What are the latest updates to lung cancer treatment?

Latest Updates in Lung Cancer Treatment

The most significant recent advances in lung cancer treatment include FDA approval of trastuzumab deruxtecan for HER2-overexpressing NSCLC, promising data on datopotamab deruxtecan for nonsquamous disease, and emerging bispecific antibodies like ivonescimab, alongside continued refinement of targeted therapies for driver alterations. 1

HER2-Targeted Antibody-Drug Conjugates

Trastuzumab Deruxtecan (FDA-Approved April 2024)

• Trastuzumab deruxtecan 5.4 mg/kg every 3 weeks is now FDA-approved for previously treated advanced NSCLC with HER2 overexpression (IHC 2+ or 3+), which occurs in 8-23% of NSCLC patients. 1

• The DESTINY-Lung01 trial demonstrated an objective response rate of 34.1% with the 5.4 mg/kg dose, with median duration of response of 6.2 months. 1

• Patients with HER2 IHC 3+ expression achieved particularly impressive results with 53% ORR and 6.9 months median duration of response. 1

• Key safety consideration: Pneumonitis occurred in 2% of patients at the approved dose, with the most common adverse events being nausea, fatigue, decreased appetite, and constipation. 1

• Preliminary phase Ib data from 2024 IASLC WCLC showed even more encouraging results with 44.4% ORR, 8.2 months median PFS, and 17.1 months median OS in previously treated patients. 1

Datopotamab Deruxtecan (Investigational)

• The TROPION-Lung01 phase III trial compared datopotamab deruxtecan 6 mg/kg versus docetaxel in patients with relapsed NSCLC after platinum-based chemotherapy and anti-PD-(L)1 therapy. 1

• Datopotamab deruxtecan improved median PFS (4.4 vs 3.7 months; HR 0.75, P=0.004) but did not meet the OS endpoint (12.9 vs 11.8 months; HR 0.94, P=0.530). 1

• Critical histology-specific finding: The PFS benefit was pronounced in nonsquamous NSCLC (5.5 vs 3.6 months; HR 0.63) but not observed in squamous histology (2.8 vs 3.9 months; HR 1.41). 1

• Grade ≥3 treatment-related adverse events were lower with datopotamab deruxtecan (25.6%) compared to docetaxel (42.1%), though interstitial lung disease occurred in 8.8% versus 4.1%. 1

• The ASCO Expert Panel deemed the evidence insufficient for formal recommendation pending further data, particularly given the unplanned subgroup nature of the histology analyses. 1

Bispecific Antibodies

Ivonescimab (Investigational)

• The phase III HARMONi-2 study evaluated ivonescimab (a PD-1 and VEGF bispecific antibody) versus pembrolizumab as first-line treatment for 398 patients with PD-L1-positive advanced NSCLC in China. 1

• Data was presented at 2024 IASLC WCLC, but the ASCO Expert Panel is awaiting peer-reviewed publication before making recommendations. 1

Targeted Therapy for Driver Alterations

• The 2024 ASCO Living Guideline emphasizes that molecular testing for targetable driver alterations (EGFR, ALK, ROS1, BRAF, MET, RET, NTRK, KRAS G12C, HER2) remains essential for all patients with stage IV NSCLC. 1

• Eight new randomized controlled trials were identified in the latest systematic review (February-October 2023), reflecting the rapid evolution of targeted therapies. 1

• The guideline provides continuously updated recommendations for first-line, second-line, and subsequent treatment options based on specific driver alterations. 1

Immunotherapy Landscape

• Immune checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab) remain standard options for selected patients with advanced NSCLC without driver alterations. 2

• Durvalumab following chemoradiation is established for locally advanced disease. 2

• Common pitfall: The benefit of immunotherapy in small cell lung cancer (SCLC) remains modest compared to NSCLC, with limited treatment options beyond the addition of immune checkpoint inhibitors to chemotherapy. 3

Key Clinical Considerations

• For HER2-overexpressing NSCLC after progression on standard therapies, use trastuzumab deruxtecan 5.4 mg/kg every 3 weeks, with vigilant monitoring for pneumonitis. 1

• For nonsquamous NSCLC progressing after platinum and immunotherapy, datopotamab deruxtecan shows promise but awaits formal guideline endorsement; docetaxel remains standard. 1

• Avoid datopotamab deruxtecan in squamous histology based on TROPION-Lung01 data showing potential harm (HR 1.41). 1

• Molecular profiling should be comprehensive and performed early to identify all actionable alterations, as targeted therapies consistently outperform chemotherapy when driver mutations are present. 1, 4