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INTRODUCTION — Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. More than 80 percent of lung cancers are classified as non-small cell lung cancer (NSCLC). Although there have been significant advances in the treatment of subsets of patients with molecularly defined NSCLC (eg, epidermal growth factor receptor [EGFR] mutant, ALK rearranged NSCLC), the prognosis in the majority of patients has improved only modestly. Clearly, a plateau has been reached with traditional chemotherapy, with minimal added benefit when chemotherapy is combined with the angiogenesis inhibitor, bevacizumab.
The emerging role of immunotherapy for advanced NSCLC using checkpoint inhibitors will be reviewed here. An overview of the current approach to treatment for advanced NSCLC is presented elsewhere. (See "Overview of the treatment of advanced non-small cell lung cancer" and "Advanced non-small cell lung cancer: Subsequent systemic therapies for previously treated patients".)
RATIONALE — Immunotherapy differs from traditional chemotherapy, which primarily targets rapidly dividing cells, and from targeted therapies, which interfere with key molecular events in tumor cells that drive tumor growth and invasion.
The aims of immunotherapy are to:
●Aid in the recognition of cancer as foreign by the immune system
●Stimulate immune responsiveness
●Relieve inhibition of the immune system that allows tolerance of tumor growth
Immunotherapeutic approaches are based upon the premise that the immune system plays a key role in surveillance and eradication of malignancy, and that tumors evolve ways to elude the immune system. The general principles and rationale of immunotherapy are discussed separately. (See "Principles of cancer immunotherapy".)
Historically, non-small cell lung cancer (NSCLC) was considered to be non-immunogenic, that is, incapable of inducing immune tumor destruction. This was based in part on failed attempts to modulate the immune system in NSCLC patients with agents such as interleukin 2 (IL-2), interferon, and Bacillus Calmette-Guerin (BCG). As a result of an improved understanding of the immune system and better technologies to facilitate drug development, newer immunotherapies that relieve suppression of anti-tumor immunity have emerged as powerful tools in the management of advanced NSCLC.
IMMUNE ACTIVATION AND CHECKPOINT INHIBITION — Several steps are required for the immune system to effectively attack tumor cells. These include tumor recognition, presentation of tumor antigen to T cells, T cell activation, and direct attack of tumor (figure 1).
●Immune recognition is initiated by antigen presenting cells (APCs) such as dendritic cells that internalize and process tumor antigen onto major histocompatibility complex (MHC) molecules, which are expressed on the surface of APCs. This process triggers expression of B7.1 and B7.2 on the APCs, which migrate to lymph nodes.
●Within the lymph node, the APC presents tumor antigen to resting T cells though interaction with the antigen-specific T cell receptor. If there is additional interaction between B7.1 or B7.2 and CD28 on the T cell, T cell activation occurs and the T cell leaves the lymph node.
●When the activated T cell comes into contact with the tumor and recognizes antigen expressed on the tumor in association with MHC, it releases cytolytic enzymes (perforin and granzyme) and cytokines, which recruit other members of the immune system, and proliferates. The result is tumor destruction and creation of memory T cells. This is the same process utilized by the immune system in other pathogenic processes such as viral infections.
Several immune checkpoints exist to dampen the immune response to protect against detrimental inflammation and autoimmunity. In the setting of malignancy, such immune checkpoints can be co-opted by tumors, leading to immune tolerance and subsequent progression of malignancy. Two well-characterized checkpoints being targeted in non-small cell lung cancer (NSCLC) clinical trials are the cytotoxic T-lymphocyte antigen 4 (CTLA-4) and the programmed death receptor 1 (PD-1) (figure 1).
●CTLA-4 primarily regulates early T cell activity and is upregulated on T cells after exposure to antigen (figure 1). CTLA-4 competes with CD28 for binding to B7.1 and B7.2 with much higher affinity, delivering a negative signal to the T cell and blocking the co-stimulatory signal resulting from B7.1/2/CD28 interaction needed for T cell activation.
