Immunotherapy in non-small cell lung cancer: Do the benefits outweigh the risks?
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Immunotherapy drugs have presented new options for treating patients with cancer, including non-small cell lung cancer, but patient selection and toxicity management still present challenges for clinicians.
Immunotherapy drugs are designed to target inhibitory checkpoint molecules (Figure), including PD-1 and its ligand, PD-L1, or CTLA-4.1 The promising therapeutic activity in both squamous and nonsquamous NSCLC led to FDA approval of two anti–PD-1 (nivolumab [Opdivo, Bristol-Myers Squibb] and pembrolizumab [Keytruda, Merck]) and two anti–PD-L1 antibodies (atezolizumab [Tecentriq, Genentech] and durvalumab [Imfinzi, AstraZeneca]).
Approved immunotherapy drugs for NSCLC
Durvalumab
Durvalumab is approved for treating patients with urothelial carcinoma and received breakthrough therapy designation for patients with NSCLC in July 2017. Ongoing trials are investigating durvalumab as monotherapy and in combination with tremelimumab (MedImmune), an anti–CTLA-4 agent, as first-line therapy in patients with NSCLC.
The PACIFIC trial investigated durvalumab as maintenance therapy for patients with stage III NSCLC who are ineligible for surgery. Patients treated with durvalumab had improved progression-free survival, response rates and response duration compared with patients receiving placebo. Patients receiving durvalumab also had a longer time to death or distant metastasis compared with patients receiving placebo. Similar rates of adverse events occurred in both groups, with approximately 15% of patients discontinuing the drug because of these adverse events.
Nivolumab
Nivolumab is a fully human anti–PD-1 antibody designed to disrupt T-cell activation and proliferation, which leads to restored antitumor immunity. Nivolumab is approved for treating patients with squamous NSCLC after chemotherapy failure.
In a meta-analysis of previously treated patients with advanced NSCLC, those who received nivolumab had a pooled objective response rate of 20%, disease control rate of 36%, 1-year overall survival rate of 47% and 1-year PFS rate of 21%. Of note, only 8% of patients reported grade 3 to 4 adverse events.
Patients with 5% or greater PD-L1 expression had a significantly greater ORR compared with patients with PD-L1 expression of less than 5% (31% vs. 12%). Although PD-L1–negative patients had a lower ORR, patients did respond and reported manageable adverse events, suggesting that nivolumab may be used as a second-line agent in patients with previously treated advanced NSCLC.
Pembrolizumab
Pembrolizumab, a PD-1 inhibitor that improves antitumor immunity, is approved in combination with pemetrexed (Alimta, Eli Lilly) and carboplatin for the treatment of treatment-naïve patients with metastatic nonsquamous NSCLC. In a recent study, 55% of patients receiving pembrolizumab plus chemotherapy achieved an objective response compared with 29% of patients receiving chemotherapy alone.
Treatment-related adverse event rates were similar between groups. Patients receiving pembrolizumab plus chemotherapy most frequently reported grade 3 or worse treatment-related adverse events of anemia, decreased neutrophil count, acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, sepsis and thrombocytopenia. Pembrolizumab was discontinued in 10% of patients because of adverse events.
Although positive PD-L1 expression levels were not required for treatment, patients with at least 50% PD-L1 expression who received pembrolizumab plus chemotherapy had higher response rates compared with patients receiving chemotherapy alone (80% vs. 35%).
Pembrolizumab also has a National Comprehensive Cancer Network category 1 recommendation as subsequent therapy for patients with metastatic nonsquamous NSCLC and PD-L1 expression. In the phase 2/3 KEYNOTE-010 trial, patients receiving pembrolizumab had significantly prolonged OS compared with patients receiving docetaxel. Additionally, patients receiving pembrolizumab reported fewer grade 3 to 5 treatment-related adverse events.
In the phase 1 KEYNOTE-001 trial, patients with metastatic NSCLC and 50% or greater PD-L1 expression levels who were treated with pembrolizumab had an improved response rate, PFS, and OS compared with the entire patient population (Table 1). Serious grade 3 or higher toxicity was reported in less than 10% of patients.
Table 1. Survival results from KEYNOTE-001 correlate with PD-L1 expression
| PD-L1 Expression | ORR | PFS (months) | OS (months) |
| ≥50% | 45.2% | 6.3 | NR |
| 1%-49% | 16.5% | 3.3 | 8.8 |
| < 1% | 10.7% | 2.3 | 8.8 |
Abbreviations: NR, not reported; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.
Atezolizumab
Atezolizumab, a selective humanized monoclonal IgG1 antibody against PD-L1, was granted breakthrough therapy designation in 2015 for treating patients with PD-L1–positive NSCLC who progressed during or after standard treatment.
Results from the FIR trial demonstrated that PD-L1 expression was associated with response to atezolizumab. Patients with the highest levels of PD-L1 expression demonstrated ORRs between 25% and 29%, with a median PFS of between 2.3 months and 5.4 months. No unexpected immune-related adverse events were reported.
In the POPLAR trial, patients receiving atezolizumab exhibited significantly improved survival compared with docetaxel chemotherapy. Notably, OS was not different between treatment groups in patients with PD-L1–negative tumors. Fewer grade 3 to 5 adverse events were reported in patients treated with atezolizumab compared with docetaxel chemotherapy.
The BIRCH trial included patients with positive PD-L1 tumor expression who were chemotherapy-naïve or previously treated patients with advanced NSCLC without brain metastases. Among patients with the highest PD-L1 expression, objective response rates reached 26%, with 6-month survival rates of 75% to 80%. No new safety signals were reported.
