Overcoming Drug Resistance: The EGFR Enigma, Part 2

Part 2: Overcoming resistance to anti-EGFR antibody therapies

In an earlier post, we looked at the challenges and potential treatment strategies for lung cancer patients whose epidermal growth factor receptor (EGFR)-mutant tumors develop drug resistance following treatment with EGFR tyrosine kinase inhibitors (TKIs). EGFR TKIs are small molecules that bind to the intracellular (cytoplasmic) domain of the EGFR to inhibit downstream signaling. In this post, let’s look at the challenge we face with anti-EGFR monoclonal antibody therapies and new strategies researchers have developed to overcome resistance to these therapies. Unlike EGFR TKIs, anti-EGFR antibodies bind to the extracellular domain of the EGFR to block ligand-induced EGFR tyrosine kinase activation.

Two anti-EGFR antibodies, cetuximab (Erbitux) and panitumumab (Vectibix), are currently being used for the treatment of certain cancers. Cetuximab is approved by the U.S. Food and Drug Administration for the treatment of metastatic colorectal cancer and squamous cell cancer of the head and neck, and panitumumab is approved for the treatment of metastatic colorectal cancer. Although patients with EGFR-mutated tumors benefit from these treatments initially, their tumors eventually resist such targeted therapies through evolution and heterogeneity.

A couple of studies discussed below have explored the feasibility of using first-in-class EGFR antibody therapies that are rationally designed to circumvent resistance to cetuximab and panitumumab in patients with solid cancers.

A Mixture Approach

Josep Tabernero, MD, PhD, senior author of the study in Cancer Discovery.

Josep Tabernero, MD, PhD, senior author of the study in Cancer Discovery.

In a study published in Cancer Discovery, investigators took an antibody mixture-approach to tackle resistance to anti-EGFR antibody therapies in colorectal cancer patients.

The researchers studied the activity of a first-in-class anti-EGFR antibody therapy called Sym004. This treatment is a 1:1 mixture of two synergistic EGFR antibodies, which bind to different regions of the extracellular portion of EGFR but are administered in the same infusion bag. Unlike cetuximab and panitumumab, the double targeting of the receptor by Sym004 creates a heavy macro-complex that causes superior EGFR internalization and degradation, explained senior author of the study Josep Tabernero, MD, PhD, head of the medical oncology department at Vall d’Hebron University Hospital and director of the Vall d’Hebron Institute of Oncology in Barcelona.

In a phase I clinical trial, Tabernero and colleagues tested Sym004 in patients with advanced epithelial tumors including metastatic colorectal cancer harboring wild-type KRAS and with acquired resistance to prior EGFR therapies, and reported that overall, 44 percent of the patients with metastatic colorectal cancers had some degree of tumor shrinkage during treatment with Sym004.

“This study represents one of the first examples of promising translation from preclinical findings to drug development and clinical activity against anti-EGFR antibody-resistant colorectal cancer,” Tabernero said in a press release. “The significant antitumor activity of Sym004 in patients whose tumors have become resistant to anti-EGFR therapies suggests that some colorectal cancers that progress after treatment with cetuximab or panitumumab remain dependent on EGFR signaling.”

Sym004 is currently being tested in a phase II trial in patients with metastatic colorectal cancer.

Dual Targeting Approach

In a study published in Clinical Cancer Research, investigators tested yet another approach to circumvent EGFR resistance in patients with solid tumors. This approach involved targeting other members of the EGFR family besides EGFR1 (HER1), which is the target of most anti-EGFR antibody therapies.

José Baselga, MD, PhD, senior author of the study in Clinical Cancer Research.

José Baselga, MD, PhD, senior author of the study in Clinical Cancer Research.

“For about 20 years, we have been working on the hypothesis of targeting EGFR in epithelial cancers as a fruitful approach based on our understanding that dysregulated EGFR plays an important role in tumorigenesis. What we have learned since then is that there are other players in the EGFR family, such as HER3, which are functionally similar to EGFR and, therefore, have a significant role in tumor promotion,” said senior author of the study José Baselga, MD, PhD, physician-in-chief and chief medical officer at the Memorial Sloan Kettering Cancer Center in New York, in a press release.

“We felt it is important that we hit not just EGFR alone, but also target HER3, with the goal of achieving more durable responses,” said Baselga, who is also president of the AACR.

Baselga and colleagues tested the feasibility of using MEHD7945A, an anti-HER3/EGFR humanized IgG1 antibody, in patients with advanced epithelial tumors. MEHD7945A has dual binding specificity to target both HER3 and EGFR. Each binding arm of the therapeutic attaches to unique epitopes of the receptors, thereby inhibiting the activity of multiple cancer signaling pathways.

In a phase I, multicenter, open-label study, Baselga and colleagues enrolled patients with incurable, locally advanced or metastatic epithelial cancer who had received prior systemic therapies and/or anti-EGFR therapies. The investigators reported that MEHD7945A was well tolerated as a single agent, with confirmed partial responses in patients with squamous cell cancers of the head and neck who had refractory disease, “which clearly suggests that this dual-targeting approach is a good strategy moving forward,” according to Baselga.

“We have been using antibodies to treat cancers for a while now, but recent advancements in technology are allowing us to use antibodies in a way we have not done in the past,” Baselga noted.

MEHD7945A is being tested in a phase II trial in patients with recurrent/metastatic squamous cell carcinoma of the head and neck.

Clearly, understanding the complex mechanisms of drug resistance to targeted therapies and exploring combinations of therapies are vital to turning the short-lived responses to precision medicine in to durable, long-lasting ones.