●PD-1 inhibition occurs primarily at the site of the tumor, in contrast to CTLA-4, which functions largely in lymphoid organs. PD-1 is upregulated on activated T cells, and upon recognition of tumor via the T cell receptor, PD-1 engagement by programmed death ligand 1 (PD-L1) can lead to T cell inactivation (figure 1). The primary mechanism of tumor PD-L1 expression is believed to be induction by inflammation in the tumor microenvironment, largely mediated by interferon gamma. Another possible mechanism is oncogene-driven-tumor PD-L1 tumor expression, regardless of tumor inflammation.
ANTIBODIES TO PD-1 AND PD-L1 — The excitement about using immunotherapy to treat non-small cell lung cancer (NSCLC) has been driven primarily by results from clinical studies evaluating antagonist antibodies to programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), which have demonstrated prolonged tumor responses in patients with chemotherapy-refractory metastatic NSCLC.
Randomized trials in metastatic NSCLC evaluating both anti-PD-1 and anti-PD-L1 antibodies are in progress, and other studies are investigating combination strategies (table 1). Additional efforts are ongoing to evaluate potential biomarkers of response to such therapy, in particular, expression of PD-L1 within the tumor. (See 'Biomarker studies, tumor PD-L1 expression' below.)
Distinct ligand/receptor interactions need to be considered when evaluating antibodies to PD-1 and PD-L1 (figure 2). These include binding of PD-1 by its two known ligands, PD-L1 and PD-L2, and binding of PD-L1 to B7.1, which can be additionally expressed on activated T cells. The latter interaction is also inhibitory, leading to T cell inactivation. Reverse signaling can also occur through PD-L1, inhibiting tumor cell apoptosis. Additionally, PD-1 and PD-L1 expression can be found on different types of immune cells, with varying effects if blocked.
PD-1 blocking antibodies
Nivolumab — Nivolumab is an IgG4 monoclonal antagonist antibody to PD-1 that is US Food and Drug Administration (FDA)-approved for the treatment of patients with advanced squamous NSCLC and non-squamous cell NSCLC who experience progression of disease on or after standard platinum-based chemotherapy (regardless of tumor PD-L1 protein expression). (See "Overview of the treatment of advanced non-small cell lung cancer", section on 'Subsequent treatment' and "Advanced non-small cell lung cancer: Subsequent systemic therapies for previously treated patients".)
Although studies below describe results of nivolumab used at a 3 mg/kg intravenous dose, the FDA approved dosage regimen is 240 mg intravenously every two weeks, which is similar to the 3 mg/kg intravenous dose (less than 6 percent difference), based on population pharmacokinetics analyses and dose/exposure-response analyses .
Following platinum-based chemotherapy
Squamous NSCLC – In the phase III CheckMate 017 trial, 272 patients with advanced squamous NSCLC who experienced disease progression during or after initial therapy with platinum-based doublet chemotherapy were randomly assigned to treatment with nivolumab (3 mg/kg intravenously every two weeks) or docetaxel (75 mg/m2 intravenously every three weeks) .
●Overall survival (OS), the primary endpoint of the trial, was prolonged with nivolumab compared with docetaxel (median OS 9.2 versus 6.0 months; one-year survival rate 42 versus 24 percent, hazard ratio [HR] 0.59, 95% CI 0.44-0.79).
●The objective response rate (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1) was higher with nivolumab (20 versus 9 percent), as was the duration of response (not reached with nivolumab versus eight months with docetaxel).
●Severe (grade 3 or higher) treatment-related adverse events were less frequent with nivolumab compared with docetaxel (7 versus 54 percent). Any grade pneumonitis was seen in 5 percent of patients treated with nivolumab (1 percent had grade 3 or higher pneumonitis); there were no reports of pneumonitis among patients receiving docetaxel, although there was one treatment-related death from interstitial lung disease.
Nonsquamous NSCLC – In the phase III CheckMate 057 trial, 582 patients with advanced non-squamous NSCLC who experienced disease progression during or after initial therapy with platinum-based chemotherapy were randomly assigned to treatment with nivolumab (3 mg/kg every two weeks) or docetaxel (75 mg/m2 every three weeks) [3,4]. Patients with epidermal growth factor receptor (EGFR)-mutant or anaplastic lymphoma kinase (ALK)-rearranged NSCLC could have received prior EGFR or ALK tyrosine kinase inhibitor (TKI) therapy, respectively.
