Metastatic Lung Cancer Survival Improved by the Addition of Cetuximab to Chemotherapy: FLEX Study

The results of the FLEX study of cisplatin + vinorelbine (Navelbine) with or without cetuximab (Erbitux) therapy were presented at the ASCO 2008 Annual Meeting Plenary Session, in Chicago on 6/1/08.  The study was the first demonstration of an overall survival advantage of an anti-EGFR drug used in conjunction with first-line standard chemotherapy for advanced or metastatic (“wet” Stage III-B/IV) lung cancer.  The results of this 1,125 patient study are summarized in the table below.

The important aspects of this trial design were: 1) patients were EGFR positive by IHC (immunohistochemistry), 2) patients received up to 6 cycles of chemotherapy with or without Erbitux, and those who received Erbitux during chemotherapy continued on maintenance Erbitux after completion of chemotherapy, 3) patients were not excluded for squamous cell carcinoma, central tumors, or hemoptysis (factors that associated with an increased risk pulmonary hemorrhage or fatal hemoptysis), and 4) the trial was powered to assess overall survival, rather than the “softer” endpoint of progression free survival. 

The groups were well balanced for patient factors.  The only signficant additional toxicity associated with the addition of Erbitux were uncommon infusion reactions (4% versus <1% control), grade 3 rash (10% versus <1% control), and diarrhea (5% versus 2% control). 

Of interest, the Erbitux-containing treatment arm had improved overall survival, despite the fact that 27% of the control arm (versus 17% of the Erbitux arm) received post-progression EBFR inhibitor therapy, indicating that the up-front use of chemotherapy + Erbitux followed by maintenance Erbitux is likely a superior strategy in achieving longer survival for such patients when compared to chemotherapy followed by other standard therapy upon progression (including EGFR inhibitors) for progression. 

These results must be considered in light of other prevalent studies and practice patterns in management of NSCLC.  Other studies (AVAIL, ECOG 4599) have demonstrated modest improvements in survival when bevacizumab (Avastin) is added to standard chemotherapy.  The survival impact seen for Erbitux + chemotherapy in the FLEX study appears to be of comparable magnitude to that seen with Avastin + chemotherapy.  However, there are important toxicity differences between Avastin and Erbitux.  Avastin may increase the risk of bleeding and fatal hemoptysis, so patients with large central tumors, squamous cell lung cancer, and hemoptysis are not generally considered for treatment with Avastin.  Avastin is not given to patients with CNS metastases, because of the possible risk for CNS hemorrhage.  On the basis of these general preclusions, as many as 40-45% of metastatic lung cancer patients may not be eligible for Avastin.  Erbitux eligibility is broad, with EGFR immunostaining in 85% of the patients screened in the FLEX study.  Other serious risks of Avastin (thromboses, proteinuria, hypertension, would healing delay, and rare serious events such as bowel perforation or posterior leukoencephalopathy syndrome) are not seen with Erbitux. 

The FLEX study did not exclude patients for Erbitux therapy on the basis of ras mutations.  That is an important caveat to the FLEX findings.  Many investigations in lung and colorectal cancer have demonstrated that tumors with mutated ras oncoproteins are resistant to EGFR inhibiting drugs, including TKI inhibitors (erlotinib=Tarceva, gefiinib=Iressa) and EGFR antibody inhibitors (cetuximab=Erbitux, panitumumab=Vectibix).  Ras mutations are prevalent in NSCLC, in up to 40% of patients.  Therefore, the fraction of patients who are eligible for Erbitux therapy may be reduced, if ras assessment is including in pre-treatment screening to exclude patients who are unlikely to benefit from EGFR inhibitors.  It appears likely that regulatory or insurer guidelines will adopt a policy of ras assessment in the future, because of the significant costs of EGFR inhibitors. 

While IHC assessment of EGFR status was used in FLEX, there may be better methods for “enriching” a population of patients who benefit from EGFR inhibitors.  Response rates to single-agent EGFR inhibitors of EGFR IHC+ patients are 10-15%.  EGFR amplification by FISH is positive in about 40% of patients, and responses in these patients range up to 40-50%.  A much smaller group of patients (10-15%)  harbor activating mutations in EGFR (exon 19 and 20 predominantly), and response has been reported in 70-90%.   However, patients who are EGFR IHC+ without amplification and/or mutation might still benefit from therapy, so exclusion of these patients from treatment is not an accepted strategy at the present time.

CORT is testing EGFR inhibition with Erbitux in first- and second-line therapy trials.  For more information, call 972-566-5588 (Dallas), or 972-981-4012 (Plano), and ask to speak with a Research Coordinator.  Additional information is available at the CORT website, www.CORTPA.com.

 

Tags: Avastin, bevacizumab, cetuximab, EGFR Inhibitors, Erbitux, FLEX Study, Lung Cancer, metastatic lung cancer, Ras, Stage IIIb, Stage IV