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The Lancet Oncology

Showing posts with label NSCLC. Show all posts
Showing posts with label NSCLC. Show all posts

Wednesday, September 23, 2009

Cetuximab plus Chemotherapy may Reduce Advanced Lung Cancer Death Risk

Patients with advanced non-small cell lung cancer who are given cetuximab (Erbitux, Merck KgA), an immunoglobulin (Ig) G1 chimeric monoclonal antibody against the epidermal growth factor receptor, in addition to chemotherapy are 13% less likely to die than those who receive chemotherapy alone, regardless of which chemotherapy is used, new research finds. They also experience slower disease progression and an increased chance of tumor shrinkage.

While a large study last year found that patients lived five weeks longer when the targeted drug cetuximab was added to a particular chemotherapy combination, it has not been clear whether it matters which chemotherapy combination the drug is added to, how its addition affects disease progression and what the exact magnitude of the survival benefit is.

Researchers combined the data from four trials that investigated the addition of cetuximab to various different platinum-based chemotherapy combinations in first-line treatment of advanced non-small cell lung cancer. The findings of the meta-analysis, which included a total of 2,018 patients, were presented in Berlin on Tuesday at Europe’s largest cancer congress, ECCO 15 – ESMO 34 (the 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology).

Meta-analyses, which integrate the results of several studies, are important for corroborating the findings of key studies and give a more accurate estimate of a drug’s true effects. “We found that patients who got cetuximab had a 13% lower chance of dying within the three years of follow-up compared with those who got chemotherapy alone,” said Professor Jean-Louis Pujol, chair of thoracic oncology at Montpelier Academic Hospital and professor of medicine at Montpelier University in France. “For lung cancer, considering that this disease is very resistant to treatment and that the prognosis is very poor, an improvement of that magnitude is meaningful. It’s about the same as what you get from giving chemotherapy after surgery and that’s accepted as standard treatment.”

The median survival, a more crude measure of the drug’s effect on death, was 9.4 months in the chemotherapy alone group and 10.3 months in the chemotherapy plus cetuximab group.

The meta-analysis also uncovered a 10% improvement in progression free survival, which measures the length of time a patient survives before the cancer gets worse. None of the individual studies were powerful enough to identify any effect on this outcome on their own, as it is difficult to observe this in lung cancer because the disease progresses so quickly.

The study also found that patients who received the addition of cetuximab were 48% more likely to experience tumour shrinkage.

“Fewer than 30% of patients with advanced non-small cell lung cancer respond to chemotherapy, so even though adding cetuximab increases the chance by another 48%, pushing the response rate up to about 45%, this shows than non-small lung cancer remains a disease that is very resistant to treatment,” Prof Pujol said.

The benefits for all these outcomes were seen across all subtypes of the disease. Lung cancer is particularly difficult to treat and is the leading cause of cancer death worldwide, killing an estimated 1.31 million people a year. Patients with advanced disease have few treatment options and about 70% of them die within one year of diagnosis. Fewer than two percent survive five years. Platinum-based chemotherapy is the standard treatment.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and most patients have tumours that over-express the epidermal growth factor receptor (EGFR). Cetuximab belongs to a new class of anti-cancer drugs known as monoclonal antibodies and works by blocking the EGF receptor to interrupt uncontrolled cell division.

Studies of other EGFR blockers have not shown any benefit when they are combined with chemotherapy in first-line treatment of advanced non-small cell lung cancer, although they have been shown to help in second-line treatment. One explanation for why cetuximab has shown benefit in this case while the other drugs targeting the receptor haven’t could be because it blocks the receptor in a different location. The drug is currently used to treat metastatic colorectal cancer and head and neck cancer. Frequent side effects include an acne-like rash.

“We now have enough evidence to recommend cetuximab for patients with advanced non-small cell lung cancer and we have confirmation that it doesn’t matter what kind of chemotherapy it is used with,” Prof Pujol said. “What we now need to investigate is whether this drug could also help at early stages of the disease.”

