Conor E. Steuer and Suresh S. Ramalingam

INTRODUCTION

At least 50% of patients with non–small-cell lung cancer (NSCLC) have advanced stage IV disease at the time of diagnosis. Advanced-stage NSCLC includes patients with distant metastatic disease, contralateral pulmonary involvement, and/or malignant pleural or pericardial effusions. Systemic therapy is the primary treatment modality for patients with stage IV NSCLC. Systemic therapy options now include cytotoxic chemotherapy, molecularly targeted therapy, and immunotherapy. The main goal of systemic therapy for stage IV disease is to palliate symptoms and improve survival. In many patients, radiotherapy may be given to improve symptoms such as hemoptysis, pain, or dyspnea. The armamentarium of systemic agents has increased rapidly for patients for advanced NSCLC, highlighted by the fact that the U.S. Food and Drug Administration (FDA) approved six new drugs for lung cancer in 2015. The choice of therapy in an individual patient is based on many factors, including histology, genomic status, performance status, toxicity, cost, and patient preference.

BIOMARKER TESTING

Important discoveries in the molecular biology of NSCLC have allowed for the identification of several oncogenic drivers important in tumor pathogenesis, such as mutations in the epidermal growth factor receptor (EGFR) gene, or rearrangement of the ALK and ROS1 genes. This has led to the development of targeted therapies for patients with NSCLC that harbors these genetic biomarkers, bringing precision medicine to the clinic. Therefore, it is important that the first step in the care for a patient with newly diagnosed metastatic NSCLC is consideration for biomarker analysis.

Thus far, driver mutations are recognized as therapeutic targets only in lung adenocarcinomas. Therefore, squamous cell carcinomas (SqCC) are not typically tested (1). However, SqCCs in nonsmokers and mixed-histology tumors with an adenocarcinoma component should be considered for molecular testing. Biomarker analysis consists of mutation testing by multiplex genotyping and molecular FISH analysis. While testing of EGFR, ALK, and ROS-1 can be considered the current minimal standard-of-care, more extensive testing is often being performed as new potential targets are rapidly being identified. Molecular testing has been shown to be feasible on a large scale, and aids clinicians with decisions on therapy (2). Finally, if available tumor biopsies are insufficient for molecular testing and obtaining another biopsy is not feasible, then plasma cell-free DNA testing might provide another avenue to ascertain the presence of driver mutations (3).

CHEMOTHERAPY

The role of chemotherapy in advanced NSCLC was clearly established in multiple randomized studies. Comparisons of platinum-based therapy to supportive care alone resulted in modest improvements in survival and quality of life (4). A meta-analysis published in 1995 demonstrated an absolute improvement in the 1-year overall survival rate of approximately 10% with platinum-based chemotherapy over supportive care alone (5). These data ushered in the era of systemic therapy for patients with advanced-stage NSCLC. Subsequently, several newer agents with a variety of mechanisms of action were demonstrated to be active in NSCLC, including: paclitaxel and docetaxel (microtubule-stabilizing agents); vinorelbine (vinca alkaloid); gemcitabine (ribonucleotide reductase inhibitor); irinotecan (topoisomerase I inhibitor); and pemetrexed (multitargeted antifolate). Each of these agents is associated with a single-agent response rate of 10% to 30% in patients with advanced NSCLC. Combination of these third-generation agents with cisplatin or carboplatin results in an incremental improvement in response rates and overall survival over monotherapy. Therefore, a number of combination regimens are now available for the treatment of patients with advanced-stage NSCLC.

Combination Regimens

The ECOG1594 study demonstrated comparable efficacy of four different platinum-based, two-drug chemotherapy regimens (cisplatin plus paclitaxel; carboplatin plus paclitaxel; cisplatin plus docetaxel; cisplatin plus gemcitabine) in 1,207 patients with a good performance status and advanced NSCLC, yielding response rates of 17% to 22%, median overall survival of 7.9 months, and 1-year survival rates of 30% to 40%. Despite a mild increase in progression-free survival (PFS) with cisplatin plus gemcitabine over the other regimens (median, 4.2 vs. 3.1–3.7 months), there were no significant differences in overall survival (6). Other contemporary studies demonstrated similar results and provided evidence of comparable efficacy among various two-drug combination regimens. From these observations, it was concluded that a therapeutic plateau had been reached for chemotherapy in advanced NSCLC.

