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ADCs for Lung Cancer
Latest Developments and Insights on ADCs for Lung Cancer

Released: November 05, 2024

Expiration: November 04, 2025

David Planchard
David Planchard, MD, PhD
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Key Takeaways
  • Patritumab deruxtecan (HER3-DXd) has shown activity in patients with EGFR-mutated NSCLC and various mechanisms of resistance to EGFR tyrosine kinase inhibitors.
  • Datopotamab deruxtecan (Dato-DXd), an investigational TROP2-targeted ADC, is associated with stomatitis that will be necessary to appropriately manage if this agent is approved.
  • Multiple ADCs targeting TROP2, B7-H3, and SEZ6 are being investigated in clinical trials enrolling patients with relapsed ES-SCLC.

The Role of Antibody–Drug Conjugates in Transforming Lung Cancer Care
Antibody–drug conjugates (ADCs) have emerged as a promising therapeutic strategy in lung cancer, offering a novel approach to delivering targeted chemotherapy with reduced systemic toxicity. By coupling a cytotoxic agent to a monoclonal antibody, ADCs specifically target tumor cells expressing certain antigens, minimizing damage to normal tissues. This commentary explores the current and emerging applications of ADCs in lung cancer, with a focus on therapies targeting HER2, HER3, and TROP2 in non-small-cell lung cancer (NSCLC) and ADCs targeting TROP2 and B7-H3 being investigated in small-cell lung cancer (SCLC). This commentary also serves as a “call-to-action” for us healthcare professionals to familiarize ourselves with these ADCs that will have an increasing role in the management of our patients with lung cancer.

HER2-Targeted ADCs in NSCLC
HER2 mutations occur in approximately 1% to 3% of NSCLC cases, predominantly as exon 20 insertions, and historically have been difficult to target. Early trials with HER2 tyrosine kinase inhibitors showed limited success. However, the advent of ADCs, such as trastuzumab deruxtecan (T-DXd), has changed the landscape. In the pivotal DESTINY-Lung01 trial, T-DXd 6.4 mg/kg every 3 weeks demonstrated significant efficacy in patients with HER2-mutant NSCLC, achieving an objective response rate (ORR) of 54.9%, with a median progression-free survival (PFS) of 8.2 months and a median overall survival (OS) of 17.8 months. These data were particularly impressive since these were heavily pretreated patients, many of whom had already undergone several lines of therapy.

Nevertheless, treatment with T-DXd is not without challenges. Interstitial lung disease (ILD) emerged as a concerning adverse event in this trial, occurring in approximately 13% to 28% of patients. The DESTINY-Lung02 study sought to address this by testing a lower dose of T-DXd (5.4 mg/kg every 3 weeks), which resulted in a reduced incidence of ILD while maintaining antitumor activity. This highlights the need for careful monitoring and management of ADC-associated toxicities in clinical practice.

Investigational HER3-Targeted ADCs in NSCLC
HER3 is another promising target in NSCLC, particularly in patients with EGFR-mutant tumors that have developed resistance to EGFR tyrosine kinase inhibitors (TKIs). Patritumab deruxtecan (HER3-DXd) has emerged as a key investigational agent in this space. In the phase II HERTHENA-Lung01 study, HER3-DXd demonstrated an ORR of 29.8% in patients with EGFR-mutant NSCLC who had progressed on EGFR TKIs. This ADC has shown activity regardless of the specific EGFR resistance mechanisms, making it a versatile option for these patients.

Of importance, the efficacy of HER3-DXd was not dependent on the level of HER3 expression, indicating that HER3 might serve more as a functional target rather than a biomarker for patient selection. This suggests a broader applicability of HER3-DXd in treating EGFR-mutant NSCLC, regardless of HER3 expression levels. Although the ILD rate with HER3-DXd was lower than with T-DXd, cytopenias and gastrointestinal toxicities were common, underscoring the need for ongoing management and supportive care in patients receiving this therapy. HER3-DXd is currently being evaluated in the phase III HERTHENA-Lung02 trial (NCT05338970) vs platinum-based chemotherapy for patients with EGFR-mutant NSCLC and progression on prior EGFR TKI therapy including a third-generation EGFR TKI.

