Previous anti-EGFR trials in unselected patients with gastroesophageal adenocarcinoma (GEA) were resoundingly negative. We identified
amplification in 5% (19/363) of patients at the University of ...Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy. Seven patients received ≥1 dose of treatment: three first-line FOLFOX plus ABT-806, one second-line FOLFIRI plus cetuximab, and three third/fourth-line cetuximab alone. Treatment achieved objective response in 58% (4/7) and disease control in 100% (7/7) with a median progression-free survival of 10 months. Pretreatment and posttreatment tumor next-generation sequencing (NGS), serial plasma circulating tumor DNA (ctDNA) NGS, and tumor IHC/FISH for EGFR revealed preexisting and/or acquired genomic events, including
-negative clones,
deletion,
amplification/mutation,
, and
amplification, and
mutations serving as mechanisms of resistance. Two evaluable patients demonstrated interval increase of CD3
infiltrate, including one who demonstrated increased NKp46
, and PD-L1 IHC expression from baseline, suggesting an immune therapeutic mechanism of action.
amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged.
This paper highlights the role of EGFR inhibitors in
-amplified GEA-despite negative results in prior unselected phase III trials. Using serial ctDNA and tissue NGS, we identified mechanisms of primary and acquired resistance in all patients, as well as potential contribution of antibody-dependent cell-mediated cytotoxicity to their clinical benefit.
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Gastroesophageal adenocarcinoma (GEA) has a poor prognosis and few therapeutic options. Utilizing a 73-gene plasma-based next-generation sequencing (NGS) cell-free circulating tumor DNA (ctDNA-NGS) ...test, we sought to evaluate the role of ctDNA-NGS in guiding clinical decision-making in GEA.
We evaluated a large cohort (
= 2,140 tests; 1,630 patients) of ctDNA-NGS results (including 369 clinically annotated patients). Patients were assessed for genomic alteration (GA) distribution and correlation with clinicopathologic characteristics and outcomes.
Treatment history, tumor site, and disease burden dictated tumor-DNA shedding and consequent ctDNA-NGS maximum somatic variant allele frequency. Patients with locally advanced disease having detectable ctDNA postoperatively experienced inferior median disease-free survival (
= 0.03). The genomic landscape was similar but not identical to tissue-NGS, reflecting temporospatial molecular heterogeneity, with some targetable GAs identified at higher frequency via ctDNA-NGS compared with previous primary tumor-NGS cohorts. Patients with known microsatellite instability-high (MSI-High) tumors were robustly detected with ctDNA-NGS. Predictive biomarker assessment was optimized by incorporating tissue-NGS and ctDNA-NGS assessment in a complementary manner. HER2 inhibition demonstrated a profound survival benefit in
-amplified patients by ctDNA-NGS and/or tissue-NGS (median overall survival, 26.3 vs. 7.4 months;
= 0.002), as did EGFR inhibition in
-amplified patients (median overall survival, 21.1 vs. 14.4 months;
= 0.01).
ctDNA-NGS characterized GEA molecular heterogeneity and rendered important prognostic and predictive information, complementary to tissue-NGS.
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Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such ...therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy.
We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated.
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Background
The randomized phase III RAINBOW trial established paclitaxel (pac) plus ramucirumab (ram) as a global standard for second‐line (2L) therapy in advanced gastric and gastroesophageal ...junction adenocarcinoma, together gastroesophageal adenocarcinoma (GEA). Patients (pts) receiving first‐line (1L) FOLFOX often develop neuropathy that renders continued neurotoxic agents in the 2L setting unappealing and other regimens more desirable. As such, FOLFIRI‐ram has become an option for patients with 2L GEA. FOLFIRI‐ramucirumab (ram) has demonstrated safety and activity in 2L colorectal cancer, but efficacy/safety data in GEA are lacking.
Subjects, Materials, and Methods
Patients with GEA treated with 2L FOLFIRI‐ram between August 2014 and April 2018 were identified. Clinicopathologic data including oxaliplatin neurotoxicity rates/grades (G), 2L treatment response, progression‐free survival (PFS), overall survival (OS), safety, and molecular features were ed from three U.S. academic institutions. Kaplan‐Meier survival analysis was used to generate PFS/OS; the likelihood ratio test was used to determine statistical significance.