Many studies have demonstrated that the addition of a third cytotoxic agent results in increased toxicity without an improvement in survival. Therefore, such regimens are not recommended for patients with advanced NSCLC. A large systematic review of 65 randomized trials comparing a two-drug regimen to either a single-agent or a three-drug regimen for patients with advanced NSCLC demonstrated that adding a second drug increased both the response rate (26% vs. 13%, P < .001) and overall survival (1-year, 35% vs. 30%, P < .001) over single-agent therapy. However, adding a third drug only increased toxicity, primarily infections, myelosuppression, and mucositis, without improving overall survival (1-year, OR 1.01, P = .88) (10).

Nonplatinum regimens have been extensively studied as alternatives to platinum-based chemotherapy, but have not provided added value (11). For example, a phase III study found that cisplatin plus docetaxel was equivalent to gemcitabine plus docetaxel (response rate, 32% vs. 30%; median PFS, 8 vs. 9 months; overall survival, 10 vs. 9.5 months) (12). Similarly, a three-arm study found comparable activity between cisplatin plus paclitaxel, cisplatin plus gemcitabine, and gemcitabine plus paclitaxel (response rate, 32% vs. 37% vs. 28%; median overall survival, 8.1 vs. 8.9 vs. 6.7 months) (13). In addition, there were no salient differences in toxicity, so it appears that nonplatinum, two-drug regimens do not provide any advantage over platinum-based regimens.

Non-Squamous NSCLC

Until recently, all histological sub-types of NSCLC were treated with the same platinum-based regimens. The role of histology in differential sensitivity to chemotherapy was first demonstrated in a randomized phase III study that compared cisplatin plus pemetrexed to cisplatin plus gemcitabine in patients with advanced NSCLC of any histology. In the overall study population, the efficacy of both regimens was comparable (median overall survival, 10.3 months in both arms), but cisplatin plus pemetrexed was superior in the subset of patients with non-squamous histology (median overall survival, 11.8 vs. 10.4 months, P = .005). Conversely, in patients with SqCC, cisplatin plus pemetrexed resulted in less favorable outcomes (median overall survival, 9.4 vs. 10.8 months, P = .05) (14). Based on these data, cisplatin plus pemetrexed is approved for use only in patients with nonsquamous NSCLC.

Two other studies that compared a pemetrexed-based regimen to a taxane-based regimen in patients with non-squamous NSCLC demonstrated comparable efficacy (15,16). A phase III study comparing carboplatin, paclitaxel, and bevacizumab to carboplatin, pemetrexed, and bevacizumab reported no difference in overall survival (median, 13.4 vs. 12.6 months, HR 1.0, P = .949), with only slight differences in toxicity between the two regimens. Similarly, an Asian study demonstrated similar efficacy between cisplatin plus docetaxel versus cisplatin plus pemetrexed (median PFS, 4.7 vs. 4.6 months) (17). Therefore, platinum-based regimens with either pemetrexed or one of the taxanes are deemed appropriate for the treatment of patients with non-squamous NSCLC.