●OS, the primary endpoint, was significantly prolonged with nivolumab compared with docetaxel (median OS 12.2 versus 9.4 months; one-year survival rate 51 versus 39 percent, 18-month survival rate 39 versus 23 percent, HR 0.72, 95% CI 0.60-0.88).
●Subset analysis of OS by smoking status suggested benefit with nivolumab over docetaxel in patients with a smoking history (n = 458, HR 0.7, 95% CI 0.56-0.86), but no difference between the treatments in never smokers (n = 118, HR 1.02, 95% CI 0.64-1.61).
●Any degree of tumor PD-L1 expression (at least one percent of tumor cells staining positive) was appreciated in 55 percent of evaluable samples, and was associated with improved survival with nivolumab (HRs are as follows when PD-L1 is expressed on at least the following percentages of tumor cells: 1 percent, HR 0.59 [p = 0.06]; 5 percent, HR 0.43 [p = 0.0004]; and 10 percent, HR 0.4 [p = 0.0002]). Survival was similar between nivolumab and docetaxel in patients with PD-L1-negative tumors.
Long-term follow-up is available from an earlier trial evaluating nivolumab in which 129 patients with advanced pre-treated NSCLC were enrolled, 54 percent of whom had received at least three prior systemic therapies . Patients were treated with nivolumab at 1 mg/kg, 3 mg/kg, or 10 mg/kg every two weeks.
●Median survival was 10 months, with survival rates as follows: one year, 42 percent; two-year, 24 percent; and three-year, 18 percent.
●Responses (RECIST, version 1) were seen in 17 percent of patients with a median duration of 17 months. Another 5 percent of patients had unconventional immune pattern responses (ie, tumor regression after initial growth, or the development of a new lesion in the setting of ongoing response at other sites) (table 2). (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Response to checkpoint inhibition'.)
●A higher response rate was seen in patients with a smoking history compared with non-smokers, with 30 percent of the 66 patients with at least a five pack-year smoking history achieving response versus no responses in the 11 patients with less than a five pack-year history (10 of whom were never-smokers).
First-line setting — Nivolumab has additionally been evaluated as monotherapy and in combination with standard platinum-based chemotherapy as first-line therapy for advanced NSCLC (CheckMate 012 study, NCT01454102).
●Nivolumab monotherapy – Among 52 patients treated with first-line nivolumab at 3 mg/kg every two weeks, the objective response rate (ORR) was 23 percent, with an additional 27 percent achieving stable disease . Four patients (8 percent) achieved complete response. The median duration of response was not reached (NR; range, 4.2 to 26+ months). Median OS, 18-month survival rate, and progression-free survival (PFS) were 19.4 months, 57 percent, and 3.6 months, respectively. Responses were observed in 9 of 32 patients (28 percent) with PD-L1-expressing tumors, and in 2 of 14 patients (14 percent) with no tumor PD-L1 expression.
●Nivolumab combined with platinum-based chemotherapy – Among 56 patients treated with nivolumab plus one of three standard first-line platinum chemotherapy regimens, response rates and duration of responses ranged between 33 and 47 percent, and 5.5 months to 19.6 months, respectively, depending on the study regimen used . Two-year survival rate ranged from 25 to 62 percent. Responses were observed regardless of tumor PD-L1 status. Grade 3 to 4 treatment-related adverse events occurred in 45 percent of patients, including pneumonitis (7 percent), fatigue (5 percent), and acute renal failure (5 percent). Twenty-one percent of patients discontinued study therapy due to treatment-related adverse events.
Pembrolizumab — Pembrolizumab is an IgG4 monoclonal antagonist antibody to PD-1 that is approved for use in pretreated advanced NSCLC that expresses PD-L1, as determined by the 22C3 pharmDx test. Pembrolizumab received FDA accelerated approval in October 2015 for the treatment of patients with advanced PD-L1-positive (at least 50 percent of tumor cells with membranous PD-L1 staining) squamous or non-squamous cell NSCLC who experience progression of disease on or after standard platinum-based chemotherapy. (See "Overview of the treatment of advanced non-small cell lung cancer", section on 'Subsequent treatment' and "Advanced non-small cell lung cancer: Subsequent systemic therapies for previously treated patients".)