The study was funded by a grant from Merck KGaA, which makes cetuximab.

For more information:
  • Abstract no: 9009. Lung Cancer II session, Tuesday 09.00 hrs CEST (Hall 15.2)

Also read these Pubmed Abstracts:

Images courtesy American Society of Clinical oncology (ASCO)

Monday, August 31, 2009

Diagnostic Test to Select Patient Candidates for Novel Investigational Non-Small Cell Lung Cancer Therapy

Abbott's molecular diagnostics business, headquartered in Des Plaines, Ill.,has entered into an agreement with Pfizer Oncoloy, a business unit of Pfizer Inc, committed to the discovery, investigation and development of innovative treatment options for cancer patients worldwide, to develop a molecular diagnostic test intended to screen non-small cell lung cancer (NSCLC) tumors for the presence of gene rearrangements.

Pfizer has developed a novel investigational agent that selectively targets cancer-causing genes implicated in the progress of many cancers. To be eligible to receive Pfizer's oral therapy, a particular genetic translocation (rearrangement) known to be found in NSCLC tumors and a wide variety of other cancers, but not in normal cells, must be present.

Under terms of the agreement, Abbott will develop a companion diagnostic test that will determine a patient's genetic status and will be used in patient selection for future clinical trials of PF-02341066.

"We are very pleased to partner with Abbott to develop a companion diagnostic test for non-small cell lung cancer and ensure its global availability for patients and physicians who need this information to make the best treatment decisions," said Garry Nicholson, General Manager, Pfizer Oncology Business Unit.

"This test will allow us to focus on the patient population most likely to benefit from our NSCLC candidate. Working in close partnership with the experienced Abbott team, we are confident that we will deliver yet another application of personalized medicine to address a currently unmet medical need in NSCLC."

"Pfizer's novel compound for treating non-small cell lung cancer appears to be ideally suited to individualized therapy," said Stafford O'Kelly, head of Abbott's molecular diagnostics business. "Abbott is a leader in the development and commercialization of companion diagnostics and we're delighted to collaborate with Pfizer, a leader in cancer therapeutics, on the development of a test to identify patients who might benefit from this important compound."

Monday, July 13, 2009

Erlotinib Improves Overall Survival After Initial Chemotherapy in Patients with Advanced Lung Cancer

Results from SATURN, a pivotal Phase III study, met a key secondary endpoint of extending overall survival in patients with advanced non-small cell lung cancer (NSCLC) who received erlotinib (Tarceva®, Genentech/Roche; OSI) immediately after their initial chemotherapy. A statistically significant improvement in overall survival was seen in the pre-planned final analysis of the total patient population in the study. The new data will be presented during the 13th World Conference on Lung Cancer to be held July 31 – August 4, 2009 in San Francisco.

Lung cancer is the most common cancer worldwide with 1.5 million new cases annually and NSCLC accounts for 85 – 90% of all lung cancers. Non-small cell lung cancer (NSCLC) progresses rapidly and survival rates are generally very poor. Most people are diagnosed with advanced stage disease and less than 5% of these advanced NSCLC patients survive for five years. Extending the time patients live and managing side effects are key treatment goals.

According to the American Cancer Society, lung cancer is the leading cause of cancer death in the United States. In 2009, approximately 159,000 Americans will die from the disease.
Treating patients immediately following first-line chemotherapy versus waiting for the cancer to grow or spread before giving additional treatment represents a new approach in advanced NSCLC.

A new approach
Erlotinib is, as a Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor, different from conventional chemotherapies.
Over-expression of EGFR is common in several solid tumors, such as colorectal cancer, lung carcinomas, and cancers of the head and neck. It correlates with increased metastasis, decreased survival and a poor prognosis. EGFR protects malignant tumors cells from the cytotoxic effects of chemotherapy and radiotherapy, making these treatments less effective.

