Summary Background Although trastuzumab plus chemotherapy is the standard of care for first-line treatment of HER2-positive advanced gastric cancer, there is no established therapy in the second-line ...setting. In GATSBY, we examined the efficacy and tolerability of trastuzumab emtansine in patients previously treated for HER2-positive advanced gastric cancer (unresectable, locally advanced, or metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction). Methods This is the final analysis from GATSBY, a randomised, open-label, adaptive, phase 2/3 study, done at 107 centres (28 countries worldwide). Eligible patients had HER2-positive advanced gastric cancer and progressed during or after first-line therapy. In stage one of the trial, patients were randomly assigned to treatment groups (2:2:1) to receive intravenous trastuzumab emtansine (3·6 mg/kg every 3 weeks or 2·4 mg/kg weekly) or physician's choice of a taxane (intravenous docetaxel 75 mg/m2 every 3 weeks or intravenous paclitaxel 80 mg/m2 weekly). In stage two, patients were randomly assigned to treatment groups (2:1) to receive the independent data monitoring committee (IDMC)-selected dose of trastuzumab emtansine (2·4 mg/kg weekly) or a taxane (same regimen as above). We used permuted block randomisation, stratified by world region, previous HER2-targeted therapy, and previous gastrectomy. The primary endpoint (overall survival) was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01641939. Findings Between Sept 3, 2012, and Oct 14, 2013, 70 patients were assigned to receive trastuzumab emtansine 3·6 mg/kg every 3 weeks, 75 to receive trastuzumab emtansine 2·4 mg/kg weekly, and 37 to receive a taxane in the stage 1 part of the trial. At the pre-planned interim analysis (Oct 14, 2013), the IDMC selected trastuzumab emtansine 2·4 mg/kg weekly as the dose to proceed to stage 2. By Feb 9, 2015, a further 153 patients had been randomly assigned to receive trastuzumab emtansine 2·4 mg/kg weekly and a further 80 to receive a taxane. At data cutoff, median follow-up was 17·5 months (IQR 12·1–23·0) for the trastuzumab emtansine 2·4 mg/kg weekly group and 15·4 months (9·2–18·1) in the taxane group. Median overall survival was 7·9 months (95% CI 6·7–9·5) with trastuzumab emtansine 2·4 mg/kg weekly and 8·6 months (7·1–11·2) with taxane treatment (hazard ratio 1·15, 95% CI 0·87–1·51, one-sided p=0·86). The trastuzumab emtansine 2·4 mg/kg group had lower incidences of grade 3 or more adverse events (134 60% of 224 patients treated with trastuzumab emtansine vs 78 70% of 111 patients treated with a taxane), and similar incidences of adverse events leading to death (eight 4% vs four 4%), serious adverse events (65 29% vs 31 28%), and adverse events leading to treatment discontinuation (31 14% vs 15 14%) than did taxane treatment. The most common grade 3 or more adverse events in the trastuzumab emtansine 2·4 mg/kg weekly group were anaemia (59 26%) and thrombocytopenia (25 11%) compared with neutropenia (43 39%), and anaemia (20 18%), in the taxane group. The most common serious adverse events were anaemia (eight 4%), upper gastrointestinal haemorrhage (eight 4%), pneumonia (seven 3%), gastric haemorrhage (six 3%), and gastrointestinal haemorrhage (five 2%) in the trastuzumab emtansine 2·4 mg/kg weekly group compared with pneumonia (four 4%), febrile neutropenia (four 4%), anaemia (three 3%), and neutropenia (three 3%) in the taxane group. Interpretation Trastuzumab emtansine was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer. There is still an unmet need in this patient group and therapeutic options remain limited. Funding F Hoffmann-La Roche.
Background
In the phase 3 KEYNOTE-061 study (cutoff: 10/26/2017), pembrolizumab did not significantly prolong OS vs paclitaxel as second-line (2L) therapy in PD-L1 combined positive score (CPS) ≥ 1 ...gastric/GEJ cancer. We present results in CPS ≥ 1, ≥ 5, and ≥ 10 populations after two additional years of follow-up (cutoff: 10/07/2019).
Methods
Patients were randomly allocated 1:1 to pembrolizumab 200 mg Q3W for ≤ 35 cycles or standard-dose paclitaxel. Primary endpoints: OS and PFS (CPS ≥ 1 population). HRs were calculated using stratified Cox proportional hazards models.
