Advances in First-Line Treatment of Unresectable Non-Small Cell Lung Cancer: Pemetrexed Maintenance Therapy

Chemotherapy is the initial standard-of-care treatment for unresectable (stage IIIB/IV) non-small cell lung cancer (NSCLC).  Based upon historical information, the optimal duration of initial therapy with a platinum doublet (two-drug regimen) is 4-6 cycles.  The addition of bevacizumab (Avastin) to the carboplatin and paclitaxel first-line treatment regimen has improved progression free survival (PFS) from 4.5 (placebo) to 6.2 months (bevacizumab) (ECOG 4599, Sandler et al NEJM 355: 2542-2550, 2006).  Longer therapy initial therapy has, in some cases, improved progression free survival (PFS), without improvement in overall survival (OS).  That may be a result of the benefit of second-line treatment (at the time of progression), which may also extend overall survival (OS).  

The benefit of maintenance therapy, after initial treatment, was examined by a group of international investigators, reported by Dr. Ciuleanu (Romania) at the 2008 ASCO Annual Meeting  (J Clin Oncol 26: 2008 (May 20 suppl; abstr 8011)).  Patients received initial chemotherapy, and then the patients were randomly assigned to maintenance therapy with pemetrexed (Alimta) or placebo.  The study demonstrated a significant improvement in PFS for the patients who received maintenance pemetrexed therapy, with PFS of 4 months (versus 2 months for placebo).  In the subset analysis, patients with non-squamous cell histology benefited, while squamous cancers did not.  The observation that response to pemetrexed was superior in non-squamous histology lung cancer has been observed in two previous investigations.  This study also demonstrated a strong trend (nearing statistical significance) for improved overall survival (OS) in patients with non-squamous histology who received pemetrexed maintenance therapy.  The final results of OS in this study have not yet been reported.

The use of maintenance pemetrexed with bevacizumab was also reported at the ASCO 2008 Annual Meeting (J Clin Oncol 26: 2008 (May 20 suppl; abstr 8044)).  Dr. Patel reported the results of a study in which all patients received carboplatin and pemetrexed with bevacizumab as initial therapy x 6 cycles.  Patients without progression continued on pemetrexed and bevacizumab for maintenance therapy every 3 weeks.   This was a single arm study.  The PFS was 9.2 months, and the OS was 13.5 months.  Treatment with maintenance pemetrexed and bevacizumab was very well tolerated, and 60% of patients had >6 cycles, 18% had >18 cycles, and 14% had >24 cycles. 

The PFS of the study reported by Patel et al are favorable.  If one expects a PFS with a platinum doublet + bevacizumab of 6 months, and an additional 4 months of PFS with pemetrexed maintenance therapy, the the results of the Patel study are in line with those reporte by Ciuleanu et al.  The study of Patel did give bevacizumab until progression, as was done in the ECOG 4599 study. 

These studies mark continued progress in treatment of unresectable and metastatic NSCLC.  Integration of anti-angiogenic therapy (bevacizumab) and less toxic treatment with new agents like pemetrexed have incrementally extended PFS.  Overall survival may also be impacted. 

Additional improvements may come with the integration of other sorts of maintenance treatment, for example, anti-tumor vaccine therapy.  CORT is testing the anti-MUC-1 tumor vaccine, Stimuvax, as part of the START study, for patients who have completed initial chemotherapy and radiation therapy for unresectable Stage III NSCLC.  Information about that study is available in another post.  For further information about lung cancer therapy at CORT, including the START study, visit our webpage at www.cortpa.com, or contact a Research Coordinator at 972-566-5588. 

Stimuvax Lung Cancer Vaccine Study Continues at CORT

CORT opened and enrolled in 2007 the first patient worldwide to the START Study (Stimulating Targeted Antigenic Responses To NSCLC), assessing the efficacy and safety of Stimuvax (BLP25 liposome vaccine) as a potential treatment for patients with unresectable stage III non-small cell lung cancer (NSCLC).  Our accrual to the study continues. 

Enrollment in the study, which will enroll more than 1,300 patients in approximately 30 countries, is continuing at CORT.  Currently, there are no approved maintenance therapies for patients responding to first-line treatment for unresectable stage III NSCLC.

“Patients with advanced lung cancer are in need of new therapies that effectively target cancer cells while providing better safety and tolerability,” said Dr. Frances Shepherd, Director of Medical Oncology at Princess Margaret Hospital in Toronto, Ontario and lead investigator of the START study. “Novel therapeutic vaccines such as Stimuvax may help the body’s immune system identify and destroy cancer cells without targeting normal, healthy cells.”

Lung cancer is the leading cause of cancer-related deaths in both men and women worldwide with approximately 80 percent of cases classified as NSCLC. Further, only about 15 percent of people diagnosed with NSCLC survive this disease after five years.(1) For most patients with NSCLC, current treatments provide limited success.

“The START study is the first Phase III program to evaluate a cancer vaccine in unresectable stage III non-small cell lung cancer,” said Dr. Wolfgang Wein, Senior Executive Vice President, Oncology, Merck Serono. “Our continued investment in research reflects our confidence in Stimuvax and commitment to developing innovative targeted therapies to advance treatment options for patients with cancer.”

The START study is a randomized, double-blind, placebo-controlled study that will evaluate patients with documented unresectable stage III NSCLC who have had a response or stable disease after at least two cycles of platinum-based chemo-radiotherapy. The study has been designed considering scientific advice from the European Medicines Agency (EMEA/CHMP) and has been agreed upon with the U.S. Food and Drug Administration (FDA) through a Special Protocol Assessment (SPA). Data from a randomized phase IIb study encouraged the initiation of the Phase III program.

For more information on the START study, or to find a participating center and eligibility criteria, go to http://www.nsclcstudy.com. The study is also listed on http://www.clinicaltrials.gov.   For patients interested in this study in the Dallas, Texas area, go to our website, www.cortpa.com, or call and speak with a Research Coordinator at: 972-566-5588.

About Stimuvax

Stimuvax is an innovative cancer vaccine designed to induce an immune response to cancer cells that express MUC1, a protein antigen widely expressed on common cancers. MUC1 is over expressed on many cancers such as lung cancer, breast cancer and colorectal cancer. Stimuvax is thought to work by stimulating the body’s immune system to identify and destroy cancer cells expressing MUC1.

A randomized Phase IIb study was conducted in 171 patients with stage IIIb and IV NSCLC with response or stable disease after first line therapy. While the overall study results were not statistically significant, in the randomization stratum of patients with stage IIIb locoregional disease, Stimuvax showed a median survival of 30.6 months versus 13.3 months in the control group — an improvement of 17.3 months. In the Phase IIb study, side effects were primarily limited to mild-to-moderate flu-like symptoms, GI disturbances, and mild injection site reactions.