Lung cancer: Novel drug shows promise in early-stage clinical trials

• Fusion of the ROS-1 gene with other genes accounts for about 0.9–2.6% of non-small cell lung cancers, the most common form of lung cancer.
• FDA-approved drugs, such as crizotinib and entrectinib, that target the ROS-1 fusion protein show antitumor activity, but the emergence of resistance to these drugs is common.
• Repotrectinib is a new-generation ROS-1 inhibitor designed to overcome common mutations that mediate resistance to drugs targeting the ROS-1 protein.
• A new phase I/II clinical trial shows that repotrectinib had antitumor activity in participants with ROS-1-positive advanced non-small cell lung cancer and was generally well-tolerated.

Lung cancer is the second mostTrusted Source commonly diagnosed cancer worldwide and the leading cause of cancer deaths. About 80–85%Trusted Source of all lung cancer cases belong to a category known as non-small cell lung cancer (NSCLC).

Alterations in the ROS-1 gene, a receptor tyrosine kinaseTrusted Source often involved in genetic mutations in various forms of cancer,are present in a subset of NSCLC cases.

Drugs that inhibit the tyrosine kinase encoded by the ROS-1 protein are effective, but cancer cells tend to acquire resistance to these drugs.

Recently, results from the phase I/II TRIDENT-1 clinical trial suggest that a novel tyrosine kinase inhibitor (TKI), repotrectinib, shows antitumor activity in ROS-1-positive advanced non-small cell lung cancer patients, including those previously treated with other ROS-1 inhibitors. The findings have not yet been peer-reviewed or published.

Study author Byoung Chul Cho, Ph.D., a professor of oncology at the Yonsei Cancer Center in South Korea, told Medical News Today:

“In the TRIDENT-1 trial, repotrectinib demonstrated clinically meaningful benefit in TKI naive and TKI resistant advanced ROS-1 NSCLC. Trial results provide a strong rationale to use repotrectinib in TKI naive and TKI resistant ROS-1 NSCLC.”

Prof. Cho presented the results of the clinical trial in late October at the 34th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium on Molecular Targets and Cancer Research in Barcelona, Spain.

ROS-1 genes and tyrosine kinase inhibitors in lung cancer

Around 0.9-2.6%Trusted Source of non-small cell lung cancers involve an alteration of the ROS-1 gene.

The ROS-1Trusted Source gene encodes an enzyme that belongs to the receptor tyrosine kinases family.

In healthy cells, the ROS-1 receptor tyrosine kinase is involved in several pathways associated with the growth, proliferation, and survival of cells.

Under certain circumstances, such as exposure to environmental factors that cause DNA damage, the part of the chromosome containing the ROS-1 gene can break off and fuse with another gene to form a fusion gene. The fusion of these genes can lead to the overexpression or upregulation of the activity of the hybrid ROS-1 enzyme, potentially resulting in the development of cancer.

Tyrosine kinase inhibitors (TKIs) such as crizotinib, ceritinib, and entrectinib that target the ROS-1 fusion protein have been effective in individuals with non-small cell lung cancers.

But cancer cells often acquire resistance to these therapies, thus highlighting the need for new treatments targeting the ROS-1 tyrosine kinase.

Repotrectinib is a new-generation drug that inhibits ROS-1 and other receptor tyrosine kinases, and results from in vitroassays suggest that repotrectinib is at least 90-fold more potent than crizotinib and entrectinib.

Repotrectinib has been designed to retain antitumor activity against cancer cells with mutations that confer resistance to older TKIs.

Efficacy of repotrectinib in treating lung cancer

The TRIDENT-1 clinical trial examined the efficacy of repotrectinib in people with ROS-1-fusion-positive advanced NSCLC.

The researchers divided 444 subjects receiving repotrectinib into four groups based on previous treatment with one or two other TKIs or platinum-based chemotherapy drugs, the current standard of care for non-small cell lung cancer patients.

The four groups included people with no prior exposure to TKIs, those previously treated with a different TKI, those treated with two different types of TKIs, and people who were treated with a TKI and a platinum-based drug in the past.

Previous treatment with TKIs or chemotherapy suggests the emergence of resistance to these drugs.

As a primary measure of the efficacy of repotrectinib, the researchers evaluated the objective response rateTrusted Source, which is the proportion of individuals who show at least a 30% overall decline in the size of the tumors. The objective response rate in people receiving repotrectinib who were not previously treated with a TKI was 79%.

By contrast, repotrectinib achieved an objective response rate of 38% and 28% in participants who were previously treated with one or two other TKIs, respectively, but had not received any other form of chemotherapy.

In participants who were previously treated with a different tyrosine kinase inhibitor and a platinum-based drug, repotrectinib had an objective response rate of 42%.

Marjorie Zettler, Ph.D., MPH, executive director of clinical science at Regor Pharmaceuticals, Inc., in Boston, MA, not involved in the study, told MNT:

“The data demonstrate objective responses were observed in all four cohorts, suggesting that even those who have progressed on prior ROS-1 TKI treatment can benefit from repotrectinib.”

 Studying ROS-1 mutations in non-small cell lung cancer

A specific mutation in the ROS-1 gene, G2032R, is known to mediate resistance to crizotinib and ceritinib.

The researchers found that repotrectinib had an objective response rate of 59% in participants with the ROS-1 G2032R mutation who were pretreated with one or more TKIs.

Moreover, among individuals with NSCLC whose tumors had metastasized to the brain and had not received prior TKI treatment, the objective response rate was 88%.

The researchers also measured the duration of response to repotrectinib, which is the length of time during which the drug prevents the metastasis or the growth of the tumor.

Among the subjects who had not received prior TKI treatment, 86% had a duration of response of at least 12 months.

By comparison, 30% of individuals in the group who were previously treated with two other TKIs had a duration of response of 12 months or more.

Clinical implications for lung cancer treatment

Researchers noted that common side effects of the TKI treatment included:

• dizziness
• changes in taste perception
• anemia
• fatigue
• nausea
• dyspnea

In addition, repotrectinib treatment had to be discontinued in 10% of participants, and its dose had to be reduced in 34% of participants.

The findings suggest that repotrectinib may have promise in the treatment of ROS-1-positive non-small cell lung cancer patients, especially those who had not received prior tyrosine kinase inhibitor treatment.

“These results suggest that repotrectinib is having an effect on tumors in patients with this type of lung cancer, including on tumors that have spread to the brain,” Prof. Cho said.

“There are signs that the drug could help both patients who have not been treated with a ROS TKI and those who have received previous treatment, suggesting that repotrectinib could have effects even when cancers become resistant to other treatments. I believe that further testing and development of this drug could help more patients with ROS1-positive NSCLC.”

Dr. Upal Basu Roy, Ph.D., MPH, executive director of research at the LUNGevity Foundation, told MNT the results from the TRIDENT-1 trial demonstrated that repotrectinib is “highly effective in controlling ROS1-advanced NSCLC that is either TKI-naive or tumors that have been treated with one TKI,” adding that it was well-tolerated.

“This is great news for patients diagnosed with NSCLC. The new data from the TRIDENT trial establish repotrectinib as a highly effective treatment option in both first-line and TKI-pretreated settings.”

Source - Medical News Today