Update in Immunotherapy for Advanced Non-Small Cell Lung Cancer: Optimizing Treatment Sequencing and Identifying the Best Choices
Abstract
:Simple Summary
Abstract
1. Introduction
2. Biomarkers
2.1. PD-L1
2.2. Tumor Mutational Burden (TMB)
2.3. MAJOR Histocompatibility Complex (MHC)
2.4. Tumor Microenvironment
3. Chemotherapy Free Regimens
3.1. Single Agent
3.1.1. Pembrolizumab
3.1.2. Atezolizumab
3.1.3. Cemiplimab
4. Immunotherapy Combinations
4.1. Nivolumab plus Ipilimumab
4.2. Durvalumab plus Tremelimumab
5. Combinations with Chemotherapy
5.1. Atezolizumab
5.2. Cemiplimab
5.3. Pembrolizumab
5.4. Nivolumab/Ipilimumab
5.5. Tremelimumab plus Durvalumab
6. Second-Line Therapy
7. Atezolizumab
8. Nivolumab
Pembrolizumab
9. Adverse Effects
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- Cardiovascular irAEs: Myocarditis is a significant concern due to its associated high risk of mortality. Clinical presentations of ICI-induced myocarditis vary, ranging from chest pain to acute dyspnea and circulatory collapse [67]. Fatal cases have been reported even after a single dose of ipilimumab and nivolumab. Emerging data suggest that myocarditis typically occurs early in treatment, with 81% of events happening within the first four treatment cycles (around 34 days from treatment initiation) [68]. Patients undergoing ICIs should undergo a thorough cardiac assessment if any signs of cardiac insufficiency or chest discomfort arise. Baseline electrocardiograms are recommended before initiating ICI treatment, as cardiac toxicities can manifest as isolated arrhythmias. Regular monitoring of serum troponin levels is also advised due to the potential for silent myocardial injury during the course of treatment [69].
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- Dermatologic irAEs: This affects a substantial portion of patients, ranging from one-third to over half of individuals. Common skin toxicities encompass rash, pruritus, and vitiligo, with similar occurrences in patients receiving either anti-CTLA-4 or anti-PD-1 antibodies [70]. The majority of lesions are maculopapular and affect less than 30% of the body surface area. Follicular, pustular, vesicular, and acneiform presentations have also been observed. ICI-induced rash often resolves within 1–2 months with effective management; however, some patients experience persistent or recurrent low-grade cutaneous toxicities after treatment completion. Severe cases, such as extensive exfoliative, ulcerative, or bullous dermatitis, are less common but can occur. Grade ≥3 cutaneous irAEs are typically seen in 2–3% of patients on ICI monotherapies and 4–10% on combination therapies. Special caution is needed when managing patients with active or past psoriasis or a family history of psoriasis [71].
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- Endocrine irAEs: Hypophysitis is a rare occurrence in patients treated with anti-PD-1 antibodies. However, it is notably more common in individuals who receive ipilimumab, with an incidence ranging from 12.0% to 13.3% in real-world settings [72]. Patients experience symptoms such as fatigue, weakness, headache, visual disturbances, arterial hypotension, and nausea, and there should be heightened suspicion of hypophysitis. To diagnose hypophysitis, early performance of pituitary MRI is recommended, as is an evaluation of pituitary functional status [72,73]. In contrast to hypophysitis, thyroid dysfunction is more commonly linked with antibodies that target PD-1, rather than CTLA-4. Notably, thyroid dysfunctions have only been reported in connection with anti-PD-L1 antibodies [74]. In real-world settings, nearly 20% of patients receiving anti-PD-1 antibodies exhibit thyroid dysfunction. This typically occurs early in the treatment process, with a median onset around 6 weeks after the first infusion. Thyroid irAEs often manifest without noticeable symptoms. They may present as mild thyrotoxicosis or primary hypothyroidism resulting from destructive thyroiditis. In some cases, a less common presentation involves thyrotoxicosis tied to autoimmune thyroid disease (such as Graves’ disease) [75].
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- Gastrointestinal irAEs: Colitis stands out as the most prevalent irAE observed in patients treated with ipilimumab. When undergoing endoscopic assessments, the typical findings involve a mucosa displaying widespread ulceration and edema. Interestingly, this effect can impact the entire colon rather than being confined to a specific segment [75,76]. In about a quarter of patients, there is also an associated occurrence of diffuse enteritis, a condition that can manifest even in the absence of colitis. It is essential to consider the potential presence of enteritis in cases where patients exhibit diarrhea coupled with unexplained weight loss. The incidence of colitis and/or enteritis induced by anti-PD-1 antibodies is notably lower compared to the frequency of colitis resulting from ipilimumab treatment [77]. This discrepancy underscores the potential redundancy of the PD-1 pathway in maintaining immune homeostasis within the gut [78].