Anti-Angiogenic Therapy

Bevacizumab is a humanized, monoclonal antibody that targets vascular endothelial growth factor A. The benefit of bevacizumab in NSCLC was shown in two phase III randomized clinical trials. E4599 examined carboplatin plus paclitaxel versus carboplatin, paclitaxel, and bevacizumab 15 mg/kg followed by maintenance bevacizumab in patients with advanced NSCLC patients. The addition of bevacizumab improved overall survival (median, 12.3 vs. 10.3 months, P = .003), PFS (median, 6.3 vs. 4.8 months), and response rate (35% vs. 15%) (18). The AVAiL study evaluated cisplatin plus gemcitabine alone or with bevacizumab at two doses (7.5 mg/kg or 15 mg/kg) and documented a minor improvement in PFS with bevacizumab (6.7 vs. 6.1 months, P = .003), but this did not translate to an overall survival benefit (19). The main toxicities associated with bevacizumab include hypertension, proteinuria, and bleeding. Of note, patients with SqCC were excluded from these studies based on a significantly increased rate of pulmonary hemorrhage in those treated with bevacizumab in a previous phase II study (20). Bevacizumab at 15 mg/kg is now an FDA-approved option in combination with a platinum-based, two-drug regimen in patients with advanced non-squamous NSCLC. Salient exclusion factors for the use of bevacizumab are hemoptysis, cavitary lung lesions, older patients (>75 years old), and recent mediastinal radiation therapy (RT). Unfortunately, there are presently no proven biomarkers for the selection of patients who are most likely to benefit from bevacizumab. For patients who have continued control of disease after receiving a maximum of six cycles of chemotherapy plus bevacizumab, bevacizumab can be continued as maintenance therapy until progression of disease. The role of continuation of bevacizumab beyond progression after first-line therapy is unproven and is therefore not recommended. The modest success achieved with bevacizumab led to the evaluation of several VEGF-receptor inhibitors in NSCLC, but clinical trials with these agents have failed to demonstrate an improvement in efficacy in the first-line setting.

Squamous Cell Carcinoma

Necitumumab

While pemetrexed and bevacizumab are not used in SqCC, necitumumab, an anti-EGFR monoclonal antibody, has recently been approved by the FDA in combination with chemotherapy for first-line treatment. In a large, phase III clinical trial, patients with SqCC were randomized to receive cisplatin plus gemcitabine with or without necitumumab. The addition of necitumumab resulted in a modest improvement in overall survival (median, 11.5 vs. 9.9 months, HR 0.84, P = .01), although both response rate and PFS were not significantly improved. The main side effects associated with necitumumab include rash and hypomagnesemia. The incidence of thromboembolic events was also higher with necitumumab (21). Although the level of EGFR protein expression by immunohistochemistry was not predictive of benefit with necitumumab, high EGFR gene copy number was associated with a better outcome with necitumumab in a subset analysis and warrants prospective evaluation in future clinical trials.

Nab-Paclitaxel

Nab-paclitaxel was developed in an effort to improve the safety profile of standard-formulation paclitaxel and to obviate the need for steroid premedication. Comparative studies of carboplatin plus nab-paclitaxel versus carboplatin plus paclitaxel have demonstrated a modest increment in response rate (33% vs. 25%, P = .005) and a more favorable toxicity profile. The improvement in response rate was more pronounced in patients with SqCC versus non-squamous histologies (41% vs. 24%, P < .001), though there was no difference in overall survival (12.1 vs. 11.2 months, P = .271) (22).

Biomarkers in SqCC

While biomarker testing is not as well defined in SqCC as in adenocarcinoma, investigations are underway to define predictive biomarkers for targeted therapy for these patients. One example is the LUNG-MAP multi-cooperative group umbrella trial, which tests SqCC tumors for derangements of biomarkers such as CCND1, PIK3CA, and FGFR and pairs patients with such abnormalities with investigational targeted agents (23). This design is intended to expedite the development of new drugs for the SqCC patient population.

Cisplatin Versus Carboplatin

Both cisplatin and carboplatin have been extensively studied in combination regimens for the treatment of advanced NSCLC, with the higher toxicity associated with cisplatin driving the interest in carboplatin-based regimens. Initial studies that compared cisplatin-based regimens directly to carboplatin-based regimens yielded mixed results. Subsequently, a meta-analysis of such randomized studies noted comparable survival between cisplatin and carboplatin-based regimens, when given in combination with a third-generation cytotoxic agent (median overall survival, 9.1 vs. 8.4 months, P = .1) with a slight advantage in response rate for cisplatin-based regimens (30% vs. 24%, P < .001) (24). In the United States, carboplatin-based regimens are used commonly for patients with advanced NSCLC. Given that the primary goal of treatment is palliation, the modest potential advantage in activity of cisplatin over carboplatin is counterbalanced by the lower toxicity of the later. In recent years, improvements in antiemetic therapy have lessened some of the toxicity of cisplatin-based regimens, but ototoxicity, neurotoxicity, and nephrotoxicity remain significance concerns. For younger patients with good renal function, cisplatin-based regimens may be used, but in general, carboplatin seems to be the more reasonable choice in a palliative setting. The recommended dose of cisplatin is 75 mg/m² given every 3 weeks, since higher doses do not result in improved efficacy, but add considerable toxicity.

