TREATMENT Non-Small-Cell Lung Cancer
The overall treatment approach to patients with NSCLC is shown in Fig. 36-3. OCCULT AND STAGE 0 CARCINOMAS
Patients with severe atypia on sputum cytology have an increased risk of developing lung cancer compared to those without atypia. In the uncommon circumstance where malignant cells are identified in a sputum or bronchial washing specimen but the chest imaging appears normal (TX tumor stage), the lesion must be localized. More than 90% of tumors can be localized by meticulous examination of the bronchial tree with a fiberoptic bronchoscope under general anesthesia and collection of a series of differential brushings and biopsies. Surgical resection following bronchoscopic localization has been shown to improve survival compared to no treatment. Close follow-up of these patients is indicated because of the high incidence of second primary lung cancers (5% per patient per year). SOLITARY PULMONARY NODULE AND “GROUND-GLASS” OPACITIES
A solitary pulmonary nodule is defined as an x-ray density completely surrounded by normal aerated lung with circumscribed margins, of any shape, usually 1–6 cm in greatest diameter. The approach to a patient with a solitary pulmonary nodule is based on an estimate of the probability of cancer, determined according to the patient’s smoking history, age, and characteristics on imaging (Table 36-9). Prior CXRs and CT scans should be obtained if available for comparison. A PET scan may be useful if the lesion is greater than 7–8 mm in diameter. If no diagnosis is apparent, Mayo investigators reported that clinical characteristics (age, cigarette smoking status, and prior cancer diagnosis) and three radiologic characteristics (nodule diameter, spiculation, and upper lobe location) were independent predictors of malignancy. At present, only two radiographic criteria are thought to predict the benign nature of a solitary pulmonary nodule: lack of growth over a period >2 years and certain characteristic patterns of calcification. Calcification alone, however, does not exclude malignancy; a dense central nidus, multiple punctuate foci, and “bulls eye” (granuloma) and “popcorn ball” (hamartoma) calcifications are highly suggestive of a benign lesion. In contrast, a relatively large lesion, lack of or asymmetric calcification, chest symptoms, associated atelectasis, pneumonitis, or growth of the lesion revealed by comparison with an old x-ray or CT scan or a positive PET scan may be suggestive of a malignant process and warrant further attempts to establish a histologic diagnosis. An algorithm for assessing these lesions is shown in Fig. 36-6.
Since the advent of screening CTs, small “ground-glass” opacities (GGOs) have often been observed, particularly as the increased sensitivity of CTs enables detection of smaller lesions. Many of these GGOs, when biopsied, are found to be atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), or minimally invasive adenocarcinoma (MIA). AAH is usually a nodule of <5 mm and is minimally hazy, also called nonsolid or ground glass (i.e., hazy slightly increased attenuation, no solid component, and preservation of bronchial and vascular margins). On thin-section CT, AIS is usually a nonsolid nodule and tends to be slightly more opaque than AAH. MIA is mainly solid, usually with a small (<5 mm) central solid component. However, overlap exists among the imaging features of the preinvasive and minimally invasive lesions in the lung adenocarcinoma spectrum. Lepidic adenocarcinomas are usually solid but may be nonsolid. Likewise, the small invasive adenocarcinomas also are usually solid but may exhibit a small nonsolid component. MANAGEMENT OF STAGES I AND II NSCLC Surgical Resection of Stage I and II NSCLC
Surgical resection, ideally by an experienced thoracic surgeon, is the treatment of choice for patients with clinical stage I and II NSCLC who are able to tolerate the procedure. Operative mortality rates for patients resected by thoracic or cardiothoracic surgeons are lower compared to general surgeons. Moreover, survival rates are higher in patients who undergo resection in facilities with a high surgical volume compared to those performing fewer than 70 procedures per year, even though the higher-volume facilities often serve older and less socioeconomic advantaged populations. The improvement in survival is most evident in the immediate postoperative period. The extent of resection is a matter of surgical judgment based on findings at exploration. In patients with stage IA NSCLC, lobectomy is superior to wedge resection with respect to rates of local recurrence. There is also a trend toward improvement in overall survival. In patients with comorbidities, compromised pulmonary reserve, and small peripheral lesions, a limited resection, wedge resection, and segmentectomy (potentially by video-assisted thoracoscopic surgery) may be reasonable surgical option. Pneumonectomy is reserved for patients with central tumors and should be performed only in patients with excellent pulmonary reserve. The 5-year survival rates are 60–80% for patients with stage I NSCLC and 40–50% for patients with stage II NSCLC.
