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Enhertu Shows Promise in Frontline HER2-Mutated NSCLC Treatment

• Fam-trastuzumab deruxtecan-nxki (Enhertu) is under investigation as a first-line treatment for HER2-mutated and -overexpressing non-small cell lung cancer (NSCLC). • The DESTINY-Lung01 trial revealed a 55% objective response rate and a median progression-free survival of 8.2 months in HER2-mutated NSCLC patients. • Combining ADCs with other agents like immunotherapy or chemoimmunotherapy is being explored, with ongoing trials monitoring overlapping toxicities like cytopenia and ILD. • Antibody-drug conjugates (ADCs) are demonstrating increasing efficacy in NSCLC, potentially shifting treatment paradigms in both second-line and first-line settings.

Fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) is being evaluated as a frontline treatment for HER2-mutated and -overexpressing non-small cell lung cancer (NSCLC), showing promising results in previously treated patients. This development may change the treatment landscape for this subset of lung cancer patients.

DESTINY-Lung01 Trial Results

According to Dr. Noman Ashraf, the phase 2 DESTINY-Lung01 study (NCT03505710) included cohorts of patients with HER2 overexpression and HER2 mutations. Both cohorts appeared to benefit from T-DXd, but those with HER2 mutations experienced a confirmed objective response rate (ORR) of 55% and a median progression-free survival of 8.2 months. The median overall survival was 17.8 months.
In patients overexpressing HER2 treated with T-DXd at 6.4 mg/kg, the ORR was 26.5%. However, a lower dose of 5.4 mg/kg resulted in an ORR of 34.1% with reduced toxicity. The FDA approved the lower dose of 5.4 mg/kg in 2022.

Moving ADCs to the Frontline Setting

Dr. Ashraf noted that while the DESTINY-Lung01 and DESTINY-Lung02 trials (NCT04644237) administered T-DXd in the second-line setting and beyond, ADCs are now being investigated for upfront treatment in HER2-overexpressed or HER2-mutated diseases.

Combining ADCs with Other Agents

Several studies are exploring the combination of T-DXd with standard-of-care treatments. The phase 2 DESTINY-Lung05 trial (NCT05246514) is examining frontline T-DXd in combination with immunotherapy or chemoimmunotherapy.
Combining drugs requires careful monitoring for overlapping toxicities. ADCs can cause cytopenia, similar to chemotherapy. Additionally, while chemotherapy itself doesn't typically cause interstitial lung disease (ILD), immunotherapy can cause pneumonitis, potentially increasing the risk of ILD when combined with ADCs.
Data from the phase 2 NeoCOAST-2 trial (NCT05061550), presented at the 2024 IASLC World Conference on Lung Cancer, suggests that combining some ADCs with chemotherapy is safe. Although this trial focused on TROP2-targeted ADCs, it indicates the potential for safely combining ADCs with other treatments. More studies are needed to confirm these findings.

The Future of ADCs in NSCLC

ADCs are making significant progress in NSCLC, with HER2 becoming an important target. Both HER2 mutations and overexpression are being addressed, and effective TKIs are also emerging. As research progresses, more ADCs are expected to become available, potentially transforming treatment in both second-line and first-line settings.
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HER2-Targeted Therapies Evolve in NSCLC Treatment Landscape

Fam-trastuzumab deruxtecan-nxki (T-DXd) is currently the only FDA-approved therapy for HER2-mutated NSCLC post-chemotherapy, making platinum-based chemotherapy the preferred first-line treatment.
Zongertinib, a mutant-selective HER2 inhibitor, has demonstrated promising efficacy and manageable toxicity in early trials, leading to ongoing phase 3 studies in the first-line setting.

