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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 therapy 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 therapy 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) [2,3].
●Overall survival (OS), the primary endpoint of the trial, was prolonged with nivolumab compared with docetaxel (median OS, 9.2 versus 6.0 months). The two-year OS rates with nivolumab versus docetaxel were 23 versus 8 percent.
●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). Of those with a confirmed response to nivolumab, 37 percent remained in remission after two years; none of the patients treated with docetaxel remained in remission.
●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) [3-5]. 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.
●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).
●The objective response rates (using RECIST, version 1.1) for nivolumab and docetaxel were 19 and 12 percent, respectively. Median durations of response were 17 and 6 months, respectively. Responses were ongoing in 34 percent of patients treated with nivolumab after two years' minimum follow-up but in none of those treated with docetaxel.
●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.
●Severe (grade 3 to 4) treatment-related adverse effects were seen in 10 percent of patients receiving nivolumab, compared with 54 percent in those treated with docetaxel. Any-grade pneumonitis was reported in 1 percent of patients treated with nivolumab, with another 1 percent with any-grade interstitial lung disease; there were no reports of pneumonitis or interstitial lung disease among patients receiving docetaxel.
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 — In the phase III CheckMate 026 trial, 541 patients with advanced PD-L1-positive NSCLC (at least 1 percent tumor cells with PD-L1 staining) who had not received prior systemic therapy for advanced disease were randomly assigned to treatment with nivolumab (3 mg/kg every two weeks) or standard first-line platinum-doublet chemotherapy. Results are as follows :
●Progression-free survival (PFS) in the 423 patients with >5 percent tumor PD-L1 expression, the primary endpoint, was not prolonged with nivolumab compared with platinum-doublet chemotherapy (median PFS, 4.2 versus 5.9 months with one-year PFS rate 24 versus 23 percent; HR 1.15, 95% CI 0.91-1.45).
●OS in patients with >5 percent tumor PD-L1 expression was not prolonged with nivolumab compared with platinum-doublet chemotherapy (median OS/one-year OS rate 14.4 months/56 percent versus 13.2 months/54 percent; HR 1.02, 95% CI 0.80-1.30).
●Objective response rates (ORR) in patients with >5 percent tumor PD-L1 expression for nivolumab and platinum-doublet chemotherapy were 26 and 34 percent, respectively. Median durations of response were 12.1 and 5.7 months, respectively.
●Severe (grade 3 to 4) treatment-related adverse effects were seen in 18 percent of all patients receiving nivolumab, compared with 51 percent in all those treated with platinum-doublet chemotherapy. Any-grade pulmonary adverse events were reported in 5.2 percent of patients treated with nivolumab, with severe events in 2.2 percent; any-grade pulmonary adverse events were reported in 0.4 percent of patients receiving chemotherapy.
Another phase III trial (CheckMate 227, NCT02477826) is currently comparing standard, first-line, platinum-doublet chemotherapy with nivolumab alone or nivolumab combined with ipilimumab in patients with advanced, PD-L1-positive NSCLC; platinum-doublet chemotherapy combined with nivolumab, or nivolumab combined with ipilimumab in PD-L1-negative NSCLC.
Pembrolizumab — Pembrolizumab is an IgG4 monoclonal antagonist antibody to PD-1 that is approved for use in pretreated advanced NSCLC that expresses PD-L1 (at least 1 percent of tumor cells with membranous PD-L1 staining), as determined by the 22C3 pharmDx test. In the frontline setting, it is approved for treatment of patients with metastatic NSCLC whose tumors have ≥50 percent PD-L1 expression based on this assay who do not harbor EGFR or ALK aberrations. It has also received accelerated approval for the front-line treatment of metastatic nonsquamous NSCLC in combination with pemetrexed and carboplatin, irrespective of PD-L1 expression. (See 'First-line setting' below.)
Following platinum-based chemotherapy — 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; 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). Any-grade pneumonitis was reported in 5 and 4 percent of patients receiving pembrolizumab 2 mg/kg and 10 mg/kg, respectively, with grade 5 pneumonitis in 2 percent; any-grade pneumonitis was reported in 2 percent of patients receiving docetaxel, with grade 3 to 5 pneumonitis in 1 percent.
First-line setting — Pembrolizumab monotherapy (200 mg intravenous [IV] every three weeks) was compared with standard platinum-doublet chemotherapy in a phase III trial enrolling 305 patients with advanced NSCLC having at least 50 percent tumor cell PD-L1 staining who had not received prior systemic therapy for advanced disease . Patients with EGFR mutations or ALK translocations were not included in this study. At a median follow-up of 11.2 months:
●PFS, the primary endpoint, was prolonged with pembrolizumab compared with platinum-doublet chemotherapy (median PFS, 10.3 versus 6 months; HR 0.50, 95% CI 0.37-0.68).
●OS was also prolonged with pembrolizumab compared with platinum-doublet chemotherapy (HR 0.60, 95% CI 0.41-0.89).