Accurate pathologic staging requires adequate segmental, hilar, and mediastinal lymph node sampling. Ideally this includes a mediastinal lymph node dissection. On the right side, mediastinal stations 2R, 4R, 7, 8R, and 9R should be dissected; on the left side, stations 5, 6, 7, 8L, and 9L should be dissected. Hilar lymph nodes are typically resected and sent for pathologic review, although it is helpful to specifically dissect and label level 10 lymph nodes when possible. On the left side, level 2 and sometimes level 4 lymph nodes are generally obscured by the aorta. Although the therapeutic benefit of nodal dissection versus nodal sampling is controversial, a pooled analysis of three trials involving patients with stages I to IIIA NSCLC demonstrated a superior 4-year survival in patients undergoing resection and a complete mediastinal lymph node dissection compared with lymph node sampling. Moreover, complete mediastinal lymphadenectomy added little morbidity to a pulmonary resection for lung cancer when carried out by an experienced thoracic surgeon. Radiation Therapy in Stages I and II NSCLC
There is currently no role for postoperative radiation therapy in patients following resection of stage I or II NSCLC. However, patients with stage I and II disease who either refuse or are not suitable candidates for surgery should be considered for radiation therapy with curative intent. Stereotactic body radiation therapy (SBRT) is a relatively new technique used to treat patients with isolated pulmonary nodules (≤5 cm) who are not candidates for or refuse surgical resection. Treatment is typically administered in three to five fractions delivered over 1–2 weeks. In uncontrolled studies, disease control rates are >90%, and 5-year survival rates of up to 60% have been reported with SBRT. By comparison, survival rates typically range from 13 to 39% in patients with stage I or II NSCLC treated with standard external-beam radiotherapy. Cryoablation is another technique occasionally used to treat small, isolated tumors (i.e., ≤3 cm). However, very little data exist on long-term outcomes with this technique. Chemotherapy in Stages I and II NSCLC
Although a landmark meta-analysis of cisplatin-based adjuvant chemotherapy trials in patients with resected stages I to IIIA NSCLC (the Lung Adjuvant Cisplatin Evaluation [LACE] Study) demonstrated a 5.4% improvement in 5-year survival for adjuvant chemotherapy compared to surgery alone, the survival benefit was seemingly confined to patients with stage II or III disease (Table 36-10). By contrast, survival was actually worsened in stage IA patients with the application of adjuvant therapy. In stage IB, there was a modest improvement in survival of questionable clinical significance. Adjuvant chemotherapy was also detrimental in patients with poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status = 2). These data suggest that adjuvant chemotherapy is best applied in patients with resected stage II or III NSCLC. There is no apparent role for adjuvant chemotherapy in patients with resected stage IA or IB NSCLC. A possible exception to the prohibition of adjuvant therapy in this setting is the stage IB patient with a resected lesion ≥4 cm.
As with any treatment recommendation, the risks and benefits of adjuvant chemotherapy should be considered on an individual patient basis. If a decision is made to proceed with adjuvant chemotherapy, in general, treatment should be initiated 6–12 weeks after surgery, assuming the patient has fully recovered, and should be administered for no more than four cycles. Although a cisplatin-based chemotherapy is the preferred treatment regimen, carboplatin can be substituted for cisplatin in patients who are unlikely to tolerate cisplatin for reasons such as reduced renal function, presence of neuropathy, or hearing impairment. No specific chemotherapy regimen is considered optimal in this setting, although platinum plus vinorelbine is most commonly used.