Results
366/395 patients (92.7%) with CPS ≥ 1 died. Pembrolizumab demonstrated a trend toward improved OS vs paclitaxel in the CPS ≥ 1 population (HR, 0.81); 24-month OS rates: 19.9% vs 8.5%. Pembrolizumab incrementally increased the OS benefit with PD-L1 enrichment (CPS ≥ 5: HR, 0.72, 24-month rate, 24.2% vs 8.8%; CPS ≥ 10: 0.69, 24-month rate, 32.1% vs 10.9%). There was no difference in median PFS among treatment groups (CPS ≥ 1: HR, 1.25; CPS ≥ 5: 0.98; CPS ≥ 10: 0.79). ORR (pembrolizumab vs paclitaxel) was 16.3% vs 13.6% (CPS ≥ 1), 20.0% vs 14.3% (CPS ≥ 5), and 24.5% vs 9.1% (CPS ≥ 10); median DOR was 19.1 months vs 5.2, 32.7 vs 4.8, and NR vs 6.9, respectively. Fewer treatment-related AEs (TRAEs) occurred with pembrolizumab than paclitaxel (53% vs 84%).
Conclusion
In this long-term analysis, 2L pembrolizumab did not significantly improve OS but was associated with higher 24-month OS rates than paclitaxel. Pembrolizumab also increased OS benefit with PD-L1 enrichment among patients with PD-L1-positive gastric/GEJ cancer and led to fewer TRAEs than paclitaxel.
Trial registration
ClinicalTrials.gov, NCT02370498
Abstract Background The value of second-line therapy for metastatic gastric cancer is unclear. So far there are no randomised phase III data comparing second-line chemotherapy to best supportive care ...(BSC). In this prospective, multicenter, open label, randomised phase III study we compared irinotecan to BSC to evaluate the impact on survival of second-line chemotherapy. Methods Eligible patients (pts) had metastatic or locally advanced gastro-oesophageal junction or gastric adenocarcinoma, objective tumour progression during or within 6 months after first-line chemotherapy and ECOG performance status 0–2. Stratification for time of progression after first-line therapy, ECOG PS and pretreatment secured even distribution of important prognostic factors. Treatment Arm A: Irinotecan 250 mg/m2 q3w (first cycle) to be increased to 350 mg/m2 , depending on toxicity. Arm B: BSC. Findings Between 10/2002 and 12/2006 40 pts were randomised. The study was closed prematurely due to poor accrual. Response for arm A (19 pts evaluable): No objective responses, SD 53%, PD 47%. Improvement of tumour related symptoms: Arm A 50% of pts, arm B 7%. Overall Survival : (all events in 40 pts have occurred): The hazard ratio for death was reduced to 0.48 (95%CI 0.25–0.92) in the irinotecan-arm ( p = 0.012). Median survival arm A: 4.0 months (95% CI 3.6–7.5), arm B: 2.4 months (95% CI 1.7–4.9). Interpretation Irinotecan as second-line chemotherapy significantly prolongs overall survival compared to BSC in the studied pts. Second-line chemotherapy can now be considered as a proven treatment option for metastatic or locally advanced gastric cancer. Funding The study was supported by a research grant from Aventis and Pfizer.
Perioperative chemotherapy with 5‐fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) is a mainstay in the treatment of esophagogastric adenocarcinomas (EGA). Trastuzumab improved survival ...when added to chemotherapy in patients with HER‐2‐positive metastatic EGA. We investigated the combination of trastuzumab and FLOT as perioperative treatment in patients with locally advanced EGA. A multicenter phase II study evaluated the efficacy and toxicity of perioperative FLOT (24‐hours 5‐FU 2600 mg/m2, leucovorin 200 mg/m2, oxaliplatin 85 mg/mg2, docetaxel 50 mg/m2, trastuzumab 6 mg/kg then 4 mg/kg d1, repeated d15 for four cycles preoperatively and postoperatively followed by 9 cycles of trastuzumab monotherapy) in patients with HER‐2 positive EGA. Patients had ≥cT2, any N, M0 EGA. The primary endpoint was the rate of centrally assessed pathological complete response (pCR). Secondary endpoints comprised disease‐free (DFS) and overall survival (OS), R0 resection rate, toxicity and surgical morbidity. Fifty‐six evaluable patients (median age 62 years) were included; n = 40 had tumors originating from the esophagogastric junction; T stage was (cT2/3/4/unknown): 4/42/8/2; n = 50 patients had cN+ disease. Main adverse events grades 3‐4: leukopenia (17.9%), neutropenia (46.6%) and diarrhea (17.0%). All patients underwent tumor resections. R0 resection rate was 92.9%. Eight patients had anastomotic leakage. One postoperative death occurred. pCR was found in 12 patients (21.4%) and a further n = 14 patients (25.0%) had near complete response. Median DFS was 42.5 months and the 3‐year OS rate was 82.1%. The primary endpoint of achieving a pCR >20% was reached. No unexpected safety issues were observed. Survival data are promising.
