Background: Since the success of the PACIFIC trial, durvalumab has become the clear standard of care for many patients with stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CRT). However, the duration of immune consolidation and the efficacy and safety of different immune agents remain unclear. We conducted a systematic review of relevant studies. Methods: We searched all the relevant studies in PubMed, Embase, and Cochrane Library databases. We also reviewed abstracts of relevant conferences to prevent omissions. The meta-analysis was performed using Stata version 16.0. Results: CRT combined with immunotherapy can improve progression-free survival (PFS) (hazard rate [HR]: 0.60, 95% confidence interval [CI, 0.55–0.60) and overall survival (OS) (HR: 0.59, 95% CI, 0.53–0.66) compared with no immunotherapy. The pooled 24-month PFS and 24-month OS rates were 48.1% (95% CI, 43.5–52.7%) and 71.3% (95% CI, 67.3–75.2%), respectively. Subgroup analysis showed that 24-month OS rates were 60.7% (95% CI, 51.0–70.3%) and 77.4% (95% CI, 73.2–81.7%) at 1 year and 2 years of immune consolidation, respectively. The pooled 1-year completion rate for immune consolidation was 35.6% (95% CI, 31.3–39.8%). The pooled rate of pneumonitis for all grades was 41.7% (95% CI, 31.9–51.9%). The pooled rate of pneumonitis ≥ grade 3 was 6.7% (95% CI, 5.0–8.5%). The incidence of pneumonitis ≥ grade 3 after 1 year of immunotherapy is 4.8% (95% CI, 3.1–6.5%). The incidence of pneumonitis ≥ grade 3 after 2 years of immunotherapy is 5.1% (95% CI, 2.9–7.3%). Conclusions: Prolonging the duration of immunotherapy consolidation increases survival benefits in patients with stage III NSCLC without causing higher side effects. Older patients, due to high incidence of pneumonia and low immunotherapy completion rate, have less survival benefit.

Stage III non-small cell lung cancer (NSCLC) is potentially curable and is usually treated with a variety of treatments that include radiotherapy, chemotherapy, and surgical excision [1, 2]. For patients with unresectable stage III NSCLC, sequential or concurrent chemoradiotherapy (CRT) has been the standard of care, but the survival rate beyond 5 years is still very low, at about 15–30% [3]. Since the success of the PACIFIC trial in 2017, consolidation of durvalumab after CRT has become the new standard of care for unresectable stage III NSCLC [4‒6]. This was a randomized, double-blind, phase III study using the PD-L1 immune checkpoint inhibitor durvalumab following CRT. Median follow-up time was 34.2 months. Updated survival analysis showed that 5-year overall survival (OS) rates were 42.9% (38.2–47.4%) in the durvalumab group and 33.4% (27.3–39.6%) in the placebo group, respectively. The durvalumab group also had a higher 5-year progression-free survival (PFS) rate than the placebo group [6]. The continued survival benefit supports the PACIFIC trial protocol as a new standard of care for patients with unresectable stage III NSCLC.

However, after the PACIFIC trial, many problems to be solved have been raised. For example, whether extending the duration of immunotherapy improves the effectiveness of the treatment. In the real world, what is the completion rate of immunotherapy after CRT and whether it is related to the survival benefit of patients? In the meta-analysis of Nan Bi [7], the subgroup with a median age of >65 years had a higher incidence of pneumonitis than the subgroup with a median age of <65 years. Therefore, whether age and the incidence of pneumonitis affect the completion rate of immunotherapy? These will be analyzed in our meta-analysis.

Some studies are looking at the same question. For example, the PACIFIC trial is 1 year of immune consolidation followed by CRT. The PACIFIC-6 trial also studied immune consolidation for 2 years [8]. Survival data and pneumonitis rates from the PACIFIC-6 trial were similar to those from the PACIFIC trial.

In this systematic review and meta-analysis, we included real-world study data and clinical trial data. First, we pooled the hazard rate (HR) of two-arm studies and concluded that immunotherapy after CRT improved survival benefits in patients with stage III NSCLC compared with CRT alone. In the analysis of the efficacy of CRT combined immunotherapy, we updated the data from the Nan Bi’s study [7] to extend the survival analysis time to 24 months. In subgroup analysis, we analyzed the effects of immune consolidation duration, PD-L1 expression, and peripheral blood neutrophil-to-lymphocyte ratio on the therapeutic effect. We also analyzed 1-year immunotherapy completion rates and compared 1-year immunotherapy completion rates among patients of different ages. In addition, we analyzed the safety of CRT in combination with immunotherapy, including the incidence of all-grade pneumonitis and the incidence of ≥ grade 3 pneumonitis with different types of immunotherapy drugs.

