First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma (mEGA).

Janjigian, Yelena Y.; Chou, Joanne F.; Simmons, Marc; Momtaz, Parisa; Sánchez-Vega, Francisco; Shcherba, Marina; Ku, Geoffrey Yuyat; Won, Elizabeth; Chong, Curtis R.; Gerdes, Hans; Kelsen, David P.; Ilson, David H.; Aljallad, Kathrena; Segal, Michal; Millang, Brittanie M; Schultz, Nikolaus; Shah, Pari; Solit, David B.; Capanu, Marinela; Hechtman, Jaclyn F.

doi:10.1200/jco.2019.37.4_suppl.62

Cited by 41 publications

(28 citation statements)

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“…EGFR and ALK TKIs plus immune checkpoints in NSCLC did not conclusively demonstrate higher response rates than would be expected from the TKI alone, and increased toxicity . However, concurrent immunotherapy with blockade against Her2 has shown benefit in PD‐L1 positive Her2 + breast cancer resistant to prior trastuzumab, and recently pembrolizumab plus trastuzumab plus chemotherapy showed remarkable outcomes with an objective response rate of 87% of patients with untreated Her2 positive esophageal, gastroesophageal junction, and gastric adenocarcinomas . Responses did not vary by PD‐L1 expression, however, non‐amplification of ERBB2 was associated with shorter durations of response, suggesting contribution from the trastuzumab and HER2 biology.…”

Section: Sarcomas—a Framework For Approaching Modern Immunotherapymentioning

confidence: 99%

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Wilky

2019

Immunological Reviews

167

113

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Immune checkpoint inhibitors (ICIs) have revolutionized our approach to cancer treatment in the past decade. While monoclonal antibodies to CTLA‐4 and PD‐1/PD‐L1 have produced remarkable and durable responses in a subset of patients, the majority of patients will still develop primary or adaptive resistance. With complex mechanisms of resistance limiting the efficacy of checkpoint inhibitor monotherapy, it is critical to develop combination approaches to allow more patients to benefit from immunotherapy. In this review, I approach the current landscape of ICI research from the perspective of sarcomas, a rare group of bone and soft tissue cancers that have had limited benefit from checkpoint inhibitor monotherapy, and little investigation of biomarkers to predict responses. By surveying the various mechanisms of resistance and treatment modalities being explored in other solid tumors, I outline how ICIs will undoubtedly serve as the critical foundation for future directions in modern immunotherapy.

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Section: Sarcomas—a Framework For Approaching Modern Immunotherapymentioning

confidence: 99%

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Wilky

2019

Immunological Reviews

167

113

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“…In addition, preliminary results of the phase II/III ATTRACTION-04 trial provided interim efficacy data for nivolumab in combination with oxaliplatin and S-1 or capecitabine, with an ORR of 67 % and 71 % respectively [22].…”

Section: Combination With Chemotherapymentioning

confidence: 99%

Current status of immunotherapy in gastrointestinal malignancies

et al. 2020

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Gastrointestinal (GI) malignant neoplasms have a high global incidence and a huge impact on cancer-associated mortality. In the past years, excitement was growing among oncologists and patients alike for the use of immunotherapy, specifically immune checkpoint inhibitors. The approval of several PD-1/PD-L1 and CTLA-4 inhibitors radically changed the treatment landscape in many cancer types and established immune-oncology as a new treatment strategy against cancer. Despite major breakthrough reports, shortcomings of immune checkpoint inhibitors (ICI) have been observed, including primary and acquired treatment resistance, especially in patients receiving ICIs as a single treatment. Several immunotherapies for the treatment of GI tumors have recently emerged; however, checkpoint inhibition has not yet shown similar success in GI malignancies compared to other solid tumors. Various phase I–III trials focusing on immunotherapies for GI tumors have found only moderate to unsatisfactory objective response rates (ORR), ranging between 10 % and 25 %. In particular, negative studies have been reported in gastric and pancreatic cancer. Nevertheless, small subsets of cancers, such as DNA mismatch repair deficient (dMMR)/microsatellite instable (MSI) cancers, among others, seem to benefit from treatment with immune checkpoint inhibition. Routine testing for the rare molecular features that can predict response should be implemented in clinical routine for all GI tumors, and large scale clinical trials to identify predictive biomarkers are needed. This article will address the current use and evidence for immunotherapy in GI malignancies and future trends in this area for clinical practice.

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“…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 OS of not reached [14]. A placebo-controlled, randomized phase III trial (KEYNOTE-811, NCT03615326) is currently ongoing in an attempt to confirm these promising findings.…”

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confidence: 96%

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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First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma (mEGA).

Cited by 41 publications

References 0 publications

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Current status of immunotherapy in gastrointestinal malignancies

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

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