A randomized phase II study of weekly paclitaxel ± trastuzumab in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer refractory to trastuzumab combined with fluoropyrimidine and platinum: WJOG7112G (T-ACT).

Makiyama, Akitaka; Sagara, Kosuke; Kawada, Junji; Kashiwada, Tomomi; Hosokawa, Ayumu; Horie, Yoshiki; Satake, Hironaga; Yamamoto, Yoshiyuki; Tanioka, Hiroaki; Shinozaki, Kazuo; Nishikawa, Kazuhiro; Uchino, Kenji; Sukawa, Yasutaka; Yamanaka, T.; Yamazaki, Kentaro; Hironaka, Shuichi; Boku, Narikazu; Hyodo, Ichinosuke; Esaki, Taito; Muro, Kei

doi:10.1200/jco.2018.36.15_suppl.4011

Cited by 35 publications

(43 citation statements)

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“…Moreover, in a phase 3 trial (JACOB), metastatic G/GEJ cancer patients received pertuzumab (another anti-HER2 antibody) or placebo in combination with trastuzumab plus chemotherapy (standard cisplatin/fluoropyrimidine regimen) as first-line treatment; OS was not significantly different between the pertuzumab and placebo arms (median OS, 17.5 vs 14.2 months; HR, 0.84 [95% CI 0.71-1.00]; P = 0.0565) [21]. As the secondline treatment in a randomized phase 2 study conducted by the West Japan Oncology Group (WJOG7112G [T-ACT]), trastuzumab plus paclitaxel showed no benefit over paclitaxel alone in patients with HER2+ advanced G/GEJ cancer refractory to first-line trastuzumab plus chemotherapy [8].…”

Section: Discussionmentioning

confidence: 99%

“…While trastuzumab showed a survival benefit as first-line chemotherapy for HER2+ G/GEJ cancer patients in the ToGA study, none of the other anti-HER2 drugs, such as lapatinib or trastuzumab-emtansine (T-DM1), or continuing trastuzumab beyond progression in second-line treatment showed benefits [8][9][10]. Recently, studies evaluating trastuzumab resistance mechanisms have highlighted certain pathways for resistance.…”

Section: Introductionmentioning

confidence: 99%

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Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer

et al. 2019

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Background Data on immune checkpoint inhibitor efficacy in patients with human epidermal growth factor receptor 2-positive (HER2+) advanced gastric/gastroesophageal junction (G/GEJ) cancer are lacking. Because HER2 status was not captured in the ATT RAC TION-2 trial, we used patients with prior trastuzumab use (Tmab+) as surrogate for HER2 expression status to evaluate the efficacy and safety of nivolumab as third-or later-line therapy in these patients. Methods In ATT RAC TION-2, a randomized, double-blind, placebo-controlled, phase 3 multicenter trial, patients were randomized (2:1) to receive nivolumab (3 mg/kg) or placebo every 2 weeks until disease progression or toxicity requiring study discontinuation. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were assessed. Results Of 493 enrolled patients, 81 (nivolumab, n = 59; placebo, n = 22) were Tmab+ and 412 (nivolumab, n = 271; placebo, n = 141) were Tmab−. In both groups, patients receiving nivolumab showed a longer median OS vs placebo (Tmab+, 8.3 [95% confidence interval, 5.3-12.9] vs 3.1 [1.9-5.3] months, hazard ratio, 0.38 [0.22-0.66]; P = 0.0006; Tmab−, 4.8 [4.1-6.0] vs 4.2 [3.6-4.9] months, 0.71 [0.57-0.88]; P = 0.0022). PFS was longer in both groups receiving nivolumab vs placebo (Tmab+,.0] vs 1.5 [1.3-2.9] months, 0.49 [0.29-0.85]; P = 0.0111; Tmab−, 1.6 [1.5-2.4] vs 1.5 [1.5-1.5] months, 0.64 [0.51-0.80]; P = 0.0001). Conclusions Nivolumab was efficacious and safe as third-or later-line therapy regardless of prior trastuzumab use in patients with advanced G/GEJ cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer

et al. 2019

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“…A randomized phase II study (T-ACT, WJOG7112G) examined the efficacy of TBP in combination with paclitaxel, the standard of care in the second-line setting for AGC patients, who progressed during the first-line treatment with a trastuzumab-containing regimen (Table 1) [21]. A total of 89 patients with HER2-positive AGC, who failed first-line therapy with trastuzumab plus a fluoropyrimidine and platinum agent, were randomly assigned to receive paclitaxel plus trastuzumab or paclitaxel alone.…”

Section: Trastuzumab In the Second-line Setting (Beyond Progression)mentioning

confidence: 99%

“…Negative T-ACT [21] Trastuzumab 2nd 3.2 versus 3.7 (HR, 0.91; 95% CI, 0.67-1.22; p = 0.33) 10.0 versus 10.2 (HR, 1.23; 95% CI, 0.76-1.99; p = 0.20)…”

