INTRODUCTION — Treatment of patients with lung cancer depends upon the tumor stage, histology (non-small cell lung cancer [NSCLC] versus small cell lung cancer, nonsquamous versus squamous NSCLC), molecular characteristics, and an assessment of the patient's overall medical condition. (See "Overview of the initial treatment and prognosis of lung cancer".)
Patients with stage I, II, or III NSCLC are generally treated with curative intent using surgery, chemotherapy, radiation therapy (RT), or a combined-modality approach (table 1). By contrast, palliative systemic therapy is the primary approach for patients with stage IV disease. Palliative systemic therapy is also used for patients who have relapsed with advanced disease following prior definitive treatment.
For patients without a driver mutation, initial systemic treatment generally consists of immunotherapy, cytotoxic chemotherapy, or their combination, depending on the tumor's expression of programmed cell death-ligand 1 and histology. Combinations of chemotherapy with bevacizumab, a monoclonal antibody that binds to vascular endothelial growth factor, are also sometimes used in patients with adenocarcinoma. Maintenance treatment, using components of the initial regimen or another noncross-resistant agent, is often included as part of the treatment and continued until progressive disease develops or toxicity requires cessation of therapy.
The issues surrounding the indications and choice of the initial chemotherapy regimen, including maintenance therapy, are discussed in this topic. The overall approach to the treatment of advanced NSCLC, the role of personalized therapy based upon specific driver mutations, and immunotherapy for NSCLC are discussed elsewhere:
●(See "Overview of the initial treatment of advanced non-small cell lung cancer".)
●(See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)
PATIENT SELECTION FOR CHEMOTHERAPY — Chemotherapy combined with immunotherapy is typically chosen as the front-line option for those with tumor programmed cell death-ligand 1 (PD-L1) expression of ≤50 percent and a good performance status (PS, Eastern Cooperative Oncology Group PS ≤2), in the absence of a driver mutation. For patients initially treated with pembrolizumab monotherapy (typically those with tumor PD-L1 expression >50 percent), a platinum-based doublet is appropriate subsequent-line treatment upon progression. Patients with actionable driver mutations are typically treated initially with targeted agents, with chemotherapy (with or without concurrent immunotherapy) reserved for progression upon available agents. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)
SURVIVAL BENEFIT FOR CHEMOTHERAPY OVER BEST SUPPORTIVE CARE — Systemic chemotherapy improved overall survival using a platinum-based regimen compared with best supportive care in multiple clinical trials. Despite the potential toxicities associated with chemotherapy, this can generally be achieved without impairing quality of life.
A systematic review of the literature and meta-analysis incorporated individual patient data from 2714 cases enrolled on 16 randomized trials [1]. These trials all were conducted before the identification of driver mutations was routine and included unselected populations of patients with NSCLC. Chemotherapy was associated with an improved survival (one-year survival rate, 29 versus 20 percent; hazard ratio [HR] 0.77, 95% CI 0.71-0.83). This survival benefit was independent of histology, performance status, and age. These results led to the use of four to six cycles of a platinum-based doublet followed by observation as the standard approach for patients with advanced NSCLC.
However, subsequent trials have shown that additional survival benefits may be derived from the addition of biologic agents such as bevacizumab with the chemotherapy, or from the use of single-agent chemotherapy as maintenance therapy after the initial platinum-doublet chemotherapy. In addition, better results have been observed with targeted agents in patients with a driver mutation. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)
FACTORS INFLUENCING CHOICE OF THERAPY — Systemic therapy is the standard approach for patients with advanced NSCLC, either at presentation or in patients with a recurrence after definitive therapy.
Molecular characterization of tumor — Therapy of advanced NSCLC should be individualized based upon the molecular features of the tumor. Whenever possible, tumor tissue should be assessed for the presence of a somatic driver mutation (eg, mutated epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK] fusion oncogene, c-ROS oncogene 1 [ROS1], B-Raf [BRAF] V600E), which confers sensitivity to a specific inhibitor [2]. Tumors that lack these alterations may be treated with front-line immunotherapy, chemotherapy, or the combination of immunotherapy and chemotherapy, depending on the level of tumor programmed cell death-ligand 1 (PD-L1) expression and histology. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer" and "Management of advanced non-small cell lung cancer lacking a driver mutation: Immunotherapy".)
For those patients with a driver mutation, use of a specific inhibitor is indicated either as the initial therapy or as therapy when progressive disease develops.
Effect of histology — Histology provides insight into the optimal agents to combine with a platinum compound.
Regimens containing pemetrexed are more effective in patients with adenocarcinoma and less effective than combinations without pemetrexed in patients with squamous cell carcinoma. In addition, pembrolizumab or bevacizumab is often combined with the initial chemotherapy regimen for patients with nonsquamous histology. (See "Management of advanced non-small cell lung cancer lacking a driver mutation: Immunotherapy", section on 'PD-L1 low (<50 percent) or unselected tumors'.)
The impact of histology on the results with platinum-based chemotherapy was illustrated by a phase III trial in which cisplatin plus pemetrexed was compared with cisplatin plus gemcitabine as initial therapy [3,4]. Survival in the 847 patients with adenocarcinoma was significantly prolonged with cisplatin plus pemetrexed compared with cisplatin plus gemcitabine (median, 12.6 versus 10.9 months). Conversely, cisplatin plus gemcitabine was superior to cisplatin plus pemetrexed in the 473 patients with squamous cell carcinoma (median, 10.8 versus 9.4 months).
The extent to which these results represent increased activity for pemetrexed in patients with adenocarcinoma or decreased activity of pemetrexed in those with squamous cell carcinoma is unknown. There are insufficient data to compare pemetrexed-based regimens with other combinations in patients with adenocarcinoma.