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- Neurologic irAEs: The spectrum involves the central and peripheral nervous system; therefore, it encompasses various conditions including myopathies, neuromuscular junction disorders, peripheral neuropathies (including axonal and demyelinating polyradiculoneuropathies), length-dependent and non-length-dependent neuropathies, asymmetric mononeuritis multiplex, cerebellar ataxia, retinopathy, bilateral internuclear ophthalmoplegia, and headache. It is important to note that ongoing research continues to expand our understanding of neurological irAEs, revealing diverse and often complex presentations [79,80].
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- Pulmonary irAEs: Patients treated with anti-PD-1 antibodies have a higher likelihood of experiencing pneumonitis compared to those receiving anti-CTLA-4 antibodies. Diagnosing this life-threatening complication can be particularly challenging, especially in patients with pre-existing chronic lung diseases such as lung cancer. Radiological presentations of immune-related pneumonitis include various patterns such as cryptogenic organizing pneumonia (COP), nonspecific interstitial pneumonia, hypersensitivity pneumonitis, acute interstitial pneumonia, sarcoid-type reactions, and acute respiratory distress syndrome [81]. The management of pneumonitis involves immunosuppression with steroids and, in some cases, infliximab and/or cyclophosphamide. However, the optimal approach for frail patients requiring immunosuppression is an ongoing challenge, and research is needed to develop predictive tools for guiding treatment decisions [82].
10. Future Directions
11. Discussion/Practical Considerations
11.1. Biomarkers
11.2. Regimen Selection
11.2.1. Duration of Therapy
11.2.2. Effectiveness in Target Population
11.2.3. Immunotherapy Resistance
12. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Drug | Type | Indications |
---|---|---|
Atezolizumab | Anti-PD-L1 | First-line treatment (*, **):
|
Cemiplimab | Anti-PD1 | First-line treatment (*, **):
|
Nivolumab | Anti-PD1 | Subsequent line monotherapy for the treatment mNSCLC who has been progressed after platinum-based chemotherapy. Patients with EGFR or ALK aberrations must have disease progression at least one target therapy (*, **). |
Nivolumab/Ipililumab | Anti-PD1/Anti-CTLA4 | First-line treatment (*, **):
|
Pembrolizumab | Anti-PD1 | First-line treatment (*, **):
|
Tremelimumab/Durvalumab | Anti-CTLA4/Anti-PD-L1 | First-line treatment in combination with platinum-based chemotherapy for the treatment of patients with mNSCLC without EGFR or ALK genomic tumour aberrations, regardless of histology. |
ICIs | Trial | Population | Primary Endpoint | ORR | PFS | OS | 5y-ORR | 5y-PFS | 5y-OS |
---|---|---|---|---|---|---|---|---|---|
Atezolizumab | IMpower 110 | PD-L1 ≥ 50% or IC ≥10%; squamous and non-squamous histology | OS | 38.3 vs. 28.6% | 8.1 vs. 5.0 months | 20.2 vs. 13.1 months | 40.2% | 8.2 months | 20.2 vs. 14.7 months |
Cemiplimab | EMPOWER-Lung 1 | PD-L1 ≥ 50%; squamous and non-squamous histology | OS and PFS | 39.0 vs. 20% | 8.2 vs. 5.7 months | NR vs. 14.2 months | 46.5 vs. 21.0% * | 8.1 vs. 5.3 months * | 26.1 months * |
Nivolumab plus ipilimumab | CheckMate 227 | PD-L1 ≥ 1%; squamous and non-squamous histology | OS | 35.9 vs. 30.0% | 5.1 vs. 5.6 months | 17.1 vs. 14.9 months | 24% | ||
Pembrolizumab | KEYNOTE-024 | PD-L1 ≥ 50%; squamous and non-squamous histology | PFS | 45% | 10.3 months | 26.3 months (80.2%). | 46.1 vs. 31.1% | 7.7 vs. 5.5 months | 26.3 vs. 13.4 months (31.9%) |