In the phase I dose expansion KEYNOTE-001 trial that led to FDA approval, 495 patients with advanced NSCLC, 80 percent of whom had received prior therapy, received varying doses of intravenous pembrolizumab, every two or three weeks, until disease progression based upon immune-related response criteria (irRC) or until unacceptable toxicity occurred (table 2) .
●The objective response rate was 19.4 percent, with median duration of response 12.5 months and median OS of 12 months. The trial was amended after the first NSCLC cohort to require tumor PD-L1 expression by immunohistochemistry (≥1 percent of tumor cells staining for PD-L1 using the Dako 22C3 PD-L1 assay) for all but one of the subsequent NSCLC expansion cohorts. Thus, the majority of patients treated had some degree of tumor PD-L1 tumor expression.
●In 394 patients with previously treated and 101 patients with previously untreated advanced NSCLC, results were as follows:
•Response rate: 18 and 25 percent, respectively.
•Median duration of response: 10 and 23 months, respectively.
•Median OS: 9.3 and 16 months, respectively.
Response rate appeared to be independent of the dose and schedule of pembrolizumab, and was similar in patients with squamous and non-squamous NSCLC.
●Outcomes according to percent of tumor cells with PD-L1 expression were as follows:
•At least 50 percent (73 patients): response rate 45 percent; median duration of response, 12.5 months. Among the subset of these patients previously treated with systemic therapy for advanced NSCLC (n = 57): response rate, 44 percent; progression-free survival (PFS) 6.1 months; OS not achieved.
•1 to 49 percent (103 patients): response rate 16.5 percent; PFS 4.1 months.
•No PD-L1 expression (28 patients): response rate 10.7 percent; PFS four months.
●Therapy was well tolerated, with primarily low-grade toxicities, most commonly fatigue, pruritus, and decreased appetite. Grade 3 or higher toxicities occurred in 10 percent of patients. Eighteen patients developed pneumonitis (3.6 percent), including nine patients (1.8 percent) with grade 3 or higher pneumonitis, one of whom died.
●PD-L1 prevalence (using the Dako 22C3 PD-L1 assay): Among 824 patients with advanced NSCLC screened for the KEYNOTE-001 trial, 23.2 percent of patients had ≥50 percent of tumor cells staining for PD-L1; 37.6 percent of patients had 1 to 49 percent of tumor cells staining; and 39.2 percent of patients had <1 percent of tumor cells staining.
Subsequently, the phase II/III KEYNOTE-010 study randomly assigned over 1000 patients with previously treated advanced NSCLC and at least 1 percent tumor cell PD-L1 expression to pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel . Compared with docetaxel, pembrolizumab at 2 and 10 mg/kg was associated with:
●Improved median OS in the overall patient population (10.4 and 12.7 months versus 8.5 months for the docetaxel-treated group [HR 0.71, 95% CI 0.58-0.88 and 0.61, 95% CI 0.49-0.75, respectively]).
●Similar median PFS in the overall patient population (approximately four months in all groups).
●Improved median OS and PFS among 442 patients with at least 50 percent of tumor cells expressing PD-L1 (for those treated with pembrolizumab 2 mg/kg and 10 mg/kg, median OS of 14.9 months and 17.3 months versus 8.2 months for the docetaxel-treated group [HR 0.54, 95% CI 0.38-0.77 and 0.50, 95% CI 0.36-0.70, respectively]; median PFS of 5.0 and 5.2 months versus 4.1 months for the docetaxel-treated group [HR 0.59, 95% CI 0.44-0.78 and 0.59, 0.45-0.78, respectively]).