Patient-specific factors — The patient's age, performance status, comorbidities, and concerns and preferences regarding treatment all need to be integrated into the initial treatment approach.
In particular, older adult patients and those with a poor performance status (PS) may not tolerate treatment as well as younger patients with a good PS and may not derive the same benefit from aggressive treatment. The approach to these patients is discussed separately. (See "Overview of the initial treatment of advanced non-small cell lung cancer", section on 'Older adult patients'.)
INITIAL CHEMOTHERAPY REGIMEN
Approach — For those with a good performance status (PS) in whom chemotherapy is indicated, combination chemotherapy regimens using a platinum compound (cisplatin, carboplatin) plus a second active cytotoxic agent are preferred, typically for four to six cycles. Extending the duration of treatment with the initial platinum-based chemotherapy beyond four to six cycles is not recommended given increased toxicity and only modest effect on survival [5-7]. Patients without progression upon completion of four to six cycles, however, may benefit from continuation of treatment (maintenance) with one or more components of the initial regimen, typically discontinuing the platinum agent.
Multiple cytotoxic agents in addition to cisplatin and carboplatin have antitumor activity. These include pemetrexed, taxanes (docetaxel, paclitaxel, nanoparticle albumin-bound paclitaxel [nabpaclitaxel]), gemcitabine, vinorelbine, and camptothecins (irinotecan, topotecan). Our typical approach is as follows.
For patients with programmed cell death-ligand 1 (PD-L1) expression <50 percent, lacking contraindications to immunotherapy (connective tissue, interstitial lung, or rheumatologic disease),
●Who have nonsquamous cancers, we use carboplatin and pemetrexed in combination with pembrolizumab, with pemetrexed and pembrolizumab maintenance upon completion of the initial four to six cycles, based on the KEYNOTE-189 trial [8].
●Who have squamous cancers, we use a combination of pembrolizumab, carboplatin, and either paclitaxel or nabpaclitaxel, with pembrolizumab maintenance after the initial four to six cycles, based on KEYNOTE-407 [9]. (See "Management of advanced non-small cell lung cancer lacking a driver mutation: Immunotherapy", section on 'PD-L1 low (<50 percent) or unselected tumors'.)
Pembrolizumab monotherapy is preferred for those with squamous or nonsquamous NSCLC with PD-L1 expression ≥50 percent, based on efficacy seen in these patients in KEYNOTE-024 [10], with the exception of patients with rapidly progressing disease and/or cancer-related symptoms. For such patients, a chemotherapy/immunotherapy combination is preferred in order to maximize the probability of response.
Preference for platinum-based regimens — Although the improvement with platinum-based chemotherapy is small compared with a nonplatinum-based doublet (table 2), we agree with the recommendation from the American Society of Clinical Oncology (ASCO) guidelines that first-line therapy should consist of a platinum-based doublet regimen [5].
A meta-analysis that included 4792 patients treated in 17 randomized trials found that the use of a platinum-based doublet regimen was associated with a slightly higher survival at one year (relative risk [RR] for survival 1.08, 95% CI 1.01-1.16) [11]. When the trials were analyzed according to the platinum compound used, cisplatin was associated with a significantly higher survival at one year compared with nonplatinum regimens (RR for survival 1.16, 95% CI 1.06-1.27). By contrast, carboplatin-based regimens were not better than nonplatinum regimens (RR for survival 0.95, 95% CI 0.85-1.07).
Extending the duration of treatment with the initial platinum-based chemotherapy beyond four to six cycles is not recommended [5]. Although longer treatment duration increases progression-free survival (PFS), it has at most only a moderate effect on overall survival (OS) [6].
A meta-analysis of five trials comparing six cycles versus three or four cycles failed to demonstrate a statistically significant improvement in OS (9.5 versus 8.7 months), although the difference in PFS was significant (6.1 versus 5.3 months) [7].
For patients who are not candidates for a platinum-containing regimen because of potential toxicity, regimens that may offer similar benefit based upon results of randomized trials include:
●Gemcitabine plus docetaxel [12,13]
●Gemcitabine plus paclitaxel [14-16]
●Gemcitabine plus vinorelbine [17-20]
●Paclitaxel plus vinorelbine [21]
●Pemetrexed plus gemcitabine [22-24]
Cisplatin versus carboplatin — Carboplatin is often substituted for cisplatin in combination regimens for patients with advanced NSCLC due to its more favorable toxicity profile. Overall, the evidence suggests that cisplatin gives a higher objective response rate than carboplatin, although the survival benefit is small and may not be clinically meaningful. We believe carboplatin is appropriate for the majority of patients with advanced disease, for whom quality of life is an important consideration. Carboplatin is particularly valuable in patients with metastatic NSCLC in whom cisplatin is likely to be poorly tolerated (older adult patients, those with poor PS, and those with significant comorbidities). Moreover, for patients with both nonsquamous and squamous advanced NSCLC, carboplatin-based doublets have been studied in combination with immunotherapy, but cisplatin-based doublets have not been evaluated with programmed cell death protein-1 (PD-1)/PD-L1 axis inhibitors. (See "Management of advanced non-small cell lung cancer lacking a driver mutation: Immunotherapy", section on 'PD-L1 low (<50 percent) or unselected tumors'.)
In a meta-analysis that included individual patient data from 2968 patients in nine trials, substitution of carboplatin for cisplatin was associated with a significantly lower response rate (24 versus 30 percent, odds ratio [OR] 1.37 95% CI 1.16-1.61) and a statistically nonsignificant shortening of survival (median, 8.4 versus 9.1 months; hazard ratio [HR] for death 1.07, 95% CI 0.99-1.15) [25]. In subset analyses, the difference in survival was statistically significant when the analysis was restricted to patients with nonsquamous cancers and when the platinum compound was combined with a third-generation chemotherapy agent (paclitaxel, docetaxel, or gemcitabine).