●ORRs for pembrolizumab and platinum-doublet chemotherapy were 45 and 28 percent, respectively. Median durations of response were 12.1 and 5.7 months, respectively.
●Severe (grade 3 to 5) treatment-related adverse effects were seen in 27 percent of patients receiving pembrolizumab, compared with 53 percent in those treated with platinum-doublet chemotherapy. Any-grade pneumonitis was reported in 5.8 percent of patients treated with pembrolizumab, with severe pneumonitis in 2.6 percent; 0.7 percent of patients (one patient) receiving chemotherapy developed pneumonitis.
●Of the 1653 screened patients with tumor tissue evaluable for PD-L1, 30 percent were found to have tumors with at least 50 percent PD-L1 expression.
Pembrolizumab (200 mg fixed dose every three weeks) combined with standard first-line chemotherapy (carboplatin and pemetrexed IV every three weeks) was compared with same chemotherapy alone in a phase II trial enrolling 123 patients with PD-L1-unselected, advanced, nonsquamous NSCLC who had not received prior systemic therapy for advanced disease . Patients receiving carboplatin and pemetrexed alone were allowed to receive pembrolizumab alone (200 mg IV every three weeks) after progression of disease.
●ORR, the primary endpoint, for pembrolizumab/carboplatin/pemetrexed and carboplatin/pemetrexed were 55 and 29 percent, respectively (estimated treatment difference, 26 percent; 95% CI 8 to 42 percent).
●Severe (grade 3 to 5) treatment-related adverse effects were seen in 39 percent of patients receiving pembrolizumab with carboplatin and pemetrexed, compared with 26 percent in those treated with carboplatin and pemetrexed alone. Any-grade pneumonitis was seen in 3 percent of patients treated with pembrolizumab combined with carboplatin and pemetrexed (2 percent had severe pneumonitis); there were no reports of pneumonitis among patients receiving carboplatin and pemetrexed alone.
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. It is approved by the FDA for the treatment of patients with metastatic NSCLC whose disease progressed during or following platinum-containing chemotherapy. Patients with EGFR or ALK genetic alterations should have disease progression on the appropriate targeted therapy before receiving atezolizumab.
Atezolizumab monotherapy (1200 mg IV every three weeks) was compared with standard salvage chemotherapy with docetaxel in a phase III trial enrolling 1225 patients with PD-L1-unselected advanced NSCLC that had been treated with one or more platinum based combination therapies . Patients were stratified by histology (squamous versus nonsquamous), PD-L1 expression, and prior chemotherapy regimens.
●OS in the first 850 patients enrolled, the primary endpoint, was prolonged with atezolizumab compared with docetaxel regardless of PD-L1 expression (median OS, 13.8 versus 9.6 months, with 12- and 18-month OS rates of 55 and 40 percent versus 41 and 27 percent, respectively; HR 0.73, 95% CI 0.62-0.87) and in the 55 percent of patients having tumors with at least 1 percent of tumor cells or tumor area with immune cells staining for PD-L1 (median OS, 15.7 versus 10.3 months; HR 0.74, 95% CI 0.58-0.93).
●Severe (grade 3 to 4) treatment-related adverse effects were seen in 15 percent of patients receiving atezolizumab, compared with 43 percent in those treated with docetaxel. Any-grade pneumonitis was reported in 1 percent of patients receiving atezolizumab, with severe pneumonitis (grade 3 to 4) in 0.7 percent.
●Among the 16 percent of enrolled patients with at least 50 percent of tumor cells or 10 percent of tumor area with immune cells staining for PD-L1, median OS with atezolizumab versus docetaxel was 20.5 versus 8.9 months (HR 0.41, 95% CI 0.27-0.64), with ORR of 31 versus 11 percent, respectively.
●OS was prolonged with atezolizumab versus docetaxel regardless of NSCLC histology (median OS, 15.6 versus 11.2 months in nonsquamous NSCLC; HR 0.73, 95% CI 0.60-0.89; median OS, 8.9 versus 7.1 months in squamous NSCLC; HR 0.73, 95% CI 0.54-0.98).
In a phase II trial of 659 patients with ≥5 percent tumor PD-L1-expressing tumor cells or tumor-infiltrating immune cells, objective response rates associated with atezolizumab (1200 mg IV every three weeks) were 22 percent among treatment-naïve patients, 19 percent among patients being treated in the second-line setting, and 18 percent among those receiving atezolizumab as third-line therapy . Further study is needed prior to use of atezolizumab in the frontline setting.
Atezolizumab has additionally been evaluated 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 ongoing phase III trials in patients with advanced NSCLC who have not received prior systemic therapy for advanced NSCLC (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). While results of durvalumab in advanced NSCLC are discussed here, promising results with this agent have been observed in unresectable stage III disease in the PACIFIC trial, which is discussed elsewhere. (See "Management of stage III non-small cell lung cancer" and "Management of stage III non-small cell lung cancer", section on 'Immunotherapy'.)
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.