●Higher objective response rates (RECIST v 1.1) in the overall population (18 and 18 percent versus 9 percent for the docetaxel-treated group [p = 0.0005 and p = 0.0002, respectively]) and in patients with at least 50 percent of tumor cells expressing PD-L1 (30 and 29 percent versus 8 percent [p <0.0001 and p <0.0001, respectively]).
●Fewer grade 3 to 5 treatment-related adverse events (13 and 16 percent, respectively versus 35 percent for the docetaxel-treated group).
Based on encouraging activity in the KEYNOTE-001 trial, pembrolizumab is currently being evaluated in phase III trials as either initial or salvage therapy for patients with advanced PD-L1-positive NSCLC (table 1). An independent Data Monitoring Committee has recommended that the phase III KEYNOTE-024 study, evaluating first-line pembrolizumab versus platinum-based chemotherapy for advanced NSCLC with ≥50 percent PD-L1 expression, be stopped early due to improved PFS and OS demonstrated with pembrolizumab . We await formal reporting of results from this study.
Pembrolizumab has additionally been evaluated in phase I/II trials as monotherapy for patients with advanced PD-L1 positive NSCLC with asymptomatic untreated brain metastases, and in combination with standard platinum based chemotherapy, ipilimumab, erlotinib, gefitinib, afatinib and radiation.
PD-L1 blocking antibodies
Atezolizumab — Atezolizumab (MPDL3280A) is an IgG1 antagonist antibody to PD-L1 engineered to avoid antibody-dependent cell-mediated cytotoxicity (ADCC) of activated T cells that may express PD-L1.
Atezolizumab has been evaluated in a large phase I dose escalation trial finding no maximum tolerated dose, with subsequent expansion cohorts opened in select malignancies including previously treated advanced NSCLC. Eighty-eight patients with advanced NSCLC and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were treated with atezolizumab at doses up to 20 mg/kg administered intravenously every three weeks. Sixty-six percent of patients received three or more lines of systemic therapy for metastatic disease [11,12].
●The objective response rate (RECIST, version 1.1) was 23 percent, with median duration of response of 17 months.
●Median OS was 16 months, with one-year survival rate of 63 percent.
●In the 21 patients with high PD-L1 protein expression on tumor or tumor-infiltrating immune cells (defined as >50 percent of tumor cells or >10 percent of tumor area with immune cells staining for PD-L1), results were as follows:
•Response rate: 48 percent
•Median duration of response: 25 months
•Median OS: 18 months
•One year survival rate: 68 percent
●Grade 3 to 4 treatment adverse events occurred in 11 percent of patients. There were no cases of grade 3 to 5 pneumonitis reported; four patients (5 percent) experienced low-grade pneumonitis (grade 1 to 2).
The phase II POPLAR trial randomly assigned 287 patients who had received one or two prior systemic therapies for advanced NSCLC to either atezolizumab (1200 mg intravenously every three weeks) or docetaxel (75 mg/m2 intravenously every three weeks) .
●Objective response rate (using RECIST, version 1.1) was 15 percent in both arms, with duration of response of 14.3 months in those receiving atezolizumab, and 7.2 months in those receiving docetaxel.
●Any degree of tumor PD-L1 expression (on tumor cells or tumor-infiltrating immune cells) was associated with improvement in survival with atezolizumab (HR 0.59; p = 0.005). Survival was similar with atezolizumab and docetaxel in patients with PD-L1-negative tumors (9.7 months for each).
●Grade 3 to 4 treatment-related adverse effects were seen in 11 percent of patients receiving atezolizumab, compared with 39 percent in those treated with docetaxel. Any grade pneumonitis was seen in 3 percent of patients treated with atezolizumab (information concerning grade or pneumonitis rate on docetaxel arm is not available).
Preliminary results from the phase II BIRCH trial evaluating atezolizumab (1200 mg intravenously every three weeks) in 659 patients with both chemotherapy-naïve and treated, advanced, PD-L1-positive NSCLC were also presented at the 2015 annual ESMO Cancer Conference. PD-L1 positivity was defined as at least 5 percent of tumor cells staining for PD-L1 and/or at least 5 percent of tumor area with immune cells staining for PD-L1 .