Cisplatin-containing regimens were associated with more nephrotoxicity, nausea, and vomiting, while carboplatin combinations caused more severe thrombocytopenia. Improvements in the management of chemotherapy-induced vomiting and the use of lower doses of cisplatin in newer regimens have mitigated some of the concerns about cisplatin toxicity [26]. (See "Prevention of chemotherapy-induced nausea and vomiting in adults".)
Careful adherence to full doses of carboplatin may obviate the difference between carboplatin and cisplatin. In a phase III trial, 1363 patients with advanced NSCLC were randomly assigned to gemcitabine plus one of three platinum regimens: cisplatin (50 mg/m2), cisplatin (80 mg/m2) and carboplatin (area under the curve [AUC] 6) [27]. Median survivals for the three treatment arms were 8.3, 9.5, and 10.0 months, respectively; the trial met the predetermined criteria for noninferiority of the carboplatin regimen.
Cisplatin remains the preferred platinum compound when systemic therapy is used with curative intent in conjunction with other treatments (ie, adjuvant therapy, combined-modality treatment of stage III disease). (See "Systemic therapy in resectable non-small cell lung cancer" and "Management of stage III non-small cell lung cancer".)
Number of cytotoxic agents — Evidence suggests that two-drug regimens increase response rate and OS, compared with single agents. While the addition of a third agent improves response rates, the impact on survival is inconsistent, and toxicity is clearly increased. Thus, we recommend the initial use of doublet regimens, reserving single-agent treatment for those who are not expected to tolerate a combination approach.
●Multiple randomized trials compared cisplatin-containing combinations with single-agent therapy in patients with advanced NSCLC [28]. In a meta-analysis that included 13,601 patients from 65 randomized trials, two-drug regimens significantly increased both response rate and OS compared with single-agent chemotherapy (objective response rate, 26 versus 13 percent with single-agent therapy; one-year survival rate, 35 versus 30 percent) [28].
●A 2004 meta-analysis that identified 28 trials of three versus two cytotoxic agents concluded that hematologic toxicity was significantly worse for three cytotoxic agents [28]. There was no increase in OS. However, only four of the trials in the meta-analysis included a platinum compound plus two additional third-generation agents, and these trials used attenuated doses in the three-drug regimen to minimize hematologic toxicity. Two subsequent phase III trials have suggested that three-drug regimens may modestly improve response rates but that three-drug regimens were significantly more toxic [29,30].
Weekly, lower-dose regimen — Although most regimens use a three- or four-week interval between treatment courses, weekly administration at lower doses can alter the toxicity profile [31,32].
Although further data are needed, a weekly schedule of paclitaxel plus carboplatin may be considered if neurotoxicity is a particular concern.
This approach was examined in a phase III trial in which 883 chemotherapy-naive patients were randomly assigned to paclitaxel plus carboplatin, administered either every three weeks or on a weekly schedule with reduced doses (table 3) [31]. Severe neurotoxicity was significantly less frequent with the weekly schedule compared with every three weeks (4.4 versus 9.1 percent), but grade 3 or 4 diarrhea was more common (4.2 versus 1.1 percent). The efficacy of the weekly schedule was not significantly different (response rate, 38 versus 33 percent; median time to progression, 6.1 versus 7.2 months; and median survival, 8.9 versus 9.5 months).
Addition of immunotherapy — For patients with PD-L1 expression ≤50 percent, lacking contraindications to immunotherapy (connective tissue, interstitial lung, or rheumatologic disease), a checkpoint inhibitor is typically used in combination with chemotherapy as front-line therapy. Pembrolizumab monotherapy or a histology-appropriate chemotherapy/immunotherapy combination may be used for those with squamous or nonsquamous NSCLC and PD-L1 expression >50 percent. (See "Management of advanced non-small cell lung cancer lacking a driver mutation: Immunotherapy", section on 'Chemotherapy-naive' and "Management of advanced non-small cell lung cancer lacking a driver mutation: Immunotherapy", section on 'Factors in choosing initial therapy' and "Management of advanced non-small cell lung cancer lacking a driver mutation: Immunotherapy", section on 'Others'.)
Addition of bevacizumab instead of immunotherapy in nonsquamous NSCLC — For good-PS patients with nonsquamous NSCLC, the addition of the antivascular endothelial growth factor antibody bevacizumab to a platinum-based doublet offers a higher response rate, a longer PFS, and improved OS compared with chemotherapy alone [33]. However, this approach has not been directly compared with the addition of pembrolizumab to platinum-based chemotherapy. Cross-trial comparisons, however, suggest improved outcomes with pembrolizumab rather than bevacizumab when paired with platinum-based chemotherapy.
The use of the checkpoint inhibitor atezolizumab with chemotherapy/bevacizumab has shown improved efficacy over chemotherapy/bevacizumab in nonsquamous NSCLC, irrespective of PD-L1 expression [34], although it is not our preferred option given associated side effects. These data are discussed elsewhere. (See "Management of advanced non-small cell lung cancer lacking a driver mutation: Immunotherapy", section on 'Atezolizumab in squamous NSCLC'.)
The effect of adding bevacizumab alone to platinum-based doublets is illustrated in a meta-analysis based upon four trials (2194 patients), in which the addition of bevacizumab significantly increased both OS and PFS compared with chemotherapy alone (HRs for death or progression 0.90, 95% CI 0.81-0.99 and 0.72, 95% CI 0.66-0.79, respectively) [33]. The effect on OS was significantly greater in patients with adenocarcinoma compared with other histology. The addition of bevacizumab increased the risk of grade ≥3 toxicity.
