Molecular Tumor Markers Could Reveal New Therapeutic Targets for Lung Cancer Treatment

The gist: New research looking into tumor mutations in small cell lung cancer (SCLC) and neuroendocrine tumors (NET) may open up new drug options to treat these conditions. Drugs called targeted therapies have been developed to treat people with tumors that have certain genetic mutations. Several targeted therapies are available for people with non-small cell lung cancer (NSCLC). But so far, targeted therapies have not been very useful in SCLC. Now, researchers have found that some SCLC and NET tumors may share some tumor mutations with NSCLC tumors. Theoretically, a patient with SCLC or NET could ask their oncologist for molecular testing to see whether their tumor(s) could potentially be treated off-label with an existing NSCLC drug. To learn more about SCLC treatment, see our Need to Know blog.

“Analysis of 607 small cell lung cancer (SCLC) lung tumors and neuroendocrine tumors (NET) identified common molecular markers among both groups that could reveal new therapeutic targets for patients with similar types of lung cancer, according to research presented today at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology. The Symposium is sponsored by the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), the International Association for the Study of Lung Cancer (IASLC) and The University of Chicago Medicine.

“This study examined the clinical specimens of 607 total cases of SCLC tumors (375) and lung NET (232), which included carcinoid, atypical carcinoid and large-cell neuroendocrine tumors. Biomarker testing was achieved through a combination of DNA sequencing (Next-Generation Sequencing (NGS) or Sanger-based); immunohistochemistry (IHC) to identify which proteins are present; and in situ hybridization (ISH) testing, a form of gene amplification, to determine if any of the markers that can cause cancer cells to grow or to become resistant to treatment are present…

” ‘Even cancers that appear to be very similar can be dramatically different at the molecular level, and these differences may reflect unique vulnerabilities that could positively impact therapeutic options and decisions,’ said Stephen V. Liu, MD, senior study author and Assistant Professor of Medicine in the Division of Hematology/Oncology at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. ‘We are pleased that this research confirms these rarer subtypes; it calls for additional investigation on a larger scale. Once confirmed, molecular profiling of small cell tumors and NET could become standard, as it is currently for non-small cell lung cancers, which will be especially important as more molecularly targeted chemotherapy agents are developed.’ “


Cancer Care: Post-Surgical Mortality Risk, Tumor Boards (CME/CE)

Note: This article includes three different stories for cancer patients. Two are excerpted below.

“Patients who died within a month of cancer surgery had unfavorable social and demographics that appeared to confer high risk, a review of records for more than 1 million people showed.

“The patients at highest risk of early death tended to be unmarried, uninsured, nonwhite, male, older, less education, poorer, and to have more advanced disease at surgery. The results suggest that reducing sociodemographic disparities in cancer care, including access, has the potential to improve cancer outcomes, Brandon A. Mahal, a medical student at Harvard University, reported at the American Society of Clinical Oncology Quality Care Symposium…

“Patients with advanced colorectal or small cell lung cancer (SCLC) had better survival when their oncologists participated at least weekly in tumor board meetings, according to a study of 4,600 patients and 1,600 oncologists.

“Frequent oncologist participation in tumor boards was associated with about a 30% reduction in the mortality hazard for patients with stage IV colorectal cancer and about a 40% reduction in the hazard for extensive SCLC. Oncologists who participated in weekly tumor boards also were more likely to discuss and refer patients to clinical trials and to pursue curative surgery for patients with early-stage non-small cell lung cancer (NSCLC).

” ‘Patients with disease subtypes for which we found a link between physician tumor board participation and improved outcomes may want to ask their doctor if their case will be reviewed at a multidisciplinary meeting,’ Kenneth L. Kehl, MD, of the University of Texas MD Anderson Cancer Center in Houston, said in a statement.

” ‘However, this was not a randomized study; as there were few associations overall between tumor boards and patient survival, our findings cannot demonstrate conclusively that physician tumor board participation directly affects patient outcomes.’ ”


Aldoxorubicin Receives FDA Orphan Drug Designations for Glioblastoma, Small Cell Lung Cancer, and Ovarian Cancer

The gist: When a newly developed drug for a rare (“orphan”) disease seems particularly promising for patients, the U.S. Food and Drug Administration (FDA) may choose to grant it “orphan drug designation.” The designation removes certain barriers that might otherwise keep a drug company from being able to successfully develop and profit from the drug in the U.S. A new drug called aldoxorubicin has just received an orphan drug designation for the treatment of small cell lung cancer (SCLC), glioblastoma multiforme, and ovarian cancer. Aldoxorubicin is a special version of the chemotherapy drug doxorubicin. It allows for higher doses of doxorubicin with fewer side effects.