●Response rate among patients with untreated and previously treated advanced NSCLC was 19 (26 of 139) and 17 percent (88 of 420), respectively.
•Among 302 patients with high PD-L1 expressing tumors (defined as >50 percent of tumor cells or >10 percent of tumor area with immune cells staining for PD-L1), response rates in untreated and previously treated advanced NSCLC were 26 (17 of 65) and 25 percent (60 of 237), respectively.
●Grade 3 to 4 treatment-related adverse events were seen in 11 percent of patients, with one treatment-related death (due to pneumonia). Ten patients (1.5 percent) developed grade 3 to 4 pneumonitis.
Among 1360 patients with advanced NSCLC screened for three trials evaluating atezolizumab (NCT 01846416, 01903993 and 01375842), 15 percent of patients were found to have high tumor PD-L1 expression (by the Ventana SP142 PD-L1 assay), and 30 percent of tumors had no PD-L1 expression. Thirty eight percent of patients had at least 5 percent of tumor cells staining for PD-L1 and/or at least 5 percent of the tumor area with immune cells staining for PD-L1 .
Atezolizumab has additionally been evaluated in phase I/II trials as monotherapy or in combination with platinum-based chemotherapy, and is currently being combined with other agents in early clinical trials, including erlotinib, ipilimumab, and other immunotherapies. Based on encouraging activity in early phase trials, atezolizumab is also being evaluated in several phase III trials in advanced NSCLC, including one comparing salvage atezolizumab with docetaxel after progression on or after first-line platinum based chemotherapy, and three comparing standard first-line chemotherapy with either atezolizumab alone or combination therapy with atezolizumab and chemotherapy (table 1).
Durvalumab — Durvalumab (MEDI4736) is an IgG1 antagonist antibody to PD-L1 with an engineered Fc domain to eliminate durvalumab effector function (ie, complement mediated cytotoxicity and ADCC). Results from the NSCLC cohort of a phase I dose escalation/expansion trial evaluating durvalumab administered every two or three weeks have been presented and suggest preferential activity in tumors with PD-L1 expression :
●Of 200 evaluable patients with advanced NSCLC treated with durvalumab (10 mg/kg every two weeks), 32 (16 percent) had a partial or complete response (RECIST, version 1.1). The response rate in 88 patients with squamous NSCLC was 21 percent; in 112 with non-squamous NSCLC, the response rate was 13 percent.
●PD-L1 tumor analysis was available for 176 patients. PD-L1 positivity was defined as at least 25 percent of tumor cells with membranous staining for PD-L1. Response rate was 27 percent (23 of 84) in patients with PD-L1-positive tumors and 5 percent (5 of 92) in those with PD-L1-negative tumors who received the durvalumab 10 mg/kg every-two-week schedule.
●No dose-limiting toxicities were observed. Grade 3 to 4 treatment-related adverse events were reported in 19 of 228 NSCLC patients (8 percent) receiving the durvalumab 10 mg/kg every-two-week schedule. There were no cases of grade 3 to 5 pneumonitis, with only three cases of low-grade pneumonitis reported (1 percent).
Durvalumab has additionally been evaluated in phase I trials in combination with other agents, including the anti-CTLA-4 antibody tremelimumab, gefitinib, AZD9291, and other immunotherapies. Based on encouraging activity in early trials, durvalumab is currently being evaluated in several phase III trials in NSCLC, including those focusing on locally advanced NSCLC after curative-intent chemoradiation, chemotherapy-naive advanced NSCLC, and pretreated advanced NSCLC after two lines of systemic therapy (table 1).
BMS-936559 — BMS-936559 is a fully human IgG4 antagonist antibody to PD-L1, which has been evaluated in a dose-escalation phase I trial with expansion cohorts in NSCLC, melanoma, and renal cell carcinoma . Patients received BMS-936559 every two weeks for up to two years. Of 49 evaluable patients with NSCLC, 10 percent achieved a partial response, and another 12 percent had stable disease for at least 24 weeks. Further results from this study are pending.
