A Failed Drug is Showing Unprecedented Success Against a Previously Impervious Mutation

During her years of struggle with lung cancer, Deanna Brinkman has avidly researched her specific type of disease. So when an immunotherapy drug failed to stop it in late 2016 she understood the implications all too well.

“I called my oncologist,” she recalls. “We have a superb relationship. He knew that I knew what I was talking about, and I knew and understood what he said: There’s nothing for this.”

What remained at that point were clinical trials, preferably one with a drug that targeted the genetic mutation that drove her disease – an insertion of exon 20 on the epidermal growth factor receptor gene (EGFR).

That talk with her oncologist in Richmond, Virginia, where Brinkman lives, set off a chain of events that landed her at MD Anderson in January 2017. Here, a team led by John Heymach, M.D., Ph.D., chair of Thoracic/Head and Neck Clinical Oncology, had resurrected a failed EGFR drug with lab research indicating that it might be uniquely suited to attacking exon 20 non-small cell lung cancer.

When a clinical trial of the drug, called poziotinib, opened in March, Brinkman became one of the first to enroll.

“If you could see my scans, it’s absolutely astounding,” Brinkman says. “On my first scan after poziotinib treatment, you could see there were bites taken out of the diseased tissue. It was the most incredible thing, an amazing image. Nothing is growing now.”

By the end of 2017, her disease was still responding to treatment.

“We’ve had no effective drugs for these patients, who historically have progression-free survival of about two months, and a response rate of around 10 percent for other therapies,” Heymach says.

By October, eight of 11 patients – 73% – in the clinical trial had their tumors shrink by at least 30%, with some tumors shrinking by up to 50%.

“These highly encouraging early results are unprecedented for exon 20 insertion non-small cell lung cancer,” Heymach notes. By the end of the year, 30 patients from around the world had enrolled in the trial, which will take up to 50.
This new option for a previously untreatable patient group comes courtesy of MD Anderson’s Moon Shots Program™, launched in 2012 to accelerate the development of new approaches to cancer.

Heymach is co-leader of the Lung Cancer Moon Shot™, which has funded the effort from the beginning, first identifying poziotinib through its program to screen and repurpose existing drugs, then supporting the preclinical research to confirm the drug’s potential, and finally the clinical trial.

About 2% of non-small cell lung cancer patients in the United States (about 3,500 annually) have an EGFR exon 20 insertion, although the incidence of exon 20 insertion disease is much higher in Asia. Other tyrosine kinase inhibitors against EGFR have been approved by the Food and Drug Administration, but none have proved effective against exon 20.
Poziotinib had been tried and abandoned as a general EGFR inhibitor when Heymach’s team turned up evidence of its potential against exon 20.

Postdoctoral fellow Jacqulyne Robichaux, Ph.D., tapped the moon shot’s Genomic Marker-Guided Therapy Initiative (GEMINI), which includes tumor samples and detailed clinical information on more than 4,000 lung cancer patients treated at MD Anderson since 2012. She developed EGFR exon 20 cell lines as well as mouse models with cancer derived from patient tumors, and tested a variety of EGFR inhibitors against them under the Lung Moon Shot’s drug repurposing program.

“Poziotinib is the only drug we’ve ever found that was dramatically better for exon 20 than it was for the classical EGFR mutation that everyone tests,” Heymach says.

Working with Shuxing Zhang, PharmD, Ph.D., associate professor of Experimental Therapeutics, Robichaux and colleagues identified structural aspects of the drug that explain that divergent impact.

The team took its findings to Spectrum Pharmaceuticals, a Nevada-based biotechnology company that initially developed poziotinib, leading to rapid development of the Phase II clinical trial.

Heymach notes there is still much to learn about the drug and its long-term impact for patients.

Brinkman has coped with weight loss and a debilitating condition caused by the drug called paronychia – a painful inflammation of the tissue around fingernails and toenails.

But she focuses on what she considers the important things: being mentally alert and physically able, having wonderful friendships and being happily married.

“I’m interested, curious, always learning something new, including languages. I’m 76 now, and I’m going to learn Latin.”

Source: MD Anderson Cancer Center

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