How adding bevacizumab to the platinum-based doublet and then continuing with bevacizumab maintenance compares with chemotherapy alone followed by chemotherapy maintenance is not clear. In one trial, 361 patients were randomized to either pemetrexed plus carboplatin followed by pemetrexed maintenance or to paclitaxel, carboplatin, plus bevacizumab with bevacizumab continued as maintenance [35]. There was no statistically significant difference in PFS (median, 4 versus 5 months) or OS (median, 11 versus 12 months). Both regimens were well tolerated, although the toxicity profiles differed.
Treatment with bevacizumab is generally well tolerated. In a phase IV, open-label, single arm study, grade 3 or higher adverse events included thromboembolism, hypertension, bleeding, proteinuria, and pulmonary hemorrhage (8, 6, 4, 3, and 1 percent, respectively) [36]. Treatment-related mortality occurred in 57 cases (3 percent). Although patients with known brain metastases were excluded, 281 individuals were diagnosed with brain metastases during the course of the study. In this subset, five (2 percent) had central nervous system bleeding. Subsequent data have demonstrated the safety of utilizing bevacizumab in patients with previously treated brain metastases and in patients receiving full anticoagulation. However, the risk of severe toxicity may be increased in older adult patients [37].
Hypertension is a frequent side effect of bevacizumab. Guidelines for pretreatment assessment, monitoring, and management of elevated blood pressure in patients receiving bevacizumab are available (table 4A-B). This subject is discussed elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Hypertension'.)
The toxicities associated with bevacizumab are discussed separately. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects".)
MAINTENANCE THERAPY — Maintenance therapy options for patients without a driver mutation include single-agent chemotherapy, bevacizumab, or pembrolizumab. Patients initially treated with chemotherapy with or without bevacizumab who desire a treatment break and do not appear to be at risk for rapid relapse can be watched without maintenance, using close clinical and radiographic monitoring, following an informed discussion with the patient. However, for those in whom pembrolizumab was a component of initial treatment, it is typically continued until progression, although discontinuation at two years is an appropriate alternative. (See "Management of advanced non-small cell lung cancer lacking a driver mutation: Immunotherapy", section on 'Duration of treatment'.)
Factors affecting choice of maintenance — Several factors need to be considered in deciding how and whether to continue therapy:
●The agents used in the original treatment regimen – Many patients will have received pembrolizumab, bevacizumab, or pemetrexed as part of their original combination. These agents may be continued, depending upon tolerance for these agents. Pembrolizumab may continue with pemetrexed, for patients who received both of these agents as part of their initial regimen. The same is true for bevacizumab.
●Absence or presence of a driver mutation – Most patients who received initial cytotoxic chemotherapy will not have a driver mutation in their tumor. However, occasional patients with a driver mutation will have received chemotherapy because their genotype assay results were unknown when therapy was initiated. Management of such patients is discussed elsewhere. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Those initially treated with chemotherapy in whom a mutation is subsequently identified'.)
We do not offer epidermal growth factor receptor (EGFR) inhibitors as maintenance for those without an activating EGFR mutation. (See 'Avoidance of EGFR inhibitors for those with EGFR-wildtype NSCLC' below.)
●Patient-specific factors – Comorbidities, toxicity associated with the original treatment, and desire to balance quality of life versus toxicity of immediate further treatment all are factors that need to be considered in choosing further therapy. Close observation with initiation of second-line therapy at the earliest sign of progression may be an alternative for selected patients who are well informed about the risks and benefits of such approach.
Cytotoxic chemotherapy — Pemetrexed, docetaxel, and gemcitabine all significantly prolong progression-free survival (PFS) when used as single-agent maintenance therapy after initial chemotherapy for advanced NSCLC.
There are no randomized clinical trials that compare these three agents with each other as maintenance therapy. The most extensive data are from trials using pemetrexed, which we prefer for patients with nonsquamous carcinomas, particularly if pemetrexed was used in the front-line regimen. Docetaxel is an alternative to pemetrexed for patients with nonsquamous NSCLC. Either docetaxel or gemcitabine is preferred for patients with squamous cell carcinomas, and pemetrexed is not used in this setting.
●Pemetrexed – Results from two large trials observed that single agent pemetrexed significantly prolongs both PFS and overall survival (OS) after the initial chemotherapy. In the largest phase III trial, 745 patients were treated with four cycles of a platinum-based doublet (cisplatin or carboplatin plus gemcitabine, docetaxel, or paclitaxel) [38]. Of these, 663 patients had an ongoing response or stable disease at the completion of chemotherapy and were randomly assigned to either pemetrexed or placebo. Maintenance therapy with pemetrexed increased both median PFS (4.3 versus 2.6 months; hazard ratio [HR] 0.50, 95% CI 0.42-0.61) and median OS compared with placebo (13.4 versus 10.6 months; HR 0.79, 95% CI 0.65-0.95). However, only 19 percent of those initially treated with placebo subsequently received pemetrexed. In subset analyses, the benefits of pemetrexed were limited to patients with nonsquamous histology. Similarly, in the PARAMOUNT trial, among 539 patients with an objective response or stable disease after four cycles of treatment, those randomly assigned to pemetrexed experienced improved PFS relative to placebo (median, 4.1 versus 2.8 months; HR 0.62, 95% CI 0.49-0.79), and improved OS (median, 13.9 versus 11.0 months; one-year survival rate 58 versus 45 percent) [39].
In a post-hoc analysis, older adult patients (≥70 years) had a similar improvement in PFS and OS when compared with those <70 years [40]. There was an increase in the incidence of severe anemia and neutropenia compared with those in the younger age group.
Additional evidence on the benefits of pemetrexed maintenance are derived from two large clinical trials in which maintenance with bevacizumab was combined with either pemetrexed or placebo [41-43]. (See 'Bevacizumab' below.)
●Docetaxel – Maintenance therapy with docetaxel increases PFS and may improve OS in patients who have an objective response or stable disease after completion of four cycles of chemotherapy.
