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A quarter of patients diagnosed with stage IV non-small-cell lung cancer (NSCLC) have brain metastases at diagnosis, and the long-time treatment approach, whole-brain radiation therapy, offers a modest survival benefit but takes a heavy toll on cognitive function and quality of life (QOL).

Findings from the phase II Atezo-Brain study concluded that patients with advanced NSCLC and untreated brain metastases benefited from kicking off systemic treatment with atezolizumab (Tecentriq) combined with carboplatin and pemetrexed.

Now the phase II HERTHENA-Lung01 trial has shown that treatment with the antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd) offered clinically meaningful efficacy, along with durable responses in central nervous systems (CNS) metastases, in heavily pretreated patients with EGFR-mutated NSCLC.

"After disease progression on EGFR TKI [tyrosine kinase inhibitor] therapy, patients are usually treated with platinum-based chemotherapy (PBC; with or without an immune checkpoint inhibitor and antiangiogenic therapy). Salvage therapies after disease progression on PBC have limited efficacy," explained Helena A. Yu, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

They reported in the that over half of the patients in HERTHENA-Lung01 had a history of brain metastases, while about a third had evidence of brain metastases on imaging. Previous treatment was done with TKI therapy and PBC. The median study duration was 18.9 months.

Yu's group found that among the 225 patients who got HER3-DXd once every 3 weeks, the confirmed objective response rate (ORR) was 29.8%, while the median duration of response came in at 6.4 months. Median progression-free survival (PFS) was 5.5 months and median overall survival (OS) was 11.9 months. Among patients with non-irradiated brain metastases at baseline, the confirmed CNS ORR was 33.3%.

The researchers noted that CNS metastases have been reported in 70% of patients with advanced EGFR-mutated NSCLC, so the current data add to "the emerging understanding of the potential for intracranial response with large-molecule therapies."

The team explained that the study will take a closer look at the "CNS penetration and pharmacodynamic activity of HER3-DXd in patients with CNS metastasis," while the ongoing trial continues to evaluate HER3-DXd versus PBC.

In an accompanying , Lizza E.L. Hendriks, MD, PhD, of Maastricht University Medical Center in the Netherlands, and Jordi Remon, MD, PhD, of Gustave Roussy in Villejuif, France, noted that ADCs generally suffer from a lack of data in terms of CNS efficacy and that this is an important issue in oncogene-addicted NSCLC. "The limited data of the HERTHENA-Lung01 trial suggest that patritumab deruxtecan could be beneficial in this patient population, given its intracranial ORR of 33%," Hendriks and Remon wrote.

They called out the trial, which is enrolling patients with brain or leptomeningeal metastases from NSCLC or breast cancer, along with a (Tagrisso) combination trial, as part and parcel of the research that will clarify "the role of ADCs in treating EGFR-mutated NSCLC [which currently] remains uncertain but promising."

In related research, Myung-Ju Ahn, MD, PhD, of Samsung Medical Center/Sungkyunkwan University School of Medicine in Seoul, Korea, presented data from the trial at the European Society for Medical Oncology (ESMO) 2023 meeting. The study enrolled 228 patients with activating EGFR mutation or ALK translocation at 16 sites in South Korea who were randomized to the trial regimen of atezolizumab plus bevacizumab-carboplatin-paclitaxel (ABCP) or paclitaxel-carboplatin (PC) alone. Median follow-up was 26.1 months.

What was the impetus for the study, "A phase III, randomized study of atezolizumab plus bevacizumab and chemotherapy in patients with EGFR or ALK mutated in non-small cell lung cancer (ATTLAS, KCSG-LU19-04)?"

Ahn: TKI is the current first-line treatment for metastatic NSCLC with activating EGFR mutation or ALK translocation. Despite a high initial response and prolonged PFS, almost all patients experience acquired resistance to TKIs. The of the phase III IMPower-150 study revealed the improved efficacy of of anti-PD-L1 antibody in combination with anti-angiogenic therapy, particularly in EGFR-mutated NSCLC.

The purpose of this study was to evaluate the efficacy and safety of ABCP in patients with sensitizing EGFR or ALK-mutated NSCLC who had progressed on prior TKI treatment. This [ESMO] presentation included data from the first analysis at a time point of 12 months from randomization. We'd like to highlight that more than 40% of patients had brain metastasis.

What were some of the main findings?

Ahn: ABCP significantly improved PFS vs PC [median 8.4 vs 5.62 months]. The hazard ratio [HR] was 0.62; the 1-year PFS rate was 36% vs 23%; 2-year PFS was 13% vs 9%.

The PFS benefit was observed across almost all subgroups, but patients with brain metastasis, patients with L858R mutation, and no acquired T790M mutation had more benefit with the ABCP regimen. The benefit was regardless of the PD-L1 expression, but patients with high PD-L1 expression had more benefit.

The overall response rate was 65.5% vs 41.9%; the median best percentage change in target lesion size was -44% in the ABCP arm vs -26% in PC. With a median follow-up of 26 months, there was no difference in OS [20.63% vs 20.27%].

What about AEs?

Ahn: As expected, AEs were more common in the ABCP arm; any grade ≥3 treatment-related AE was observed in 35.1% of the ABCP arm versus 15% in the PC arm. However, only 2% actually required permanent treatment discontinuation, and there were three deaths in the ABCP arm: two patients with pneumonia and one with cerebral infarction. The most common AEs in the ABCP arm (<3% for each) were peripheral neuropathy, myalgia, hypertension, fatigue, pruritus, and hyperthyroidism.

What is the take-home message from ATTLAS?

Ahn: The ABCP regimen demonstrated a statistically significant and clinically meaningful improvement in PFS over PC. The patient subgroup with EGFR L858R, without T790M mutation, and presence of brain mets showed more benefit with the ABCP regimen compared to the PC regimen. There was no difference in OS, but we need longer follow-up.

Read the HERTHENA-Lung01 study here.