HER1 and EGFR receptors are directly involved in inter-cellular signaling in systems governing cell division and proliferation. By interfering with the function of these receptors, which are highly active and often over-expressed in rapidly dividing tumor cells, erlotinib inhibits EGFR-receptor tyrosine kinase activity, and may help to initiate pathways of apoptotic cell death. The interference with the cell signaling pathways involved in cell proliferation represents a novel approach to the treatment of solid tumors.

Today, erlotinib is the first and only EGFR oral targeted agent in second line with a proven and significant survival and symptom benefit in a broad range of patients with advanced lung cancer without the side effects associated with chemotherapy. The drug has been approved in the EU since September 2005 and in the US since November 2004 for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.

Patient benefit
In the landmark registration study BR.21, a randomised controlled phase III clinical trial comparing erlotinib with placebo/best supportive care in patients with locally advanced or metastatic non-small lung cancer which took place in 17 countries around the world, erlotinib delivered effectiveness comparable to chemotherapy and significantly improves overall quality of life.

The registration study underlined that more patients on erlotinib had improvement in cough, pain, shortness of breath and overall physical function versus patients on placebo. In addition erlotinib did not induce the distressing side-effects associated with chemotherapy, such as nausea and vomiting. An added benefit, improving adherence, is that erlotinib is convenient as patients can take a tablet once a day at home rather than receive intravenous treatments in a hospital.

Global trial
SATURN, a global multicentre, double blind, randomized, prospective phase III study was designed to evaluate the efficacy of erlotinib vs. placebo in patients with advanced, recurrent or metastatic NSCLC who had not progressed following first line platinum-based chemotherapy. The study involved more than 880 patients from approximately 160 centers; 438 received erlotinib and 451 placebo.

The study met its primary endpoint demonstrating a statistically significant extension of the time patients live without their disease worsening; there was a 41% increase compared with placebo (hazard ratio= 0.71, p-value <0.0001).>


“This study has now not only confirmed that immediate treatment with Tarceva after initial chemotherapy delayed the progression of disease, but also importantly helped patients in the study live longer,” said Professor Federico Cappuzzo, M.D., Istituto Clinico Humanitas IRCCS, Milan and principal investigator of the SATURN study. “This is good news for doctors and their patients since advanced lung cancer is one of the most challenging cancers to treat and is often associated with a very short life-expectancy.”

Commenting on the study, William M. Burns, CEO Division Roche Pharmaceuticals said, “This is the second set of data from large studies that has shown Tarceva helps patients with advanced lung cancer to live longer. These results confirm that Tarceva has an important role to play in improving the lives of patients earlier in the management of this devastating disease.”

Erlotinib is already a well established treatment in second-line management of advanced NSCLC after the failure of chemotherapy and is proven to extend survival for a broad range of patients in this setting. Most recently, presentation of the SATURN primary endpoint data analysis at ASCO 2009 showed that patients who received treatment with erlotinib immediately after initial chemotherapy if their cancer had not progressed had a 41% improvement in the length of time they lived without their disease getting worse compared to placebo.

Outcome confirmed
During the Annual Society of Clinical Oncology (ASCO) Vincent A. Miller, MD., a medical oncologist from the Memorial Sloan-Kettering Cancer Center, presented results from the phase III ATLAS study supported findings in the SATURN study.

The ATLAS study, a global multicentre, randomised, double blind, placebo controlled study that enrolled 1,160 patients with locally advanced, recurrent or metastatic NSCLC, was designed to evaluate bevacizumab (Avastin®, Genentech/Roche) in combination with erlotinib (150 mg daily) versus bevacizumab alone, following bevacizumab in combination with a platin-containing doublet chemotherapy, in patients with stage IIIb/IV NSCLC.

The study showed that combined treatment with bevacizumab and erlotinib, immediately following initial therapy with bevacizumab plus chemotherapy was highly effective and significantly delayed disease progression for patients with advanced NSCLC, without the need for chemotherapy.

The positive results from these trials were encouraging because previous Phase III studies in which erlotinib was used as first-line therapy in combination with cytotoxic drugs (the TRIBUTE and TALENT studies) failed to demonstrate a survival advantage when erlotinib was added to conventional treatment regimens.