Table 8.1 provides a list of commonly used chemotherapy regimens for patients with advanced NSCLC. The choice of the second agent added to cisplatin or carboplatin should be individualized based on histology (non-squamous vs. squamous), preference for infusion schedule (e.g., every 3 weeks with pemetrexed or paclitaxel vs. multiweek infusions for gemcitabine), and toxicity. For example, severe renal insufficiency would exclude pemetrexed, while a preexisting neuropathy would make paclitaxel a less favorable choice.

Duration of Combination Chemotherapy

The optimal number of cycles of primary chemotherapy for the treatment of metastatic NSCLC has been established in a series of randomized clinical trials.

Therefore, four cycles is the accepted standard duration for first-line platinum-based chemotherapy in advanced NSCLC, with a consideration of two additional cycles if response is on-going after four cycles. However, the consideration for continuing combination chemotherapy beyond four cycles must be balanced against the cumulative toxicity of such regimens.

Maintenance Therapy

Maintenance therapy has been evaluated as a strategy to improve survival without undue toxicity in patients who benefit from first-line therapy. There are two main strategies for maintenance therapy: switch maintenance and continuation maintenance. Switch maintenance utilizes an agent not used in the first-line platinum-based chemotherapy regimen in an effort to prevent resistance, while continuation maintenance continues one or more of the agents used in the first-line regimen. The potential benefits of continuation maintenance are that the drug was already known to be part of an effective regimen for the patient, so maintenance therapy could presumably prolong that benefit. Switch maintenance was developed to delay resistance and progression by adding a different systemic agent. In both situations, maintenance therapy is started immediately after completion of the first-line course of treatment in patients with response or stability and good performance status.

Bevacizumab

In the E4599 trial discussed earlier, patients who received carboplatin, paclitaxel, and bevacizumab followed by bevacizumab maintenance therapy did better than those getting carboplatin plus paclitaxel alone. These results made continuation maintenance with bevacizumab a viable option, although the specific contribution of the maintenance therapy was not examined (18). For patients who are treated with chemotherapy plus bevacizumab as first-line treatment, continuation maintenance with bevacizumab is an appropriate option.

Pemetrexed

Pemetrexed has been studied in the maintenance setting. In the JMEN phase III trial of switch maintenance, patients with advanced NSCLC that had not progressed after platinum-based, two-drug therapy were randomized to switch maintenance with pemetrexed versus placebo until disease progression. Pemetrexed maintenance significantly improved both PFS (median, 4.3 vs. 2.6 months, HR 0.50, P < .0001) and overall survival (median, 13.4 vs. 10.6 months, HR 0.79, P = .012), and was well tolerated (27). In the PARAMOUNT phase III, continuation maintenance study, patients with advanced non-squamous NSCLC were initially treated with cisplatin plus pemetrexed and those without progression were then randomized to receive either supportive care or continuation of pemetrexed therapy. Again, pemetrexed was associated with improvements in PFS (median, 4.1 vs. 2.8 months, P = .0001) and overall survival (median, 13.9 vs. 11.0 months, P = .0195), while preserving quality of life (28–30). Based on these two trials, pemetrexed was approved by the FDA for both switch and continuation maintenance therapy.

Pemetrexed Plus Bevacizumab

The AVAPERL trial provided further insight into the validity of continuation maintenance therapy with both pemetrexed and bevacizumab in advanced NSCLC. In this trial, all patients received cisplatin, pemetrexed, and bevacizumab followed by maintenance with either pemetrexed plus bevacizumab or bevacizumab alone. While PFS was significantly improved with pemetrexed plus bevacizumab maintenance (median, 7.4 vs. 3.7 months, HR 0.48, P < .001), there was no significant difference in overall survival (median, 17.1 vs. 13.2 months, P = .29) (15,31). The question of whether pemetrexed, bevacizumab, or the combination of the two is the best maintenance treatment for advanced lung adenocarcinoma is currently unknown, and will be answered in the ongoing clinical trial, E5508 (NCT01107626).

