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Maintenance therapy after first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy)
Source: Non-Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version, National Cancer Institute.
Source updated: May 15, 2025 · Captured 2026-09-09.
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One extensively investigated treatment strategy in NSCLC is maintenance therapy after initial response to chemotherapy. Options for maintenance therapy that have been investigated include:
Continuing the initial combination chemotherapy regimen.
Continuing only single-agent chemotherapy.
Introducing a new agent as maintenance.
Multiple randomized trials have evaluated the efficacy of continuing first-line combination cytotoxic chemotherapy beyond three to four cycles.
Evidence (maintenance therapy following first-line chemotherapy):
None of the trials of continued cytotoxic combinations showed a significant OS advantage with additional or longer durations beyond four cycles. For patients with nonsquamous NSCLC, two studies have demonstrated improved PFS and OS with either switch or continuous maintenance chemotherapy (e.g., maintenance pemetrexed after initial cisplatin and gemcitabine or maintenance pemetrexed after initial cisplatin and pemetrexed).[41]
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Three trials found statistically significantly improved PFS or time to progression with additional chemotherapy.[42-44]
No consistent improvement in quality of life was reported.[43,45,46]
Chemotherapy-related toxicities were greater with prolonged chemotherapy.[45,46]
These data suggest that PFS and OS for patients with nonsquamous NSCLC may be improved either by continuing an effective chemotherapy beyond four cycles or by immediate initiation of alternative chemotherapy. The improvement in PFS, however, is tempered by an increase in adverse events including additional cytotoxic chemotherapy and no consistent improvement in quality of life. For patients who have stable disease or who respond to first-line therapy, evidence does not support the continuation of combination cytotoxic chemotherapy until disease progression or the initiation of a different chemotherapy before disease progression. Collectively, these trials suggest that first-line cytotoxic combination chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is not responding to treatment; it can be administered for no more than six cycles.[42,43,45,46] For patients with nonsquamous NSCLC who have a response or stable disease after four to six cycles of platinum combination chemotherapy, maintenance chemotherapy with pemetrexed should be considered.[41]
Evidence (first-line platinum-based combination chemotherapy followed by pemetrexed):
The findings of two randomized trials (NCT00102804 and NCT00789373) have shown improved outcomes with the addition of pemetrexed after standard first-line platinum-based combination chemotherapy.[44,47]
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In the first trial, 663 patients with stage IIIB/IV disease who had not progressed during four cycles of nonpemetrexed platinum–based chemotherapy were randomly assigned (in a 2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]
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In the first trial, 663 patients with stage IIIB/IV disease who had not progressed during four cycles of nonpemetrexed platinum–based chemotherapy were randomly assigned (in a 2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]
Both the primary end point of PFS and the secondary end point of OS were statistically significantly prolonged with the addition of maintenance pemetrexed (median PFS, 4.3 months vs. 2.6 months; HR, 0.50; 95% CI, 0.42–0.61; P < .0001; median OS, 13.4 months vs. 10.6 months; HR, 0.79; 95% CI, 0.65–0.95; P = .012).
In the first trial, 663 patients with stage IIIB/IV disease who had not progressed during four cycles of nonpemetrexed platinum–based chemotherapy were randomly assigned (in a 2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]
Benefit was not seen in patients with squamous histology.
In the first trial, 663 patients with stage IIIB/IV disease who had not progressed during four cycles of nonpemetrexed platinum–based chemotherapy were randomly assigned (in a 2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]
Higher than grade 3 toxicity and treatment discontinuations that resulted from drug-related toxic effects were higher in the pemetrexed group than in the placebo group.
In the first trial, 663 patients with stage IIIB/IV disease who had not progressed during four cycles of nonpemetrexed platinum–based chemotherapy were randomly assigned (in a 2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]
No pemetrexed-related deaths occurred.
In the first trial, 663 patients with stage IIIB/IV disease who had not progressed during four cycles of nonpemetrexed platinum–based chemotherapy were randomly assigned (in a 2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]
Relatively fewer patients in the pemetrexed group than in the placebo group received systemic postdiscontinuation therapy (227 [51%] vs. 149 [67%]; P = .0001).
In the first trial, 663 patients with stage IIIB/IV disease who had not progressed during four cycles of nonpemetrexed platinum–based chemotherapy were randomly assigned (in a 2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]
Quality of life during maintenance therapy with pemetrexed was similar to placebo, except for a small increase in loss of appetite and significantly delayed worsening of pain and hemoptysis as assessed using the Lung Cancer Symptom Scale.[48] The quality-of-life results require cautious evaluation because there was a high degree of censoring (>50%) with the primary quality-of-life end point, which was time to worsening of symptoms.
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In the first trial, 663 patients with stage IIIB/IV disease who had not progressed during four cycles of nonpemetrexed platinum–based chemotherapy were randomly assigned (in a 2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]
Trials have not evaluated maintenance pemetrexed versus pemetrexed at progression.
In the second trial, 539 patients with nonsquamous NSCLC with nonprogression after treatment with pemetrexed and cisplatin were randomly assigned to continued pemetrexed or placebo.[44]
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In the second trial, 539 patients with nonsquamous NSCLC with nonprogression after treatment with pemetrexed and cisplatin were randomly assigned to continued pemetrexed or placebo.[44]
There was a statistically significant improvement in the primary end point of PFS (4.1 months vs. 2.8 months, HR, 0.62; 95% CI, 0.49–0.79) and in the secondary end point of OS (13.9 months vs. 11 months, HR, 0.78; 95% CI, 0.64–0.96).[41,44][Level of evidence B1]
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