In a phase III trial, 566 patients were initially treated with four cycles of gemcitabine plus carboplatin [44]. The 309 patients without evidence of disease progression after completion of their chemotherapy were randomly assigned to immediate treatment with single-agent docetaxel for up to six cycles or to observation with docetaxel treatment when disease progression occurred.
PFS from randomization was significantly increased with docetaxel compared with observation (median, 5.7 versus 2.7 months). Immediate treatment with docetaxel was associated with a trend toward prolonged survival, measured from randomization (median, 12.3 versus 9.7 months with delayed chemotherapy; p = 0.09). However, among those assigned to delayed treatment, only 63 percent actually were treated with docetaxel, and patients who were treated with docetaxel as delayed therapy had a comparable outcome to those who received it early.
●Gemcitabine – Gemcitabine maintenance therapy has been studied in one phase III trial, which demonstrated a statistically significant improvement in PFS and a trend toward improved OS. It may be used as an alternative to docetaxel for those with squamous cell NSCLC.
In a French multicenter trial, 834 patients with advanced NSCLC were treated with cisplatin plus gemcitabine [45]. The 464 patients with an objective response or stable disease after four cycles of chemotherapy were randomly assigned to observation, maintenance with gemcitabine, or maintenance with erlotinib. Pemetrexed was planned as the second-line therapy on all three arms for progression. The trial was designed to compare both gemcitabine and erlotinib with observation, but was not powered to compare gemcitabine with erlotinib.
PFS was significantly prolonged in patients receiving the gemcitabine maintenance regimen compared with observation (3.8 versus 1.9 months; HR 0.56). There was a statistically nonsignificant trend toward improved OS with gemcitabine maintenance compared with observation (median survival, 12.1 versus 10.7 months; HR 0.89, 95% CI 0.69-1.15).
Bevacizumab — Bevacizumab is sometimes included with a platinum-based doublet in the initial chemotherapy regimen for nonsquamous NSCLC. For those who have completed treatment with a pemetrexed- and bevacizumab-containing regimen, either agent may be continued singly as maintenance therapy, but we do not suggest using the combination of the two agents as maintenance, given the lack of survival benefit and increase in toxicity. (See 'Addition of bevacizumab instead of immunotherapy in nonsquamous NSCLC' above.)
In the Eastern Cooperative Oncology Group (ECOG) 5508 trial, 1516 patients with advanced, nonsquamous NSCLC were initially treated with carboplatin, paclitaxel, and bevacizumab and then randomly assigned to maintenance with pemetrexed alone, bevacizumab alone, or the combination of these two agents [46]. OS results were similar with the combination (16.4 months) versus either agent singly (14.4 months for bevacizumab and 15.9 months for pemetrexed). While PFS was improved with the combination (7.5 versus 4.2 months for bevacizumab and 5.1 months for pemetrexed), grade ≥3 toxicities were also more frequent (50 versus 30 and 37 percent, respectively).
Similarly, in the COMPASS trial, among 599 patients with advanced, nonsquamous NSCLC who received induction treatment with carboplatin, pemetrexed, and bevacizumab without progression, those assigned to maintenance therapy with pemetrexed and bevacizumab had similar OS as those assigned to maintenance bevacizumab only (23.3 versus 19.6 months; HR 0.87, 95% CI 0.73-1.05), though PFS was improved (5.7 versus 4 months; HR 0.67, 95% CI 0.57-0.79) [47]. Grade ≥3 toxicities were generally comparable between the two groups, although neutropenia (14 versus 1 percent) and anemia (5 versus 0 percent) were more frequent in the combination group. Although this trial excluded patients with confirmed EGFR 19-deleted or L858R-mutated NSCLC, 9 percent had uncommon EGFR mutations or could not be evaluated. When analysis excluded these patients, maintenance pemetrexed and bevacizumab resulted in a statistically significant improvement in OS relative to pemetrexed (23.3 versus 18.8 months; HR 0.82, 95% CI 0.68-0.99).
Previous trials of patients of patients with advanced, nonsquamous NSCLC receiving combined pemetrexed and bevacizumab maintenance have suggested PFS, but not OS, benefits and increased toxicities [43,48,49]. Overall, the data are inconclusive but offer only a nonsignificant trend toward benefit with maintenance bevacizumab in patients who are on a chemotherapy/bevacizumab-containing regimen. In this setting, it is reasonable either to continue bevacizumab or not, depending on how well it is being tolerated, potential cost issues, and other clinician or patient preferences.
PROGRESSIVE DISEASE ON OR AFTER CHEMOTHERAPY — When progressive disease develops during the initial treatment or during the maintenance phase, patients may derive benefit from additional systemic therapy or treatment targeted against specific sites of metastases.
Selection of single-agent chemotherapy — For patients in whom progression has occurred on or after available targeted therapies, combination chemotherapy, and immunotherapy, the appropriate next option is single-agent chemotherapy, if patients remain candidates for treatment. We typically do not incorporate immunotherapy into the subsequent-line management for patients receiving immunotherapy in the front line.
Selection of subsequent chemotherapy agent depends on histology and past treatment history and is summarized below:
●Nonsquamous histology – Among patients with nonsquamous histology, either pemetrexed or docetaxel is an appropriate option for single-agent chemotherapy. However, we typically prefer pemetrexed for patients who have not been treated with this agent previously given a favorable side effect profile.
For patients who have received pemetrexed in an earlier line of treatment, we utilize docetaxel.
●Squamous histology – Docetaxel is the preferred chemotherapy agent among those with squamous histology. Pemetrexed is not indicated for patients with squamous NSCLC given inferior response rates and survival compared with other agents.
