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Researchers are studying the effectiveness of osimertinib in treating some types of lung cancer. Yulia Naumenko/Getty Images
  • Adjuvant chemotherapy is prescribed to people with non-small cell lung cancer (NSCLC) after the surgical removal of the tumor to prevent disease recurrence, but these patients are still at a high risk of relapse and death.
  • NSCLC patients with a mutation in the epidermal growth factor receptor (EGFR) gene are at a greater risk of cancer recurrence after surgical removal of the tumor than those with the wild-type EGFR gene.
  • Although drugs that inhibit EGFR activity are effective in preventing recurrence in NSCLC patients after tumor resection, these benefits are often short-lived.
  • A phase 3 randomized clinical trial now shows that the use of osimertinib, a next-generation drug that inhibits EGFR, as adjuvant chemotherapy after tumor removal in NSCLC patients with EGFR mutations produced a greater increase in both overall and disease-free survival than placebo.

Adjuvant chemotherapy is less effective in people with non-small cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR) gene than those with the wild-type version of the gene.

Researchers now report that the use of EGFR inhibitors can improve survival in these patients, but the emergence of resistance to these targeted treatments poses a challenge.

A recent phase 3 randomized clinical trial published in the New England Journal of Medicine shows that adjuvant treatment with osimertinib, a next-generation EGFR inhibitor, improved 5-year overall survival in early-stage NSCLC with an EGFR mutation after complete surgical removal of the tumor.

Their findings were presented at the 2023 annual meeting of the American Society of Clinical Oncology (ASCO).

“The study demonstrated that adjuvant osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), notably improves overall survival and reduces the risk of disease recurrence or death in patients with completely resected, early-stage, EGFR-mutated NSCLC,” said Dr. Wael Harb, a hematologist and medical oncologist at MemorialCare Cancer Institute at Orange Coast Medical Center in California and vice president of medical affairs at Syneos Health.

“This is particularly important as previous adjuvant therapies, including chemotherapy and first- or second-generation EGFR-TKIs, have not shown such benefits,” Harb, who was not part of the study, told Medical News Today.

“These results suggest that osimertinib is a new standard of care for resected, EGFR-mutated NSCLC, which can prevent or delay cancer from coming back or spreading to other parts of the body and potentially cure more patients with this type of lung cancer,” he added.

Non-small cell lung cancer is one of the two primary types of lung cancer that accounts for 80% to 85% of lung cancer cases.

Based on the spread and size of the tumor, cancers can be assigned to stages 1 to 4, with a higher stage referring to greater progression of the disease.

Stage 1 and 2 cancers describe tumors that are either restricted to the tissue of origin or have spread to the adjacent tissue. Unlike stage 3 or 4 cancers, these tumors have not spread to nearby lymph nodes or metastasized to other parts of the body. As a result, stage 1 and 2 tumors can generally be completely resected or surgically removed.

In stage 3 of non-small cell lung cancer, the tumor has spread to a lymph node. However, in early-stage non-small cell lung cancers, such as stage 3A and 3B, the tumor can still be completely resected in some cases.

Oncologists often recommend chemotherapy or radiotherapy to reduce the risk of the recurrence of cancer after the surgical removal of the tumor. This course of treatment is prescribed to prevent the recurrence of cancer is known as adjuvant therapy.

However, past data has suggested that adjuvant chemotherapy in people with early-stage or locally advanced NSCLC confers limited benefits. Adjuvant chemotherapy is particularly less effective in individuals showing a mutation in the gene for the epidermal growth factor receptor (EGFR). EGFR is a protein that spans the membrane of human cells and activates other proteins upon its stimulation by the epidermal growth factor.

Through the activation of specific downstream pathways, the EGFR protein controls cell division and survival. Certain mutations in the EGFR protein, such as those observed in NSCLC, can enhance cell proliferation and cause drug resistance.

Considerable progress has been made in the development of drugs such as gefitinib and erlotinib that inhibit the part of the EGFR protein that activates downstream pathways. However, patients often develop resistance to these drugs within 10 to 14 months after treatment onset.

Osimertinib is a new-generation EGFR protein inhibitor that has shown efficacy in people with locally advanced NSCLC as well as in those with NSCLC whose tumor has metastasized to the central nervous system.

The Food and Drug Administration has approved osimertinib for the treatment of NSCLC based on data from the phase 3 ADAURA clinical trial. At the time of the approval, there was data showing that osimertinib enhances disease-free survival, which is the length of time from diagnosis or onset of treatment to the recurrence of cancer or death.

The gold standard for assessing the efficacy of cancer treatments in randomized clinical trials is overall survival. Overall survival refers to the fraction of surviving patients after a set period of time, generally 5 years, from treatment onset.

However, the impact of osimertinib on overall survival has not been examined.

As a continuation of the phase 3 ADAURA randomized clinical trial, the present study examined the benefits of osimertinib as adjuvant chemotherapy in improving overall survival.

This randomized controlled trial consisted of 682 adults with stage 1B, 2, or 3A lung cancer whose tumors had been completely removed by surgery. All patients included in the study had a specific type of mutation in the EGFR gene.

The participants were randomized to receive either osimertinib or a placebo as adjuvant therapy for 3 years. The treatment duration was shorter in case of disease recurrence or discontinuation by participants. The patients were regularly monitored over a duration of about 5 years to estimate overall survival.

The researchers reported that adjuvant therapy with osimertinib conferred greater overall survival benefits in patients with stage 2 to 3A lung cancer. Specifically, the 5-year survival rate in people receiving osimertinib was 85%, whereas the placebo group had an overall survival rate of 73%.

The 5-year overall survival in all patients, including those with stage 1B, 2, and 3 NSCLC, receiving osimertinib was 88%. In contrast, the participants that were administered the placebo had a 5-year survival rate of 78%.

In their previous publication, the researchers reported that people receiving osimertinib showed lower rates of disease recurrence than the placebo group. Furthermore, in the current study, the researchers found that 22% of people in the osimertinib group required additional treatment due to recurrence, compared with 54% in the placebo group.

Although these results are promising, Harb cautioned that the study had a few limitations. He noted that the clinical trial only included patients with specific types of EGFR mutations.

“The trial did not include patients with other types of EGFR mutations, such as exon 20 insertions, which may respond differently to Osimertinib,” Harb said. “It also did not compare osimertinib with other EGFR-TKIs, such as gefitinib or erlotinib, which are also utilized as adjuvant therapies in some settings.”

“The long-term safety and efficacy of osimertinib remain unknown as the median duration of treatment was only 22 months. These factors should be taken into account when interpreting the study’s findings,” he added.