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Table of Contents

    Topic review

    Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer

    Subjects: Oncology
    View times: 4
    Submitted by: Kyoichi Kaira

    Definition

    Immune checkpoint inhibitors (ICIs) are standard treatments for patients with lung cancer. PD-1/PD-L1 or CTLA4 antibodies are chosen as the first-line therapy, contributing to the long-term survival and tolerability. Unlike molecular targeting agents, such as gefitinib, lung cancer patients with a poor performance status (PS) display unsatisfactory clinical improvements after ICI treatment. 

    1. Introduction

    Immune checkpoint inhibitors (ICIs), such as programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies, are widely administered to patients with several types of cancers. In particular, it is surprising that long-term survival of more than 5 years was observed in patients with advanced malignant melanoma and metastatic/recurrent non-small-cell lung cancer (NSCLC) after the initiation of PD-1 blockade monotherapy [1][2]. Thus, we believe that a PD-1 blockade may also bring clinical benefits to cancer patients with a poor performance status (PS). Unfortunately, several previous reports demonstrated that PD-1 blockade monotherapy was not effective in such patients [3][4][5]. As a first-line setting, chemotherapeutic regimens, including a PD-1 blockade, are universally established as standard treatment for patients with advanced NSCLC without any driver mutations. Unlike molecular targeting agents, such as gefitinib, advanced or recurrent NSCLC patients with poor PSs displayed unsatisfactory clinical improvements after ICI treatment. Several previous reports also showed that the PS is one of the most important prognostic factors for predicting poor outcomes after ICI treatment [3][4][5]. However, first-line pembrolizumab or atezolizumab seemed to be effective for NSCLC patients with a PS of 2 if PD-L1 expression was greater than 50%.

    2. PS as a Prognostic Factor after a PD-1 Blockade

    Recently, several studies demonstrated that the Eastern Cooperative Oncology Group (ECOG) PS was an independent factor for predicting worse outcomes after PD-1 blockade monotherapy in patients with advanced or recurrent NSCLC [4][5][6][7]. Fujimoto et al. retrospectively analyzed the prognostic significance in 613 patients that were treated with nivolumab in a second-line or over setting [4]. Of the 613 patients, an ECOG PS of 0 or 1 was observed in 472 patients, an ECOG PS of 2 in 94 patients, and an ECOG PS of 3 or 4 in 47 patients. The objective response rate (ORR) of patients with an ECOG PS of 0 or 1, ECOG PS of 2, and ECOG PS of 3 or 4 were 24, 11, and 4%, respectively. A statistically significant difference in the progression-free survival (PFS) was observed between the patients with an ECOG PS of 0 or 1 and an ECOG PS of 2 (p < 0.001), and between those with an ECOG PS of 2 and an ECOG PS of 3 or 4 (p = 0.022). Their multivariate analysis identified never-smokers, poor ECOG PS, and epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements as independent predictors of worse PFS. Katsura et al. also investigated the difference in efficacy between an ECOG PS of 0–1 (good PS, n = 43) and an ECOG PS of 2–4 (poor PS, n = 20) in previously treated NSCLC patients receiving nivolumab [6]. The median overall survival (OS) was 412 days for an ECOG PS of 0 or 1, 32 days for an ECOG PS of 2–4, and 31 days in best supportive care (ECOG PS of 0 or 1 vs. ECOG PS of 2–4, p < 0.001; ECOG PS of 2–4 vs. best supportive care, p = 0.137). Moreover, a statistically significant difference in the ORR was recognized between an ECOG PS of 0 or 1 and an ECOG PS of 2–4 (23% vs. 0%, p < 0.001). Imai et al. evaluated the efficacy of first-line pembrolizumab monotherapy in elderly patients with NSCLC with PD-L1 ≥ 50% [3]. Thirty-seven (78.7%) of 47 patients had an ECOG PS of 0 or 1, 7 (15.0%) had an ECOG PS of 2, and 3 (6.3%) had an ECOG PS of 3 or 4. An ECOG PS of 2 or 3 was identified as an independent factor for predicting poor outcomes using multivariate analysis. Other studies also demonstrated that an ECOG PS of 2–4 was identified as an independent factor for predicting worse outcomes in NSCLC patients that were treated with nivolumab or pembrolizumab [5][7]. In previous retrospective studies, the ECOG PS was the most important prognostic factor for predicting worse outcomes after PD-1 blockade treatment in patients with NSCLC. However, the relationship between a worse ECOG PS and the failed efficacy of PD-1 blockade remains unclear. Table 1 shows several studies that examined the prognostic factors in NSCLC patients who received PD-1 blockade.
    Table 1. Independent prognostic factors in NSCLC patients that were treated with a PD-1 blockade.

