Version May 2024
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".)
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. 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.
Despite advances in the initial treatment of advanced NSCLC, trials suggest that the median time to progression on initial chemoimmunotherapy is on the order of six to ten months. This topic will review appropriate next line therapy in patients whose cancers lack a targetable driver mutation.
The issues surrounding the indications and choice of the initial chemotherapy and immunotherapy, or targeted therapy (if appropriate), 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".)
●(See "Initial management of advanced non-small cell lung cancer lacking a driver mutation".)
PATIENTS TREATED WITH INITIAL IMMUNOTHERAPY ONLY — Data are evolving in regards to management of resistance to programmed cell death protein 1 (PD-1) axis inhibitors. Our approach is as follows.
Platinum-based doublet, for most patients — In general, patients who have progressed on a checkpoint inhibitor may be offered chemotherapy upon progression, with a platinum-based doublet, if they are chemotherapy naïve.
Data regarding platinum-based chemotherapy were largely conducted prior to the era of immunotherapy. These data are discussed in detail elsewhere. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'Choice of chemotherapy to pair with checkpoint inhibitor'.)
Possible exceptions
Long interval between immunotherapy and progression — If progression occurs several months or years after the last dose of PD-1 or programmed cell death ligand 1 blockade, rechallenge may be attempted, as responses have been reported [1,2]. A reasonable time period might be at least six months since last immune checkpoint inhibitors (ICI) therapy, although data are limited to support any specific timeframe.
●Results from randomized trials suggest benefit in patients with immunotherapy rechallenge among patients who discontinued at two years without progression. As an example, in KEYNOTE-024, among 12 patients who received a second course of pembrolizumab, four had an objective response (33 percent) and six patients (50 percent) had stable disease as their best response [3].
●In a retrospective study in 59 patients with advanced NSCLC who had achieved complete response, partial response, or stable disease for ≥6 months with ICI therapy and experienced subsequent progression, nivolumab retreatment demonstrated an objective response rate of 8.5 percent (5 patients) [2]. Although median progression-free survival (PFS) was 2.6 months overall, the median PFS among the five responders was 11.1 months. On multivariate analysis, ICI-free interval was a predictive factor of PFS (hazard ratio [HR] 2), while prior efficacy was not.
Oligometastatic disease — If progression on a PD-1 axis inhibitor after initial response is limited to one or two sites ("oligoprogression"), local therapy to the site(s) of progression (ie, radiation, thermal ablation, or surgery) with continuation of systemic therapy with the PD-1 axis inhibitor may represent an alternative to salvage systemic therapy, recognizing that data supporting this approach are limited. In a retrospective analysis of 26 patients with acquired resistance to PD-1 axis inhibitor therapy, 88 percent had recurrence limited to one or two sites [4]. Fifteen patients (58 percent) received local therapy to site(s) of oligoprogression without initiation of salvage systemic therapy; 11 continued their respective PD-1 axis inhibitor after local therapy. The two-year survival rate among these 15 patients was 92 percent.
PATIENTS TREATED WITH INITIAL CHEMOIMMUNOTHERAPY — When progressive disease develops during or after initial chemotherapy and immunotherapy, 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 initial chemoimmunotherapy who remain candidates for treatment, the appropriate next option is single-agent chemotherapy (with or without ramucirumab, if docetaxel is selected as the chemotherapy agent). (See 'Docetaxel (with or without ramucirumab)' below.)
We typically do not incorporate immunotherapy into the subsequent line management for patients receiving immunotherapy in the frontline. Data regarding ramucirumab and pembrolizumab after progression on immunotherapy are discussed below, although this strategy remains investigational. (See 'Patients treated with initial immunotherapy only' above.)
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.
Nonsquamous histology
Pemetrexed or docetaxel (with or without ramucirumab) — Among patients with nonsquamous histology, either pemetrexed or docetaxel is an appropriate later line option. However, we typically prefer pemetrexed for patients who have not been treated with this agent previously given a favorable side effect profile. Pemetrexed should be administered with folic acid and vitamin B12 to decrease the incidence of hematologic toxicity. For patients who have received pemetrexed in an earlier line of treatment, we utilize docetaxel (with or without ramucirumab). (See 'Docetaxel (with or without ramucirumab)' below and 'Gemcitabine' below.)
In a phase III trial in patients with recurrent NSCLC, docetaxel versus pemetrexed resulted in similar objective response rate (9 percent for both agents) and overall survival (OS; 8 months in each group) [5,6]. 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 was less effective in patients with squamous carcinomas [7]. 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.
Squamous histology — Subsequent line chemotherapy options, in patients whose initial treatment included chemotherapy, have only limited efficacy. Participation in a clinical trial or supportive care alone are acceptable strategies.
Docetaxel (with or without ramucirumab) — Docetaxel has demonstrated activity both among patients with nonsquamous and squamous histologies who have progressed on prior platinum-based chemotherapy. Some UpToDate providers offer ramucirumab to patients with a good performance status, given a modest, but statistically and arguably clinically significant, improvement in OS. However, others tend to avoid it, given the relatively small observed benefits and associated toxicities.
●Ramucirumab plus docetaxel – Ramucirumab, a monoclonal antibody that targets the vascular endothelial growth factor receptor 2, is the only agent that has been shown in a randomized trial to improve OS when added to chemotherapy in the second-line setting (10.5 versus 9.1 months with docetaxel alone; HR 0.86, 95% CI 0.75-0.98) [8,9]. However, it increases the rates of bleeding and hypertension and, rarely, can cause intestinal perforation and arterial thrombosis.