The overall survival data fron SATURN will be used to support the European and US applications for use of erlotinib as a first-line maintenance treatment for patients with advanced NSCLC. These applications were made to the European Medicines Agency (EMEA) and US Food and Drug Administration (FDA) in March 2009 and are based on the pivotal Phase III SATURN trial. The FDA Prescription Drug User Fee Act (PDUFA) review date will be on or about January 18, 2010.

Commenting on the overal product development, Colin Goddard, Ph.D., Chief Executive Officer of OSI Pharmaceuticals, Roche's US partner, said:"We are pleased with the launch of Tarceva in the U.S. to date and we continue to believe that Tarceva will emerge as a fundamentally important new agent in changing the paradigm for the treatment of cancer patients around the world. With our partners, Genentech and Roche, we are committed to executing a post-approval development plan, studying Tarceva in earlier stage lung cancer patients, in patients with other tumor types and combinations with other targeted therapies."

For more information:

ASCO 2009 Annual meeting:

Also read these PubMed abstracts:

Information for your patient:

Images courtesy American Society of Clinical oncology (ASCO)


Sunday, July 12, 2009

Pemetrexed First Agent Approved in Europe as Maintenance Therapy for Advanced, Nonsquamous Non-Small Cell Lung Cancer

The European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP) has granted approval for the use of pemetrexed for injection (Alimta ®, Eli Lilly and Company) as monotherapy for maintenance treatment of patients with other than predominantly squamous cell histology in locally-advanced or metastatic non-small cell lung cancer (NSCLC), whose disease has not progressed immediately following platinum-based chemotherapy. This approval is based on data that showed pemetrexed improved overall survival in other than predominantly squamous NSCLC patients in the maintenance setting.

Globally, lung cancer is the most common form of cancer and the biggest killer, causing 1.3 million cancer deaths annually. This is more than breast, colon and prostate cancer taken together. About 85 - 90 percent of all lung cancers are non-small cell lung cancer (NSCLC). Survival rates are very poor.

Major disease forms
Non-small cell lung cancer (NSCLC) is defined as a group of histologies, that is, tumor types differentiated by cellular structure. The most predominant is squamous cell carcinoma (also known as epidermoid carcinoma) which accounts for 30 - 40% of all NSCLC cases. Formed from round cells that replace damaged cells along the epithelium of the main, lobar or segmental bronchi, this disease is a relatively slow growing carcinoma with a relatively good prognosis. Recurrence rates for resected squamous cell carcinoma are relatively low compared top other types of NSCLC, with distant metastases less common given the same treatment at the same stage.

Also referred to as nonsquamous histology, adenocarcinoma, which account for more than half of all NSCLC diagnoses, usually arises from mucus-producing cells of the lung. Aproximately two-thirds of adenocarcinomas develop in the outer regions of the lung, while the remaining one-third develop centrally. The majority of adenocarcinomas are asymptomatic until they have progressed to an advanced stage. As a consequence, the prognosis is generally worse compared to that of squamous cell carcinoma. On the other hand, once diagnosed, adenocarcinomas generally respond better to treatment than other NSCLC histologies.

Squamous cell carcinoma tends to metastasize in the bone, adrenal glands, liver, small intestines and brain. Because this disease is almost always caused by smoking, occurrence has decreased over the past 30 - 35 years.

Other types of NSCLC include bronchoalveolar carcinoma (BAC), a subclassification of adenocarcinoma with distinct clinical and pathologic properties and large cell carcinoma.

The majority of patients with NSCLC eventually develop metastatic disease or disease that is not a candidate for surgical interventions. this makes them potential candidates for systemic therapies. However, the decision on whether a patient receives therapy, greatly depends upon a number of factors, including the disease stage. In general, the more advanced the disease is, the more likely that a physician will prescribe a drug therapy.

Staging of Lung Cancer
Lung Cancer is often classified according to the American Joint Commitee on Cancer (AJCC) TNM staging system, and has five-tier staging, starting at 0 and rising to the severity of stage IV.

