Erlotinib (Tarceva) and Bevacizumab (Avastin): Combination Therapy for NSCLC
Ryan Smith, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 14, 2003
Faculty Disclosure: Roy S. Herbst, MD
This presentation by Dr. Herbst will discuss the use of bevacizumab and erlotinib in the treatment of lung cancer which has not been approved by the FDA.
Presenter: Roy S. Herbst, MD
Affiliation: M.D. Anderson Cancer Center
Lung cancer remains a difficult disease to treat, causing the most cancer deaths in the United States. The majority of patients that are diagnosed with lung cancer will succumb to their disease. This is despite significant recent advances with combination chemotherapeutic regimens, leading many to believe that scientists and physicians are approaching the maximum amount of benefit that can be achieved with chemotherapy. Hence, the development of biologic agents has moved to the forefront of cancer research. This is true in many cancers, lung cancer included.
Two of the more common targets for biological therapy are vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (HER1/EGFR). Bevacizumab is a humanized anti-VEGF monoclonal antibody used as an anti-angiogenesis agent. It has a demonstrated survival advantage in metastatic colorectal cancer and is currently being tested in phase III trials in breast and lung cancer. Erlotinib is a highly selective HER1/EGFR tyrosine kinase inhibitor. It is currently being tested in phase III trials in lung and pancreatic cancer. Additionally, in preclinical studies, erlotinib prevents the expression of, among others, VEGF. Therefore, there is interest that these two agents may work synergistically, and in fact, in colorectal cancer, there was at least an additive effect noted.
This presentation reported on a phase I/II study using both bevacizumab and erlotinib in patients with stage IIIB/IV/recurrent NSCLC. Patients were required to have failed at least one prior chemotherapy regimen with no CNS disease. Additionally, because of concerns with hemorrhage noted in other phase I trials, patients with squamous cell cancer were excluded. In the phase I portion of the trial, three patients were enrolled in escalating regimens of bevacizumab and erlotinib. Dose level one was bevacizumab 7.5 mg/kg every 3 weeks with erlotinib 100 mg per day. Dose level two was bevacizumab 15 mg/kg every 3 weeks with erlotinib 100 mg per day. Dose level three was bevacizumab 15 mg/kg every 3 weeks with erlotinib 150 mg per day. Three patients were treated at dose level one, three patients were treated at dose level two, and six patients were treated at dose level three. No dose limiting toxicities were seen in any patient at any dose level. Therefore, dose level three was used in the phase II trial.
A total of 38 patients have been enrolled in the phase I/II trial thus far. Sixteen had adenocarcinoma and six had NSCLC not otherwise specified, with the remainder with bronchoalveolar cancer. Most had had two to three prior chemotherapy regimens. Data presented were based on 23 of the patients. There continued to be no grade 3 or 4 toxicities noted in the study. Most common toxicities were rash (83%), diarrhea (75%), nausea (58%), and pruritis (42%). Again, none were more than mild to moderate in intensity. None had a complete response, four had a partial response, five had stable disease, and 14 patients had progressive disease. Pharmacokinetic studies were also done, which showed no interaction between the two drugs.
It was felt that this represented a possible advance in the treatment of NSCLC. Although not astounding, there are many responses seen to this regimen in a population of patients that are left with few other options. In addition, though there were no grade 3 or 4 toxicities noted, there were quite a few grade 1 and 2 toxicities. Granted these are not severe in intensity or life-threatening, but they can be very annoying to the patients being treated. Therefore, this treatment is not completely benign. The results of the full patient population along with other studies on this potentially synergistic treatment regimen are anticipated.