Some UpToDate experts use ramucirumab concurrently when treating with docetaxel for patients who have a good performance status (PS). Despite limited data, gemcitabine is a subsequent option for both nonsquamous and squamous histologies. Phase II data are also available on the activity of multiple other agents when given as monotherapy for NSCLC (eg, paclitaxel, nanoparticle albumin-bound paclitaxel [nabpaclitaxel], vinorelbine, topotecan, irinotecan). However, randomized data regarding the efficacy of these agents in this setting are lacking.
We continue a given line of treatment until disease progression or unacceptable toxicity occurs. We typically monitor for disease progression every two cycles using contrast-enhanced chest computed tomography (CT), with additional imaging of metastatic sites, as warranted. Subsequent lines of treatment may be offered to patients who have adequate PS, at the discretion of the treating clinician and depending on patient preferences.
Efficacy and toxicities — Studies of chemotherapy in the setting of subsequent-line therapy have largely included both squamous and nonsquamous histologies, without specific testing for driver mutations. Available data are presented below.
Docetaxel — Docetaxel has demonstrated activity both among patients with nonsquamous and squamous histologies. Severe or significant toxicities of treatment include neutropenia, febrile neutropenia, pneumonitis, stomatitis, diarrhea, excessive tearing, and neuropathy. More information on toxicities associated with docetaxel is found elsewhere. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Taxanes' and "Taxane-induced pulmonary toxicity" and "Infusion reactions to systemic chemotherapy", section on 'Taxanes' and "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Docetaxel'.)
The efficacy of subsequent-line, single-agent docetaxel was demonstrated in a trial in which 104 patients with advanced, pretreated NSCLC were randomly assigned to docetaxel (100 mg/m2 or 75 mg/m2 every three weeks) or best supportive care [50]. Patients assigned to docetaxel 75 mg/m2 (but not 100 mg/m2) had significantly longer overall survival (OS) (median, 7.5 versus 4.6 months; one-year survival rate, 37 versus 19 percent). Furthermore, patients treated with docetaxel had improved pain control and significantly less deterioration in quality of life compared with those managed only with best supportive care, in whom pain control worsened over the course of the study [51]. Randomized trials that compared docetaxel with older agents also support the activity of second-line docetaxel therapy [52].
Administration of docetaxel on a weekly schedule, rather than every three weeks, may minimize toxicity [53]. This was illustrated by a trial in which 220 patients with NSCLC were randomly assigned to second-line treatment with docetaxel every three weeks (75 mg/m2) versus weekly (33.3 mg/m2) for six of every eight weeks [54]. Median survival and one-year survival rates were similar (29 versus 25 weeks and 21 versus 31 percent, respectively, differences that were not statistically significant). Weekly administration of docetaxel caused significantly less grade 3 or 4 hematologic toxicity (6 versus 25 percent with the three-week schedule). However, other toxicities were more common, including excessive tearing due to stenosis of the tear ducts [55]. (See "Ocular side effects of systemically administered chemotherapy", section on 'Epiphora and docetaxel'.)
Ramucirumab plus docetaxel — Some UpToDate providers offer ramucirumab to patients with a good performance status, although others tend to avoid it given small observed benefits and associated toxicities. Ramucirumab, a monoclonal antibody that targets the vascular endothelial growth factor receptor 2, is the only agent that has shown improvement in OS when used in conjunction with docetaxel in the second-line setting. However, it increases the rates of bleeding and hypertension and, rarely, can cause intestinal perforation and arterial thrombosis.
In the REVEL trial, 1253 patients with NSCLC who had progressed on initial platinum-based therapy were randomly assigned to docetaxel (75 mg/m2 every 21 days) with or without ramucirumab (10 mg/kg every 21 days) [56,57]. Prior treatment had included bevacizumab in 14 percent of cases. Twenty-six percent of the patients had squamous cell carcinoma.
Results of the trial include the following:
●OS, the primary endpoint of the trial, was increased in patients assigned to docetaxel plus ramucirumab (median, 10.5 versus 9.1 months; hazard ratio [HR] 0.86, 95% CI 0.75-0.98). Results were similar across histologic subgroups.
●Progression-free survival was also increased with the combination (median, 4.5 versus 3 months; HR 0.76, 95% CI 0.68-0.86).
●The overall incidence of grade 3 or 4 toxicity was increased in patients assigned to docetaxel plus ramucirumab (79 versus 72 percent). The most significant difference was an increase in bleeding (26.5 versus 12.9 percent), but was predominantly grade 1 or 2.
Pemetrexed — Pemetrexed is as active as docetaxel among patients with previously treated, nonsquamous, advanced NSCLC but is not indicated for patients with squamous NSCLC, given its low efficacy. Although it is also associated with neutropenia, febrile neutropenia, and nausea, these toxicities are less frequent than with docetaxel. Furthermore, while docetaxel is associated with pneumonitis, hypersensitivity reactions, and neuropathy, these risks are minimal with pemetrexed. Pemetrexed should be administered with folic acid (350 to 1000 mcg daily) and vitamin B12 (1000 mcg every nine weeks) to decrease the incidence of hematologic toxicity. B12 should be started ≤1 to 3 weeks prior to pemetrexed (although the US Food and Drug Administration notes that B12 should be administered at least one week prior to pemetrexed, subsequent data suggest it may be started less than one week prior to treatment, without detrimental effect [58]). It is also administered with dexamethasone (4 mg twice daily for three days) to decrease cutaneous toxicities, which can occur in 10 to 14 percent of patients. (See "Cutaneous adverse effects of conventional chemotherapy agents", section on 'Exanthematous (maculopapular) eruptions'.)
The efficacy of pemetrexed was established in a phase III trial in which 571 patients with recurrent NSCLC were randomly assigned to docetaxel (75 mg/m2) or pemetrexed (500 mg/m2), each given every three weeks [59,60]. Treatment was continued until there was disease progression or unacceptable toxicity.