Neoadjuvant chemotherapy, which is the application of chemotherapy administered before an attempted surgical resection, has been advocated by some experts on the assumption that such an approach will more effectively extinguish occult micrometastases compared to postoperative chemotherapy. In addition, it is thought that preoperative chemotherapy might render an inoperable lesion resectable. With the exception of superior sulcus tumors, however, the role of neoadjuvant chemotherapy in stage I to III disease is not well defined. However, a meta-analysis of 15 randomized controlled trials involving more than 2300 patients with stage I to III NSCLC suggested there may be a modest 5-year survival benefit (i.e., ~5%) that is virtually identical to the survival benefit achieved with postoperative chemotherapy. Accordingly, neoadjuvant therapy may prove useful in selected cases (see below). A decision to use neoadjuvant chemotherapy should always be made in consultation with an experienced surgeon.
In should be noted that all patients with resected NSCLC are at high risk of recurrence, most of which occurs within 18–24 months of surgery, or developing a second primary lung cancer. Thus, it is reasonable to follow these patients with periodic imaging studies. Given the results of the NLST, periodic CT scans appear to be the most appropriate screening modality. Based on the timing of most recurrences, some guidelines recommend a contrasted chest CT scan every 6 months for the first 3 years after surgery, followed by yearly CT scans of the chest without contrast thereafter. MANAGEMENT OF STAGE III NSCLC
Management of patients with stage III NSCLC usually requires a combined-modality approach. Patients with stage IIIA disease commonly are stratified into those with “nonbulky” or “bulky” mediastinal lymph node (N2) disease. Although the definition of “bulky” N2 disease varies somewhat in the literature, the usual criteria include the size of a dominant lymph node (i.e., >2–3 cm in short-axis diameter as measured by CT), groupings of multiple smaller lymph nodes, evidence of extracapsular nodal involvement, or involvement of more than two lymph node stations. The distinction between nonbulky and bulky stage IIIA disease is mainly used to select potential candidates for upfront surgical resection or for resection after neoadjuvant therapy. Many aspects of therapy of patients with stage III NSCLC remain controversial, and the optimal treatment strategy has not been clearly defined. Moreover, although there are many potential treatment options, none yields a very high probability of cure. Furthermore, because stage III disease is highly heterogeneous, no single treatment approach can be recommended for all patients. Key factors guiding treatment choices include the particular combination of tumor (T) and nodal (N) disease, the ability to achieve a complete surgical resection if indicated, and the patient’s overall physical condition and preferences. For example, in carefully selected patients with limited stage IIIA disease where involved mediastinal lymph nodes can be completed resected, initial surgery followed by postoperative chemotherapy (with or without radiation therapy) may be indicated. By contrast, for patients with clinically evident bulky mediastinal lymph node involvement, the standard approach to treatment is concurrent chemoradiotherapy. Nevertheless, in some cases, the latter group of patients may be candidates for surgery following chemoradiotherapy. Absent and Nonbulky Mediastinal (N2, N3) Lymph Node Disease
For the subset of stage IIIA patients initially thought to have clinical stage I or II disease (i.e., pathologic involvement of mediastinal [N2] lymph nodes is not detected preoperatively), surgical resection is often the treatment of choice. This is followed by adjuvant chemotherapy in patients with microscopic lymph node involvement in a resection specimen. Postoperative radiation therapy (PORT) may also have a role for those with close or positive surgical margins. Patients with tumors involving the chest wall or proximal airways within 2 cm of the carina with hilar lymph node involvement (but not N2 disease) are classified as having T3N1 stage IIIA disease. They too are best managed with surgical resection, if technically feasible, followed by adjuvant chemotherapy if completely resected. Patients with tumors exceeding 7 cm in size also are now classified as T3 and are consider stage IIIA if tumor has spread to N1 nodes. The appropriate initial management of these patients involves surgical resection when feasible, provided the mediastinal staging is negative, followed by adjuvant chemotherapy for those who achieve complete tumor resection. Patients with T3N0 or T3N1 disease due to the presence of satellite nodules within the same lobe as the primary tumor also are candidates for surgery, as are patients with ipsilateral nodules in another lobe and negative mediastinal nodes (IIIA, T4N0 or T4N1). Although data regarding adjuvant chemotherapy in the latter subsets of patients are limited, it is often recommended.