Duration of treatment — In general, we recommend continuation of PD-1 axis inhibitor until progression or unacceptable toxicity occurs. This approach is based upon the randomized clinical trials leading to FDA approval of PD-1 axis inhibitors, in which respective agents were continued until progression. Additional clinical trials evaluating alternatives to indefinite continuous dosing are warranted (eg, maintenance PD-1 axis inhibitor with less frequent dosing intervals, discontinuation after complete response and/or predefined progression-free period), based upon the potential for durable responses to PD-1 axis inhibitors, anecdotal responses to rechallenge after progression off therapy, and the high cost of therapy. (See 'PD-1 blocking antibodies' above and 'PD-L1 blocking antibodies' above.)
The CheckMate-153 safety trial did evaluate duration of nivolumab monotherapy, but as an exploratory endpoint. Patients with pretreated advanced PD-1 axis inhibitor-naïve NSCLC received nivolumab 3 mg/kg intravenous every two weeks. Patients who completed one year of therapy were then randomized to continuous therapy or observation with the option to resume therapy on progression. Two hundred and twenty patients were randomized, with survival results from the 163 patients without progressive disease at the time of randomization reported at the 2017 annual ESMO meeting . Those who continued treatment with nivolumab experienced an improvement in PFS (median PFS not reached versus 10.3 months; HR 0.42, 95% CI 0.25-0.71). There was no significant improvement in OS at the time of analysis, although there was a trend towards improvement with continued nivolumab (median OS not reached versus 23.2 months; HR 0.63, 95% CI 0.33-1.22).
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'.)
Based upon results from a phase II trial suggesting a benefit from combining ipilimumab with the standard chemotherapy combination of carboplatin plus paclitaxel , a phase III trial was conducted in patients with chemotherapy-naϊve metastatic squamous NSCLC . In this trial, 388 patients were treated with chemotherapy plus ipilimumab and 361 were treated with chemotherapy plus placebo.
In contrast to the phase II results, there was no improvement in overall survival with the addition of ipilimumab compared with placebo (median, 13.4 versus 12.4 months; hazard ratio [HR] 0.91, 95% CI 0.77-1.07). Median progression-free survival was 5.6 months for both groups (HR 0.87, 95% CI 0.75-1.01).
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" and "Ocular side effects of systemically administered chemotherapy", section on 'Immune checkpoint inhibitors'.)
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) and has become integrated into the clinical approach for management of NSCLC. (See 'Immune activation and checkpoint inhibition' above and 'Antibodies to PD-1 and PD-L1' above.)
•For patients who have not received systemic therapy for advanced NSCLC and lack contraindications to immunotherapy (eg, an active autoimmune condition requiring immunosuppressive treatment), we assess tumor programmed death ligand 1 (PD-L1, using the Dako 22C3 PD-L1 assay).
-For patients with nonsquamous NSCLC that lacks a driver mutation and has less than 50 percent of tumor cells staining for PD-L1, the combination of pembrolizumab, carboplatin, and pemetrexed can be used as an alternative to platinum-based doublet chemotherapy alone or combined with bevacizumab. (See 'First-line setting' above.)
(See "Systemic therapy for the initial management of advanced non-small cell lung cancer without a driver mutation", section on 'Approach to treatment' and "Overview of the treatment of advanced non-small cell lung cancer", section on 'Low or intermediate PD-L1 expression'.)
-The initial management of patients with targetable driver mutations is discussed elsewhere. (See "Overview of the treatment of advanced non-small cell lung cancer", section on 'Driver mutation present' and "Overview of the treatment of advanced non-small cell lung cancer", section on 'Low or intermediate PD-L1 expression'.)
•For patients without a driver mutation who have progressed on prior chemotherapy for advanced NSCLC, we recommend immunotherapy with either an anti-programmed death receptor 1 (PD-1) or anti-PD-L1 antibody (Grade 1A). For those with EGFR or ALK genetic alterations who have progressed on available targeted agents as well as at least one line of chemotherapy, either immunotherapy or further lines of single-agent chemotherapy are acceptable options.
-For patients who have progressed on chemotherapy and will receive immunotherapy, nivolumab or atezolizumab are appropriate options (regardless of tumor PD-L1 expression). If tumor PD-L1 has been identified on at least 1 percent of tumor cells (using the Dako 22C3 PD-L1 assay), pembrolizumab is also an option. A choice among these agents depends on provider familiarity and local practice patterns, given a lack of data directly comparing these agents.
•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).
●For patients treated with an immune checkpoint inhibitor, we suggest continued treatment until progression or unacceptable toxicity occurs (Grade 2B).
●The selection of patients for immunotherapy versus other forms of treatment is discussed separately. (See "Advanced non-small cell lung cancer: Subsequent systemic therapy for previously treated patients".)
- FDA label http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125554s017s018lbl.pdf?et_cid=38363328&et_rid=931310737&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2016%2f125554s017s018lbl.pdf (Accessed on September 15, 2016).
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- Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016; 375:1823.
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