Enhertu goes head-to-head with Keytruda in lung cancer

PFS extended by 6 months versus Keytruda combination…ORR reaches 70%

No OS advantage seen…imbalance in subsequent HER2 therapy may have served as a factor

Enhertu significantly improved progression-free survival (PFS) versus a Keytruda-based standard regimen in a head-to-head trial in HER2-mutant non-small cell lung cancer (NSCLC).

Median PFS was longer with Enhertu than with Keytruda plus platinum-based chemotherapy, while the objective response rate (ORR) was also higher with Enhertu. Overall survival (OS), however, showed no advantage over Keytruda at the first interim analysis.

Julia Rotow, professor at Dana-Farber Cancer Institute in the US, presented key results from the Phase III DESTINY-Lung04 trial, which directly compared Enhertu (trastuzumab deruxtecan) with a Keytruda (pembrolizumab)-based standard regimen, during a Presidential Session of the World Conference on Lung Cancer (WCLC) on the 14th.

HER2 (ERBB2) mutations occur in about 2%–4% of nonsquamous NSCLC cases. First-line treatment has traditionally centered on immuno-oncology drugs combined with platinum-based chemotherapy, while HER2-targeted therapies have mainly been used as later-line therapies.

DESTINY-Lung04 is the first head-to-head trial in NSCLC evaluating a HER2-targeted therapy as a first-line treatment compared to the standard of care (platinum-pemetrexed.

Enhertu shows PFS superiority versus Keytruda combination

The study enrolled 454 patients with unresectable locally advanced or metastatic nonsquamous NSCLC harboring HER2 exon 19 or 20 mutations.

Patients were randomized 1:1 to Enhertu monotherapy or Keytruda plus platinum-based chemotherapy and pemetrexed. Patients eligible for the study had not received prior systemic therapy for advanced disease and had stable or treated brain metastases.

Median PFS by blinded independent central review (BICR), the primary endpoint, was 14.3 months with Enhertu versus 8.3 months in the control arm.

Phase III DESTINY-Lung04 study design

Enhertu reduced the risk of disease progression or death by 37%, with the PFS benefit generally consistent across major subgroups, including those defined by brain metastasis status, age, and sex.

Response rates were also higher with Enhertu. BICR-assessed ORR was 70.0% with Enhertu versus 44.5% in the control arm. Median duration of response (DOR) was also longer at 13.4 months versus 9.7 months, respectively.

Rotow said, “These results demonstrate the high tumor response and durability of response achieved with Enhertu and suggest its potential as a new first-line treatment option for HER2-mutant lung cancer.”

OS benefit not yet demonstrated…differences in subsequent therapy may affect results

Unlike PFS, no OS advantage was observed.

At the first interim OS analysis, median OS was 29.3 months with Enhertu versus 33.1 months with the Keytruda combination, with a hazard ratio of 1.15.

The analysis, however, was conducted when OS data maturity stood at 46.9%. No formal hypothesis testing for OS was planned at this point, with formal testing to be conducted in a future analysis.

Investigators noted that differences in subsequent treatment between the two groups could affect interpretation of the OS results.

The proportions of patients receiving additional anticancer therapy after discontinuing study treatment were similar between the groups, but more patients in the Keytruda combination arm subsequently received HER2-targeted therapy.

Julia Rotow, a professor at Dana-Farber Cancer Institute in the United States, gives a presentation at WCLC.

In particular, subsequent HER2-targeted therapies, including HER2 ADCs and HER2 TKIs, were used more actively in the Keytruda combination arm. By contrast, a higher proportion of patients in the Enhertu arm subsequently received immunotherapy plus chemotherapy.

Rotow said, “These differences in treatment sequencing need to be considered when interpreting long-term survival outcomes.”

The safety profile was generally consistent with the known profiles of Enhertu and the Keytruda-based combination regimen.

Rates of Grade 3 or higher drug-related adverse events were similar between the two groups, with no major differences in treatment discontinuations or dose reductions.

Interstitial lung disease (ILD)/pneumonitis, however, again emerged as a key management issue with Enhertu. ILD/pneumonitis was reported in approximately one in five patients in the Enhertu arm. Most cases were low grade, but severe and fatal events also occurred.

Rotow emphasized, “Early detection and appropriate management of ILD are critical during Enhertu treatment.”

“A step forward, but the story has just begun”

In a review session that followed, James Chih-Hsin Yang, professor at National Taiwan University, described the findings as “a step forward, but the story has just begun.”

Yang said Enhertu’s high response rate and PFS improvement as monotherapy represent meaningful progress in the treatment of HER2-mutant lung cancer.

In particular, he saw Enhertu’s demonstration of PFS superiority against an active comparator of immunotherapy plus chemotherapy as positive.

The OS results, however, remain an unresolved issue.

Yang suggested that the relatively high use of subsequent HER2-targeted therapies among control-arm patients may have influenced survival outcomes. He cautioned, however, that the current findings are insufficient to attribute the OS difference solely to subsequent therapy.

Ultimately, DESTINY-Lung04 provides evidence that Enhertu can improve PFS over the existing standard regimen as first-line treatment for HER2-mutant lung cancer.

However, with OS data still immature and ILD management and treatment sequencing also requiring consideration, further analyses will be needed to determine Enhertu’s ultimate place in the treatment landscape.