Antibody-drug combo sparks lung tumor shrinkage in most NSCLC patients with HER2 mutation

Reuters Health - 20/09/2021 - A phase 2 study of a treatment for patients with a rare type of lung cancer -- most of whom were young and had never smoked -- has shown that the targeted drug can significantly extend their lives when other therapies have failed.

The results apply to people with nonsquamous non-small cell lung cancer whose tumors carry a HER2 mutation.

In all 91 patients in the study, treatment with trastuzumab deruxtecan, a HER2 antibody-drug conjugate, produced a response rate of 55% and a median duration of response of 9.3 months.

"For typical second-line chemotherapy, the duration of response is usually on the order of two to four months. The response rate is typically 10% to 20%," said lead author Dr. Bob Li of the Memorial Sloan Kettering Cancer Center in New York

"This is a very meaningful advancement in therapeutics for these patients," he told Reuters Health in a telephone interview. "I have patients responding a year or two into the treatment and doing very well. For these patients, this is a real lifesaver."

Median progression-free survival was 8.2 months and median overall survival was 17.8 months. The study did not have a control group.

The results were released at the European Society for Medical Oncology Congress and online by the New England Journal of Medicine.

The drug is sold under the brand name Enhertu by Daiichi Sankyo and AstraZeneca, which paid for the study. Daiichi Sankyo designed and oversaw the test.

Of all lung cancers, about 87% are non-small cell tumors. Of those, about three quarters are nonsquamous. Among that group, only about 3% are HER2 mutant cases, said Dr. Li.

"It's rare in terms of percentages. But you're still talking about 5,000 patients who are diagnosed with this each year. They tend to be young female never-smokers who you would never suspect would get lung cancer. Up to 50% develop brain metastases,," Dr. Li said. "The youngest patient was 29 years old and never smoked. These patients need better treatment."

The DESTINY-Lung01 study was done at 21 sites in North America, Japan and Europe. The patients had already received as many as seven types of therapies, although the median was two. Nearly all had received a platinum-based regimen.

The patients were treated every three weeks. The findings were based on a median duration of treatment of 6.9 months. Median follow-up was 13 months.

Ultimately, 92% showed at least some reduction in tumor size.

"Responses were also observed in patients who had received a variety of previous cancer treatments, including immunotherapy, and in patients who had central nervous system metastasis at baseline," the researchers said.

On the negative side, "49% of patients had drug-related grade 3 or higher adverse events, which were generally hematologic or gastrointestinal in nature," they said. "However, 26% of patients had adjudicated drug-related interstitial lung disease; 75% of these events were of grade 1 or 2, but 4 patients had grade 3 pulmonary toxic effects, and 2 patients died. However, the development of this toxic effect was not predictable; as a consequence, patients must be carefully monitored."

The most common side effects were nausea (seen in 73% of patients), fatigue (53%), alopecia (46%) and vomiting (40%). The most common grade 3 problems were neutropenia (15%), anemia (10%) and nausea (9%). Grade 4 neutropenia was seen in 3% of the subjects.

Other HER2 antibody conjugates are under development but "this is the first HER2 positive agent to get an FDA breakthrough therapy designation for lung cancer," said Dr. Li. "It has a good shot for getting FDA accelerated approval."

A phase 3 study of the drug is not yet underway, in part because it can be so hard to find patients.

Dr. Li speculated that the success rate would be even higher if the treatment could be given earlier.

"Currently, the data are only in a refractory setting. I do hope this treatment can do better in the first-line setting when the tumors are not as chemoresistant and are probably earlier to treat," he said. "I would personally like to see this treatment in a first line setting. It would require an international effort to test because it's a rare mutation."

SOURCE: https://bit.ly/3kjkQuE The New England Journal of Medicine, online September 18, 2021.

By Gene Emery



Posted on 20 September 202128 September 2021