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Lung Cancer

Pathways & Targets

AbbVie is exploring a vast array of pathways and proteins implicated in lung cancer cell growth, survival, and motility in order to identify possible therapeutic targets. Selected pathways and potential targets include, but are not limited to, poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) and DLL3.

Lung cancer

Lung cancer is the leading cause of cancer-related mortality throughout the world, accounting for approximately 19.4% of the total number of deaths.1 In the United States, the incidence of lung cancer is second only to that of prostate cancer in men and breast cancer in women.2

PARP & DNA Repair

Although cisplatin and carboplatin are cornerstones of chemotherapy for non-small cell lung cancer (NSCLC), less than 30% of patients respond to these agents.3,4 Somatic defects in double-strand DNA repair mechanisms are frequently observed in NSCLC5 and may cause a heightened dependence on PARP-mediated repair.6 Increased DNA repair capacity may contribute to the chemoresistance to DNA-damaging agents frequently observed.3,7 PARP inhibitors may sensitize cells to the effects of DNA-damaging chemotherapy.8

DLL3 & Tumor-Initiating Cells

DLL3 was discovered as a highly expressed protein in high-grade pulmonary neuroendocrine tumors (NETs), making it a potential biomarker for those tumor types.9 While normally localized to the Golgi, overexpressed DLL3 localizes at the surface of SCLC tumor-initiating cells and a large proportion of treatment-naïve (72%) and previously treated (85%) SCLC tumors.9,10 Likewise, minimal-to-no expression is detected in normal tissues or other non-neuroendocrine tumor types, making DLL3 an attractive target for antibody-drug conjugate therapy.9

Additional information:

NSCLC is associated with poor prognosis and limited treatment options beyond platinum chemotherapy.11-13 PARP1/2 inhibition targets an essential tumor survival pathway that is implicated in promoting disease progression and resistance to platinum-based chemotherapy.12,14

Squamous Non-Small Cell Lung Cancer (sqNSCLC)

The 2 major types of NSCLC are squamous cell carcinoma and non-squamous cell carcinoma (adenocarcinoma, large-cell carcinoma and other cell types).15 Patients with sqNSCLC represent approximately 27% of NSCLC cases and have worse overall survival (OS) than patients with adenocarcinoma.16,17

Mechanism of Disease

sqNSCLC begins in the thin, flat squamous cells in the larger bronchi of the lung and is largely attributable to smoking.18

The development of sqNSCLC involves a multistep process that includes multiple genetic and epigenetic alterations, particularly activation of growth-promoting pathways and inhibition of tumor suppressor pathways. Identified changes include mutations in the KRAS, EGFR, MEK and HER2 genes; alterations in the BRAF, PI3K and PARP pathways; amplification of the FGFR1 and DDR2 genes; and structural rearrangements in ALK, ROS1 and RET.19-21

Dysregulation of DNA repair is also associated with platinum resistance in NSCLC and significantly correlates with the relative risk of death in patients with NSCLC who are treated with chemotherapy only.3,7

Diagnosis & Staging

Because the majority of early stage patients eventually progress to advanced disease, the primary goal when lung cancer is suspected is an early diagnosis with accurate staging. Over 75% of patients are diagnosed at an advanced stage (III or IV).22 Advanced stage at diagnosis is a strong predictor of poor prognosis and high mortality.22,23

Accurate staging combined with the patient's unique features provides valuable prognostic information and determines the appropriate therapy.

Challenges in Treatment

Lung cancer patients typically have poor performance status at diagnosis and cannot tolerate aggressive chemotherapy.4

Current treatment options for patients with sqNSCLC are inadequate, as there are limited treatment options beyond the standard platinum-based chemotherapy doublet.4

Unmet Need

Lung cancer leads to the highest number of deaths per year among all cancers in the United States and the European Union.2,24

There is a need to improve the efficacy of platinum-based therapy in patients with sqNSCLC. Although the addition of chemotherapy to radiation therapy provides a modest improvement over radiation alone, 5-year survival remains at less than 20%.23 The lack of targeted therapies that effectively address sqNSCLC and increase overall survival is the largest unmet need in this cancer.

AbbVie is committed to helping address these challenges and is actively conducting research in this area to help address this unmet need.