Patients with T4N0-1 were reclassified as having stage IIIA tumors in the seventh edition of the TNM system. These patients may have involvement of the carina, superior vena cava, or a vertebral body and yet still be candidates for surgical resection in selected circumstances. The decision to proceed with an attempted resection must be made in consultation with an experienced thoracic surgeon often in association with a vascular or cardiac surgeon and an orthopedic surgeon depending on tumor location. However, if an incomplete resection is inevitable or if there is evidence of N2 involvement (stage IIIB), surgery for T4 disease is contraindicated. Most T4 lesions are best treated with chemoradiotherapy.
The role of PORT in patients with completely resected stage III NSCLC is controversial. To a large extent, the use of PORT is dictated by the presence or absence of N2 involvement and, to a lesser degree, by the biases of the treating physician. Using the Surveillance, Epidemiology, and End Results (SEER) database, a recent meta-analysis of PORT identified a significant increase in survival in patients with N2 disease but not in patients with N0 or N1 disease. An earlier analysis by the PORT Meta-analysis Trialist Group using an older database produced similar results. Known Mediastinal (N2, N3) Lymph Node Disease
When pathologic involvement of mediastinal lymph nodes is documented preoperatively, a combined-modality approach is recommended assuming the patient is a candidate for treatment with curative intent. These patients are at high risk for both local and distant recurrence if managed with resection alone. For patients with stage III disease who are not candidates for initial surgical resection, concurrent chemoradiotherapy is most commonly used as the initial treatment. Concurrent chemoradiotherapy has been shown to produce superior survival compared to sequential chemoradiotherapy; however, it also is associated with greater host toxicities (including fatigue, esophagitis, and neutropenia). Therefore, for patients with a good performance status, concurrent chemoradiotherapy is the preferred treatment approach, whereas sequential chemoradiotherapy may be more appropriate for patients with a performance status that is not as good. For patients who are not candidates for a combined-modality treatment approach, typically due to a poor performance status or a comorbidity that makes chemotherapy untenable, radiotherapy alone may provide a modest survival benefit in addition to symptom palliation.
For patients with potentially resectable N2 disease, it remains uncertain whether surgery after neoadjuvant chemoradiotherapy improves survival. In an NCI-sponsored Intergroup randomized trial comparing concurrent chemoradiotherapy alone to concurrent chemoradiotherapy followed by attempted surgical resection, no survival benefit was observed in the trimodality arm compared to the bimodality therapy. In fact, patients subjected to a pneumonectomy had a worse survival outcome. By contrast, those treated with a lobectomy appeared to have a survival advantage based on a retrospective subset analysis. Thus, in carefully selected, otherwise healthy patients with nonbulky mediastinal lymph node involvement, surgery may be a reasonable option if the primary tumor can be fully resected with a lobectomy. This is not the case if a pneumonectomy is required to achieve complete resection. Superior Sulcus Tumors (Pancoast Tumors)
Superior sulcus tumors represent a distinctive subset of stage III disease. These tumors arise in the apex of the lung and may invade the second and third ribs, the brachial plexus, the subclavian vessels, the stellate ganglion, and adjacent vertebral bodies. They also may be associated with Pancoast syndrome, characterized by pain that may arise in the shoulder or chest wall or radiate to the neck. Pain characteristically radiates to the ulnar surface of the hand. Horner’s syndrome (enophthalmos, ptosis, miosis, and anhydrosis) due to invasion of the paravertebral sympathetic chain may be present as well. Patients with these tumors should undergo the same staging procedures as all patients with stage II and III NSCLC. Neoadjuvant chemotherapy or combined chemoradiotherapy followed by surgery is reserved for those without N2 involvement. This approach yields excellent survival outcomes (>50% 5-year survival in patients with an R0 resection). Patients with N2 disease are less likely to benefit from surgery and can be managed with chemoradiotherapy alone. Patients presenting with metastatic disease can be treated with radiation therapy (with or without chemotherapy) for symptom palliation. MANAGEMENT OF METASTATIC NSCLC