“The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designations to aldoxorubicin in three indications: glioblastoma multiforme, small cell lung cancer, and ovarian cancer. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to albumin, allowing greater doses of the chemotherapeutic agent to be administered while reducing its toxic side effects.

“Aldoxorubicin is currently being studied in a global phase III clinical trial evaluating the efficacy and safety of aldoxorubicin as a second-line treatment for patients with soft-tissue sarcoma. CytRx, a biopharmaceutical research and development company, is also evaluating aldoxorubicin in two phase II clinical trials, one in patients with late-stage glioblastoma multiforme and the other in HIV-related Kaposi’s sarcoma. A global phase IIb trial in patients with relapsed small cell lung cancer is expected to commence later this month, and the company is undertaking a phase Ib combination study of aldoxorubicin plus gemcitabine as a potential precursor to a trial in relapsed ovarian cancer.”


Thoracic RT Improves Long-Term Survival in Extensive-Stage SCLC

The gist: This article discusses the results of a clinical trial—a research study with volunteer patients. The goal of the trial was to examine the effectiveness of a new treatment for extensive-stage small cell lung cancer (ES-SCLC). The treatment adds thoracic (chest) radiotherapy to standard treatment with chemotherapy and cranial (head) radiotherapy. Patients in the trial who received the new treatment had significantly improved outcomes.

“The addition of thoracic radiotherapy to chemotherapy and prophylactic cranial irradiation significantly improved 2-year survival and other outcomes in patients with extensive-stage small-cell lung cancer (ES-SCLC), according to results of a new phase III randomized trial.

“Survival for ES-SCLC is poor, and has improved little in recent decades,” wrote study authors led by Ben J. Slotman, MD, of VU University Medical Center in Amsterdam. Though previous research has shown prophylactic cranial irradiation can improve outcomes, intrathoracic disease often remains a problem. In this study, the investigators compared 247 patients who received thoracic radiotherapy with 248 patients who did not; all patients underwent prophylactic cranial irradiation. The results were published online ahead of print on September 14 in the Lancet.

“The median overall survival at 1 year was no different between the groups, at 33% in the thoracic radiotherapy group and 28% in the control patients, for a hazard ratio (HR) of 0.84 (95% CI, 0.69-1.01; P = .066). But a secondary analysis of 2-year survival did show improvement, at 13% in the radiotherapy group vs 3% in the control patients (P = .004). The number of patients needed to treat to avoid one death was 10.6.”


Some Lung Cancer Patients Could Live Longer When Treated with New Radiotherapy Strategy

The gist: A type of radiation treatment called thoracic radiotherapy may help some lung cancer patients live longer after chemotherapy. That was the conclusion of a recent clinical trial—a research study with volunteer patients.

“The authors say that as the thoracic radiotherapy is well tolerated, it should to be routinely offered to all SCLC patients with extensive disease whose cancer responds to chemotherapy.

“SCLC is an aggressive cancer that accounts for about 13% of all lung cancers. The majority of patients present with extensive disease that has spread to other areas of the body.

” ‘In recent years, we have made some progress in improving survival by giving prophylactic cranial radiotherapy (radiation to the head to reduce the risk of the cancer spreading to the brain) after chemotherapy, and this is now considered the standard of care. However, survival for patients with extensive disease remains poor (2-year survival of less than 5%) and the likelihood of the cancer recurring and spreading to other parts of the body remains high’, explains Ben Slotman, lead author and Professor of Radiation Oncology at the VU University Medical Center in Amsterdam, Netherlands…

“Writing in a linked Comment, Jan P van Meerbeeck from Ghent and Antwerp University in Belgium and David Ball from The University of Melbourne in Australia point out, ‘Refreshingly, the radiotherapy in Slotman and colleagues’ study was not technically complex and it would be easy to provide at low cost in even the most modestly resourced radiotherapy departments.’ “


Novel Oncogenic RET Mutation Found in Small Cell Lung Cancer

Editor’s note: An oncologist will sometimes test a patient’s tumor for specific mutations in order to decide what the best treatment options are. Tumors that have certain mutations can sometimes be treated with certain so-called targeted therapy drugs. This approach has worked well for many people with non-small cell lung cancer (NSCLC). However, there are no FDA-approved targeted therapies for small cell lung cancer (SCLC). A new discovery might change that. Researchers found a mutation called RET M918T in a metastatic SCLC tumor. Two targeted drugs were found to fight against tumor cells with the mutation in the lab. The drugs—ponatinib and vandetanib—are already FDA-approved to treat other types of cancer.