●The objective response rates were similar (9 percent for both agents), as was OS (median, eight months in each group). However, pemetrexed caused lower rates of grade 3 or 4 neutropenia (5 versus 40 percent), febrile neutropenia (2 versus 13 percent), need for granulocyte colony-stimulating factor support (3 versus 19 percent), and hair loss (6 versus 38 percent).
●In a secondary analysis, pemetrexed showed a trend towards improved survival compared with docetaxel in patients with nonsquamous tumors (median OS, 9.3 versus 8.0 months; HR for death 0.78, 95% CI 0.61-1.00) [61]. By contrast, pemetrexed was less effective in patients with squamous carcinomas (OS, 6.2 versus 7.4 months; HR 1.56, 95% CI 1.08-2.26). This impact of histology on response to treatment with pemetrexed is consistent with the preferential activity of pemetrexed for patients with nonsquamous NSCLC in the first-line setting. (See 'Effect of histology' above.)
Gemcitabine — Although there are limited data, gemcitabine may be offered as a subsequent therapy option for those in whom single-agent chemotherapy is warranted but other treatment options are exhausted. Gemcitabine used in this setting may provide palliation rather than a survival benefit. Gemcitabine is often well tolerated but is associated with flu-like symptoms and hair loss, as well as a low incidence of neutropenia, nausea, and pulmonary toxicity.
In a randomized study of 300 patients with symptomatic, locally advanced, or metastatic NSCLC, gemcitabine was associated with improvement in quality of life measures within the first two months of treatment versus a decline in these measures among patients receiving best-supportive care (BSC) only [62]. OS was not different between the two arms (5.7 months for those treated with gemcitabine and 5.9 months for those receiving BSC only). Tumor response was observed in 19 percent of patients receiving gemcitabine. The incidence of grade 3 and 4 toxicity with gemcitabine was low, with 13 percent experiencing neutropenia, 9 percent with nausea, and 3 percent with pulmonary toxicity. Flu-like symptoms and hair loss were each observed in almost one-third of patients.
SPECIAL CONSIDERATIONS
Older and medically complicated patients — Fit, older adult patients with good performance status have been found to benefit from systemic therapy for NSCLC to the same degree as younger patients. The general strategy of choosing a systemic agent for the fit, older patient is the same as for younger patients, and advanced age alone should not preclude receipt of therapy. However, the presence of comorbidities may influence choice of treatment. For example, we avoid the use of docetaxel in those with diabetic neuropathy. Tools to assess the fitness of older adults for cancer treatment are discussed elsewhere. (See "Comprehensive geriatric assessment for patients with cancer" and "Systemic chemotherapy for cancer in older adults".)
In a subset analysis of a trial comparing pemetrexed and docetaxel in previously treated patients [59,60], both agents were well tolerated in patients 70 years of age or older who had received prior chemotherapy [63]. Survival was similar in the 86 patients older than 70 years of age compared with younger patients (9.5 versus 7.8 months, respectively, with pemetrexed and 7.7 versus 8.0 months, respectively, with docetaxel).
Retreatment after initial response — In general, patients who have progressed after one chemotherapy regimen are treated with a noncross-resistant regimen. However, for patients who have responded to an initial chemotherapy regimen and are stable for at least six months after chemotherapy discontinuation (either on or off bevacizumab), we offer retreatment with the same regimen upon progression, particularly for those with a good performance status (PS). Given limited data with this approach, however, others may reasonably opt instead to proceed with the next line of treatment. Moreover, the potential for cumulative toxicity should be taken into account if retreatment is being considered, as typically tolerance for a given regimen decreases with increased exposure.
In a retrospective study of 66 patients with response to first-line therapy, 28 patients were retreated with the same regimen upon progression and 38 were treated with docetaxel as the second-line regimen [64]. The two groups were well matched with the exception that the retreatment group had more advanced stages of disease. The median interval from the end of first-line chemotherapy to relapse was five months. The overall response rate among those being retreated was 29 percent versus 8 percent among those receiving docetaxel. The median survival from the beginning of retreatment was 17 months versus 9 months among those receiving docetaxel.
Relapse after definitive therapy — Many patients who receive definitive therapy, which often includes adjuvant chemotherapy, eventually relapse. Defining the appropriate treatment strategy, including the possible readministration of drugs used in the adjuvant regimen and the use of noncross-resistant regimens, has become an important issue [65]. Recognizing that there are no randomized trials in this setting, our approach is as follows:
●If relapse occurs more than 12 months after the completion of adjuvant therapy or definitive chemoradiation, patients are typically managed as chemotherapy-naϊve, first-line patients.
●If relapse occurs less than six months after adjuvant therapy or definitive chemoradiation, patients are generally offered the appropriate second-line therapy.
●If relapse occurs between 6 and 12 months after adjuvant chemotherapy or definitive chemoradiation, the decision is individualized based on patient and provider preferences, taking into account the current extent of disease and the patient's PS. For example, a patient with a good PS and a large burden of disease may have a window of opportunity to experience benefit from retreatment, particularly if the magnitude of response to initial treatment was large. (See "Systemic therapy in resectable non-small cell lung cancer".)
Local management of metastases — Although systemic therapy is the primary approach to the management of metastatic disease, local therapy directed against specific sites of disease may also play an important role in some patients, particularly those with symptomatic metastases, those with metastatic disease involving the central nervous system, and those on targeted therapy who develop a solitary metastasis with no progression in other sites. These issues are discussed separately. (See "Overview of the initial treatment of advanced non-small cell lung cancer", section on 'Management of specific metastatic sites'.)
Avoidance of EGFR inhibitors for those with EGFR-wildtype NSCLC — Epidermal growth factor receptor (EGFR) inhibitors do not have an established role for those without an activating EGFR mutation, either as first-line therapy, maintenance, or second-line therapy. Representative data for several agents are as follows.
