Targeted Treatments in Lung Cancer by Histology

The World Health Organization (WHO) classifies lung cancer into 2 major categories based on histology, prognosis, and treatment: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).¹SCLC has a propensity for widespread, early metastases and a rapid doubling time. Cigarette smoking and exposure to secondhand smoke are responsible for most cases of SCLC.^1,2

The treatment goal for patients with localized SCLC is to achieve a cure via chemotherapy plus thoracic radiotherapy. Patients with extensive disease may experience improvement in symptoms and increased survival, although long-term survival is rare.^3-6Unfortunately, the use of targeted agents to treat SCLC has not been promising to date.⁷

NSCLC represents approximately 85% of all lung cancer cases and is divided histologically into nonsquamous carcinoma (adenocarcinoma, large-cell carcinoma, and other types) and squamous cell (epidermoid) carcinoma.¹

Targeted Therapies for NSCLC

Adenocarcinoma is the most common histologic type of lung cancer in most geographic areas, including the United States.¹Subtypes of adenocarcinoma include acinar, papillary, bronchioloalveolar (nonmucinous, mucinous, and mixed), and solid with mucin formation. Unfortunately, mixtures of histologic subtypes are more common than tumors consisting of just 1 subtype, which presents challenges in terms of classification and treatment.^1,8Several predictive and prognostic biomarkers have been explored in association with NSCLC. Predictive biomarkers include epidermal growth factor receptor (EGFR), the ALK fusion oncogene, HER2 and BRAF mutations, MET amplification, and ROS- 1 and RET rearrangements. The most common EGFR mutations identified in patients with NSCLC are deletions in exon 19 and a mutation in exon 21, both of which result in activation of the tyrosine kinase domain; and are therefore sensitive to the small molecule tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib. Although the presence of the EGFR exon 19 deletion or exon 21 L858R mutation does not appear to predict survival for patients with NSCLC regardless of therapy, the presence of the EGFR exon 19 deletion or exon 21 L858R mutation is predictive of responsiveness to EGFR-TKI therapy.^9-11Other gene rearrangements such as ROS-1 and RET have recently been identified to be susceptible to specific targeted therapies.^12-14

Bevacizumab was approved by the US Food and Drug Administration (FDA) in 2006 for treatment of unresectable, locally advanced, recurrent, or metastatic non-squamous NSCLC. The Eastern Cooperative Oncology Group (ECOG) recommends that bevacizumab be used in combination with paclitaxel and carboplatin for select patients with NSCLC.¹⁵Bevacizumab should be used with caution with any regimen that is associated with a high risk of bleeding.¹

Erlotinib was approved in 2004 for treatment of patients with locally advanced or metastatic NSCLC who have failed at least 1 prior chemotherapy regimen. It is also a category 1 recommendation as first-line therapy in patients with advanced, recurrent, or metastatic non-squamous NSCLC who have known EGFR mutations regardless of performance status. This recommendation is based on results of the phase III IPASS study.¹⁶Patients in this study who received gefitinib experienced an increased progression-free survival (PFS) and response rate as well as improved quality of life and fewer adverse events compared with patients who received chemotherapy.¹⁶Of note, patients who had been assigned to receive chemotherapy were able to subsequently receive TKIs if they were found to have EGFR mutation. Erlotinib, which is orally active and well tolerated, is the TKI typically used in the US.¹

In several studies of patients with advanced NSCLC with EGFR mutations, treatment with TKIs was associated with a 67% response rate and overall survival of about 2 years.¹⁷Results of the TORCH trial indicate that EGFR mutational testing should be conducted in patients with NSCLC; in that study, improved survival rates were seen in patients with wild-type EGFR who received firstline chemotherapy compared with those who received erlotinib first followed by second-line chemotherapy.¹⁸In addition, the OPTIMAL trial found that PFS was increased in patients with EGFR who received erlotinib.^1,19Patients with pure squamous cell carcinoma are not likely to have EGFR mutations; therefore, mutational testing is recommended only for patients with non-squamous NSCLC (adenocarcinoma).¹

Afatinib was approved in 2013 for first-line treatment of patients with metastatic NSCLC and EGFR mutations.1 In a recent trial, afatinib was demonstrated to improve PFS compared with chemotherapy in patients with metastatic adenocarcinoma and EGFR mutations (11.1 months vs 6.9 months; P = .001).20 It is also recommended for second-line therapy in patients who have progressed after first-line treatment with chemotherapy.¹

Based on results from a phase II trial, crizotinib is FDA approved for patients with locally advanced or metastatic NSCLC who are positive for the ALK gene rearrangement. Response rates in excess of 80% were demonstrated in this trial in patients who had previously experienced disease progression.^21,22Clinical improvements in symptoms (cough, dyspnea, and pain) have also been reported with crizotinib treatment.^21,22

Targeted Therapies for SCLC

In the phase III FLEX trial, the addition of cetuximab to cisplatin/vinorelbine was demonstrated to slightly increase overall survival in patients with advanced NSCLC compared with cisplatin/vinorelbine alone.²³This treatment is considered an option for patients with advanced NSCLC regardless of histology and without EGFR mutations or ALK rearrangements. However, this combination is associated with an increased risk for adverse events, particularly neutropenia.¹As mentioned previously, targeted therapies as treatment for SCLC have not been promising to date. However, current studies are evaluating various pathway targets to improve these results. Specifically, targeted pathways include the hedgehog pathway, epigenetic regulatory pathways, and DNA damage repair mediated by poly(ADP-ribose) polymerase- 1 (PARP1).⁷

While preclinical studies have shown promising activity of hedgehog inhibitors, improved clinical outcomes have not been reported with the combination of the hedgehog inhibitor vismodegib combined with chemotherapy in patients with advanced SCLC.⁷A phase II/III study targeting the DNA damage pathway is enrolling patients to evaluate the combination of PARP1 inhibitor veliparib with chemotherapy in patients with extensivestage SCLC.²⁴

References

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