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Lung Cancer

Oncogene Alterations Affect the Response to Targeted Therapies in Patients with Non–Small-Cell Lung Cancer and ALK Rearrangements

November 2020 – Lung Cancer
Chase Doyle

Increasing numbers of therapies for lung cancer are being developed specifically for patients with certain types of biomarkers or genetic changes associated with lung cancer, focusing on genetic mutations (changes) or alterations that affect the tumor’s response to treatment. A common biomarker linked to lung cancer is the mutation in the ALK gene.

Now researchers have found that specific alterations in oncogenes (genes linked to cancer), such as the ALK gene, may influence the treatment of patients with non–small-cell lung cancer (NSCLC), the most common type of lung cancer, that is associated with the ALK gene mutation.

D. Ross Camidge, MD, PhD

This information comes from the phase 3 ALTA-1L clinical trial, which was presented at the 2020 ASCO annual meeting by D. Ross Camidge, MD, PhD, Director, Thoracic Oncology Clinical Program, University of Colorado, in Aurora, Colorado.

Analysis of this study showed that the ALK inhibitor Alunbrig (brigatinib)—a newer ALK inhibitor with broad benefits in the treatment of lung cancer with ALK mutation or rearrangements—had superior results compared with Xalkori (crizotinib)—an older type of ALK inhibitor—as the first-line treatment in all patients with NSCLC, regardless of the type of gene alterations.

However, unlike other patients with NSCLC and ALK mutation in this study, the patients who had the oncogene alteration EML4-ALK variant 3 had worse results than the others and poor survival, regardless of which of the 2 therapies they received.

This means that some patients with NSCLC and ALK rearrangements have specific alterations in the ALK gene that inhibit the tumor from responding to current targeted therapies that are effective for other patients with NSCLC and the ALK mutation.

In addition, in patients with NSCLC and TP53 mutations, the results showed a strong trend toward less time without disease progression for those patients compared with other patients in the study.

These findings suggest that some patients with NSCLC and ALK mutations or rearrangements have specific oncogene alterations that require new treatments that will target these alterations specifically. No treatments are currently available for these types of genetic alterations.

“These findings won’t change your immediate treatment decisions, but they may help define areas of greatest unmet need. There appears to be a higher risk group of patients with ALK-positive disease that may need specific clinical trials in the future,” Dr. Camidge said.

NSCLC & EML4-ALK Variants

The phase 3 ALTA-1L study compared the effectiveness and safety of Alunbrig versus Xalkori in patients with advanced NSCLC and ALK mutations who have not received a targeted therapy with an ALK inhibitor before.

The results showed that Alunbrig was more effective than Xalkori and had acceptable side effects, said Dr. Camidge, making it a promising first-line treatment option for patients with ALK-positive NSCLC.

However, in a subgroup of patients, neither of the 2 targeted therapies was successful. Although patients who received Alunbrig had a better overall response and improved time without disease progression compared with patients who received Xalkori, the subgroup of patients who had the EML4-ALK variant 3 alteration had less time without disease progression than patients with EML4-ALK variants 1 and 2, regardless of the treatment used.

“This variant [EML4-ALK variant 3] may not change the response rate, but we suspect that it changes the ability to control the disease long-term,” said Dr. Camidge. “Recent data suggest that the variant may influence resistance mutations that a patient acquires, which is probably why the variant is impacting progression-free response more than response rate.”

TP53 Mutation with ALK Rearrangements

The TP53 mutation is common in patients with NSCLC and ALK rearrangements.

Among patients with NSCLC and ALK fusion, those who also had the TP53 mutation had lower overall response to therapy and less time without disease progression compared with patients without the TP53 mutation.

Although Alunbrig showed improved overall response to therapy and time without disease progression, regardless of TP53 status, patients with TP53 mutations had a trend toward reduced time without disease progression, regardless of the treatment used.

These trends, Dr. Camidge said, “are very intriguing and suggest that TP53 could be an additional independent poor prognostic biomarker. This trend persisted despite multivariate analyses and is worthy of further investigation in a larger sample size.”

Key Points

  • Current targeted therapies for lung cancer are being developed for patients with specific types of biomarkers or genetic changes to increase response to treatment
  • The ALK gene mutation is a common biomarker in lung cancer that is being targeted by several new drugs
  • Alunbrig is a newer drug targeting ALK mutations and rearrangements in patients with lung cancer
  • This study compared the benefit of Alunbrig and the older ALK inhibitor Xalkori in patients with advanced NSCLC and ALK mutations
  • The results showed a clear benefit for treatment with Alunbrig versus Xalkori in patients with advanced NSCLC and ALK mutations
  • However, in 2 subgroups of patients, including patients with the EML4-ALK variant 3 alteration and patients with a TP53 mutation and ALK rearrangements, neither therapy was successful
  • These results indicate that certain alterations in the ALK gene require new types of targeted therapies

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Last modified: November 20, 2020

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