TROP2-Directed ADCs Show Promise and Challenges in NSCLC Treatment

Datopotamab deruxtecan (Dato-DXd) shows promise in EGFR-mutated NSCLC, with a new BLA submitted for accelerated approval after a previous withdrawal based on the TROPION-Lung01 trial.
Post hoc analysis of TROPION-Lung01 reveals Dato-DXd prolonged PFS in nonsquamous NSCLC patients with brain metastases compared to docetaxel, but overall survival was not significantly improved.

T-DXd-Pembrolizumab Combination Shows Promise in HER2-Positive NSCLC with 80% Response Rate in First-Line Setting

A phase 1b study reveals that combining trastuzumab deruxtecan (T-DXd) with pembrolizumab demonstrates significant antitumor activity in HER2-expressing and HER2-mutant non-small cell lung cancer. The combination achieved particularly impressive results in previously untreated patients, with response rates of 62.5% and 80% in HER2-expressing and HER2-mutant NSCLC respectively.

Trastuzumab Deruxtecan Shows Promise in HER2-Overexpressing NSCLC

Trastuzumab deruxtecan (T-DXd) is now approved for HER2-positive solid tumors after prior systemic therapy, impacting treatment strategies for NSCLC.
Clinical trials like DESTINY-Lung01 and DESTINY-Lung03 provide data supporting T-DXd's use in HER2-overexpressing NSCLC.

Trastuzumab Deruxtecan's Expanding Role in HER2-Expressing Solid Tumors

Trastuzumab deruxtecan (T-DXd) received FDA approval for HER2-positive solid tumors, marking a significant expansion beyond breast, lung, gastric, and colorectal cancers.
Clinical trials like DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 demonstrated T-DXd's efficacy across various tumor types, especially those with high HER2 expression.

Trastuzumab Deruxtecan Shows Promise in HER2-Mutated NSCLC

Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with previously treated HER2-mutated non-small cell lung cancer (NSCLC).
The DESTINY-Lung01 trial showed a 55% objective response rate in HER2-mutated NSCLC patients treated with T-DXd at 6.4 mg/kg.

Danaher Collaboration Aims to Enhance HER2 Testing Accuracy for Breast Cancer ADCs

A new, high-sensitivity HER2 assay developed by Dr. Rimm's lab aims to improve the accuracy and sensitivity of HER2 testing, crucial for identifying patients who may benefit from ADCs.
The assay utilizes immunofluorescence to measure HER2 antibody binding, offering a more quantitative approach compared to traditional methods, potentially increasing sensitivity by tenfold.

HER2-Directed ADCs Expand Treatment Spectrum Across Solid Tumors

Trastuzumab deruxtecan (T-DXd) shows promise across breast, gynecologic, gastrointestinal, lung, and genitourinary cancers, targeting HER2-positive, -mutated, and -amplified diseases.
In gynecologic cancers, the DESTINY-PanTumor02 trial demonstrated significant response rates with T-DXd in endometrial, cervical, and ovarian cancers, particularly in HER2 IHC3+ patients.

New HER2 Test Could Expand Trastuzumab Deruxtecan Eligibility for Lung Cancer Patients

A novel, more sensitive test for HER2 protein in lung cancer tissues has been developed, potentially expanding the number of patients eligible for trastuzumab deruxtecan (T-DXd).
The new assay detected elevated HER2 levels in 63% of lung cancer samples, a significant increase compared to the 2% identified by current standard tests.

BAY 2927088 Demonstrates Promising Activity in HER2-Mutant NSCLC

BAY 2927088, a novel oral TKI, showed a 72.1% objective response rate in pretreated HER2-mutant NSCLC patients in the SOHO-01 trial.
The disease control rate with BAY 2927088 was 83.7%, with a median duration of response of 8.7 months and progression-free survival of 7.5 months.

Reference News

[1]
ADCs May Change the Landscape of HER2-Mutant NSCLC - Oncology Nursing News
oncnursingnews.com · Oct 27, 2024

T-DXd showed higher ORRs in HER2-mutated NSCLC, with 55% ORR and 17.8 months median overall survival. HER2-overexpressin...

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