●Erlotinib – Erlotinib is an EGFR tyrosine kinase inhibitor. Although erlotinib has shown improvement in progression-free survival (PFS) and overall survival (OS) as maintenance therapy in unselected patients or in those with activating EGFR mutations [45,66,67], evidence for a PFS benefit is mixed among those with wildtype EGFR, without evidence for an improvement in OS [66,68,69].
●Cetuximab – Cetuximab is a monoclonal antibody that binds to EGFR, thus interfering with the epidermal growth factor pathway. Although in one randomized trial, the addition of cetuximab to chemotherapy improved OS by approximately a month in treatment-naïve patients with advanced NSCLC [70], three other trials did not show statistically significant OS benefits, and none of the four trials demonstrated statistically significant improvements in PFS [71-73]. Cetuximab is associated with significant increases in the incidence of rash, febrile neutropenia, diarrhea, and infusion-related reactions.
●Necitumumab – Necitumumab is a monoclonal antibody that targets the EGFR, which is detectable in most cases of advanced squamous cell NSCLC. Although necitumumab is approved for use in combination with gemcitabine and cisplatin for first-line treatment of patients with metastatic squamous cell lung cancer, we prefer the incorporation of immunotherapy, as discussed above, rather than necitumumab. Although one randomized trial of almost 1100 patients with squamous cell carcinoma demonstrated an approximate OS benefit of 1.5 months with the addition of necitumumab to a platinum-based doublet [74], a second trial did not [75]. Toxicities among those receiving necitumumab were greater in both trials, specifically hypomagnesemia, skin rash, and venous thromboembolism.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Non-small cell lung cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Non-small cell lung cancer treatment; stage IV cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Overview – Systemic therapy (chemotherapy, immunotherapy or targeted therapy) can significantly prolong overall survival and help to maintain quality of life of patients who present with stage IV non-small cell lung cancer (NSCLC) or who develop advanced disease following their initial definitive treatment. (See "Overview of the initial treatment of advanced non-small cell lung cancer".)
●Molecular characterization of tumor – Patients with advanced NSCLC should have tumor assessed for the presence of a somatic driver mutation (eg, epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK] fusion oncogene, ROS1 and BRAF V600E) and for expression of programmed cell death-ligand 1 (PD-L1). The choice of initial therapy (chemotherapy versus molecularly targeted agents versus immunotherapy) is guided by this information. This information is also useful in guiding subsequent therapy. (See 'Molecular characterization of tumor' above and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer" and "Management of advanced non-small cell lung cancer lacking a driver mutation: Immunotherapy", section on 'Chemotherapy-naive' and "Management of advanced non-small cell lung cancer lacking a driver mutation: Immunotherapy", section on 'Factors in choosing initial therapy'.)
●Immunotherapy only for most PD-L1-high tumors – For most patients without a targetable driver alteration in whom at least 50 percent of tumor cells stain for PD-L1, we opt for pembrolizumab monotherapy rather than chemotherapy (with or without immunotherapy). However, for patients with rapidly progressive disease, or such a high tumor burden that early progression might lead to a functional decline that would preclude chemotherapy in the second-line setting, we offer the combination of pembrolizumab with chemotherapy. (See "Management of advanced non-small cell lung cancer lacking a driver mutation: Immunotherapy", section on 'PD-L1-high tumors (at least 50 percent)'.)
We recognize that chemotherapy with pembrolizumab has not been directly compared with pembrolizumab monotherapy, and therefore some experts may reasonably offer the combination of chemotherapy and pembrolizumab more broadly, even among those with high PD-L1 expression.
●Incorporation of chemotherapy for PD-L1-low or intermediate tumors – For patients with PD-L1 expression <50 percent, lacking contraindications to immunotherapy (connective tissue, interstitial lung, or rheumatologic disease),
•Who have nonsquamous cancers, we use carboplatin and pemetrexed in combination with pembrolizumab, with pemetrexed and pembrolizumab maintenance upon completion of the initial four to six cycles.
•Who have squamous cancers, we use a combination of pembrolizumab, carboplatin, and either paclitaxel or nabpaclitaxel, with pembrolizumab maintenance after the initial four to six cycles. (See 'Approach' above.)
●Preference for platinum-based regimens as initial therapy – Combinations using cisplatin have a slightly higher response rate but inconsistent survival benefits compared with carboplatin-based regimens. For the majority of patients who will receive a chemotherapy doublet, we suggest using a carboplatin-based regimen (Grade 2C). However, a cisplatin-based regimen is a reasonable alternative in appropriate patients. (See 'Cisplatin versus carboplatin' above and 'Preference for platinum-based regimens' above.)
We recommend that the duration of treatment with the initial doublet chemotherapy regimen be limited to four to six cycles (Grade 1A). (See 'Approach' above.)
●Maintenance therapy – For patients without a driver mutation with an objective response following the initial cycles of platinum-based chemotherapy, we suggest that patients continue on maintenance therapy (Grade 2B). Options include single-agent chemotherapy, and if they were components of the initial treatment, pembrolizumab or bevacizumab. (See 'Maintenance therapy' above.)
●Progressive disease – For patients who have progressed on immunotherapy, combination chemotherapy, and targeted agents (if applicable) and remain candidates for further treatment, we opt for single-agent chemotherapy.
•For patients with nonsquamous tumors receiving single-agent chemotherapy as a subsequent-line option, we suggest pemetrexed if this agent has not been previously utilized (Grade 2B). For such patients who have previously received pemetrexed, we use docetaxel.
•For patients with squamous tumors receiving single-agent chemotherapy, we suggest docetaxel (Grade 2C), with or without ramucirumab. (See 'Docetaxel' above.)