    First Author

    [Ref.]

    No. of Pts

    Drug Type

    (Treatment Line)

    PD-L1 (%)

    Smoking

    Yes/No

    (Patient’s Number)

    ECOG PS

    0–1/≥2

    (Patient’s Number)

    Independent Prognostic Factors for Predicting Negative Outcome (Multivariate Analysis)

    Imai H.

    [3]

    47

    Pembro

    (1st-line)

    ≥50%

    43/4

    37/10

    PS (0–1/2–3), smoking (yes/no), response (non-PD/PD)

    Fujimoto D. [4]

    613

    Nivo

    (2nd-line~)

    Any

    482/131

    472/141

    PS (0–1/2–4), smoking (yes/no), driver mutations (yes/no)

    Ichiki Y.

    [7]

    44

    Nivo or Pembro

    (1st- or 2nd-line~)

    Any

    8/36

    32/12

    PS (0–1/2–4), histology (Ad/Sq), PET (SUV) (SD), WBC (SD), Neutro (SD), NLR (SD), LDH (SD), Alb (SD)

    Ahn B. C.

    [5]

    155

    Nivo or Pembro

    (1st- or 2nd-line~)

    Any

    104/51

    121/34

    PS (0–1/2–3), PD-L1 (<50%/≥50%), driver mutations (yes/no), liver metastasis(yes/no)

    Kano H.

    [8]

    527

    Nivo or Pembro

    (1st- or 2nd-line~)

    Any

    445/94

    448/79

    Staging, smoking (yes/no), PS (0–1/2–4), treatment line (1st/2nd)

    Abbreviations: Ref., reference; NSCLC, non-small cell lung cancer; Nivo, nivolumab; Pembro, pembrolizumab; PD-L1, programmed death ligand-1; no. of pts, number of patients; PS, performance status; PD, progressive disease; driver mutations, EGFR mutations or ALK translocation; PET, positron emission tomography; SUV, standardized uptake value; SD, standard deviation; WBC, white blood cell; Neutro, neutrophil; NLR, neutrophil-to-lymphocyte ratio; LDH, lactate dehydrogenase; Alb, albumin; Ad, adenocarcinoma; Sq, squamous cell carcinoma.

    3. Efficacy of a PD-1 Blockade in NSCLC Patients with a PS of 2

    Recently, Kano et al. reported the clinical features of a PD-1 blockade in patients with NSCLC with a poor PS [8]. They retrospectively analyzed and compared the prognostic significance after PD-1 blockade initiation in 448 patients with an ECOG PS of 0–1 to 79 patients with an ECOG PS of 2–4. The median PFS was 4.1 months for an ECOG PS of 0–1 and 2.0 months for an ECOG PS of 2–4, with a significant difference (p < 0.001). The patients with an ECOG PS of 0–1 exhibited a better OS (median, 17.4 months) than those with an ECOG PS of 2–4 (median, 4.0 months) (p < 0.001). In the analysis according to the ECOG PS level, the median PFS was 6.9 months for a PS of 1, 3.5 months for an ECOG PS of 2, 2.3 months for an ECOG PS of 2, and 1.1 months for an ECOG PS of 3–4. Their multivariate analysis also demonstrated that the ECOG PS was an independent predictor of worse outcomes. It is noteworthy that there was no statistically significant difference in the PFS (8.1 months vs. 7.3 months; p = 0.321) and OS (reached vs. not reached; p = 0.148) between the patients with an ECOG PS of 0–1 and an ECOG PS of 2 harboring PD-L1 ≥ 50%. However, the median PFS (3.5 months vs. 2.0 months; p < 0.001) and OS (16.7 months vs. 4.7 months; p < 0.001) in patients with any PD-L1 expression displayed a significant difference between patients with an ECOG PS of 0–1 and those with an ECOG PS of 2. The results of this study suggest that a PD-1 blockade is effective in a limited population of NSCLC patients with PD-L1 ≥ 50%. Next, we focus on the efficacy of a PD-1 blockade in NSCLC patients with an ECOG PS of 2 in a previous literature review (Table 2).
    Table 2. Review of ICI blockade efficacy in patients with a PS of 2.

    First Author

    [Ref.]

    Study Design

    Drug Type

    Histology

    Treatment Setting

    PD-L1 Status

    No. of Pts (PS = 2)

    ORR (%)

    mPFS (Months)

    mOS (Months)

    Felip E.

