Key messages
• Taking EGFR TKIs after lung cancer surgery may help people stay cancer-free for longer than chemotherapy or no further treatment.
• EGFR TKIs probably help people live longer compared to no treatment, but may make little to no difference in survival compared to chemotherapy.
• EGFR TKIs have fewer serious side effects than chemotherapy, but they may cause more mild-to-moderate side effects.
• More research is needed to understand if continuing EGFR TKIs for longer improves survival.
What is lung cancer, and how is it treated?
Lung cancer is one of the most common cancers worldwide. Non-small-cell lung cancer (NSCLC) is the most frequent type. Some NSCLC tumours have mutations in a gene called EGFR.
Surgery is the main treatment for early-stage NSCLC, but cancer can return after surgery. To reduce this risk, people may receive additional treatment (adjuvant therapy), such as chemotherapy or EGFR TKIs.
We wanted to find out whether taking EGFR TKIs after surgery helps people live longer and prevents the cancer from returning. We also looked at side effects.
What did we do?
We searched for studies comparing EGFR TKIs with a placebo (an inactive or 'dummy' medicine)/best supportive care or chemotherapy in people with stage I to III NSCLC who had undergone surgery. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 15 studies with 2603 participants. Nine studies were completed, and six are ongoing. The included studies compared:
• EGFR TKIs versus placebo or best supportive care (five studies);
• EGFR TKIs versus chemotherapy (four studies).
Main results
EGFR TKIs versus placebo/best supportive care
• Overall survival: EGFR TKIs probably help people live longer.
• Cancer returning: EGFR TKIs may help people stay cancer-free for longer, but the evidence is very uncertain.
• Serious side effects: these may be similar between the two groups, but the evidence is very uncertain.
• Mild-to-moderate side effects: EGFR TKIs may cause more mild-to-moderate side effects, but the evidence is very uncertain.
• People taking EGFR TKIs generally didn’t feel worse than those not taking EGFR TKIs.
• Cancer returning after stopping treatment: the risk of cancer coming back may be similar between groups.
EGFR TKIs versus chemotherapy
• Overall survival: there is probably little to no difference in survival between EGFR TKIs and chemotherapy.
• Cancer returning: EGFR TKIs may help people stay cancer-free longer than chemotherapy.
• Serious side effects: fewer serious side effects may occur with EGFR TKIs than with chemotherapy.
• Mild-to-moderate side effects: EGFR TKIs may cause more mild-to-moderate side effects.
• Overall quality of life is probably about the same in the two groups.
• Cancer returning after stopping treatment: there is no clear difference between the groups.
What are the limitations of the evidence?
Our confidence in the evidence ranged from very low to moderate, for several reasons. People in some studies were aware of which treatment they were getting, which could affect the results. Not all the studies provided data about everything that we were interested in, including overall survival of participants. The studies reported cancer relapse in different ways.
More research is needed to see if longer treatment with EGFR TKIs improves survival.
How current is this evidence?
The evidence is current to 9 December 2024.
อ่านบทคัดย่อฉบับเต็ม
Postoperative adjuvant epidermal growth factor receptor (EGFR) inhibitor osimertinib is the standard care for stage IB-IIIB non-small-cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R mutation, following complete tumour resection, with or without prior platinum-based adjuvant chemotherapy. However, the role of EGFR tyrosine kinase inhibitors (TKIs) in this setting is debated, particularly concerning long-term curative effects versus recurrence delay. Uncertainties persist around treatment duration, harms, and effectiveness across disease stages, prior chemotherapy, or EGFR-sensitising mutation types.
วัตถุประสงค์
To assess the effectiveness and harms of adjuvant EGFR tyrosine kinase inhibitors (TKIs) in people with resected stage I to III non-small-cell lung cancer (NSCLC) harbouring an activating EGFR mutation.
วิธีการสืบค้น
We searched major databases (CENTRAL, MEDLINE, Embase) to 9 December 2024, along with conference proceedings (from 2019) and clinical trial registries.