KEYNOTE-042 | PD-L1 ≥ 1%; squamous and non-squamous histology | OS | 27 vs. 27% | 5.4 vs. 6.5 months | 16.7 vs. 12.1 months | 27.3% | 5.6 months | 16.4 months |
ICIs | Trial | Population | Primary Endpoint | ORR | PFS | OS | 5y-ORR | 5y-PFS | 5y-OS |
---|---|---|---|---|---|---|---|---|---|
Atezolizumab plus Bevacizumab plus CT | IMpower150 | Any PD-L1 and Non-squamous histology | PFS and OS | 63.5% (ABCP) vs. 48.0% (BCP) | 8.3 vs. 6.8 months ABCP vs. BCP HR 0.62 (95% CI 0.52–0.74) | 19.5 vs. 14.7 months ABCP vs. BCP: HR 0.78 (95% CI 0.64–0.96) | 8.4 vs. 6.8 months ABCP vs. BCP HR 0.57 (95% CI 0.48–0.67) | 19.5 vs. 14.7 months HR 0.80 (95% CI 0.67–0.95) | |
Atezolizumab plus platinum plus paclitaxel/nab paclitaxel | IMpower130 | Any PD-L1 and Non-squamous histology | PFS and OS | 49.2% vs. 31.9% | 7.0 versus 5.5 months (HR 0.64; 95% CI 0.54–0.77) | 18.6 versus 13.9 months (HR 0.79; 95% CI 0·64–0·98) | - | - | - |
Atezolizumab plus platinum plus paclitaxel/nab paclitaxel | IMpower131 | Any PD-L1 and squamous histology | PFS and OS | 49.4% vs. 41.3% | 6.3 vs. 5.6 months HR 0.71 (95% CI 0.60–0.85) | 14.2 versus 13.5 months (HR 0.88; 95% CI 0.73–1.05) | - | - | - |
Atezolizumab plus platinum plus pemetrexed | IMpower132 | Any PD-L1 and Non-squamous histology | PFS and OS | 47% vs. 32% | 7.6 versus 5.2 months; HR 0.60, 95% CI 0.49–0.72 | 18.1 versus 13.6 months; HR 0.81, 95% CI 0.64–1.03 | - | - | 17.5 vs. 13.6 months *; HR 0.86 (0.71–1.06) |
Cemiplimab plus platinum-doublet chemotherapy | EMPOWER-Lung 3 | Any PD-L1; squamous and Non-squamous histology | OS | 43.3% vs. 22.7% | 8.2 vs. 5.0 months HR = 0.56; 95% CI, 0.44–0.70 | 21.9 vs. 13.9 months; HR 0.71; 95% CI, 0.53–0.93 | 43.6% versus 22.1% | 8.2 months versus 5.5 months (HR 0.55, 95% CI 0.44–0.68 | 21.1 versus 12.9 months; HR 0.65, 95% CI 0.51–0.82 |
Nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy | CheckMate 9LA | Any PD-L1; squamous and Non-squamous histology | OS | 37.7% vs. 25.1% | 6.8 vs. 5.0 months HR 0.70 [97·48% CI 0.57–0.86 | 14.1 versus 10.7 months; HR 0.69; 96.71% CI 0.55–0.87 | 38% vs. 25% * | 6.4 versus 5.3 months * | 15.8 versus 11 months *; HR 0.74, 95% CI 0.62–0.87 |
Pembrolizumab plus platinum (carboplatin or cisplatin) plus pemetrexed | KEYNOTE-189 | Any PD-L1 and Non-squamous histology | PFS and OS | 47.6% vs. 18.9% | 8.8 vs. 4.9 months HR 0.52 (95% CI 0.43–0.64) | NR vs. 11.3 months; HR 0.49; 95% CI 0.38–0.64 | 48.3% vs. 19.9% | 9.0 versus 4.9 months; HR 0.5; 95% CI 0.42–0.60 | 22.0 versus 10.6 months; HR 0.6; 95% CI 0.50–0.72 |
Pembrolizumab plus platinum (carboplatin or cisplatin) plus Paclitaxel or nab-paclitaxel | KEYNOTE-407 | Any PD-L1 and squamous histology | PFS and OS | 57.9% vs. 38.4% | 6.4 versus 4.8 months; HR 56; 95% CI 0.45–0.70 | 15.9 months and 11.3 months HR 0.64; 95% CI 0.49–0.85 | 66.2% vs. 38.8% | 8 versus 5.1 months; HR 0.62; CI 0.52–0.74 | 17.2 versus 11.6 months HR 0.71; 95% CI 0.59–0.85 |
Tremelimumab plus durvalumab plus CT | POSEIDON | Any PD-L1; squamous and Non-squamous histology | PFS and OS | 46.3% vs. 33.4% | 6.2 v 4.8 months; HR 0.72; 95% CI 0.60–0.86 | 14.0 versus 11.7 months; HR 0.77; 95% CI 0.65–0.92 | - | - | - |
ICIs | Trial | Population | Primary Endpoint | ORR | PFS | OS |
---|---|---|---|---|---|---|
Atezolizumab | OAK | Patients with NSCLC, any histology, who had received one or two previous chemotherapy regimens for stage IIIB or IV, except docetaxel, CD137 agonists, anti-CTLA4, anti PD-L1 or PD-1. | OS | 14% vs. 13% | 2.8 VS. 4.0 months; HR 0.95 95% CI 0.82–1.10 | 13.8 vs. 9.6 months; HR 0.73; 95% CI 0.62–0.87. 4y rate: 15.5% vs. 8.7%. |
