Researchers Aim to Refine Use of VEGF, EGFR Inhibitors in NSCLC

Alberto A. Chiappori, MD

Researchers are exploring VEGF and EGFR inhibitors in combination with other therapies for patients with non—small cell lung cancer (NSCLC) in hopes of maximizing clinical outcomes while keeping toxicity levels low.

An ongoing phase I study is investigating the VEGFR2 inhibitor ramucirumab (Cyramza) versus the EGFR inhibitor necitumumab (Portrazza), both in combination with the EGFR inhibitor osimertinib (Tagrisso) in patients with advanced, T790M-positive, EGFR-mutant NSCLC who progress on treatment with an EGFR tyrosine kinase inhibitor (NCT02789345).

The VEGF inhibitor bevacizumab (Avastin) is being studied across several settings and in combination with various regimens. For example, the angiogenesis inhibitor is being studied in combination with carboplatin/gemcitabine beyond progression in patients with locally advanced/metastatic NSCLC who have not received prior systemic therapy in a phase II trial (NCT00702975).

OncLive: At this meeting, you discussed antibodies targeting angiogenesis and EGFR. What is important to share in this area?

Aside from these available agents, are there novel therapies coming down the pipeline?

What is a key challenge that researchers still face with these drugs?

What do you see occurring in the lung cancer field in the next 5 to 10 years?

In an interview during the 2016 OncLive State of the Science Summit on Advanced Non—Small Cell Lung Cancer, Alberto A. Chiappori, MD, a senior member in the Department of Thoracic Oncology at Moffitt Cancer Center, spoke on monoclonal antibodies targeting VEGF and EGFR, their benefits and limitations, and how he sees the field evolving.Chiappori: I presented information regarding monoclonal antibodies against angiogenesis and EGFR pathways. Basically, I presented information on 4 drugs: 2 are monoclonal antibodies against the VEGF receptor and 2 are against the EGFR pathway. These drugs are bevacizumab, ramucirumab, cetuximab (Erbitux), and necitumumab.Angiogenesis and the VEGFR and EGFR pathways are the old members of all of the new biological therapies. Therefore, along the lines of monoclonal antibodies for those pathways, I don’t believe that there is anything—or I’m not aware of anything—new that is coming down the pipeline.By far, the main thing is the absence of a biomarker that may allow us to select the patients or patient populations with tumors that may be particularly sensitive to these agents that we are talking about. We know that EGFR mutations or ALK translocations predict sensitivity to tyrosine kinase inhibitors. In patients who have PD-L1 expression, we know that will predict sensitivity to immunotherapy agents. We do have biomarkers for [some of] these patients.There are 2 things that are really expanding right now. One is that we identify more and more mutations in patients who have the development of the malignant phenotype of the cancer. Therefore, if that can be targeted, then that phenotype can be reversed. That is definitely 1 area where a multitude of drugs will be developed over the next several years. I am not necessarily just talking about lung cancer, but all tumors in general.

What do you hope community oncologists learned from your lecture?

You mentioned benefits and limitations. What are these specifically?

The other area is, certainly, immunotherapy. It is going to be immunotherapy beyond single-agent checkpoint inhibition. It will be combination immunotherapy with other types of immunomodulatory agents and checkpoint inhibitors—and vaccines, for example. Those are the main areas where certainly lung cancer therapeutic development is moving forward and, really, for any cancer.I hope that they will recognize the benefits of the agents that we reviewed, and that they also recognize the limitations of the agents, such as their safety parameters. This is important so that we can be efficient in recognizing—in the absence of a biomarker—with the clinical data that are available, who may be the best patient for whom each of these different drugs may be a good fit and, therefore, are beneficial agents for patients.To a certain degree, we can debate what a sufficiently clinically meaningful benefit is, but we need to accept as the standard that the studies conducted were positive studies. This means that these studies met their endpoint. All of these drugs have reached or have proven a certain benefit in terms of survival for patients. Additionally, these agents, in the context of the design of the studies, provided us a survival benefit for the patients, leading to an overall benefit for patients with these therapies. Unfortunately, the benefit still falls short to what we would hope that any agent would do for our patients.

The other limitation is safety. [Adverse events can be] bleeding, hemorrhage, and thrombosis events. With the EGFR monoclonal antibodies, these are traditionally associated with skin rash, diarrhea, some infusion reactions, and hypersensitivity reactions that can be frequently severe in some patient populations.