เกณฑ์การคัดเลือก
We included randomised controlled trials (RCTs) reporting benefits or harms of adjuvant EGFR TKIs in adults with resected stage I-III NSCLC. Trials compared EGFR TKIs with platinum-based chemotherapy, placebo/best supportive care (BSC), or second- and/or third-generation EGFR TKIs versus first- and/or second-generation EGFR TKIs. Participants were adults with histologically confirmed stage I-III NSCLC.
การรวบรวมและวิเคราะห์ข้อมูล
Three review authors independently assessed search results, resolving disagreements with a fourth author. Primary outcomes were overall survival (OS), disease-free survival (DFS), and adverse events (AEs); secondary outcomes included health-related quality of life (HRQoL), relapse risk during drug-off time, and brain relapse risk. We conducted meta-analyses using random-effects and fixed-effect models with hazard ratios (HRs) or risk ratios (RRs) and 95% confidence intervals (CIs). We assessed heterogeneity with the I² statistic.
ผลการวิจัย
We included nine RCTs involving 2603 participants, and identified six ongoing trials. Five trials compared EGFR TKIs with placebo/BSC, and four compared them with chemotherapy. We found no trials comparing second- and/or third-generation to first- and/or second-generation EGFR TKIs. Six trials had low selection bias risk; most had unclear or high risk for detection or performance bias; and four were high risk for other biases. The certainty of the evidence (GRADE) ranged from moderate to very low, depending on the outcome.
First-, second-, and/or third-generation EGFR TKIs versus placebo/BSC
EGFR TKIs probably improve overall survival compared to placebo/BSC (HR 0.54, 95% CI 0.40 to 0.73; 3 studies, 864 participants; moderate-certainty evidence).
TKIs may improve disease-free survival compared to placebo/BSC, but the evidence is very uncertain (HR 0.34, 95% CI 0.28 to 0.41; 5 studies, 1153 participants).
We are uncertain if there is a difference between groups in serious adverse events (≥ grade 3) as the evidence is very uncertain, with wide confidence intervals spanning both potential harm and no effect (RR 2.52, 95% CI 0.44 to 14.37; 4 studies, 1134 participants).
Mild-to-moderate adverse events (grades 1 and 2) may be more frequent with EGFR TKIs compared to placebo/BSC, but the evidence is very uncertain (RR 1.57, 95% CI 1.08 to 2.29; 4 studies, 1134 participants).
One study assessed HRQoL, with no clinically meaningful decline compared to placebo/BSC (592 participants; moderate-certainty evidence).
First-, second-, and/or third-generation EGFR TKIs versus chemotherapy
Overall survival was similar between EGFR TKIs and chemotherapy (HR 0.79, 95% CI 0.52 to 1.18; 4 studies, 878 participants; moderate-certainty evidence).
TKIs may have improved disease-free survival compared to chemotherapy (HR 0.54, 95% CI 0.35 to 0.83; 4 studies, 878 participants; low-certainty evidence).
TKIs may have reduced serious adverse events (≥ grade 3) compared to chemotherapy (RR 0.31, 95% CI 0.18 to 0.52; 4 studies, 811 participants; low-certainty evidence).
TKIs may have increased mild-to-moderate adverse events (grades 1 and 2) (RR 2.13, 95% CI 1.20 to 3.78; 4 studies, 811 participants; low-certainty evidence).
Two studies assessed HRQoL, showing no clear difference compared to chemotherapy, as assessed with the Functional Assessment of Cancer Therapy-Lung instrument (2 studies, 399 participants) and the Lung Cancer Symptom Scale (2 studies, 400 participants), both with moderate-certainty evidence.
ข้อสรุปของผู้วิจัย
Adjuvant EGFR TKIs may improve disease-free survival compared to both placebo/BSC and chemotherapy. There is moderate-certainty evidence that EGFR TKIs increase overall survival compared to placebo/BSC. However, they likely result in little to no difference in overall survival compared to chemotherapy. We could not rule out a potential survival benefit of adjuvant chemotherapy in people with EGFR-mutant NSCLC. Approximately 50% of participants experienced relapse or death within one year of stopping TKI therapy, indicating that the disease-free survival benefit may wane after withdrawal. This raises the possibility that prolonged adjuvant TKI therapy could be associated with improved long-term outcomes, although further research is needed to clarify this.