Erlotinib

Erlotinib has been approved by the FDA for maintenance therapy based on the results of the SATURN trial, in which patients with advanced NSCLC were treated with platinum-based chemotherapy × four cycles and then randomized to receive either placebo or erlotinib until progression. While there was a modest, but statistically significant, improvement in PFS with erlotinib (12.3 vs. 11.1 weeks, P < .0001), the clinical significance of this finding is unclear (32). In addition, the relevance of this trial has now declined given the high prevalence of upfront EGFR mutation testing and the use of first-line targeted therapy for patients with a sensitizing EGFR mutation. For patients with wild-type EGFR, the efficacy of erlotinib is relatively modest with limited potential to improve outcomes.

Recommendations for Maintenance Therapy

•    Maintenance therapy can be considered for patients who achieve a response or have stable disease with platinum-based combination regimens.

•    The decision on whether or not to initiate maintenance therapy should be based on performance status, disease-related symptoms, and tolerance of prior chemotherapy, disease burden, and patient preference.

•    Pemetrexed is approved as both switch and continuation maintenance therapy in patients with non-squamous NSCLC, while bevacizumab can be used as continuation maintenance in these patients.

•    Erlotinib is approved for switch maintenance therapy in patients with any histology based on a very modest improvement in outcome.

•    Patients who do not receive maintenance therapy should undergo close radiographic surveillance every 2 to 3 months with initiation of second-line therapy upon evidence of progressive disease.

TARGETED THERAPY

EGFR-Mutated NSCLC

The discovery of oncogenic driver mutations in NSCLC and the subsequent development of targeted therapy have resulted in a major paradigm shift in the treatment of patients with NSCLC. EGFR-mutated NSCLC has emerged at the forefront of precision medicine. Prior to the discovery of EGFR mutations, the EGFR signaling pathway was known to be up-regulated in NSCLC and was believed to play an important role in pathogenesis and disease progression (33,34). Therefore, specific EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib, were developed and evaluated in NSCLC (35–37).

Erlotinib first received FDA approval based on the BR.21 trial, which reported an overall survival benefit with erlotinib over placebo in unselected patients with previously treated advanced NSCLC (median, 7.0 vs. 4.7 months, HR 0.70, P < .001) (38). Several groups subsequently identified mutations in the EGFR gene that predicted response to EGFR TKIs (39–41). Specifically, deletions in exon 19, the exon 21 L858R point mutation, and the less frequent deletions in exon 18 were shown to be predictive biomarkers. Sensitizing EGFR mutations are found in 10% to 15% of lung adenocarcinomas in the U.S. population (2). With this new information, development of EGFR TKIs focused on the selection of patients with sensitizing EGFR mutations. While EGFR mutations are found more commonly in patient subgroups with specific clinical features (i.e., women, adenocarcinoma histology, never-smokers, East Asian ethnicity), patient selection for first-line use of EGFR TKIs should not be based on these parameters since they have a greater chance of having wild-type EGFR than an EGFR mutation and chemotherapy is superior to EGFR TKIs in patients with wild-type EGFR. Therefore, molecular testing for identification of EGFR mutations should be performed in all patients with stage IV lung adenocarcinoma, and an EGFR TKI should be used as first-line therapy for patients with a known sensitizing mutation.

Gefitinib and erlotinib are first-generation EGFR TKIs, and afatinib is considered a second-generation agent. Erlotinib and gefitinib are reversible inhibitors of the EGFR kinase domain, while afatanib is an irreversible inhibitor of several ErbB family members. Clinical trials that compared an EGFR TKI to chemotherapy in patients with sensitizing EGFR mutations have consistently demonstrated superior response rates (55%–65%) and PFS (9–13 months) with targeted therapy (Table 8.2). The PFS benefit did not generally translate into an improvement in overall survival in these studies due to the high prevalence of cross over from chemotherapy to an EGFR inhibitor upon disease progression. However, a pooled subset analysis of two afatinib versus chemotherapy trials did demonstrate improved overall survival with afatinib in patients with exon 19 deletions, but not in those with L858R mutations.