●Docetaxel alone – Subsequent line docetaxel has been shown in a randomized trial to improve OS relative to supportive care by 2.9 months, with less deterioration in quality of life [10,11]. Severe or significant toxicities of treatment include neutropenia, febrile neutropenia, pneumonitis, stomatitis, diarrhea, excessive tearing, and neuropathy. Administration of docetaxel on a weekly schedule, rather than every three weeks, may minimize some toxicities (eg, hematologic), although others may be more frequent (eg, excessive tearing) [12]. 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' and "Ocular side effects of systemically administered chemotherapy", section on 'Epiphora and docetaxel'.)
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 [13]. 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.
Retreatment with initial treatment, as an alternative in select patients — In general, patients who have progressed after one chemotherapy or chemoimmunotherapy regimen are treated with a noncross-resistant regimen. However, for patients who have responded to an initial regimen and are stable for at least six months after discontinuation, we offer retreatment with the same regimen upon progression, particularly for those with a good performance status. 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 [14]. 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.
Investigational approaches — Many strategies are being investigated in advanced NSCLC. As examples:
●Ramucirumab plus pembrolizumab – Ramucirumab plus pembrolizumab has shown promising results after progression on an immune checkpoint inhibitors (ICI); however, this approach remains investigational, pending further data.
In a randomized phase II trial, among 136 patients with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 12 weeks after initiation of ICI, those assigned to ramucirumab plus pembrolizumab experienced an improved OS relative to investigator's choice standard treatment (14.5 versus 11.6 months, HR 0.80, 95% CI 0.51-0.92) [15]. Progression-free survival and response rates were similar between arms. Grade ≥3 treatment related adverse events occurred in 42 percent of patients receiving ramucirumab plus pembrolizumab and 60 percent in the standard treatment arm. Preliminary data also suggest activity of cabozantinib, with or without atezolizumab, in patients with advanced NSCLC previously treated with ICI [16]. Further data are needed prior to routine clinical use of these approaches, and phase III trials evaluating them are ongoing.
●Tumor Treating Fields – Tumor Treating Fields (TTFields) are electric fields that are delivered locoregionally and noninvasively to the tumor site via two pairs of arrays placed on the skin of the patient's thorax. In a randomized trial in patients with progression on previous platinum-based chemotherapy, use of TTFields in addition to standard systemic therapy improved overall survival relative to systemic therapy alone (13.2 versus 9.9 months; HR 0.74, 95% CI 0.56-0.98), but increased the rate of serious adverse events (53 versus 38 percent) [17]. Several features limit the broad application of findings from this trial. Benefit observed was limited to the subset of patients who received TTFields with an immune checkpoint inhibitor in the second-line; benefit was not observed in those who received TTFields combined with docetaxel-based chemotherapy. However, in contemporary practice, immunotherapy is typically included in first-line treatment and not deferred as later line monotherapy. Moreover, application of TTFields is cumbersome, requiring wearing an apparatus and carrying a battery pack for the majority of the day, making it unappealing or not feasible for many patients.
DURATION OF TREATMENT — 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 performance status, at the discretion of the treating clinician and depending on patient preferences.
SPECIAL CONSIDERATIONS
Older and medically complicated 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. The approach to older patients with NSCLC is discussed in detail elsewhere. (See "Systemic chemotherapy for cancer in older adults" and "Systemic chemotherapy for cancer in older adults", section on 'Palliative chemotherapy'.)
In a subset analysis of a trial comparing pemetrexed and docetaxel in previously treated patients [5,6], both agents were well tolerated in patients 70 years of age or older who had received prior chemotherapy [18]. 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).
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 [19]. 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 patients with chemotherapy-naϊve, first-line NSCLC. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'Immunotherapy'.)
●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 performance status. For example, a patient with a good performance status 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'.)
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 – Despite advances in the initial treatment of advanced non-small cell lung cancer (NSCLC), trials suggest that the median time to progression on initial chemoimmunotherapy is on the order of six to ten months. The treatment upon progression depends upon the initial treatment strategy, as well as on patient and disease factors. (See 'Introduction' above.)
●Patients initially treated with immunotherapy only – For most patients who have experienced progression on checkpoint inhibitor monotherapy, we suggest a platinum based doublet (Grade 2C). Possible exceptions to this approach include those with a long interval between the last dose of immunotherapy and progression, and those with oligometastatic disease, with progression in a small number of sites. (See 'Patients treated with initial immunotherapy only' above.)
●Duration of therapy – 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 CT, with additional imaging of metastatic sites, as warranted.
●Patients treated with initial chemotherapy and immunotherapy – For most patients who experience progression on initial chemotherapy and immunotherapy, options include pemetrexed (if nonsquamous histology) or docetaxel, with or without ramucirumab. Participation in a clinical trial or supportive care are also appropriate options; or we choose an agent from a class that has not previously been used for a given patient, also considering toxicity profiles.
●Special considerations for older adults – 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. The approach to older patients with NSCLC is discussed in detail elsewhere. (See "Systemic chemotherapy for cancer in older adults" and "Systemic chemotherapy for cancer in older adults", section on 'Palliative chemotherapy'.)
●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 "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'Carboplatin typically preferred over cisplatin'.)
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