    [9]

    Phase 2

    Nivo

    SQC

    2nd-line~

    NA

    103

    2

    NA

    5.2

    Spigel D. R. [10]

    Phase 3

    Nivo

    All-comers

    2nd-line~

    NA

    128

    20

    NA

    4.0

    Barlesi F. [11]

    Phase 3

    Nivo/Ipi

    All-comers

    1st-line

    NA

    139

    20

    3.6

    NA

    Middleton G. [12]

    Phase 2

    Pembro

    All-comers

    1st or 2nd

    Yes

    60

    27

    4.4

    9.8

    <1%

    27

    11

    3.7

    8.1

    1–49%

    15

    33

    8.3

    12.6

    ≥50%

    15

    47

    12.6

    14.6

    Fujimoto D. [4]

    Retro

    Nivo

    All-comers

    2nd-line~

    NA

    94

    11

    1.2

    NA

    Alessi J. V.

    [13]

    Retro

    Pembro

    All-comers

    1st-line

    ≥50%

    39

    25.6

    4.0

    7.4

    Kano H.

    [8]

    Retro

    Pembro

    All-comers

    1st-line

    ≥50%

    11

    NA

    7.3

    NR

    Nivo/Pembro

    2nd-line~

    NA

    53

    NA

    2.0

    4.7

    Abbreviations: Nivo, nivolumab; Pembro, pembrolizumab; SQC, squamous cell lung cancer; NA, not applicable; NR, not reached; PD-L1, programmed death-1; no. of pts, number of patients; PS, performance status; ORR, objective response rate; mPFS, median progression-free survival; mOS, median overall survival; ref., reference.
    In three studies that focused on PD-L1 ≥ 50% in a first-line setting, the median PFS was 4.0 to 12.3 months and the median OS was greater than 7.4 months [8][12][13]. Aside from the high PD-L1 expression, the median PFS yielded 1.2 to 8.3 months, indicating the difference in efficacy of the PD-1 blockade according to the expression of PD-L1 in patients with an ECOG PS of 2 (Table 2). Regarding tumor shrinkage, the ORR of patients with PD-L1 ≥ 50% seemed to be favorable compared with those with any PD-L1 expression. PePS2 was a prospective phase 2 study that investigated the efficacy and safety of pembrolizumab according to PD-L1 expression in NSCLC patients with a PS of 2 [12]. Sixty patients were eligible for the analysis, and the ORR was 21% in first-line patients (n = 24) and 31% in subsequent-line patients (n = 36); the ORR was 11% in patients with PD-L1 < 1% (n = 27), 33% in those with PD-L1 of 1–49% (n = 15), and 47% in those with PD-L1 ≥ 50% (n = 15). The median PFS and OS were 3.7 and 8.1 months, respectively, in patients with PD-L1 less than 1%, 8.3 and 12.6 months, respectively, in those with PD-L1 of 1–49%, and 12.6 and 14.6 months, respectively, in those with PD-L1 of 50% or greater. Adverse events were recognized in 28% of patients without early death or grade 5 treatment-associated toxicity. The authors concluded that pembrolizumab can be safely administered with comparable efficacy to patients with an ECOG PS of 0–1 with no increase in the occurrence of immune-related toxicities [12]. Patients with an ECOG PS of 2 represent 20–30% of the proportion that is diagnosed with advanced NSCLC and are sometimes candidates for carboplatin doublets, although their prognosis is dismal [14]. The therapeutic efficacy of PD-1 blockade monotherapy in second or further lines for NSCLC patients with an ECOG PS ≥ 2, an ORR of 3 to 11%, a median PFS of less than 2 months, and a median OS of 3.5–6.0 months is disappointing [15]. Considering the results of previous reports, pembrolizumab in a first-line setting serves as a suitable regimen for advanced NSCLC patients with an ECOG PS of 2 if their PD-L1 expression is ≥50%.