Results
We identified 29 pts who received 2L FOLFIRI‐ram. All pts received 1L platinum + fluoropyrimidine, and 23 of 29 (79%) had post‐1L neuropathy; 12 (41%) had G1, and 11 (38%) had G2. Patients were evenly split between esophagus/gastroesophageal junction (12; 41%) and gastric cancer (17; 59%). Among evaluable pts (26/29), the overall response rate was 23% (all partial response) with a disease control rate of 79%. Median PFS was 6.0 months and median OS was 13.4 months among all evaluable pts. Six‐ and 12‐month OS were 90% (n = 18/20) and 41% (n = 7/17). There were no new safety signals.
Conclusion
We provide the first data suggesting FOLFIRI‐ram is a safe, non‐neurotoxic regimen comparing favorably with the combination of pac + ram used in the seminal RAINBOW trial.
Implications for Practice
Results of this study provide initial support for the safety and efficacy of second‐line (2L) FOLFIRI‐ramucirumab (ram) after progression on first‐line platinum/fluoropyrimidine in patients with gastroesophageal adenocarcinoma (GEA). The overall response, progression‐free survival, overall survival, and toxicity profile compare favorably with paclitaxel (pac) + ram and highlight the importance of the ongoing phase II RAMIRIS trial examining FOLFIRI‐ram versus pac + ram in 2L GEA (NCT03081143). FOLFIRI‐ram may warrant consideration for inclusion as an alternate regimen in consensus guidelines for GEA.
摘要
背景。随机 III 期 RAINBOW 试验制定了紫杉醇 (pac) 和雷莫芦单抗 (ram) 作为晚期胃部和胃食管结合部腺癌，统称为胃食管腺癌 (GEA)，二线 (2L) 治疗的全球标准。接受一线 (1L) FOLFOX 治疗的患者 (pt) 通常会出现神经病变，这使得在 2L 环境中持续使用神经毒剂不具吸引力，而其他疗法则更为可取。因此，FOLFIRI‐雷莫芦单抗 (ram) 成为 2L GEA 患者的一种选择。FOLFIRI‐ ram已在 2L 结直肠癌治疗中显示出安全性和活性，但是，在 GEA 治疗中尚缺乏有效性/安全性数据。
受试者、材料和方法。我们找出在 2014 年 8 月至 2018 年 4 月期间接受 2L FOLFIRI‐ram 治疗的 GEA 患者。从三个美国学术机构中提取包括奥沙利铂神经毒性率/等级 (G)、2L 治疗反应、无进展生存期 (PFS)、总生存期 (OS)、安全性以及分子特性在内的临床病理数据。Kaplan‐Meier 生存分析用于生成 PFS/OS；似然比检验用于确定统计显著性。
结果。我们找到 29 名接受 2L FOLFIRI‐ram 治疗的患者。所有患者均接受 1L 铂类 + 氟尿嘧啶类治疗，29 名患者中的 23 名患者 (79%) 出现 1L 后神经病变；12 名患者 (41%) 为 G1，11 名患者 (38%) 为 G2。患者均匀地分布于食道/胃食管结合部癌症(12 名患者；41%)和胃癌(17 名患者；59%)之间。在可评价的患者(29 名患者中的 26 名患者)中，总缓解率为 23%(全部为部分缓解)，疾病控制率为 79%。在所有可评价的患者中，中位 PFS 为 6.0 个月，中位 OS 为 13.4 个月。6 个月 OS 和 12 个月 OS 分别占 90% (n = 18/20) 和 41% (n = 7/17)。没有新的安全信号。
结论。我们提供了首个数据表明 FOLFIRI‐ram 是一种不会毒害神经的安全疗法，可以与创新性 RAINBOW 试验中使用的 pac + ram 联合治疗相媲美。
实践意义:本研究结果对胃食管腺癌 (GEA) 患者在一线铂类/氟尿嘧啶类治疗出现进展后的二线 (2L) FOLFIRI‐雷莫芦单抗(ram) 治疗提供初步支持。总体反应、无进展生存期、总生存期以及毒性特征可以与紫杉醇 (pac) + ram 相媲美，并强调了旨在于 2L GEA (NCT03081143) 中检验 FOLFIRI‐ram 对比 pac + ram 的正在进行的 II 期 RAMIRIS 试验的重要性。可能值得考虑的是，将 FOLFIRI‐ram 作为一种替代疗法列入 GEA 的共识指南。
FOLFIRI‐Ram has emerged as a reasonable second‐line option for patients with advanced gastroesophageal adenocarcinoma. This article examines the safety and efficacy of second‐line FOLFIRI‐ram across a clinically‐annotated and molecularly characterized U.S. cohort.