“For the first time, an oncogenic somatic mutation at amino acid 918 in the rearranged during transfection protein has been identified in small cell lung cancer tumors and enforced expression of this mutation within small cell lung cancer tumor cell lines produced increased intracellular signaling and cell growth.

“SCLC is a highly malignant form of lung cancer representing 15% of all lung cancers and is strongly associated with tobacco smoking. NSCLC, representing 85% of lung cancer, has been extensively examined for genomic alterations and targeted therapies are approved for patients with certain mutations, however SCLC has not been examined with the same rigor and there are no approved targeted therapies for SCLC.

“Investigators at Case Western University examined 6 SCLC tumors, 3 each from primary and metastatic tumors, for 238 somatic mutations across 19 oncogenes. RET wild type and mutant protein was then overexpressed in SCLC cell lines and these cell lines were examined for cell signaling, cell growth and responsiveness to two tyrosine kinase inhibitors of RET.”


Adding Ziv-Aflibercept to Topotecan Improves Progression-Free Survival but Increases Toxicity in Platinum-Treated Small Cell Lung Cancer

Editor’s note: A recent clinical trial with volunteer patients tested whether a treatment that combines a drug called ziv-aflibercept (Zaltrap) with the drug topotecan would be better than toptecan alone for people with small cell lung cancer (SCLC). All participating patients had previously been treated with platinum-based chemotherapy and had been treated for brain metastases. Patients were randomly assigned to be treated with either topotecan alone, or the topotecan/ziv-aflibercept combination. The researchers found that the combination treatment significantly increased the number of patients who survived three months or more without their disease worsening. However, the combo treatment had worse side effects and did not improve overall survival.

“The phase II Southwest Oncology Group (SWOG) S0802 trial reported in the Journal of Clinical Oncology by Allen et al showed that adding ziv-aflibercept (Zaltrap) to topotecan improved 3-month progression-free survival, but increased toxicity and had no effect on overall survival, in patients with platinum-treated small cell lung cancer (SCLC)…

“In the trial, 189 patients who had experienced disease progression after one line of platinum-based chemotherapy and had treated brain metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, and no recent vascular events or bleeding diatheses were randomly assigned to receive weekly topotecan at 4 mg/m2 with (n = 97) or without (n = 92) ziv-aflibercept at 6 mg/kg every 21 days. Patients were stratified as platinum-refractory (n = 55 vs 51) or platinum-sensitive (n = 42 vs 41). Progression-free survival at 3 months was the primary endpoint.”


New Drug Active Against Most Aggressive Type of Lung Cancer Cells

Cancer cells

Editor’s note: New research has uncovered a potential new treatment option for people with small cell lung cancer (SCLC). A drug called AZD3965 has been shown to be effective in killing SCLC cells in the laboratory and in mice. Scientists also found evidence that the drug would work best in patients who have elevated levels of a protein called MCT1. AZD3965 has been tested and found to be effective for some patients with other cancer types, but it has not yet been tested in people with SCLC in clinical trials.

Excerpt:

“Manchester scientists have shown that a new drug could prove useful in treating small cell lung cancer – the most aggressive form of lung cancer.

“Scientists from the Cancer Research UK Manchester Institute, based at The University of Manchester and part of the Manchester Cancer Research Centre, teamed up with experts at AstraZeneca, as part of a collaboration agreed in 2010, to test a drug – known as AZD3965 – on small cell lung cancer cells.

“The research, published in the journal Clinical Cancer Research, also helps identify which patients are most likely to respond to the treatment.”


Chemo Combo Increases Survival, Toxicity in Sensitive Relapsed SCLC

“Cisplatin, etoposide, and irinotecan outperformed topotecan as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer (SCLC) in a Japanese trial, though there was substantially increased toxicity with the regimen.

“ ‘Topotecan is the only drug approved in the United States and the European Union for relapsed SCLC,’ said Koichi Goto, MD, PhD, of the National Cancer Center Hospital East in Chiba, Japan. He presented results of the new trial at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. Sensitive relapse refers to cancers that respond to initial chemotherapy and relapse more than 3 months after completion of that therapy, while refractory cancers do not respond initially or relapse within that 3 month window.”

Editor’s note: This story is about a clinical trial with volunteer patients to test a new treatment for small cell lung cancer (SCLC). The new treatment is specifically for people with SCLC who were treated with chemotherapy successfully, but whose cancer returned more than 3 months after chemo—this is known as “sensitive relapsed SCLC.” The new treatment combines three chemo drugs: cisplatin, etoposide, and irinotecan. In the clinical trial, some patients took the chemo combo and some were treated with the chemo drug topotecan, which is a standard treatment for the condition. Patients who took the new treatment lived longer, but they had more toxic side effects than the patients who took topotecan.