Targeted Therapies Explored in Small Cell Lung Cancer

Charles M. Rudin, MD

While targeted and immunotherapy drugs have recently shown promise in non-small cell lung cancer (NSCLC), similar developments in small cell lung cancer (SCLC) have not materialized.

“Standard combination chemotherapy for advanced, extensive-stage SCLC has not changed substantially in the last 30 years,” said Charles M. Rudin, MD, PhD, chief of the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center in New York. Rudin provided an overview of the biology of the malignancy as well as ongoing research to identify and test new drugs targeted at SCLC during the 8th Annual New York Lung Cancer Symposium in New York City on November 9.

“There is a critical need for effective therapy in advanced forms of this disease,” said Rudin. Although Rudin said there have been recent advances in the use of radiotherapy to treat limited-stage SCLC, he noted that two-thirds of patients with SCLC present with extensive-stage disease at diagnosis.

A particularly aggressive type of lung cancer, SCLC is related to smoking or exposure to secondhand smoke, comprises approximately 15% of all lung cancer cases, and is characterized by rapid progression and a median survival of less than 12 months. Patients initially respond to chemotherapy but almost all those with extensive disease subsequently relapse.

To understand the molecular biology of SCLC and create a roadmap of the key driver mutations in these tumors, researchers have sequenced the SCLC genome and found a high density of mutations likely due to the carcinogenic effect of tobacco smoke. “Finding driver mutations is a real challenge,” said Rudin.

Part of the challenge in identifying potential targeted therapies is the prevalence of inactivating mutations in tumor suppressor genes such as TP53, PTEN, and RB1, and only infrequent gain-of-function mutations in oncogenes such as PI3K3CA or MYC family members. “The bottom line is that many of the mutations we find are tumor suppressors, rather than oncogenes,” said Rudin. “These tumor suppressors are not each targets for therapy.”

Researchers are now focusing on finding those mutations that are relevant to tumor growth and progression and distilling out passenger mutations. An important goal is to identify anticancer drugs that kill tumor cells that are resistant to chemotherapy, since additional agents that kill the same chemotherapy-sensitive cells are not likely to lead to a survival improvement, according to Rudin.

One approach has been to identify gene families and pathways. The SOX2 gene has been found to be unregulated in some of these tumors. In vitro data show that inhibiting SOX2 can almost completely inhibit the growth of SCLC cell lines overexpressing SOX2. As a transcription factor, this protein may be difficult to target with drugs, Rudin noted, but genes downstream of SOX2 may be feasible targets to inhibit signaling of this pathway.

Current studies are focusing on the Hedgehog pathway, epigenetic regulatory pathways, and DNA damage repair mediated by PARP1. While preclinical studies have shown promising activity of Hedgehog inhibitors, this activity has not translated to improved outcome when vismodegib was combined with the chemotherapy agents cisplatin and etoposide in patients with advanced SCLC.

An ongoing study targeting the DNA damage pathway is a combination phase I/II trial of chemotherapy with the PARP inhibitor veliparib that includes patients with extensive-stage SCLC.¹ Investigators are seeking to randomize 168 patients with SCLC or several other types of lung cancer to cisplatin and etoposide with or without veliparib as frontline therapy.

Researchers also are exploring whether combining veliparib with temozolomide provides greater benefit than temozolomide alone in patients with relapsed or refractory SCLC.² A previous study showed that temozolomide is active in patients who have progressed after one or two chemotherapy regimens, including patients with brain metastases.³

Agents that inhibit proteins from the bromodomains and extra terminal (BET) domain family are also being studied in SCLC. BET proteins regulate epigenetic alterations and chromatin remodeling. The BET inhibitor GSK525762 currently is being tested in a phase I trial in patients with various tumor types, including patients with SCLC.⁴

References

1. Cisplatin and etoposide with or without veliparib in treating patients with extensive stage small cell lung cancer or metastatic large cell neuroendocrine non-small cell lung cancer. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01642251. Updated November 4, 2013.
2. Temozolomide with or without veliparib in treating patients with relapsed or refractory small cell lung cancer. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01638546. Updated September 18, 2013.
3. Pietanza C, Kadota K, Huberman K, et al. Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker [published online ahead of print January 6, 2012]. Clin Cancer Res. 2012;18(4):1138-1145.
4. A study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK525762 in subjects with nut midline carcinoma (NMC) and other cancers. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01587703. Updated September 12, 2013.

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