First-line trastuzumab deruxtecan extended median PFS to 14.3 months in HER2-mutant NSCLC

A hazard ratio of 0.63, and six months of additional progression-free survival

On the primary endpoint, trastuzumab deruxtecan monotherapy reduced the risk of disease progression or death by 37.0% against pembrolizumab with chemotherapy, on a hazard ratio of 0.63 (95% CI 0.50–0.79; p<0.0001). Median progression-free survival was 14.3 months against 8.3 months, assessed by blinded independent central review.

DESTINY-Lung04 is a global, randomised, open-label trial of 454 patients with unresectable, locally advanced or metastatic non-squamous NSCLC carrying a HER2 exon 19 or exon 20 mutation, enrolled at sites in Asia, Europe and North America and randomised 1:1. The comparator is the current first-line standard of care in this population, a platinum-pemetrexed doublet given with pembrolizumab. HER2 mutations have been reported in approximately 2 to 4% of patients with non-squamous NSCLC, occurring predominantly in younger women and in people with no smoking history, and have been associated with an increased incidence of brain metastases.

Responses in 70.0% of patients, lasting a median of 13.4 months

The objective response rate was 70.0% with trastuzumab deruxtecan against 44.5% with pembrolizumab and chemotherapy. Median duration of response was 13.4 months against 9.7 months. Response rate and duration of response are secondary endpoints, assessed by both blinded independent central review and investigators; the release reports one set of figures without saying which assessment they come from.

AstraZeneca reported a favourable progression-free survival trend across key subgroups, and listed brain metastases, liver metastases, smoking status, HER2 mutation status by exon, and de novo or recurrent disease as prespecified stratification factors. The trial description in the same release says randomisation was stratified by smoking history and by the presence or history of brain metastasis. No subgroup hazard ratios were released.

No overall survival benefit at 46.9% maturity, with subsequent treatment imbalanced

Overall survival data were 46.9% mature at the time of this analysis and no formal hypothesis testing was performed. No overall survival benefit was observed. AstraZeneca states that varied and imbalanced patterns of subsequent therapy between the arms may limit the interpretation of that result.

The imbalances given are that HER2-directed therapies were used afterwards in 48.0% of patients in the pembrolizumab and chemotherapy arm against 23.3% in the trastuzumab deruxtecan arm, and that subsequent immunotherapy with chemotherapy was used in 23.8% of the trastuzumab deruxtecan arm. No median overall survival, hazard ratio or confidence interval was released for either arm, so the overall survival result is not on the record in numbers.

“HER2-mutant non-small cell lung cancer is an aggressive disease with limited responses to current first-line standard of care, and many patients experience disease progression within a year of starting treatment. With seventy per cent of patients responding and a median progression-free survival of 14.3 months, trastuzumab deruxtecan has the potential to become an important new first-line treatment option for these patients.”Julia Rotow, MD, Assistant Professor of Medicine at Dana-Farber Cancer Institute and lead investigator of the trial

Interstitial lung disease adjudicated in 20.8%, including four Grade 5 events

Interstitial lung disease or pneumonitis occurred in 20.8% of patients treated with trastuzumab deruxtecan, as determined by an independent adjudication committee. Most events were low grade: Grade 1 in seven patients (3.1%) and Grade 2 in 30 patients (13.3%).

The remainder were five Grade 3 events (2.2%), one Grade 4 (0.4%) and four Grade 5 (1.8%). The four Grade 5 events were recorded in a trial that reported a six-month gain in median progression-free survival and no overall survival benefit at this analysis. No corresponding adjudicated figure for the comparator arm was released.

Grade 3 or higher treatment-related events at 34.1% against 33.6%, on longer exposure

AstraZeneca reported that the safety profile of trastuzumab deruxtecan in DESTINY-Lung04 was generally consistent with its known profile, with no new safety concerns identified. Grade 3 or higher treatment-related adverse events were comparable between the arms, at 34.1% with trastuzumab deruxtecan and 33.6% with pembrolizumab and chemotherapy.

That comparison is made on unequal time on treatment: median exposure was 12.3 months in the trastuzumab deruxtecan arm against 7.1 months in the comparator arm. The most common Grade 3 or higher adverse event reported in 5% or more of patients in both arms was neutropenia, at 11.1% with trastuzumab deruxtecan and 14.1% with pembrolizumab and chemotherapy. Trastuzumab deruxtecan is currently approved in more than 80 countries for patients with unresectable or metastatic NSCLC carrying activating HER2 mutations who have already received a prior systemic therapy.