The primary T1 tumor, generally smaller than 3 centimeter, is usually easy to define on computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET).

TNM stage T3 tumors include tumors of any size with direct extension into the chest wall, diaphragm, mediastinal pleura or pericardium. Stage T4 tumors invade the mediastinum, great vessels, trachea, oesophagus and vertebral bodies.

Lung cancer in metastatic stage becomes aggressive. In this stage a therapy to shrink tumour size, stabilize the disease and relieve debilitating symptoms, with minimal toxic effects of the drug is required. Pemetrexed is the most promising molecule in that aspect. The drug provides better survival, progression free time and response and has superior tolerability than other cytotoxic drugs used for the same condition.

Mechanism of action
Pemetrexed is a multitargeted antifolate currently approved for first-line treatment of advanced, other than predominantly squamous NSCLC in combination with a platinum-based chemotherapy, and as a single agent in the second-line setting for advanced, other than predominantly squamous NSCLC patients with recurrent disease. Pemetrexed is chemically similar to folic acid and is in the class ofchenotheray drugs called folate antimetabolites. It works by inhibiting three enzymes used in purine and pyrimidine synthesis—thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT).

Improve Overall Survival in a Maintenance Setting
The concept of maintenance therapy represents a paradigm shift in the treatment of advanced, other than predominantly squamous NSCLC.
Traditionally, patients who respond to first-line chemotherapy are monitored until the disease recurs and are then treated with a second-line regimen. In maintenance therapy, rather than halting further treatment until disease progression, patients who respond to a first-line therapy are treated immediately with a maintenance regimen.

"The idea behind ALIMTA as maintenance therapy for nonsquamous, non-small cell lung cancer is to treat patients immediately following their initial course of therapy, in an effort to prolong survival," said Richard Gaynor, M.D., vice president, cancer research and global oncology platform leader at Lilly. "The study that led to this approval was the first that showed improved overall survival in the maintenance setting for NSCLC. This was also the third trial to show the benefit of tailoring ALIMTA treatment to the nonsquamous NSCLC patient population."

Overall survival data for pemetrexed as a maintenance therapy for NSCLC was presented on May 31, 2009, at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) by Chandra P Belani M.D.

The trial compared efficacy with respect to overall survival of pemetrexed plus best supportive care versus placebo plus best supportive care in 663 patients with stage IIIB/IV NSCLC whose disease had not progressed after four cycles of platinum-based induction chemotherapy. Pemetrexed was not included among the induction regimens studied in the maintenance trial. The trial supported two previous studies looking at the use of histology to tailor treatment for patients with advanced, other than predominantly squamous NSCLC.

Patients in the trial were treated with pemetrexed (500 mg/m2 on day one of each 21-day cycle) plus best supportive care or placebo plus best supportive care. All patients were supplemented with vitamin B12, folic acid and dexamethasone.

Pemetrexed was initially approved by the FDA in 2004 for the treatment of mesothelioma, with subsequent approval for second-line treatment of NSCLC.

This latest approval for pemetrexed - the fourth in Europe - follows an initial positive opinion issued by the European Medicines Agency's (EMEA) Committee for Medicinal Products for Human Use (CHMP) on May 29, 2009, and the recent approval by the U.S. Food and Drug Administration (FDA) of pemetrexed for maintenance therapy in advanced, nonsquamous NSCLC patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

Apart from the existing approvals in the EU and U.S. for the use of pemetrexed in the treatment of patients with locally-advanced or metastatic other than predominantly squamous NSCLC, pemetrexed is also approved, in combination with cisplatin, in both the EU and U.S. for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma.

For more information:
Also read these PubMed abstracts:

How to help your patients:

  • Encourage your patients to have an open, honest talk with you. Tell them that they should feel free to ask any question that’s on their mind, no matter how small it might seem. Also, encourage your patients to talk to other healthcare professionals, including nurses, social workers, and other members of the healthcare team.
Patient resources:

Images courtesy American Society of Clinical oncology (ASCO)