A recent study compared gefitinib 250 mg/day to afatinib 40 mg/day as front-line therapy in patients with EGFR-mutated NSCLC, and demonstrated an improved response rate (70% vs. 56%, P = .008) and PFS (median, 11 vs. 10.9 months, HR = 0.73, P = .016) with afatinib (42). This modest clinical benefit should be balanced with the higher incidence of skin and mucosal toxicity with afatinib when selecting therapy for patients with a sensitizing EGFR mutation, since nearly 40% of patients treated with afatinib required a dose–reduction to 30 mg/day.

Treatment with an EGFR TKI should be continued until clinically significant progression of disease. If progression is limited to one or two sites, the use of local therapy, such as RT, followed by continuation of the EGFR TKI is a reasonable approach. Similarly, for patients who develop progression only in the brain, the EGFR TKI can be continued after appropriate local therapy.

The most common side effects seen with EGFR TKIs are rash, nail changes/paronychia, diarrhea, and increased liver enzymes. Skin toxicities are typically managed with a combination of topical steroids and topical or oral antibiotics based on severity. Diarrhea usually responds to antidiarrheal medications. Dose–reductions may also be used in conjunction with appropriate supportive care measures to improve quality of life and tolerance of therapy.

Resistance

Despite the impressive responses seen with EGFR TKIs in patients with sensitizing mutations, the typical time to progression is only 9 to 13 months (43,44). Research into the mechanisms of resistance to the first- and second-generation EGFR TKIs revealed that approximately 60% of patients develop a secondary exon 20 T790M mutation, which adds a bulky methionine residue within the tyrosine kinase domain, thereby inhibiting EGFR TKI binding (45). Additional mechanisms of resistance include MET amplification, epithelial-to-mesenchymal transition, activation of the PI3K pathway, and histological transformation to small cell carcinoma (2%–5%) (45,46). Patients who progress on a first-line EGFR TKI should undergo repeat biopsy for evaluation for the T790M mutation since third-generation EGFR TKIs with activity against this mutation are now available.

Third-Generation EGFR TKIs

The third-generation EGFR TKIs have been developed specifically to target the T790M resistance mutation. Osimertinib is an orally administered, irreversible, mutation-specific EGFR inhibitor that was recently approved by the FDA for patients with T790M-mediated resistance to first-line TKI therapy. In a phase I study, osimertinib demonstrated a response rate of 64% in patients with tumors harboring a T790M mutation, with a median PFS of 10 to 13 months. Due to greater selectivity for the mutant receptor relative to the wild-type receptor, osimertinib is associated with considerably less skin and GI toxicity than first-generation EGFR TKIs (47). Other T790M-selective inhibitors are in clinical development. For patients with T790M-negative recurrence, chemotherapy utilizing a standard first-line regimen remains a reasonable option.

Recommendations for EGFR-Mutated NSCLC

•    Molecular testing should be conducted for all patients with stage IV lung adenocarcinoma and for never-smokers with any histologic subtype.

•    For patients with EGFR exon 19 deletions or L858R mutations, a first or second generation TKI is recommended as first-line therapy (erlotinib 150 mg/day, gefitinib 250 mg/day, afatinib 40 mg/day).

•    A repeat biopsy for T790M testing is recommended for patients who develop acquired resistance to first-line EGFR TKI therapy.

•    Osimertinib (80 mg/day) is approved for patients’ tumors harboring a T790M mutation.

•    Chemotherapy is recommended for patients with T790M-negative tumors after progression on a first-line EGFR TKI.

ALK-Rearranged NSCLC

The EML4-ALK rearrangement that occurs in 3% to 6% of patients with NSCLC defines another molecular subset of patients that benefit from targeted therapy (48). Nearly all patients with ALK-rearranged NSCLC have adenocarcinoma and are never or light-former smokers. Initially reported in 2007, an inversion within the short arm of chromosome 2 leads to a fusion protein in which the N-terminal domain of the EML4 is joined to the intracellular kinase domain of ALK, leading to an oncogenic, constitutive activation of the ALK signal transduction pathway (49).