Approximately 40% of NSCLC patients present with advanced, stage IV disease at the time of diagnosis. These patients have a poor median survival (4–6 months) and a 1-year survival of 10% when managed with best supportive care alone. In addition, a significant number of patients who first presented with early-stage NSCLC will eventually relapse with distant disease. Patients who have recurrent disease have a better prognosis than those presenting with metastatic disease at the time of diagnosis. Standard medical management, the judicious use of pain medications, and the appropriate use of radiotherapy and chemotherapy form the cornerstone of management. Chemotherapy palliates symptoms, improves the quality of life, and improves survival in patients with stage IV NSCLC, particularly in patients with good performance status. In addition, economic analysis has found chemotherapy to be cost-effective palliation for stage IV NSCLC. However, the use of chemotherapy for NSCLC requires clinical experience and careful judgment to balance potential benefits and toxicities. Of note, the early application of palliative care in conjunction with chemotherapy is associated with improved survival and a better quality of life. First-Line Chemotherapy for Metastatic or Recurrent NSCLC
A landmark meta-analysis published in 1995 provided the earliest meaningful indication that chemotherapy could provide a survival benefit in metastatic NSCLC as opposed to supportive care alone. However, the survival benefit was seemingly confined to cisplatin-based chemotherapy regimens (hazard ratio 0.73; 27% reduction in the risk of death; 10% improvement in survival at 1 year). These data launched two decades of clinical research aimed at detecting the optimal chemotherapy regimen for advanced NSCLC. For the most part, however, these efforts proved unsuccessful because the overwhelming majority of randomized trials showed no major survival improvement with any one regimen versus another (Table 36-11). On the other hand, differences in progression-free survival, cost, side effects, and schedule were frequently observed. These first-line studies were later extended to elderly patients, where doublet chemotherapy was found to improve overall survival compared to single agents in the “fit” elderly (e.g., elderly patients with no major comorbidities) and in patients with an ECOG performance status of 2. An ongoing debate in the treatment of patients with advanced NSCLC is the appropriate duration of platinum-based chemotherapy. Several large phase III randomized trials have failed to show a meaningful benefit for increasing the duration of platinum-based doublet chemotherapy beyond four to six cycles. In fact, longer duration of chemotherapy has been associated with increased toxicities and impaired quality of life. Therefore, prolonged front-line therapy (beyond four to six cycles) with platinum-based regimens is not recommended. Maintenance therapy following initial platinum-based therapy is discussed below.
Although specific tumor histology was once considered irrelevant to treatment choice in NSCLC, with the recent recognition that selected chemotherapy agents perform quite differently in squamous versus adenocarcinomas, accurate determination of histology has become essential. Specifically, in a landmark randomized phase III trial, patients with nonsquamous NSCLC were found to have an improved survival when treated with cisplatin and pemetrexed compared to cisplatin and gemcitabine. By contrast, patients with squamous carcinoma had an improved survival when treated with cisplatin and gemcitabine. This survival difference is thought to be related to the differential expression of thymidylate synthase (TS), one of the targets of pemetrexed, between tumor types. Squamous cancers have a much higher expression of TS compared to adenocarcinomas, accounting for their lower responsiveness to pemetrexed. By contrast, the activity of gemcitabine is not impacted by the levels of TS. Bevacizumab, a monoclonal antibody against VEGF, has been shown to improve response rate, progression-free survival, and overall survival in patients with advanced disease when combined with chemotherapy (see below). However, bevacizumab cannot be given to patients with squamous cell histology NSCLC because of their tendency to experience serious hemorrhagic effects. Agents That Inhibit Angiogenesis