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Approximately 20% of lung tumors exhibit neuroendocrine differentiation and are classified as high-grade pulmonary neuroendocrine tumors (NETs).25,26 These include small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), which account for 13% to 15% and 2% to 3% of all lungs cancers, respectively.16,27,28 SCLC is the most aggressive form of lung cancer, with an overall 5-year survival rate of <7%.27,29 SCLC is strongly associated with heavy smoking.25,27

While a number of biomarker-guided therapies have become available to treat patients with non-small cell lung cancer (NSCLC), few treatment advances have been made in standard of care for SCLC in >30 years.25

Mechanism of Disease

Normal adult lung epithelium contains several distinct progenitor and stem cell populations that maintain the differentiated basal, ciliated, non-ciliated, and neuroendocrine cells that line the airways.29 High-grade pulmonary NETs are believed to develop from neuroendocrine progenitor cells that have acquired mutations, most often from exposure to the carcinogens in cigarette smoke.29 In fact, comprehensive sequencing studies demonstrate that SCLC has one of the highest mutation rates compared with other tumor types.30

SCLC tumor cells overexpress transcription factors critical for normal primary neuroendocrine cell development, including ASCL1, NEUROD1, SOX2, TTF1, and Myc family members. Genes that appear mutated in nearly all SCLC tumors include the tumor suppressors TP53 and RB1 (loss of function) and the proto-oncogene Myc family members (upregulation). KRAS mutations are rare or non-existent.29 Inactivating mutations in NOTCH family genes have been observed in 25% of human SCLC.31

In addition to the high mutation load, high-grade NETs are also characterized by a rapid doubling time, high growth fraction, and early development of metastases.32

Diagnosis & Staging

While the TNM system for staging SCLC is used in clinical trials, the Veterans Administration Lung Study Group's (VALG) 2-stage system of limited stage (LS) vs extensive stage (ES) is still most commonly used for clinical decision-making.33

  • LS-SCLC—disease confined to the ipsilateral hemithorax (can be safely encompassed within a radiation field)
  • ES-SCLC—disease beyond the ipsilateral hemithorax and cannot be included in a single radiation field

While two-thirds of patients present with ES-SCLC, accurate staging is critical as it provides important prognostic information and will determine appropriate treatment approach.33,34

Treatment Challenges

Overall, the 5-year relative survival for patients with SCLC is only 6.4%.16 Based on the TNM staging system, the 5-year survival rate for stage 1 SCLC is 31%, 19% for stage 2, 8% for stage 3, and only 2% for stage 4 disease.34 The majority of patients with newly diagnosed SCLC have ES at presentation.35 While the median survival with treatment is 18 to 24 months for LS, it is only 6 to 12 months for ES SCLC. The 2-year survival for ES-SCLC has only improved by 2.2% (from 3.4% to 5.6%) since the introduction of chemotherapy regimens 40 years ago.27

First-line therapeutic options have remained largely unchanged for over 3 to 4 decades.35,36 The current standard of care (SOC) for newly diagnosed LS-SCLC is concurrent chemoradiation. The current SOC for newly-diagnosed ES-SCLC is a platinum-based chemotherapy doublet, with response rates ranging from 60% to 75%.27

Unfortunately, the majority of patients, including the up to 80% of patients with LS- and ES-SCLC who were initially responsive to chemoradiation or chemotherapy, develop chemoresistance and will suffer relapse within months of completing initial therapy.25,36

Unmet Need

In contrast to the era of personalized medicine in non-small cell lung cancer (NSCLC), there are no biomarker-guided therapies currently available to target SCLC tumor cells.35

If relapse has occurred more than 6 months after first-line therapy, retreatment with initial therapy is the usual course of action. However, for patients who relapse less than 6 months after first-line therapy, second-line options are limited, and include topoisomerase inhibitors, taxanes, immune-oncologics, and nucleoside analogs. Treatment in this setting is usually palliative, as median survival for these patients is only 4 to 5 months after treatment. No SOC currently exists for relapsed/refractory SCLC in the third-line and beyond settings.27,37

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PARP

See how the PARP-mediated DNA repair pathway promotes tumor cell survival.

Related Pathways & Targets

Related Pathways & Targets

References

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