Crizotinib

At the time, crizotinib was already in clinical development as a MET inhibitor, so given its known ability to inhibit ALK activity, clinical trials were rapidly designed in this new population. In the expanded phase I study of patients with ALK-rearranged NSCLC, crizotinib demonstrated a response rate of 60%, a disease control rate of 90%, and a median PFS of approximately 10 months, resulting in the approval of crizotinib for treatment of patients with ALK-rearranged NSCLC. In a phase III study, crizotinib was compared to second-line chemotherapy with docetaxel or pemetrexed in patients with ALK-rearranged NSCLC. Both response rate (65% vs. 20%, P < .001) and PFS (median, 7.7 vs. 3.0 months, P < .001) were superior with crizotinib. Another phase III trial reported the superiority of PFS for crizotinib over platinum-based chemotherapy in the first-line setting for patients with ALK-rearranged NSCLC (median, 10.9 vs. 7.0 m, P < .001) (50,51). Common toxicities of crizotinib include visual disturbances, increased liver enzymes, and nausea/vomiting. Supportive medications, dose interruptions, and dose–reductions are the typical interventions used to control these side effects.

Second-Generation ALK Inhibitors

Upon progression, many mechanisms of resistance to crizotinib have been identified, including secondary mutations in the ALK gene. Common acquired resistance mutations include L1196M, G1269A, C1156Y, L1152R, G1202R, S1206Y, and 1151Tins (52). The second-generation ALK TKIs, ceritinib, and alectinib, have been approved for the treatment of patients who develop resistance to crizotinib. Both of these agents are associated with a response rate of 40% to 55% in this setting with a median PFS of 7 to 9 months. Another important advantage of these second-generation agents is their ability to achieve greater activity against brain metastasis. The main side effects of ceritinib are nausea, vomiting, and diarrhea, while alectinib can induce constipation and fatigue (53,54). Table 8.3 summaries selected clinical trials of the FDA-approved ALK inhibitors. Many newer ALK inhibitors are in clinical development.

Recommendations for ALK-Rearranged NSCLC

•    Crizotinib (250 mg BID) is approved for the treatment of ALK-rearranged NSCLC.

•    Ceritinib (750 mg/d) and alectinib (600 mg BID) are preferred options for treatment of acquired resistance to or intolerance of crizotinib.

•    Both ceritinib and alectinib have higher level of activity against brain metastasis than crizotinib.

Uncommon Mutations: BRAF, ROS1, RET, MET

In addition to EGFR mutations and ALK-rearrangements, several other driver mutations have been identified in lung adenocarcinoma and rational therapies targeting these pathways are currently undergoing clinical investigation. Randomized data in these patient subsets will be difficult to generate given the rarity of each of these biomarkers. However, promising phase I and II data provide support for the use of targeted agents in the following molecularly defined patient subsets after progression on platinum-based, first-line therapy.

ROS1

ROS1-rearrangements occur in approximately 1% of lung adenocarcinomas. In a phase I trial, crizotinib yielded a response rate of 72% in patients with ROS1-rearranged NSCLC with a median PFS of 19 months (55). Recently, the U.S. FDA approved crizotinib for the treatment of patients with ROS1-rearranged NSCLC.

MET

Mutations in the MET oncogene can result in “skipping” of exon 14 in 2% to 3% of patients with NSCLC (56). They appear to be more common in patients with adenocarcinoma and sarcomatoid carcinoma. Targeting this pathway with MET inhibitors, such as crizotinib, has demonstrated promising clinical responses in select cases, and clinical trials are underway to more fully evaluate this strategy (57).

RET

A RET translocation occurs in 1% to 2% of pulmonary adenocarcinomas. Early clinical data have demonstrated responses with the RET inhibitor, cabozantinib (58).

BRAF

While best known as a therapeutic target in melanoma, patients NSCLC with a BRAF V600 mutation have had a response rate of 42% when treated with vemurafenib (59). In addition, the combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, resulted in a response rate of 66% with a median PFS of approximately 9 months. The role of these agents in tumors with non-V600 BRAF mutations is unclear at this time.

