Lung Cancer (Bronchial Carcinoma): Drug Therapy

Therapeutic targets

  • Improvement of prognosis
  • Slowing of tumor growth
  • Palliative (preservation of quality of life)

Therapy recommendations

Depending on the histological (“fine tissue”) findings, there are different approaches to chemotherapy of bronchial carcinoma. No dosages of cytostatic drugs (substances that inhibit cell growth or cell division) are given below, because therapy regimens are constantly being modified. Small Cell Lung Cancer (SCLC) (13-15%)

  • In “limited disease” (LD), adjuvant polychemotherapy (therapy that follows surgical resection of a tumor) with cisplatin/etoposide in addition to resection (surgical removal of the tumor) and thoracic radiotherapy (TRT)/limited to the ipsilateral hemithorax (thoracic/chest half on the affected side) and its regional lymph nodes. Followed by prophylactic whole-brain irradiation (PCI; prophylactic cranial irradiation) with curative (curative) goals (approximately 15-20% of cases).
    • To date: Standard chemotherapy: combination therapy with a platinum derivative plus etoposide (4-6 cycles) with response rates of 60-80%.
    • Fall 2019: Immunochemotherapy: combination platinum derivative/ etoposide with checkpoint inhibitor (atezoliumab) in the first-line setting; additional immunotherapy options are currently being evaluated in clinical trials.
  • In “Extensive Disease” (ED), polychemotherapy with cisplatin/etoposide or adriamycin or epirubicin/cyclophosphamide/vincristine (ACO or EpiCO) [4 chemotherapy cycles]; thoracic radiotherapy (TRT) and PCI (see radiotherapy below); palliative goal (preservation of quality of life).

Non-small cell lung cancer (NSCLC)* (10-15%).

  • Up to stage IIb adjuvant/neoadjuvant (administration of drugs before therapy) chemotherapy (NACT; currently being tested in trials) and resection.
  • In stage III chemotherapy and radiotherapy, neoadjuvant if necessary; surgery if necessary; in recurrence, palliative bevacizumab (monoclonal antibody which binds to VEGF and thus prevents binding to the VEGF surface receptor), EGFR inhibitors, docetaxel, permetrexed
    • The IgG1 antibody necitumumab is available for first-line therapy in advanced squamous non-small cell lung cancer (NSCLC). Administered in addition to gemcitabine/cisplatin, the antibody prolongs median overall survival from 10 to 11.7 months.
    • PACIFIC trial: consolidative administration of the PD-L1 inhibitor durvalumab in unresectable stage III non-small cell lung cancer reduced mortality risk by as much as 41% in patients with tumor PD-L1 expression of ≥ 1%.
  • In stage IV, alignment of therapeutic strategy with molecular targets:
    • In the presence of an activating EGFR mutation in patients with ECOG status 0-2 → first-line therapy with an EGFR tyrosine kinase inhibitor (TKI; e.g., afatinib, erlotinib, or gefitinib)) [present in approximately 10% of patients with non-squamous cell carcinoma]
    • In the presence of ALK fusion gene (ALK = anaplastic lymphoma kinase; persistently activated in 3-5% of patients with non-small cell lung cancer (NSCLC)) → first-line therapy with crizotinib, ceritinib, and alectinib ALK test positive + progression (progression of disease) after standard platinum-based chemotherapy → crizotinib if no ALK inhibitor has been used as first-line therapy. If therapy with crizotinib fails, ALK-positive NSCLC patients should be offered a second-generation ALK inhibitor.

* NSCLC must be routinely tested for EGFR gene mutation because if positive, therapy with a tyrosine kinase inhibitor (TKi, e.g., afatinib, erlotinib, or gefitinib) is more effective as first-line therapy than standard first-line chemotherapy. Sooner or later, resistance to EGFR inhibitors occurs, the cause of which is often the so-called gatekeeper mutation T790M.In this setting, osimertinib (kinase inhibitor) enables targeted treatment for the first time.A randomized trial demonstrated that osimertinib therapy prolongs survival in patients with advanced non-small cell lung cancer (NSCLC) in first-line therapy compared to two older tyrosine kinase inhibitors.Most common are EGFR mutations (15-20%), KRAS mutations (25-30%) and ALK mutations (5-10%). In case of progression or recurrence of the disease:

