Lung cancer drug poised for global approval, says MWC investigator

Drug’s progress a testament to MWC research capabilities

The positive results seen in the ARCHER 1050 trial have been welcomed by researchers at the Maurice Wilkins Centre, especially those who were instrumental in pioneering dacomitinib’s discovery and championing its subsequent selection as a clinical candidate.

Associate Investigator Dr Jeff Smaill, based at the Auckland Cancer Society Research Centre (ACSRC), University of Auckland, led the New Zealand side of a research collaboration with Pfizer Ann Arbor that sought to optimise an earlier clinical candidate they had developed called canertinib. The project resulted in the discovery and selection of dacomitinib for clinical development in 2003. The story of their medicinal chemistry-based lead optimisation work was finally published in the Journal of Medicinal Chemistry in 2016.[1] Book chapters describing this work and the process optimisation leading to production of 400 kg of active pharmaceutical ingredient were also published later that same year.[2,3]

Dr Jeff Smaill, Senior Researcher at the Auckland Cancer Society Research Centre (ACSRC) and an Associate Investigator with the Maurice Wilkins Centre, led the New Zealand side of a research collaboration that resulted in the discovery of dacomitinib. 

“Chemists in New Zealand and the US spent about a year making well over a hundred compounds and testing them. And of those, two close analogues were particularly interesting and were advanced to detailed evaluation where dacomitinib ended up being the winner,” Dr Smaill said. “It went into clinical trials and it's taken this long to come through the process and complete this large phase III trial.”

“The drug optimisation process was relatively successful, and it's very gratifying for the team of chemists in Auckland that did the hard work to see it do well in phase III and come out as a leading compound of its type, Dr Smaill added. “There's no doubt it's a very good EGFR inhibitor clinically.”

The ARCHER 1050 trial - study details and key findings

The ARCHER 1050 study, a multinational, randomised, open-label phase III trial involving 452 patients with newly diagnosed EGFR mutation-positive NSCLC, found that first-line treatment (in 28-day cycles) with oral dacomitinib 45 mg/day significantly improved median progression-free survival (PFS) compared with oral gefitinib 250 mg/day (14.7 vs 9.2 months, respectively [HR 0.59, 95% CI 0.47-0.74; p<0.0001]).[4]

Higher rates of adverse events, in particular gastrointestinal and dermatological-related, were associated with dacomitinb compared with gefitinib. However, the study authors suggested that it should be considered a new treatment option for these type of patients given its much superior efficacy and duration of response. 

“Dacomitinib is a more potent, second-generation EGFR inhibitor that shares the issue of increased side effects in the skin and gastrointestinal tract, like afatinib,” said lead study author Dr Tony Mok, professor and chair of the Department of Clinical Oncology at the Chinese University of Hong Kong. “In spite of this, the activity seen in this study should allow for consideration of this effective therapy in this patient population.”

Encouraging signs dacomitinib could be approved

Asked whether the latest ARCHER 1050 trial results could help get dacomitinib over the line in terms of being approved for use in the treatment of patients with NSCLC, Dr Smaill expressed a high degree of optimism.

“We always knew it was a good compound based on the preclinical data…we knew it was one of the red hot compounds.  Although anything can happen, with Pfizer’s resources and expertise, such a big improvement [in PFS] – that’s statistically significant and prospectively demonstrated - I would say it's poised for approval,” he said.

“Research is a rewarding career.  If you have a great idea and really chase a goal – an optimised drug or an approach that you think [will work] – it can stand the test of time and it can make it all the way.  There is no doubt in my mind that New Zealand scientists are able to make a significant contribution globally.”

References

1. Smaill JB, Gonzales AJ, Spicer JA, Lee H, et al. Tyrosine kinase inhibitors. 20. Optimization of substituted quinazoline and pyrido[3,4-d]pyrimidine derivatives as orally active, irreversible inhibitors of the epidermal growth factor receptor family. J Med Chem 2016;59:8103-8124. DOI: 10.1021/acs.jmedchem.6b00883.

2. Reed JE, Smaill JB. The discovery of dacomitinib, a potent irreversible EGFR inhibitor. Chapter 8, pp 207-233, DOI: 10.1021/bk-2016-1239.ch008. Published in Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage Process Development Volume 1. Editors: Ahmed F. Abdel-Magid, Jaan Pesti, Rajappa Vaidyanathan, Volume 1239, ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

3. Yu S, Dirat O. Early and late stage process development for the manufacture of dacomitinib. Chapter 9, pp 235-252, DOI: 10.1021/bk-2016-1239.ch009. Published in Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage Process Development Volume 1. Editors: Ahmed F. Abdel-Magid, Jaan Pesti, Rajappa Vaidyanathan, Volume 1239, ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

4. Wu Y-L, Cheng Y, Zhou X, Lee KH, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 2017; DOI: 10.1016/ S1470-2045(17)30608-3.