The one-year and median overall survival (mOS) rates of advanced gastroesophageal adenocarcinomas (GEA) are ∼50% and <12 months, respectively. Baseline spatial and temporal molecular heterogeneity of ...targetable alterations may be a cause of failure of targeted/immunooncologic therapies. This heterogeneity, coupled with infrequent incidence of some biomarkers, has resulted in stalled therapeutic progress. We hypothesized that a personalized treatment strategy, applied at first diagnosis then serially over up to three treatment lines using monoclonal antibodies combined with optimally sequenced chemotherapy, could contend with these hurdles. This was tested using a novel clinical expansion-platform type II design with a survival primary endpoint. Of 68 patients by intention-to-treat, the one-year survival rate was 66% and mOS was 15.7 months, meeting the primary efficacy endpoint (one-sided
= 0.0024). First-line response rate (74%), disease control rate (99%), and median progression-free survival (8.2 months) were superior to historical controls. The PANGEA strategy led to improved outcomes warranting a larger randomized study. SIGNIFICANCE: This study highlights excellent outcomes achieved by individually optimizing chemotherapy, biomarker profiling, and matching of targeted therapies at baseline and over time for GEA. Testing a predefined treatment strategy resulted in improved outcomes versus historical controls. Therapeutic resistance observed in correlative analyses suggests that dual targeted inhibition may be beneficial.
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Patients with locally advanced gastroesophageal adenocarcinoma (ie, stage ≥T3 and/or node positive) have high rates of recurrence despite surgery and adjunctive perioperative therapies, which also ...have high toxicity profiles. Evaluation of pharmacogenomically dosed perioperative gFOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and UGT1A1 genotype-directed irinotecan) to optimize efficacy while limiting toxic effects may have value.
To evaluate the coprimary end points of margin-negative (R0) resection rates and pathologic response grades (PRGs) of gFOLFIRINOX therapy among patients with locally advanced gastroesophageal adenocarcinoma.
This single-group phase 2 trial, conducted at 2 academic medical centers from February 2014 to March 2019, enrolled 36 evaluable patients with locally advanced adenocarcinoma of the esophagus, gastroesophageal junction, and gastric body. Data analysis was conducted in May 2019.
Patients received biweekly gFOLFIRINOX (fluorouracil, 2400 mg/m2 over 46 hours; oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2 for UGT1A1 genotype 6/6, 135 mg/m2 for UGT1A1 genotype 6/7, or 90 mg/m2 for UGT1A1 genotype 7/7; and prophylactic peg-filgastrim, 6 mg) for 4 cycles before and after surgery. Patients with tumors positive for ERBB2 also received trastuzumab (6-mg/kg loading dose, then 4 mg/kg).
Margin-negative resection rate and PRG.
A total of 36 evaluable patients (27 78% men; median range age, 66 27-85 years; 10 28% with gastric body cancer; 24 67% with intestinal-type tumors; 6 17% with ERBB2-positive tumors; 19 53% with UGT1A1 genotype 6/6; 16 44% with genotype 6/7; and 1 3% with genotype 7/7) were enrolled. Of these, 35 (97%) underwent surgery; 1 patient (3%) died after completing neoadjuvant chemotherapy while awaiting surgery. Overall, R0 resection was achieved in 33 of 36 patients (92%); 2 patients (6%) with linitis plastica achieved R1 resection. Pathologic response grades 1, 2, and 3 occurred in 13 patients (36%), 9 patients (25%), and 14 patients (39%), respectively, and PRG 1 was observed in 11 of 24 intestinal-type tumors (46%). Median disease-free survival was 30.1 months (95% CI, 15.0 months to not reached), and median overall survival was not reached (95% CI, 8.3 months to not reached). There were no differences in outcomes by UGT1A1 genotype group. A total of 38 patients, including 2 (5%) with antral tumors, were evaluable for toxic effects. Grade 3 or higher adverse events occurring in 5% or more of patients during the perioperative cycles included diarrhea (7 patients 18%; 3 of 19 patients 16% with genotype 6/6; 2 of 16 patients 13% with genotype 6/7; 2 of 3 patients 67% with genotype 7/7), anemia (2 patients 5%), vomiting (2 patients 5%), and nausea (2 patients 5%).
In this study, perioperative pharmacogenomically dosed gFOLFIRINOX was feasible, providing downstaging with PRG 1 in more than one-third of patients and an R0 resection rate in 92% of patients.
ClinicalTrials.gov Identifier: NCT02366819.
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