    This entry is adapted from 10.3390/medicina57111273

    References

    1. Gettinger, S.; Horn, L.; Jackman, D.; Spigel, D.; Antonia, S.; Hellmann, M.; Powderly, J.; Heist, R.; Sequist, L.V.; Smith, D.C.; et al. Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: Results from the CA209-003 study. J. Clin. Oncol. 2018, 36, 1675–1684.
    2. Garon, E.B.; Hellmann, M.D.; Rizvi, N.A.; Carcereny, E.; Leighl, N.B.; Ahn, M.J.; Eder, J.P.; Balmanoukian, A.S.; Aggarwal, C.; Horn, L.; et al. Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: Results from the phase I KEYNOTE-001 study. J. Clin. Oncol. 2019, 37, 2518–2527.
    3. Imai, H.; Wasamoto, S.; Yamaguchi, O.; Suzuki, K.; Sugiyama, T.; Uchino, J.; Minemura, H.; Osaki, T.; Ishii, H.; Umeda, Y.; et al. Efficacy and safety of first-line pembrolizumab monotherapy in elderly patients (aged ≥ 75 years) with non-small cell lung cancer. J. Cancer Res. Clin. Oncol. 2020, 146, 457–466.
    4. Fujimoto, D.; Yoshioka, H.; Kataoka, Y.; Morimoto, T.; Kim, Y.H.; Tomii, K.; Ishida, T.; Hirabayashi, M.; Hara, S.; Ishimoto, M.; et al. Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study. Lung Cancer 2018, 119, 14–20.
    5. Ahn, B.C.; Pyo, K.H.; Xin, C.F.; Jung, D.; Shim, H.S.; Lee, C.Y.; Park, S.Y.; Yoon, H.I.; Jong, M.H.; Cho, B.C.; et al. Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice. J. Cancer Res. Clin. Oncol. 2019, 145, 1613–1623.
    6. Katsura, H.; Suga, Y.; Araya, T.; Kita, T.; Yoneda, T.; Tanaka, N.; Kawabata, A.; Ishita, S.; Mase, H. Efficacy and safety of nivolumab in patients with advanced non-small-cell lung cancer and poor performance status. J. Cancer 2019, 100, 2139–2144.
    7. Ichiki, Y.; Taira, A.; Chikashi, Y.; Matsumiya, H.; Mori, M.; Kanayama, M.; Nabe, Y.; Shinohara, S.; Kuwata, T.; Taneka, M.; et al. Prognostic factors of advanced or postoperative recurrent non-small cell lung cancer targeted with immune check point inhibitors. J. Thorac. Dis. 2019, 11, 1117–1123.
    8. Kano, H.; Ichihara, E.; Harada, D.; Inoue, K.; Kayatani, H.; Hosokawa, S.; Kishino, D.; Watanabe, K.; Ochi, N.; Oda, N.; et al. Utility of immune checkpoint inhibitors in non-small-cell lung cancer patients with poor performance status. Cancer Sci. 2020, 111, 3739–3746.
    9. Felip, E.; Ardizzoni, A.; Ciuleanu, T.; Cobo, M.; Laktionov, K.; Szilasi, M.; Califano, R.; Carcereny, E.; Griffiths, R.; Paz-Ares, L.; et al. CheckMate 171: A phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS 2 and elderly populations. Eur. J. Cancer 2020, 127, 160–172.
    10. Spigel, D.R.; McCleod, M.; Jotte, R.M.; Einhorn, L.; Horn, L.; Waterhouse, D.M.; Creelan, B.; Babu, S.; Leighl, N.B.; Chandler, J.C.; et al. Safety, efficacy, and patients-reported health-related quality of life and symptom burden with nivolumab in patients with advanced non-small cell lung cancer, including patients aged 70 years or older or with poor performance status (CheckMate 153). J. Thorac. Oncol. 2019, 14, 1628–1639.
    11. Barlesi, F.; Audigier-Valette, C.; Felip, E.; Ciuleanu, T.; Jao, K.; Rijavec, E.; Urban, L.; Aucoin, J.; Zannori, C.; Vermaelen, K.; et al. CheckMate 817: First-line nivolumab+ipilimumab in patients with ECOG PS 2 and other special populations with advanced NSCLC. J. Thorac. Oncol. 2019, 14, S214–S215.
    12. Middleton, G.; Brock, K.; Savage, J.; Mant, R.; Summers, Y.; Connibear, J.; Shah, R.; Ottensmeier, C.; Shaw, P.; Lee, S.M.; et al. Pembrolizumab in patients with non-small-cell lung cancer of performance status 2 (PePS2): A single arm, phase 2 trial. Lancet Respir. Med. 2020, 8, 895–904.
    13. Alessi, J.V.; Ricciuti, B.; Jimenez-Aguilar, E.; Hong, F.; Wei, Z.; Nishino, M.; Plodkowski, A.J.; Sawan, P.; Luo, J.; Rizvi, H.; et al. Outcome to first-line pembrolizumab in patients with PD-L1-high (≥50%) non-small cell lung cancer and a poor performance status. J. Immunother. Cancer 2020, 8, e001007.
    14. Su, C.; Zhou, F.; Shen, J.; Zhao, J.; O’Brien, M. Treatment of elderly patients or patients who are performance status 2 (PS2) with advanced non-small cell lung cancer without epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations-still a daily challenge. Eur. J. Cancer 2017, 83, 266–278.
    15. Facchinetti, F.; Mazzaschi, G.; Barbieri, F.; Passiglia, F.; Mazzoni, F.; Berardi, R.; Proto, C.; Cecere, F.L.; Pilotto, S.; Scotti, V.; et al. First-line pembrolizumab in advanced n0n-small cell lung cancer patients with poor performance status. Eur. J. Cancer 2020, 130, 155–167.
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