Section: Positivementioning

confidence: 99%

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Mitani

Kawakami

2020

Cancers

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Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody-drug conjugates that are under development and have shown promising antitumor activity in early studies. basis of these results, trastuzumab was approved for AGC with a high HER2 expression level, and trastuzumab-containing regimens are now a standard option for the first-line treatment of such patients, who accounted for 7% to 17% of all individuals with gastric cancer [3-5]. Derivatives of the ToGA Regimen in the First-Line SettingThe ToGA trial adopted a regimen of cisplatin combined with either 5-fluorouracil (5-FU) or capecitabine, whereas subsequent prospective studies found similar treatment outcomes with regimens containing oxaliplatin or tegafur-gimeracil-oteracil (S-1). In a single-arm, nonrandomized phase II trial (HER2-based strategy in stomach cancer (HERBIS)-1) performed in Japan [6], trastuzumab in combination with S-1 plus cisplatin yielded a confirmed ORR of 68%, with a median OS and a median PFS of 16.0 and 7.8 months, respectively, in HER2-positive AGC patients with measurable lesions, with these results being similar to those of the ToGA trial [2]. Similar efficacy was also apparent in AGC patients without measurable lesions (HERBIS-1B study) [7]. Three phase II studies that assessed the combination of trastuzumab with capecitabine plus oxaliplatin reported a median OS, a median PFS, and an ORR of 13.8 to 21.0 months, 7.1 to 9.8 months, and 46.7% to 67.3%, respectively [8][9][10]. Trastuzumab in combination with S-1 plus oxaliplatin was also shown to provide a similar treatment outcome in a phase II study, with a median OS, a median PFS, and an ORR of 18.1 months, 8.8 months, and 70.7%, respectively [11]. A meta-analysis of data from these trials revealed that S-1 or oxaliplatin can substitute effectively for capecitabine or 5-FU or for cisplatin, respectively [12].Immune checkpoint inhibitors such as antibodies to programmed cell death-1 (PD-1) have recently revolutionized treatment strategies for advanced cancer. Given that trastuzumab was found to stimulate T cell responses [13], the combination of trastuzumab-containing regimens with antibodies to PD-1 is receiving attention. A phase II study including 37 patients with HER2-positive AGC treated in the first-line setting with capecitabine, oxaliplatin, and trastuzumab in combination with the anti-PD-1 antibody pembrolizumab reported an ORR of 83%, with a median PFS of 11.4 months and a median ...

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“…A retrospective study reported that trastuzumab beyond progression increased PFS and OS in HER2-positive GC [28]. However, in a prospective phase II study, trastuzumab beyond progression as second line failed to improve PFS and the ORR in patients with HER2-positive GC, indicating that the role of trastuzumab beyond progression remains controversial in HER2-positive GC [29].…”

Section: Discussionmentioning

confidence: 99%

A phase I/II study of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer

et al. 2019

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Background Poziotinib (HM781-36B) is an irreversible pan-HER tyrosine kinase inhibitor which targets EGFR, HER2, and HER4. This prospective, multicenter, open-label, phase I/II study determined the maximum tolerated dose (MTD) and evaluated the safety and efficacy of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer (GC). Methods Patients with HER2-positive GC previously treated with one line of chemotherapy received oral poziotinib (8 mg or 12 mg) once daily for 14 days, followed by 7 days off. Paclitaxel (175 mg/m 2 infusion) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg infusion) were administered concomitantly with poziotinib on day 1 every 3 weeks. Results In the phase I part, 12 patients were enrolled (7 at dose level 1, 5 at dose level 2). One patient receiving poziotinib 8 mg and 2 receiving poziotinib 12 mg had dose-limiting toxicities (DLTs); all DLTs were grade 4 neutropenia, one with fever. The most common poziotinib-related adverse events were diarrhea, rash, stomatitis, pruritus and loss of appetite. The MTD of poziotinib was determined to be 8 mg/day and this was used in the phase II part which enrolled 32 patients. Two patients (6.3%) had complete responses and 5 (15.6%) had partial responses (objective response rate 21.9%). Median progressionfree survival and overall survival were 13.0 weeks (95% CI 9.8-21.9) and 29.5 weeks (95% CI 17.9-59.2), respectively. Conclusions The MTD of poziotinib combined with paclitaxel and trastuzumab was 8 mg/day. This combination yielded promising anti-tumor efficacy with manageable toxicity in previously treated patients with HER2-positive GC.

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A randomized phase II study of weekly paclitaxel ± trastuzumab in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer refractory to trastuzumab combined with fluoropyrimidine and platinum: WJOG7112G (T-ACT).

Cited by 35 publications

References 0 publications

Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer

Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

A phase I/II study of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer

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