METGastric, METLung Findings Add To Doubts On Onartuzumab Efficacy

Onartuzumab fails to demonstrate a survival benefit for patients with gastro-oesophageal or non-small-cell lung cancer receiving standard care

medwireNews: Phase III trial results have failed to show survival benefits with the addition of the mesenchymal–epithelial transition (MET) antibody onartuzumab to standard care treatment of patients with HER2-negative, MET-positive gastro-oesophageal cancer or those with locally advanced or metastatic non-small-cell lung cancer.

The METGastric trial, published in JAMA Oncology, assigned patients with metastasis unamenable to curative therapy to receive first-line fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) therapy with or without onartuzumab 10 mg/kg given every 2 weeks.

The addition of onartuzumab did not improve overall survival (OS, median 11.3 vs 11.0 months) or progression-free survival (PFS, median 6.8. vs 6.7 months), report David Cunningham, from the Royal Marden Hospital in London, UK, and co-authors.

And the overall response rate (ORR) was a comparable 46.1% with onartuzumab versus 40.6% without the agent.

Nor did subanalyses of patients by MET positivity – measured by immunohistochemical staining of at least 50% of tumour cells – point to an improvement in survival or ORR with onatuzumuab treatment.

However, a subpopulation of 125 non-Asian patients who had not previously undergone gastrectomy and were positive for MET immunohistochemistry did seem to derive benefit from onartuzumab therapy, with a hazard ratio (HR) for death of 0.51.

“Although METGastric failed to meet its co–primary end points, further research is required to better elucidate which patient populations may potentially derive clinical benefits from onartuzumab”, the researchers say.

The METLung trial results were also negative, indicating that OS was poorer in the 250 patients given onartuzumab 15 mg/kg on day 1 of a 21-day cycle plus erlotinib 150 mg/day than in the 249 patients given placebo plus daily erlotinib, at a median of 6.8 versus 9.1 months, although the difference did not reach significance.

As reported in the Journal of Clinical Oncology, PFS was comparable in the onartuzumab and placebo groups (2.7 vs 2.6 months), as was the ORR (8.4 vs 9.6%).

Exploratory analyses suggested a trend towards shorter OS in patients with an epidermal growth factor receptor mutation than those without (HR=4.68), observe David Spigel, from the Sarah Cannon Research Institute in Nashville, Tennessee, USA, and co-investigators.

But stratifying patients by MET protein or gene expression did not reveal any impact of these factors on patient outcome, they add.

Safety analyses pointed to grade 3–5 events in 56.0% of patients given onartuzumab versus 51.2% of those given placebo, with serious adverse events reported in 33.9% and 30.7%, respectively.

The authors note that onartuzumab plus standard care has also shown “disappointing efficacy results” in phase II and III studies of triple-negative breast cancer, recurrent glioblastoma and colorectal carcinoma.

They conclude: “These findings, together with the results from the METLung trial, suggest that MET inhibition via ligand-blocking antibodies may not be an effective therapeutic strategy.”

References

Shah MA, Bang Y-J, Lordick F, et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: The METGastric randomized clinical trial. JAMA Oncol; Advance online publication 1 December 2016. doi:10.1001/jamaoncol.2016.5580  

Spigel DR, Edelman MJ, O’Byrne K, et al. Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METlung. J Clin Oncol; Advance online publication 12 December 2016. DOI: 10.1200/JCO.2016.69.2160

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