What’s Wrong with Avastin?

Nothing really. It’s a wonderful drug that incorporates the brilliant insights originally articulated by Judah Folkman, MD, at Harvard University. Dr. Folkman reasoned that:

  1. Cancers require oxygen and nutrients
  2. These would need to be delivered by a blood supply
  3. Tumors would avidly seek their own blood supply via humoral factors.

His groundbreaking work ultimately lead to the discovery of VEGF, as well as the FDA approval of Avastin, the monoclonal antibody that binds and inactivates circulating VEGF in patients. The problem isn’t with Avastin, it’s with the practice of oncology – the clinical trial process and the muddied waters that surround clinical utility of any drug, new or old.

There are no perfect drugs. There are simply drugs that work for certain patients. VEGF down-regulation is an attractive and highly appropriate therapy for a subset of cancer patients with many different diagnoses whose tumors use the VEGF pathway to their advantage. Avastin combined with carboplatin and taxol has improved the survival of lung cancer patients. Avastin plus folfox has improved survival for colon cancer patients. Avastin plus chemotherapy improves the survival of some breast cancer patients. The problem is that it doesn’t improve the survival of all breast cancer patients.

When the FDA rules on the clinical utility of a drug, they use a broad-brush approach that looks at the global outcomes of all patients, determining whether these glacial trends reflect a true climate change. The problem is that while Bethesda, Maryland may not be noticing significant changes in ocean levels, people who live on the Maldives are having a very different experience. As these scientists ponder the significance of Avastin, some breast cancer patients are missing out on a treatment that could quite possibly save their lives.

One breast cancer patient’s life saving therapy is another’s pulmonary embolism without clinical benefit. Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another. Our solution to this problem has been to investigate the VEGF targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patient’s outcome. Our results to date in patients with non-small cell lung cancer, colorectal cancer and even rare tumors (like medullary carcinoma of the thyroid) suggest this to be a highly productive direction for future development.

New Drugs Are Not Always Better Drugs

The most common form of renal carcinoma is the clear cell variant. These tumors are driven by mutations in the VHL gene and are associated with hyper-vascularity. Understanding the pathogenesis of this disease has enabled researchers to develop new classes of drugs that target VEGF, both at the protein level (Bevacizumab) and at the tyrosine kinase level (sorafenib, sunitinib, etc.). An additional class of drugs targets the intracellular metabolic pathway known as mTOR. Patients newly diagnosed with renal cell carcinoma of the clear cell type are treated with drugs that target these pathways. However, responses occur in the minority of patients. It is unclear why some patients respond to these interventions while others fail.

The EVA-PCD™ analysis is equally applicable to classic cytotoxic drugs and the newer classes of targeted agents, which include Sunitinib and Sorafenib and the rapalogs like Everolimus and Temsirolimus. This enables our lab to explore whether renal cell carcinoma patients are likely to respond to vascular or mTOR targeting classes of drugs. Interestingly, patients who do not respond to these classes of drugs may nonetheless have sensitivity to cytotoxic chemotherapeutic agents. One example currently undergoing therapy is a 51 year old male who was presented in February 2009 with widely metastatic renal cell carcinoma, and a destructive lesion of the right femur requiring open surgical stabilization. Tissue removed from the patient’s femur at the time of the orthopedic surgery was submitted for an EVA-PCD™ analysis. The results were highly instructive, indicating clear resistance to the VEGF targeting agents and the rapalogs but substantial sensitivity to a novel combination of cytotoxic drugs. The patient received an opinion from a renowned renal cell expert who immediately placed him on sunitinib (Sutent™). When he failed sunitinib he was then placed upon Everolimus (Afinitor). Again the patient failed to respond. Progression of his disease was heralded by brain metastases that required both neurosurgery and cranial irradiation. He then revealed rapidly progressive pulmonary metastases as well as large painful bilateral axillary lymphadenopathy and large painful subcutaneous lesions. In light of the patient’s failure of targeted agents, he was treated with a three-drug combination identified to be active in the EVA-PCD™ analysis. The response to date has been dramatic, with complete resolution of subcutaneous lesions and lymph nodes , and objective improvement in the pulmonary metastases by CT scan. The patient remains on therapy, with continued excellent response.

This is but one example of an unexpectedly good response to classic cytotoxic drugs following a failure to respond to the newest classes of targeted agents. These experiences reinforce the need for cancer therapies to be individualized. They also remind us, as physicians, that it is the good outcome of the patient not the therapy applied that constitute successful application of the healing arts.