TROP2-Targeted ADCs in NSCLC
TROP2 is a transmembrane glycoprotein overexpressed in many epithelial tumors, including lung cancer. The phase III TROPION-Lung01 trial evaluated datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated patients with advanced NSCLC. This ADC demonstrated a higher ORR vs docetaxel (26.4% vs 12.8%, respectively) and longer PFS benefit compared with docetaxel (HR: 0.75). Dato-DXd had a favorable toxicity profile, although ILD and stomatitis were notable adverse events associated with it. Of interest, Dato-DXd showed greater efficacy than docetaxel in nonsquamous NSCLC, whereas its efficacy in squamous cell carcinoma appeared to be limited.

Another TROP2-targeted ADC, sacituzumab govitecan, has been evaluated in the phase III EVOKE-01 trial. This trial did not meet its primary endpoint for OS benefit compared with docetaxel in previously treated patients with NSCLC. However, sacituzumab govitecan showed promise in a prespecified subgroup of patients who were nonresponders to prior immunotherapy. This suggests that TROP2-targeted ADCs may have a role in specific patient populations, particularly those who are refractory to standard treatments. Notable adverse events associated with sacituzumab govitecan include myelosuppression (neutropenia) and diarrhea. Another TROP2-targeted ADC, sacituzumab tirumotecan, is being evaluated in a phase III trial vs single-agent chemotherapy in previously treated patients with advanced NSCLC and an actionable genomic alteration. In addition, various TROP2-targeted ADC combination trials are underway in NSCLC.

ADC Therapy in SCLC
Although much of the focus on ADCs has been in NSCLC, their potential in SCLC is also being explored. SCLC is a notoriously aggressive form of lung cancer associated with nearly universal functional loss of TP53 and RB1 and frequent MYC amplification and mutations in epigenetic regulators. Currently, SCLC has limited treatment options after first-line chemoimmunotherapy. Emerging data on ifinatamab deruxtecan (I-DXd), an ADC targeting the novel antigen B7-H3 in SCLC, is showing promise in early-phase trials. I-DXd 12 mg/kg demonstrated a 55% response rate and a median PFS of 5.5 months in a cohort of previously treated patients with SCLC in the IDeate-Lung01 trial, which is encouraging. As with T-DXd, ILD is associated with I-DXd. The ongoing phase III IDeate-Lung02 trial (NCT06203210) is evaluating I-DXd vs current standard-of-care therapy in patients with relapsed SCLC who have received 1 previous line of platinum-based chemotherapy. Additional ADCs targeting TROP2 (sacituzumab govitecan and SHR-A1921) and SEZ6 (ABBV-001 and ABBV-706) are showing promise in this difficult-to-treat disease.

Call to Action for Healthcare Professionals
Despite the promising clinical data, there remains significant uncertainty among healthcare professionals regarding the integration of ADCs into clinical practice. A recent survey of global healthcare professionals by CCO revealed that many are unfamiliar with the targets of ADCs like Dato-DXd, HER3-DXd, and I-DXd, and most are not confident in their ability to manage ILD associated with T-DXd. This underscores the need for us to seek further education and training on the use of ADCs in lung cancer, particularly on monitoring and managing their unique toxicities and the latest evidence-based recommendations for optimally integrating these agents into existing treatment paradigms to ultimately improve patient outcomes.

Your Thoughts?
How are you currently incorporating ADCs into your lung cancer treatment strategies? What challenges have you encountered in managing ADC-related toxicities, particularly ILD? Share your experiences and insights in the comments below and let us know what topics you would like to learn more about by answering the polling question.

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