What are the latest updates on 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, emerging data on datopotamab deruxtecan for nonsquamous disease, and expanding roles for KRAS G12C inhibitors following first-line therapy. 1

HER2-Targeted Therapy: Major Breakthrough

Trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks received FDA approval in April 2024 for previously treated advanced NSCLC with HER2 overexpression (IHC 2+ or 3+). 1

• HER2 overexpression occurs in 8-23% of NSCLC patients using the gastroesophageal scoring system 1
• In patients with HER2 IHC 3+ expression, the objective response rate reached 53% with median duration of response of 6.9 months 1
• The 5.4 mg/kg dose demonstrated superior safety compared to 6.4 mg/kg, with lower rates of pneumonitis (2% vs 8%) and no grade ≥3 neutropenia 1
• Preliminary phase Ib data shows ORR of 44.4%, median PFS of 8.2 months, and median OS of 17.1 months in heavily pretreated patients (52.8% received prior treatment) 1

Common adverse events include nausea, fatigue, decreased appetite, constipation, and alopecia, with pneumonitis being the most critical toxicity requiring monitoring. 1

Antibody-Drug Conjugates for Second-Line Treatment

Datopotamab deruxtecan shows promise specifically for nonsquamous NSCLC but failed to demonstrate OS benefit in the overall population. 1

• The TROPION-Lung01 trial compared datopotamab deruxtecan 6 mg/kg versus docetaxel 75 mg/m² every 3 weeks in previously treated patients 1
• Median PFS improved overall (4.4 vs 3.7 months; HR 0.75, P=0.004) but OS did not reach significance (12.9 vs 11.8 months; HR 0.94, P=0.530) 1
• The benefit was histology-dependent: nonsquamous patients had PFS of 5.5 vs 3.6 months (HR 0.63), while squamous patients showed no benefit (2.8 vs 3.9 months; HR 1.41) 1
• Grade ≥3 treatment-related adverse events were lower with datopotamab (25.6%) versus docetaxel (42.1%), though interstitial lung disease occurred in 8.8% versus 4.1% 1

KRAS G12C Inhibitors: Established Second-Line Options

Both sotorasib and adagrasib are FDA-approved for previously treated KRAS G12C-mutated NSCLC following progression on platinum-based chemotherapy and/or immunotherapy. 1

• These agents target a mutation associated with particularly poor prognosis 1
• Ongoing trials are evaluating combinations with chemotherapy and/or immunotherapy, as well as potential first-line use 1

EGFR-Mutated NSCLC: Refined Treatment Algorithm

For EGFR-mutated NSCLC, osimertinib remains the strong first-line recommendation for activating mutations (exon 19 deletions, L858R, G719X, L861Q, S768I). 1

• Following progression on first- or second-generation EGFR TKIs with emergent T790M resistance, osimertinib is strongly recommended 1
• For patients progressing on osimertinib without T790M or other targetable alterations, platinum-based chemotherapy following nondriver alteration guidelines is recommended 1
• Chemotherapy plus amivantamab represents a strong alternative option for activating mutations 1
• Critical practice point: Repeat tissue and/or blood NGS testing at progression to identify potentially targetable resistance mechanisms 1

Immunotherapy Updates

Atezolizumab has expanded indications across the NSCLC treatment continuum: 2

• Adjuvant setting: Following resection and platinum-based chemotherapy for Stage II-IIIA NSCLC with PD-L1 ≥1% tumor cell expression, administered as 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks for up to 1 year 2
• First-line metastatic: As monotherapy for high PD-L1 expression (TC ≥50% or IC ≥10%) without EGFR/ALK alterations 2
• First-line combinations: With bevacizumab, paclitaxel, and carboplatin OR with paclitaxel protein-bound and carboplatin for metastatic nonsquamous NSCLC without EGFR/ALK alterations 2

For extensive-stage small cell lung cancer, atezolizumab combined with carboplatin and etoposide remains the first-line standard with modest OS benefit. 2, 3

Critical Monitoring Requirements

Immune-mediated adverse reactions require vigilant surveillance: 2

• Baseline and periodic monitoring of liver enzymes, creatinine, and thyroid function is mandatory 2
• Severe or fatal immune-mediated reactions can affect any organ system, including pneumonitis, colitis, hepatitis, endocrinopathies, dermatologic reactions, nephritis, and solid organ transplant rejection 2
• Dose modifications or permanent discontinuation depend on severity and type of reaction 2

Essential Testing Requirements

Comprehensive genomic profiling is critical before initiating therapy to identify targetable alterations and guide treatment selection. 1

• Testing should include EGFR, ALK, ROS1, BRAF V600E, KRAS G12C, HER2, and PD-L1 expression 1
• HER2 testing should utilize the gastroesophageal scoring system for IHC 1

Common Pitfalls to Avoid

• Do not use datopotamab deruxtecan in squamous histology NSCLC, as it showed worse outcomes than docetaxel 1
• Do not administer KRAS G12C inhibitors before platinum-based chemotherapy and/or immunotherapy, as they are only approved for previously treated disease 1
• Do not skip repeat molecular testing at progression, as new targetable resistance mechanisms may emerge 1
• Do not use atezolizumab monotherapy in patients with EGFR or ALK alterations who have not progressed on targeted therapy 2