Patients receiving second-line atezolizumab in the OAK trial had significantly increased overall survival compared with patients receiving docetaxel (13.8 vs. 9.6 months). In addition, PD-L1–negative patients also had significantly prolonged OS with atezolizumab compared with docetaxel (12.5 vs. 8.9 months). Fewer adverse events were reported with atezolizumab compared with docetaxel, and no new safety signals were reported.
Immune-mediated adverse events
Patients receiving immunotherapy experience a different toxicity profile than what is seen with cytotoxic chemotherapy. These adverse events are often better tolerated, allowing patients to continue treatment.
In the PACIFIC study, nearly three times as many patients treated with durvalumab reported immune-mediated adverse events as patients receiving placebo. Immune-mediated adverse events included pneumonitis, rash, dermatitis, hypothyroidism and hyperthyroidism. Reports of grade 3/4 immune-mediated adverse events were similar between treatment groups.
Management for immune-mediated adverse events included systemic glucocorticoids in 14.3% of patients treated with durvalumab and 5.6% of patients treated with placebo, high-dose glucocorticoids in 8.2% and 4.3% of patients, endocrine therapy in 10.7% and 1.3% of patients, and other immunosuppressive agents in 0.4% of patients treated with either agent.
In the combined safety database of 1,414 patients, reported immune-mediated adverse events related to durvalumab treatment included pneumonitis, hepatitis, colitis, endocrinopathies and rash. Other rare immune-mediated adverse events reported in 1% or fewer patients included aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, nephritis and ocular inflammatory toxicity.
Of patients with NSCLC who received nivolumab treatment, approximately 50% reported immune-mediated adverse events. The most frequently reported immune-mediated adverse events included skin toxicity (mainly rash and pruritus), gastrointestinal events and pneumonitis. In most cases, these adverse events were of low grade. Other less common immune-mediated adverse events included endocrinopathies, nephrotoxicity (mainly consisting of blood creatinine elevation), rare infusion reactions and elevation of blood liver function parameters. Other anti–PD-1 and anti–PD-L1 compounds showed a comparable safety pattern.
A recent meta-analysis was designed to determine the overall incidence of pneumonitis, a potentially fatal immune-mediated adverse event, which is associated with PD-1 and PD-L1 inhibitor use. PD-1 inhibitor use was associated with a significantly higher incidence of any grade pneumonitis and grade 3/4 pneumonitis compared with PD-L1 inhibitor use. Also, treatment-naïve patients had a significantly higher incidence of any grade pneumonitis compared with patients who had previously received PD-1 or PD-L1 inhibitors.
Biomarkers for immunotherapy
Trials evaluating PD-1/PD-L1 pathway inhibitors in several tumor types have reported conflicting results regarding the role of PD-L1 expression on tumor cells for predicting treatment response (Table 2). A large meta-analysis conducted to further explore the role of PD-L1 as predictive factor revealed that patients treated with either a PD-1 or a PD-L1 inhibitor who were PD-L1–positive had a significantly higher response rate compared with PD-L1–negative patients.8
This difference in response rate was also significant in the subgroup of patients treated with nivolumab and among patients with NSCLC. These findings highlight the fact that PD-L1–negative patients do respond to anti–PD-1 or anti–PD-L1 treatments.
Table 2. PD-L1 values in immunotherapy trials
| Atezolizumab | Durvalumab | Nivolumab | Pembrolizumab | |
| Positive cutoff used in trials | 1%-10% | n/a | 1%-5% | 1%-50% |
| ORR in PD-L1–positive patients | 31%-83% | 26% | 13%-31% | 19%-47% |
| ORR in PD-L1–negative patients | 18%-20% | 10% | 10%-17% | 9%-13% |
Abbreviation: ORR, objective response rate.
In a larger cohort of NSCLCs, no association was reported between PD-L1 status and either overall survival or objective response rate. Data from phase 3 trials suggest that PD-L1 expression may be predictive of better nivolumab efficacy in terms of OS, PFS, and ORR for patients with nonsquamous NSCLC.
Other trials have reported objective responses and longer durations of response in patients with both PD-L1–positive and PD-L1–negative NSCLC. Of note, no significant differences have been reported for various levels of PD-L1 expression (1%, 5% or 10% positive tumor cells).
Besides PD-1 and PD-L1, high tumor mutation burden may be a biomarker for immunotherapy activity. In the phase 3 CheckMate-227 trial, the combination of nivolumab and ipilimumab (Yervoy, Bristol-Myers Squibb) led to improved progression-free survival compared with chemotherapy in treatment-naïve patients with NSCLC and high tumor mutation burden. These results suggest that tumor mutation burden may be used to predict which NSCLC patients may benefit from the combination of nivolumab and ipilimumab in the first-line setting.
Conclusion
Immunotherapies have altered the treatment approach to NSCLC. Although these drugs have a different toxicity profile with more frequent immune-mediated adverse events, they are generally better tolerated than cytotoxic chemotherapy. Now, the challenge will be to determine how to identify those patients most likely to benefit by identifying predictive biomarkers.
References
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Khunger M, Rakshit S, Pasupuleti V, et al. Incidence of pneumonitis with use of programmed death 1 and programmed death-ligand 1 inhibitors in non-small cell lung cancer: a systematic review and meta-analysis of trials. Chest. 2017;152(2):271-281.
Carbognin L, Pilotto S, Milella M, et al. Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers. PLoS One. 2015;10(6):e0130142.