  • Repeat chemotherapy (second-line therapy) with docetaxel, pemetrexed (in patients with non-squamous lung cancer), or the EGFR tyrosine kinase inhibitor erlotinib.
  • In tumors in which the tyrosine kinase ALK (anaplastic lymphoma kinase) is expressed (approximately 5% of patients with NSCLC), it can be blocked with a specific inhibitor:
    • In patients with advanced, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) who have been pretreated with crizotinib, ceritinib (750 mg/d) can be used. Ceritinib is a tyrosine kinase inhibitor. Note manufacturer’s warnings: severe, sometimes fatal, cases of heart failure have been reported post-marketing. Patients should be monitored for signs and symptoms of heart failure (dyspnea, edema, rapid weight gain).
    • Brigatinib (tyrosine kinase inhibitor; epidermal growth factor receptor inhibitor; in the presence of ALK translocation of NSCLC); For monotherapy of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) after pretreatment with crizotinibStudy of patients with ALK-positive stage IIIB/IV NSCLC who had not previously received an ALK inhibitor: 1-year PFS (progression-free survival) of 67% in the brigatinib group and of 43% in the crizotinib group (hazard ratio: 0.49; p<0.001).
    • Similarly, the tyrosine kinase inhibitor alectinib comes into play here for first-line (L1) therapy in advanced, ALK-positive non-small cell lung cancer (NSCLC). Note: Alectinib is new L1 standard because it is superior to crizotinib in efficacy while being less toxic.
  • Atezolizumab (checkpoint inhibitor: binds selectively to the protein PD-L1 (programmed death ligand-1, programmed cell death ligand 1). The OAK study (phase III trial) had randomized patients with advanced NSCLC to treatment with docetaxel or atezolizumab (1,200 mg intravenously) after failure of taxane-based chemotherapy. Atezolizumab prolonged median survival from 9.6 to 13.8 months.
  • Nivolumab (PD-1 immune checkpoint inhibitor) prolonged median survival from 6 to 9 months in metastatic non-small cell lung cancer.Indication: adult patients with locally advanced or metastatic non-small cell lung cancer with squamous cell histology (SQ-NSCLC) after prior chemotherapy.
    • Combination nivolumab/ipilimumab and two cycles of platinum-based chemotherapy is approved for first-line treatment of adults with metastatic non-small cell lung cancer (NSCLC). Note: Tumors should not have a sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation.
  • Pembrolizumab in adults with PD-L1 (programmed cell death ligand 1) expressing tumors after prior chemotherapy. Indication: therapy for locally advanced or metastatic non-small cell lung cancer (NSCLC); monotherapy at a dose of 2 mg/kg body weight every three weeks. Pembrolizumab achieved better therapeutic results than chemotherapy for the first time in first-line non-small cell lung cancer (NSCLC).It is expected that biomarker-based first-line pembrolizumab therapy for metastatic NSCLC will be included in the new S3 guidelines.
  • Ramucirumab (monoclonal antibody that binds to angiogenesis-inducing cell surface VEGF receptor-2 and interrupts the downstream signaling cascade to the nucleus; thus, angiogenesis is abrogated) combined with docetaxel in pretreated adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) regardless of histologic subtype.
    • RELAY trial: patients with progressive non-small cell lung cancer with activating EGFR mutation live longer without progression (progression-free survival (PFS)) when treated with erlotinib plus ramucirumab instead of erlotinib alone; compared with erlotinib plus placebo, PFS increased from 12.4 to 19.4 months; also better was the 1-year PFS rate under the combination (71.9 vs 50.7%).
  • Durvalumab (monoclonal antibody targeting programmed death-ligand 1 (PD-L1)) is designed to prevent tumors from evading natural immune defenses; significantly prolonged progression-free survival in patients with advanced stage non-small cell lung cancer (NSCLC) (placebo group experienced tumor re-progression after a median of 5.6 months; durvalumab group after a median of 16.8 months).Side effects: Myasthenia gravis (rare); dose adjustment or permanent discontinuation may be required.

Other palliative measures:

  • In advanced stages, palliative therapy (palliative treatment) is given:
    • Enteral nutrition, e.g., feeding via a PEG (percutaneous endoscopic gastrostomy: endoscopically created artificial access from the outside through the abdominal wall into the stomach).
    • Infusion therapy via a port catheter (port; permanent access to venous or arterial blood circulation).
    • Pain therapy (according to WHO staging scheme; see “Chronic pain” below).
  • See also under “Further therapy”.

Secondary prevention

  • Researchers found that cell lines of non-small cell lung cancer (NSCLC) with K-Ras mutation were inhibited in their growth by statins.
  • One study found that statins can positively affect cancer-specific mortality (death rate) in lung cancer patients:
    • Statin use before diagnosis onset: 12% reduction in disease-associated mortality risk.
    • Statins were prescribed at least twelve times: 19% lower mortality risk
    • Statin use after diagnosis onset: 11% reduced cancer-specific mortality risk.

    The study found no difference between small cell and non-small cell lung cancer.