IMMUNOTHERAPY

The discovery of the efficacy of immunotherapy in advanced NSCLC is one of the most impactful recent developments in the field. The immune checkpoint inhibitors have dramatically altered the care for this patient population, and their role in progressive disease is discussed in Chapter 9. Clinical trials are now examining immune checkpoint inhibitors in the first-line setting. Recently, pembrolizumab, an anti-PD1 antibody, was compared to chemotherapy as first-line therapy in patients with advanced NSCLC whose tumors expressed PD-L1 in ≥50% of tumor cells (60). In this selected population (about 30% of patients), pembrolizumab was superior to chemotherapy in terms of PFS (median, 10.3 vs. 6.0 months, P < .001), overall survival (HR 0.60, P = .005), response rate (45% vs. 28%), and duration of response (not reached vs. 6.3 months). Based on these data, pembrolizumab should soon become the standard first-line treatment option for patients with advanced NSCLC with high PD-L1 expression.

OLIGOMETASTATIC DISEASE

Advanced NSCLC is an incurable disease. However, patients who present with a low burden of metastatic disease deserve further discussion since long-term survival has been seen in those with such oligometastatic disease (61). Oligometastasis is broadly defined as a state of minimal systemic metastatic tumors for which local therapy can be pursued with curative intent (62). However, there is no clear consensus on the number of lesions that would define a patient with “oligometastatic” disease.

CNS Metastasis

One of the most common sites of oligometastatic disease is the brain. It is estimated that approximately 7% of patients with metastatic NSCLC will present with a solitary metastatic brain lesion (63). For patients with widespread disease, treatment of brain metastasis typically consists of corticosteroids and RT, and the prognosis remains poor. However, for patients with disease that is oligometastatic to the brain, aggressive local therapy is often utilized. Multiple retrospective studies have reviewed the role of surgical resection of isolated brain metastases, reporting promising outcomes with aggressive treatment (64). Several older prospective clinical trials have also found that surgery plus whole brain RT prolongs survival and quality of life for patients with solitary brain metastasis (65,66). More recently, stereotactic radiosurgery has become an attractive treatment modality for isolated brain metastasis as a way to spare patients the neurocognitive side effects of whole brain RT (67–72). A randomized trial from Japan assessed stereotactic radiosurgery with or without whole brain RT, and found no difference in overall survival, but patients who did not receive whole brain RT upfront had a higher incidence of intracranial recurrence (67).

Other Oligometastatic Sites

A solitary adrenal metastasis should also be considered for aggressive local therapy, with potential adrenalectomy when feasible, provided it is the sole site of metastatic disease (73,74). Similarly, patients with bilateral lung involvement with solitary lesions in each lung may have two separate primaries or metastatic disease. In this situation, long-term survival has been reported, particularly when there is no involvement of mediastinal lymph nodes (75). When considering aggressive resection of the primary lung tumor and a solitary metastatic lesion elsewhere, it is important to exclude involvement of mediastinal nodes, since N2-positivity portends a poor prognosis in the setting of an aggressive surgical approach.

Finally, for patients with a good response to systemic therapy, residual oligometastatic lesions or sites of localized progression can be treated with local modalities other than surgery, such as RT or radiofrequency ablation. This is particularly true for patients with driver mutations who experience localized progression while on targeted therapy. For patients with oligometastatic NSCLC or localized progression on systemic therapy, a multidisciplinary discussion should be held to assess potential treatment options. The decision to take an aggressive approach for oligometastatic disease should be made carefully, as treatment comes with the risks of more aggressive interventions. However, the potential for long-term disease control is compelling for appropriately selected patients.

CONCLUSION

Significant advances have been made in the treatment of advanced NSCLC. Chemotherapeutic agents with improved tolerability have been developed allowing for disease control with a more favorable therapeutic index. The identification of the molecular drivers of NSCLC, including EGFR, ALK, and ROS1, has already led to the development of well-tolerated and effective targeted agents. These advances, along with progress in immunotherapy, have now translated into a multitude of treatment options for patients that can improve quality of life and prolong survival.

 

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