VEGF inhibition in gastric cancer has a proven benefit in the second line setting. Pazopanib, an oral tyrosine kinase inhibitor, selectively inhibits VEGFR‐1, ‐2 and ‐3, c‐kit and PDGF‐R resulting in ...inhibition of angiogenesis. This open‐label randomized phase II trial (2:1) investigated the efficacy of combining pazopanib with FLO (5‐fluorouracil, oxaliplatin) vs FLO alone (internal control arm) as first‐line treatment in patients with advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Eighty‐seven patients were randomized and 78 patients were eligible and evaluable (PaFLO arm 51 patients, FLO arm 27 patients). The PFS rate at 6 months (primary endpoint) was 34% in the PaFLO arm vs 30% in the FLO arm. Comparing PaFLO with FLO median PFS was 4.66 months (95% confidence interval CI 2.87‐6.46) vs 4.47 months (95% CI 1.79‐7.14) (95% CI, hazard ratio HR 0.96 (0.60‐1.55), P = .882 exploratory); median OS was 10.19 months (95% CI 5.46‐14.92) vs 7.33 months (95% CI 4.93‐9.73), (95% CI HR 1.01 0.62‐1.65, P = .953, exploratory), disease control rate was 72% vs 59%. PaFLO was well tolerable, toxicities were slightly higher in the PaFLO arm. Major adverse events were loss of appetite, nausea, fatigue, diarrhea, neutropenia and thrombocytopenia. Adding pazopanib to chemotherapy shows signs of efficacy but no major improvement in this randomized phase 2 trial. The PFS at 6 months in both arms was lower than expected from the literature. Biomarkers identifying subgroups who benefit and novel combinations are needed. ClinicalTrials.gov: NCT01503372.
What's new?
Pazopanib is an oral angiogenesis inhibitor. In this randomized, phase II clinical trial, the authors added pazopanib to standard chemotherapy as a first‐line treatment in patients with advanced gastro‐esophageal cancer. This combination was compared to chemotherapy alone. The results indicated that the addition of pazopanib to 5‐FU/oxaliplatin was well tolerated and showed some efficacy, but didn't yield a major benefit over standard therapy. Further research into other novel treatment combinations, as well as into biomarkers to identify subgroups who might benefit, are urgently needed.
Treatment of esophageal carcinoma has changed dramatically following several landmark trials, which have proven the benefit of immunotherapy. The selective PD-1 (programmed cell death ...ligand-1)-inhibitor nivolumab has been shown to improve DFS in the adjuvant therapy setting (CheckMate-577). In the first-line treatment, PD-L1 positive (CPS ≥ 10) squamous cell carcinoma patients (pts) have been shown to have an increased OS following treatment with the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). Nivolumab also improved overall survival in the first line setting either combined with ipilimumab or with chemotherapy (CheckMate 648) compared to chemotherapy alone. In Asian first-line patients, phase III trials investigating camrelizumab (ESCORT 1), toripalimab (JUPITER 06), or sintilimab (ORIENT 15) in addition to chemotherapy also showed significant survival benefits. In the second-line setting, monotherapy with nivolumab (ATTRACTION-03), pembrolizumab (KEYNOTE-181), camrelizumab (ESCORT), and tislelizumab (RATIONALE 302) demonstrated a benefit in OS in comparison to chemotherapy. Here we will review these trials and integrate them into the current treatment algorithm.
Background
Prespecified exploratory biomarker analyses of the phase II/III GATSBY study (NCT01641939) assessed whether patient subgroups experienced a survival benefit from trastuzumab emtansine ...(T-DM1) versus taxane therapy, and to advance understanding of HER2-positive advanced gastric/gastroesophageal junction cancer (AGC) disease biology.
Methods
Adults with HER2-positive AGC whose disease progressed during/after first-line therapy were enrolled and randomized to receive T-DM1 Stage 1: 3.6 mg/kg q3w, 2.4 mg/kg qw, or taxane (docetaxel/paclitaxel); Stage 2: 2.4 mg/kg qw or taxane. Primary efficacy endpoint was overall survival (OS). Prespecified exploratory biomarkers included HER2, HER3, PTEN,
PIK3CA
mutation status, FcγR, and cMET. Tumor samples from patients who received 2.4 mg/kg T-DM1 (
n
= 228) or taxane (
n
= 117) were included.
Results
Median OS was longer in subgroups with HER2 immunohistochemistry (IHC) 3+ 9.5 versus 8.3 months for T-DM1 versus taxane; hazard ratio (HR) 0.99 (95% CI 0.68–1.43) versus HER2 IHC 2+/in situ hybridization-positive 5.2 versus 9.2 months for T-DM1 versus taxane; HR 1.53 (95% CI 0.94–2.50) tumors. Trends towards increased median OS were also observed in subgroups with > versus ≤ median
HER2
mRNA expression, higher versus lower
HER2
gene copy number,
HER2
gene ratio and H score, and homogenous or nonfocal HER2 IHC staining. T-DM1 was not associated with superior OS versus taxane in any subgroup.
Conclusions
Patients with previously treated HER2-positive AGC with higher HER2 expression experienced a better treatment effect from T-DM1 than those with lower HER2 expression and may derive comparable survival benefits from T-DM1 and taxane therapy.
Clinical trials registration
NCT01641939 (
https://clinicaltrials.gov/ct2/show/NCT01641939
).
Recently some progress has been made in the palliative treatment of gastric cancer. It was shown that second-line chemotherapy and VEGF-R2-directed treatment can prolong survival. Despite these ...advances most patients with metastatic gastric cancer live for less than 2 years. Immune-checkpoint blockade with anti-CTLA4, anti-PD-1 and anti-PD-L1 antibodies has revolutionised the treatment of many cancers. Significant benefit was also proven in gastric adenocarcinomas. Nivolumab improves overall survival as third-line treatment in Asian gastric cancer patients and is already registered in Japan. Pembrolizumab shows significant efficacy, especially in PD-L1-positive patients as third-line treatment and is FDA approved for this indication. Trials with avelumab are promising and studies with atezolizumab and durvalumab are also on the way. To extend the subgroup of benefitting patients combinations of PD-1/PD-L1 antibodies with CTLA4, or VEGF-R2 antibodies or combination with chemotherapy are investigated and show promising results. In this article, the existing evidence of PD1 and PD-L1 blockade as monotherapy or in combination with anti-CTLA4, anti-VEGF-R2 and chemotherapy in gastro-oesophageal adenocarcinoma is reviewed and put into perspective.
FOLFOX plus nivolumab represents a standard of care for first‐line therapy of advanced gastroesophageal cancer (aGEC) with positive PD‐L1 expression. The efficacy of second‐line VEGFR‐2 inhibition ...with ramucirumab (RAM) plus chemotherapy after progression to immunochemotherapy remains unclear. Medical records of patients with aGEC enrolled in the randomized phase II AIO‐STO‐0417 trial after treatment failure to first‐line FOLFOX plus nivolumab and ipilimumab were retrospectively analyzed. Patients were divided into two groups based on second‐line therapy: RAM plus chemotherapy (RAM group) or treatment without RAM (control group). Eighty three patients were included. In the overall population, progression‐free survival (PFS) in the RAM group was superior to the control (4.5 vs 2.9 months). Responders (CR/PR) to first‐line immunochemotherapy receiving RAM containing second‐line therapy had prolonged OS from start of first‐line therapy (28.9 vs 16.5 months), as well as second‐line OS (9.6 vs 7.5 months), PFS (5.6 vs 2.9 months) and DCR (53% vs 29%) compared to the control. PD‐L1 CPS ≥1 was 42% and 44% for the RAM and the control, respectively. Patients with CPS ≥1 in the RAM group showed better tumor control (ORR 25% vs 10%) and improved survival (total OS 11.5 vs 8.0 months; second‐line OS 6.5 vs 3.9 months; PFS 4.5 vs 1.6 months) compared to the control. Prior exposure to first‐line FOLFOX plus dual checkpoint inhibition followed by RAM plus chemotherapy shows favorable response and survival rates especially in patients with initial response and positive PD‐L1 expression and has the potential to advance the treatment paradigm in aGEC.
What's new?
Evidence suggests that immunochemotherapy followed by second‐line treatment with ramucirumab, a vascular endothelial growth factor receptor (VEGF) inhibitor, potentially boosts treatment response in patients with advanced gastroesophageal cancer (aGEC). Here, to more thoroughly explore this possibility, the authors analyzed data from a phase II trial involving aGEC patients treated with ramucirumab after failing first‐line immunochemotherapy. Improved tumor control and lengthened survival were observed in patients following second‐line ramucirumab‐containing therapy. The benefit was greatest among patients who initially responded to first‐line therapy and whose tumors expressed programmed‐death ligand‐1. The findings indicate that integration of VEGF‐targeted agents into immunochemotherapy‐based regimens improves aGEC survival.
PDF
