First-Line Triple Regimen Shows Promise For HER2-Positive Metastatic Oesophagogastric Cancer

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: The combination of pembrolizumab, trastuzumab and chemotherapy is feasible and has shown signs of activity against metastatic HER2-positive oesophagogastric cancer in a phase II open-label trial. 

The study included 37 patients with an ECOG performance status of 0–2 and a left ventricular ejection fraction of at least 53% who had not previously received treatment for their metastatic disease, explain Yelena Janjigian, from Memorial Sloan Kettering Cancer Center in New York, USA, and co-investigators. 

Treatment began with an induction cycle of pembrolizumab 200 mg plus trastuzumab 8 mg/kg, followed by a 3-week cycle with a day 1 dosing of pembrolizumab 200 mg, trastuzumab 6 mg/kg and either oxaliplatin 130 mg/m2 or cisplatin 80 mg/m2. In addition, capecitabine 850 mg/m2 was given twice daily for the first two of every 3 weeks of treatment. 

Median progression-free survival (PFS) was 13.0 months, with 70% of patients alive and free from progression at 6 months, meeting the study’s primary endpoint. Median overall survival was 27.3 months with a 12-month rate of 80%.  

All patients achieved disease control, the researchers report in The Lancet Oncology. Analysis of the 35 patients with RECIST measureable disease showed tumour regression of between 20% and 100%, including a complete response in 17%, a partial response in 74% and stable disease in 9%. 

And post-hoc analysis indicated that patients showed evidence of a response to treatment within a median of 2 months and that response continued for a median of 9.4 months. 

“Although all 37 treated patients exhibited evidence of clinical benefit, the duration of clinical benefit was highly variable, and non-target escape lesions represented the only site of progressive disease in 12 (55%) of 22 patients at the time of discontinuation of study therapy”, Yelena Janjigian et al write.

Overall, 13 patients were continuing treatment at time of data lock, 22 patients discontinued treatment because of disease progression and two following serious episodes of grade 3 nephritis. Twelve patients died. 

Treatment-related adverse events included grade 3 and 4 events in 49% and 8% of patients, respectively, most commonly decreased lymphocyte counts, electrolyte disturbances and anaemia. 

Analysis indicated that PFS did not significantly correlate with PD-L1 expression, median tumour mutation burden, DNA copy number alterations or HER2 gene amplification as assessed by next-generation sequencing. But PFS was significantly longer in patients with high levels of cell-free HER2 amplification after adjusting for tumour DNA shedding than those with low levels, and for patients with an RTK–RAS pathway alteration than their wild-type counterparts. 

While acknowledging the single-centre study’s limitations, including lack of a control arm and inadequate baseline tissue for full biomarker analysis, the researchers believe their findings “suggest that the addition of pembrolizumab to trastuzumab and chemotherapy is safe and active in treatment metastatic oesophagogastric cancer.” 

They conclude: “The data reported thus represent the basis for the ongoing, international, randomised, double-blind, phase 3 KEYNOTE 811 trial (NCT03615326) of pembrolizumab versus placebo in combination with trastuzumab and chemotherapy.”

Reference 

Janjigian YY, Maron SB, Chatila WK, et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesphageal junction cancer: an open-label, single-arm, phase 2 trial. Lancet Oncol; Advance online publication 18 May 2020. https://doi.org/10.1016/S1470-2045(20)30169-8