Nivolumab | CheckMate-057 | Patients with metastatic non-squamous NSCLC who progressed after the first line with platinum-based doublet CT. | OS | 19% vs. 12% | 2.3 vs. 4.7 months (HR 0.92; 95% CI 0.77–1.11 | 12.2 vs. 9.4 months (HR 0.73; 95% CI 0.59–0.89 |
CheckMate-017 | Patients with metastatic squamous NSCLC who progressed after the first line with platinum-based doublet CT. | OS | 20% vs. 9% | 3.5 versus 2.8 months (HR 0.62; 95% CI 0.47–0.81 | 9.2 vs. 6.0 months HR 0.59; 95% CI 0.44–0.79 | |
Pembrolizumab | KEYNOTE-010 | Previously treated patients with PD-L1 positive (≥1%) advanced NSCLC, regardless histology | PFS and OS | 18% vs. 9% | 4.0 versus 4.0 months (HR 0·79, 0.66–0.94 | 12.7 vs. 5.5 months HR 0.71; 95% CI 0.58–0.88 5y: 11.8 months versus 8.4 months (HR 0.70; CI 0.61–0.80) |
Drug | Dose | Diarrhea | Colitis | Pulmonary | Rash | Neurological | Endocrinopathy | Hepatic | Renal |
---|---|---|---|---|---|---|---|---|---|
Atezolizumab Trials | |||||||||
Impower 110 | 1200 mg 3-weekly | - | - | 4.9% | - | - | - | - | - |
Impower 150 | 1200 mg 3-weekly | 20.6% | - | - | 13.3% | 49.4% (neuropathy included) | - | - | |
Oak | 1200 mg 3-weekly | 15.4% | 0.3% | 1% | - | - | - | 0.3% | - |
Cemiplimab Trials | |||||||||
Empower-Lung 1 | 350 mg 3-weekly | 5% | 1% | 6% | 5% | 3% | - | 6% | 1% |
Empower-Lung 1 | 350 mg 3-weekly | 10.6% | - | 12.5% | - | - | - | 30% | - |
Nivolumab Trials | |||||||||
CheckMate 057 | 3 mg/kg, 2-weekly | 8% | 1% | 4.9% | 9% | 0.3% | 10.5% | 10.8% | 2% |
Nivolumab/Ipililumab | |||||||||
Check Mate 227 | 1 mg/kg 6-weekly ipilimumab plus 3 mg/kg 2-weekly nivolumab (576) | 16.3% | 1% | 3% | 16.7% | - | 12.3% | 3.5% | - |
Pembrolizumab Trials | |||||||||
Keynote-054 | 200 mg, 3-weekly | 19.1% | 3.7% | 4.7% | 16.1% | - | 23.4% | 1.8% | 0.4% |
Keynote-010 | 10 mg/kg, 3-weekly | 6% | 1% | 4% | 13% | - | 16.5% | 1% | - |
Keynote-189 | 200 mg, 3-weekly | - | 2.2% | 4.4% | 2% | - | 12.8% | - | 1.7% |
Keynote-042 | 200 mg, 3-weekly | 5% | 1% | 8% | 7% | 1% | 18% | 7% | <1% |
Tremelimumab/Durvalumab | |||||||||
Poseidon | 13.9% | 3.9% | 3.6% | 3.9% | - | - | - | - |
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Roque, K.; Ruiz, R.; Mas, L.; Pozza, D.H.; Vancini, M.; Silva Júnior, J.A.; de Mello, R.A. Update in Immunotherapy for Advanced Non-Small Cell Lung Cancer: Optimizing Treatment Sequencing and Identifying the Best Choices. Cancers 2023, 15, 4547. https://doi.org/10.3390/cancers15184547
Roque K, Ruiz R, Mas L, Pozza DH, Vancini M, Silva Júnior JA, de Mello RA. Update in Immunotherapy for Advanced Non-Small Cell Lung Cancer: Optimizing Treatment Sequencing and Identifying the Best Choices. Cancers. 2023; 15(18):4547. https://doi.org/10.3390/cancers15184547
Chicago/Turabian StyleRoque, Katia, Rossana Ruiz, Luis Mas, Daniel Humberto Pozza, Marina Vancini, José Antônio Silva Júnior, and Ramon Andrade de Mello. 2023. "Update in Immunotherapy for Advanced Non-Small Cell Lung Cancer: Optimizing Treatment Sequencing and Identifying the Best Choices" Cancers 15, no. 18: 4547. https://doi.org/10.3390/cancers15184547
APA StyleRoque, K., Ruiz, R., Mas, L., Pozza, D. H., Vancini, M., Silva Júnior, J. A., & de Mello, R. A. (2023). Update in Immunotherapy for Advanced Non-Small Cell Lung Cancer: Optimizing Treatment Sequencing and Identifying the Best Choices. Cancers, 15(18), 4547. https://doi.org/10.3390/cancers15184547