenhauer EA,
    2. Therasse P,
    3. Bogaerts J,
    4. Schwartz LH,
    5. Sargent D,
    6. Ford R,
    7. Dancey J,
    8. Arbuck S,
    9. Gwyther S,
    10. Mooney M,
    11. Rubinstein L,
    12. Shankar L,
    13. Dodd L,
    14. Kaplan R,
    15. Lacombe D,
    16. Verweij J
    : New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45(2): 228-247, 2009. DOI: 10.1016/j.ejca.2008.10.026
    OpenUrlCrossRefPubMed
  7. ↵
    1. Kanda Y
    : Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48(3): 452-458, 2013. DOI: 10.1038/bmt.2012.244
    OpenUrlCrossRefPubMed
  8. ↵
    1. Japanese Gastric Cancer Association
    : Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition). Gastric Cancer 26(1): 1-25, 2023. DOI: 10.1007/s10120-022-01331-8
    OpenUrlCrossRefPubMed
  9. ↵
    1. Kang YK,
    2. Boku N,
    3. Satoh T,
    4. Ryu MH,
    5. Chao Y,
    6. Kato K,
    7. Chung HC,
    8. Chen JS,
    9. Muro K,
    10. Kang WK,
    11. Yeh KH,
    12. Yoshikawa T,
    13. Oh SC,
    14. Bai LY,
    15. Tamura T,
    16. Lee KW,
    17. Hamamoto Y,
    18. Kim JG,
    19. Chin K,
    20. Oh DY,
    21. Minashi K,
    22. Cho JY,
    23. Tsuda M,
    24. Chen LT
    : Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390(10111): 2461-2471, 2017. DOI: 10.1016/S0140-6736(17)31827-5
    OpenUrlCrossRefPubMed
  10. ↵
    1. Shitara K,
    2. Doi T,
    3. Dvorkin M,
    4. Mansoor W,
    5. Arkenau HT,
    6. Prokharau A,
    7. Alsina M,
    8. Ghidini M,
    9. Faustino C,
    10. Gorbunova V,
    11. Zhavrid E,
    12. Nishikawa K,
    13. Hosokawa A,
    14. Yalçın Ş,
    15. Fujitani K,
    16. Beretta GD,
    17. Cutsem EV,
    18. Winkler RE,
    19. Makris L,
    20. Ilson DH,
    21. Tabernero J
    : Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 19(11): 1437-1448, 2018. DOI: 10.1016/S1470-2045(18)30739-3
    OpenUrlCrossRefPubMed
  11. ↵
    1. Janjigian YY,
    2. Shitara K,
    3. Moehler M,
    4. Garrido M,
    5. Salman P,
    6. Shen L,
    7. Wyrwicz L,
    8. Yamaguchi K,
    9. Skoczylas T,
    10. Campos Bragagnoli A,
    11. Liu T,
    12. Schenker M,
    13. Yanez P,
    14. Tehfe M,
    15. Kowalyszyn R,
    16. Karamouzis MV,
    17. Bruges R,
    18. Zander T,
    19. Pazo-Cid R,
    20. Hitre E,
    21. Feeney K,
    22. Cleary JM,
    23. Poulart V,
    24. Cullen D,
    25. Lei M,
    26. Xiao H,
    27. Kondo K,
    28. Li M,
    29. Ajani JA
    : First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 398(10294): 27-40, 2021. DOI: 10.1016/S0140-6736(21)00797-2
    OpenUrlCrossRefPubMed
  12. ↵
    1. Kang YK,
    2. Chen LT,
    3. Ryu MH,
    4. Oh DY,
    5. Oh SC,
    6. Chung HC,
    7. Lee KW,
    8. Omori T,
    9. Shitara K,
    10. Sakuramoto S,
    11. Chung IJ,
    12. Yamaguchi K,
    13. Kato K,
    14. Sym SJ,
    15. Kadowaki S,
    16. Tsuji K,
    17. Chen JS,
    18. Bai LY,
    19. Oh SY,
    20. Choda Y,
    21. Yasui H,
    22. Takeuchi K,
    23. Hirashima Y,
    24. Hagihara S,
    25. Boku N
    : Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 23(2): 234-247, 2022. DOI: 10.1016/S1470-2045(21)00692-6
    OpenUrlCrossRefPubMed
  13. ↵
    1. Komatsu Y,
    2. Hironaka S,
    3. Tanizawa Y,
    4. Cai Z,
    5. Piao Y,
    6. Boku N
    : Treatment pattern for advanced gastric cancer in Japan and factors associated with sequential treatment: a retrospective administrative claims database study. Adv Ther 39(1): 296-313, 2022. DOI: 10.1007/s12325-021-01931-3
    OpenUrlCrossRefPubMed
  14. ↵
    1. Hironaka S,
    2. Ueda S,
    3. Yasui H,
    4. Nishina T,
    5. Tsuda M,
    6. Tsumura T,
    7. Sugimoto N,
    8. Shimodaira H,
    9. Tokunaga S,
    10. Moriwaki T,
    11. Esaki T,
    12. Nagase M,
    13. Fujitani K,
    14. Yamaguchi K,
    15. Ura T,
    16. Hamamoto Y,
    17. Morita S,
    18. Okamoto I,
    19. Boku N,
    20. Hyodo I
    : Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol 31(35): 4438-4444, 2013. DOI: 10.1200/JCO.2012.48.5805
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Nishimura T,
    2. Iwasa S,
    3. Nagashima K,
    4. Okita N,
    5. Takashima A,
    6. Honma Y,
    7. Kato K,
    8. Hamaguchi T,
    9. Yamada Y,
    10. Shimada Y,
    11. Boku N
    : Irinotecan monotherapy as third-line treatment for advanced gastric cancer refractory to fluoropyrimidines, platinum, and taxanes. Gastric Cancer 20(4): 655-662, 2017. DOI: 10.1007/s10120-016-0670-9
    OpenUrlCrossRefPubMed
  16. ↵
    1. Kadowaki S,
    2. Sakai D,
    3. Kawabata R,
    4. Hara H,
    5. Yasui H,
    6. Takahashi M,
    7. Hirao M,
    8. Imai H,
    9. Minashi K,
    10. Kawakami T,
    11. Satake H,
    12. Matsuyama J,
    13. Sakamoto Y,
    14. Sawada K,
    15. Kataoka M,
    16. Kawakami H,
    17. Shimokawa T,
    18. Boku N,
    19. Satoh T
    : LBA76 The primary results of an intergroup phase III randomized controlled trial comparing ramucirumab plus irinotecan with irinotecan in the third or later line treatment beyond progression after ramucirumab for advanced gastric cancer (RINDBeRG trial). Ann Oncol 34: S1317-S1318, 2023. DOI: 10.1016/j.annonc.2023.10.077
    OpenUrlCrossRef
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Ramucirumab Beyond Disease Progression After Paclitaxel Plus Ramucirumab in Gastric Cancer: A Phase II Trial
YASUYOSHI SATO, HIROHARU YAMASHITA, KOICHI YAGI, SACHIYO NOMURA, YASUYUKI SETO
Anticancer Research Jul 2024, 44 (7) 3125-3131; DOI: 10.21873/anticanres.17126
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords