Trastuzumab Deruxtecan Shows Promise For Previously Treated Breast, Gastric Cancer

The novel antibody–drug conjugate trastuzumab deruxtecan has a favourable safety profile and demonstrates antitumour activity in patients with advanced breast, gastric or gastro-oesophageal cancer with an inadequate response to standard therapy

medwireNews: Phase I trial findings from Japan indicate that trastuzumab deruxtecan is well tolerated and may have efficacy in patients with unresectable or metastatic breast, gastric or gastro-oesophageal cancer refractory to treatment.

The 24 patients included in the open-label study’s dose-escalation stage had previously received at least one prior regimen; 18 patients had used an anti-HER2 agent, such as trastuzumab or trastuzumab emtansine.

“If these data are supported by our ongoing expansion study, trastuzumab deruxtecan might become a new treatment option for salvage-line treatment in these settings”, say Toshihiko Doi, from National Cancer Center Hospital East in Chiba, and co-investigators.

Patients received a trastuzumab deruxtecan dose of between 0.8 and 8.0 mg/kg on a 21-day cycle and the researchers did not identify a maximum tolerated dose for the antibody–drug conjugate, which consists of a humanised antibody against HER2, a novel enzyme-cleaveable linker and a topoisomerase I inhibitor payload.

There were no dose-limiting toxicities, substantial cardiovascular adverse events or deaths associated with the treatment, although grade 3 and 4 adverse events were numerically more common with doses above 3.2 mg/kg.

Of the 23 evaluable patients, 10 (43%) achieved an objective partial response and 21 (91%) achieved disease control, including a partial response in one (17%) of the six patients with low HER2-expressing tumours.

In addition, 53% of the 17 breast cancer patients who had previously received trastuzumab and 58% of the 12 patients with HER2-positive breast cancer who had previously used trastuzumab emtansine, with corresponding disease control rates of 94% and 100%. Among four patients with HER2-positive gastric cancer previously treated with trastuzumab, there was a 50% partial response rate and a 100% disease control rate.

Most of the objective responses occurred in patients given a dose of 5.4 mg/kg or above, suggesting a dose–response relationship, the authors say, and after a median of 12.1 weeks. At time of data cutoff, 46% of patients had received at least 6 months of treatment and 12% were continuing with treatment after 1 year. Median progression-free survival was not yet reached.

“The dose-expansion portion of the trial (at 5.4 mg/kg or 6.4 mg/kg administered intravenously once every 3 weeks) and additional work to further refine and justify the recommended phase 2 dosing of trastuzumab deruxtecan are ongoing”, the researchers conclude.

Discussing the findings in an accompanying comment, Manish Shah, from Weill Cornell Medicine and New York Presbyterian Hospital in the USA, writes that the “challenge in terms of drug development for this drug is to identify a patient population in which the drug can show its own unique benefit.”

He questions whether there is evidence to suggest trastuzumab deruxtecan is truly active in low-HER2 disease defined by immunohistochemistry (IHC) 0, 1+ or 2+ expression status, noting that two of the three patients in this group who had a partial response were HER2-positive by fluorescent in situ hybridisation (FISH) and the third had FISH-negative gastric cancer, which has known HER2 heterogeneity.

“[W]e know that trastuzumab deruxtecan can be given safely to patients, and there is activity in a select group of patients with HER2 positivity (IHC 3+ or FISH-positive), we do not quite know how it kills cancer cells nor do we have confidence in the efficacy of trastuzumab deruxtecan in patients with low HER2 expression”, the commentator cautions.

References

Doi T, Shitara K, Naito Y, et al. Safety, pharmacokinetics, and the antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody–drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol; Advance online publication 13 October 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30604-6

Shah MA. Antibody–drug conjugates: can the payload improve activity in HER2 expressing cancers? Lancet Oncol; Advance online publication 13 October 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30720-9

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