Biomarker studies, tumor PD-L1 expression — Although the aggregate of data from clinical trials evaluating PD-1 and PD-L1-blocking antibodies in NSCLC suggest that increasing tumor PD-L1 expression by immunohistochemistry correlates with benefit from such therapies, several challenges remain before adopting tumor PD-L1 as an exclusive criterion for treatment with all PD-1 axis inhibitors:
●Diagnostic PD-L1 immunohistochemistry assays vary, with each pharmaceutical company utilizing its own test, potentially leading to discordant results. Furthermore, while all such companies consider PD-L1 expression on tumor cells when defining “PD-L1 positivity,” only one (Genentech, atezolizumab) additionally considers PD-L1 expression on tumor-infiltrating immune cells.
●Different thresholds of PD-L1 positivity, ranging between 1 and 50 percent, have been used in trials when correlating response or survival to respective PD-1 or PD-L1 inhibitor therapy.
●There can be considerable PD-L1 heterogeneity within tumors and between tumor sites, which may not be accurately accounted for in small tumor biopsy specimens often used to diagnose NSCLC.
●Tumor PD-L1 expression may change over time and after systemic and local therapies; thus, archived tumor samples may not be ideal in determining current PD-L1 tumor status.
●Responses to PD-1 axis inhibitor therapy have been seen in 5 to 20 percent of patients with reported PD-L1-negative tumors across trials.
ANTIBODIES TO CTLA-4: IPILIMUMAB — Ipilimumab is an IgG1 cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibody that prolongs overall survival in patients with metastatic melanoma. (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Ipilimumab'.)
An ongoing phase III trial is comparing standard chemotherapy with carboplatin and paclitaxel with the same regimen combined with concurrent ipilimumab for patients with chemotherapy-naϊve metastatic squamous non-small cell lung cancer (NSCLC) (NCT01285609).
This trial was designed based upon results from a phase II randomized trial comparing two schedules of concurrent carboplatin, paclitaxel, and ipilimumab to standard therapy with carboplatin and paclitaxel alone for patients with advanced chemo-naϊve NSCLC (any histology) . A subset analysis of the trial based upon histology suggested that the addition of ipilimumab primarily benefited patients with squamous cell NSCLC. Ipilimumab is also currently being evaluated in earlier-phase NSCLC trials, where it is being combined with erlotinib or crizotinib (NCT01998126) and other immunotherapy.
TOXICITY OF IMMUNE CHECKPOINT INHIBITORS — Immune-related toxicities associated with programmed death receptor 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibodies are discussed in more detail separately. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)
SUMMARY AND RECOMMENDATIONS
●Cancer immunotherapy aims to augment recognition of cancer as foreign, stimulate immune responsiveness, and relieve inhibition of the immune system that allows tolerance of tumor survival and growth. (See 'Rationale' above.)
●Inhibition of immune checkpoints has shown promise in treating advanced non-small cell lung cancer (NSCLC) (see 'Immune activation and checkpoint inhibition' above and 'Antibodies to PD-1 and PD-L1' above):
•Nivolumab, a monoclonal antibody directed against programmed death 1 (PD-1) expressed on activated effector T cells, has an established role in the management of patients with advanced NSCLC regardless of tumor programmed death ligand 1 (PD-L1) expression after progression on or after standard first-line, platinum-based doublet chemotherapy. (See 'Nivolumab' above.)
•Pembrolizumab, another monoclonal antagonist antibody to PD-1, is an option for patients with PD-L1 high advanced NSCLC after progression on or after standard first-line platinum-based doublet chemotherapy (PD-L1 high defined as at least 50 percent of tumor cells with membranous tumor PD-L1 protein expression using the 22C3 pharmDx test). (See 'Pembrolizumab' above.)
•Multiple immune checkpoint inhibitors are currently in clinical development either as monotherapy or in combination with other immunotherapies, chemotherapy, targeted therapy, or radiation. Results from ongoing phase III clinical trials will further define the role of immune checkpoint inhibitors in the treatment of NSCLC (table 1).
●The selection of patients for immunotherapy versus other forms of treatment is discussed separately. (See "Advanced non-small cell lung cancer: Subsequent systemic therapies for previously treated patients".)
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