Bevacizumab, a monoclonal antibody directed against VEGF, was the first antiangiogenic agent approved for the treatment of patients with advanced NSCLC in the United States. This drug primarily acts by blocking the growth of new blood vessels, which are required for tumor viability. Two randomized phase III trials of chemotherapy with or without bevacizumab had conflicting results. The first trial, conducted in North America, compared carboplatin plus paclitaxel with or without bevacizumab in patients with recurrent or advanced nonsquamous NSCLC and reported a significant improvement in response rate, progression-free survival, and overall survival in patients treated with chemotherapy plus bevacizumab versus chemotherapy alone. Bevacizumab-treated patients had a significantly higher incidence of toxicities. The second trial, conducted in Europe, compared cisplatin/gemcitabine with or without bevacizumab in patients with recurrent or advanced nonsquamous NSCLC and reported a significant improvement in progression-free survival but no improvement in overall survival for bevacizumab-treated patients. A randomized phase III trial compared carboplatin/pemetrexed and bevacizumab to carboplatin/paclitaxel and bevacizumab as first-line therapy in patients with recurrent or advanced nonsquamous NSCLC and reported no significant difference in progression-free survival or overall survival between treatment groups. Therefore, currently carboplatin/paclitaxel and bevacizumab or carboplatin/pemetrexed and bevacizumab are appropriate regimens for first-line treatment for stage IV nonsquamous NSCLC patients. Of note, there are many small-molecule inhibitors of VEGFR; however, these VEGFR TKIs have not proven to be effective in the treatment of NSCLC. Maintenance Therapy for Metastatic NSCLC
Maintenance chemotherapy in nonprogressing patients (patients with a complete response, partial response, or stable disease) is a controversial topic in the treatment of NSCLC. Conceptually, there are two types of maintenance strategies: (1) switch maintenance therapy, where patients receive four to six cycles of platinum-based chemotherapy and are switched to an entirely different regimen; and (2) continuation maintenance therapy, where patients receive four to six cycles of platinum-based chemotherapy and then the platinum agent is discontinued but the agent it is paired with is continued (Table 36-12). Two studies investigated switch maintenance single-agent chemotherapy with docetaxel or pemetrexed in nonprogressing patients following treatment with first-line platinum-based chemotherapy. Both trials randomized patients to immediate single-agent therapy versus observation and reported improvements in progression-free and overall survival. In both trials, a significant portion of patients in the observation arm did not receive therapy with the agent under investigation upon disease progression; 37% of study patients never received docetaxel in the docetaxel study and 81% of patients never received pemetrexed in the pemetrexed study. In the trial of maintenance docetaxel versus observation, survival was identical to the treatment group in the subset of patients who received docetaxel on progression, indicating this is an active agent in NSCLC. These data are not available for the pemetrexed study. Two additional trials evaluated switch maintenance therapy with erlotinib after platinum-based chemotherapy in patients with advanced NSCLC and reported an improvement in progression-free survival and overall survival in the erlotinib treatment group. Currently, maintenance pemetrexed or erlotinib following platinum-based chemotherapy in patients with advanced NSCLC are approved by the U.S. FDA. However, maintenance therapy is not without toxicity and, at this time, should be considered on an individual patient basis. Targeted Therapies for Select Molecular Cohorts of NSCLC
As the efficacy of traditional cytotoxic chemotherapeutic agents plateaued in NSCLC, there was a critical need to define novel therapeutic treatment strategies. These novel strategies have largely been based on the identification of somatic driver mutations within the tumor. These driver mutations occur in genes encoding signaling proteins that, when aberrant, drive initiation and maintenance of tumor cells. Importantly, driver mutations can serve as Achilles’ heels for tumors, if their gene products can be targeted therapeutically with small-molecule inhibitors. For example, EGFR mutations have been detected in 10–15% of North American patients diagnosed with NSCLC. EGFR mutations are associated with younger age, light (<10 pack-year) and nonsmokers, and adenocarcinoma histology. Approximately 90% of these mutations are exon 19 deletions or exon 21 L858R point mutations within the EGFR TK domain, resulting in hyperactivation of both EGFR kinase activity and downstream signaling. Lung tumors that harbor activating mutations within the EGFR kinase domain display high sensitivity to small-molecule EGFR TKIs. Erlotinib and afatinib are FDA-approved oral small-molecule TKIs that inhibit EGFR. Outside the United States, gefitinib also is available. Several large, international, phase III studies have demonstrated improved response rates, progression-free survival, and overall survival in patients with EGFR mutation–positive NSCLC patients treated with an EGFR TKI as compared with standard first-line chemotherapy regimens (Table 36-13).
Although response rates with EGFR TKI therapy are clearly superior in patients with lung tumors harboring activating EGFR kinase domain mutations, the EGFR TKI erlotinib is also FDA approved for second- and third-line therapy in patients with advanced NSCLC irrespective of tumor genotype. The reason for this apparent discrepancy is that erlotinib was initially evaluated in lung cancer before the discovery of EGFR activating mutations. In fact, EGFR mutations were initially identified in lung cancer by studying the tumors of patients who had dramatic responses to this agent. With the rapid pace of scientific discovery, additional driver mutations in lung cancer have been identified and targeted therapeutically with impressive clinical results. For example, chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene on chromosome 2 have been found in ~3-7% of NSCLC. The result of these ALK rearrangements is hyperactivation of the ALK TK domain. Similar to EGFR, ALK rearrangements are typically (but not exclusively) associated with younger age, light (<10 pack-year) and nonsmokers, and adenocarcinoma histology. Remarkably, ALK rearrangements were initially described in lung cancer in 2007, and by 2011, the first ALK inhibitor, crizotinib, received FDA approval for patients with lung tumors harboring ALK rearrangements.
In addition to EGFR and ALK, other driver mutations have been discovered with varying frequencies in NSCLC, including KRAS, BRAF, PIK3CA, NRAS, AKT1, MET, MEK1 (MAP2K1), ROS1, and RET. Mutations within the KRAS GTPase are found in approximately 20% of lung adenocarcinomas. To date, however, no small-molecule inhibitors are available to specifically target mutant KRAS. Each of the other driver mutations occurs in less than 1–3% of lung adenocarcinomas. The great majority of the driver mutations are mutually exclusive, and there are ongoing clinical studies for their specific inhibitors. For example, the BRAF inhibitor vemurafenib and the RET inhibitor cabozantinib have already demonstrated efficacy in patients with lung cancer harboring BRAF mutations or RET gene fusions, respectively. Most of these mutations are present in adenocarcinoma; however, mutations that may be linked to future targeted therapies in squamous cell carcinomas are emerging. In addition, there are active research efforts aimed at defining novel targetable mutations in lung cancer as well as defining mechanisms of acquired resistance to small-molecule inhibitors used in the treatment of patients with NSCLC. Second-Line Chemotherapy and Beyond
Second-line therapy for advanced NSCLC was almost never recommended until a seminal study in 2000 showed that docetaxel improved survival compared to supportive care alone. As first-line chemotherapy regimens improve, a substantial number of patients will maintain a good performance status and a desire for further therapy when they develop recurrent disease. Currently, several agents are FDA approved for second-line use in NSCLC including docetaxel, pemetrexed, erlotinib (approved for second-line therapy regardless of tumor genotype), and crizotinib (for patients with ALK-mutant lung cancer only). Most of the survival benefit for any of these agents is realized in patients who maintain a good performance status. Immunotherapy
For more than 30 years, the investigation of vaccines and immunotherapies in lung cancer has yielded little in the way of meaningful benefit. Recently, however, this perception has changed based on preliminary results of studies using monoclonal antibodies that activate antitumor immunity through blockade of immune checkpoints. For example, ipilimumab, a monoclonal antibody directed at cytotoxic T lymphocyte antigen-4 (CTLA-4), was studied in combination with paclitaxel plus carboplatin in patients with both SCLC and NSCLC. There appeared to be a small but not statistically significant advantage to the combination when ipilimumab was instituted after several cycles of chemotherapy. A randomized phase III trial in SCLC is under way to validate these data. Antibodies to the T cell programmed cell death receptor 1 (PD-1), nivolumab and pembrolizumab, have been shown to produce responses in lung cancer, renal cell cancer, and melanoma. Many of these responses have had very long duration (i.e., >1 year). Monoclonal antibodies to the PD-1 ligand (anti-PDL-1), which may be expressed on the tumor cell, have also been shown to produce responses in patients with melanoma and lung cancer. Preliminary studies in melanoma suggest that the combination of ipilimumab and nivolumab could produce higher response rates compared to either agent alone. A similar strategy is being investigated in SCLC patients. Further evaluation of these agents in both NSCLC and SCLC is ongoing in combination with already approved chemotherapy and targeted agents. Supportive Care
No discussion of the treatment strategies for patients with advanced lung cancer would be complete without a mention of supportive care. Coincident with advances in chemotherapy and targeted therapy was a pivotal study that demonstrated that the early integration of palliative care with standard treatment strategies improved both quality of life and mood for patients with advanced lung cancer. Aggressive pain and symptom control is an important component for optimal treatment of these patients.