Search Strategy

A meta-analysis of the literature was performed according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) systematic review guidelines [9]. We performed a structured search of the Embase, PubMed, and Cochrane Library databases for studies published until December 21, 2022. For example, The Embase search the following structured and free text search terms: (“non-small cell lung cancer”/exp OR “non-small cell lung cancer”) AND (“immunotherapy”/exp OR immunotherapy OR “durvalumab”/exp OR durvalumab OR “pembrolizumab”/exp OR pembrolizumab OR “nivolumab”/exp OR nivolumab OR “camrelizumab”/exp OR camrelizumab OR “tislelizumab”/exp OR tislelizumab OR “atezolizumab”/exp OR atezolizumab OR “ipilimumab”/exp OR ipilimumab OR “sugemalimab”/exp OR sugemalimab) AND (“chemoradiotherapy”/exp OR chemoradiotherapy). The PubMed search the following structured and free text search terms: (stage III non-small cell lung cancer) AND ((immunotherapy) OR (durvalumab) OR (pembrolizumab) OR (nivolumab) OR (camrelizumab) OR (tislelizumab) OR (atezolizumab) OR (ipilimumab) OR (sugemalimab)) AND (chemoradiotherapy). We also reviewed abstracts of relevant conferences, including ASCO, ASTRO, WCLC, ESMO, to prevent omissions.

Inclusion and Exclusion Criteria

According to the 8th edition of the American Joint Committee on Cancer (AJCC), we included studies of patients with stage III NSCLC using CRT in combination with immunotherapy, either sequential or concurrent. Trials that enroll earlier than phase III patients are also included if the majority of patients are phase III patients. Included studies must contain efficacy data, excluding studies in which efficacy data could not be extracted. In this meta-analysis, retrospective cohort studies and prospective clinical trials, as well as conference abstracts (where possible), were included in our analysis to achieve maximum analysis of the data. Two authors independently searched the studies and assessed the sources of eligibility and bias, and any disagreements were resolved by the senior authors.

Data Extraction

We collected the following data from consistent studies: basic information including first author’s name, year of publication or presentation; anticancer information including sequential CRT or concurrent CRT, interval between CRT and immunotherapy, and duration of immunotherapy; efficacy information including OS and PFS rates at 12 and 24 months; toxic information including the incidence of pneumonitis. These data were extracted in a standard spreadsheet.

Study Quality Assessment

Randomized controlled trials used the Cochrane bias risk tool to assess study quality [10]. For nonrandomized trials, we used the methodological index for nonrandomized studies (MINOR) [11].

Statistical Analysis

The I-squared (I2) statistic was used to evaluate statistical heterogeneity, and values greater than 50% were considered to have significant heterogeneity. In the analysis of efficacy, ES is the pooled of PFS rate, OS rate, and pneumonia incidence. In addition, survival with a 95% confidence interval (CI) was used as the primary summary statistic. In analyzing the incidence of pneumonitis, the incidence of pneumonitis with a 95% CI was used as the primary aggregate statistic. Egger’s linear regression test was used to evaluate publication bias. In the subgroup analysis, p < 0.05 for heterogeneity between groups was considered to have significant differences. All analyses were performed using Stata 16.

Eligible Studies

Our search strategy yielded 2,116 results. After removing 120 duplicate records, 1,996 abstracts were selected. After reading the abstract, we selected 97 articles for comprehensive review. Ultimately, we found 38 studies that met the prespecified inclusion criteria (Fig. 1).

Fig. 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram. CRT, chemoradiotherapy.

Fig. 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram. CRT, chemoradiotherapy.

Close modal

Baseline Characteristics

38 studies [6, 8, 12‒47] involving 5,348 patients were included. There were 11 clinical trials and 27 real-world studies. In clinical trials, the immune drugs included nivolumab, sugemalimab, durvalumab, and pembrolizumab. The only immune drug used in the real-world studies we included was durvalumab. Most of the studies we included used PFS, OS, and pneumonitis as co-primary endpoints. Among them, PFS or OS was the only primary endpoint in the 7 studies. 8 studies had pneumonitis as the only primary endpoint. The basic characteristics of the included studies are summarized in a table (Table 1).

Table 1.

Characteristics of included studies

Author (year)Study typeYearsInterventionPatients, ncCRT or sCRTNumber of immunetherapy completion in 1 year, n1‐year treatment effect2‐year treatment effectPneumonitis, n≥ Grade 3 pneumonitis, nDuration of immunotherapy
Sankar [41] (2022) RWS 69 (64–72) CRT→D 1,006 cCRT 314 12-month PFS: 57.1% 24-month PFS: 42.7% — — At least 1 dose 
12-month OS: 77.0% 24-month OS: 61.9% 
Kishi [45] (2022) RWS 70 (64–75) CRT→D 136 cCRT 60 12-month PFS: 57.4% 24-month PFS: 40.4% — — At least 1 dose 
12-month OS: 88.2% 24-month OS: 69.1% 
Saad [15] (2022) RWS 67 (40–82) CRT→D 71 cCRT 39 12-month PFS: 83.1% 24-month PFS: 83.1% — — 1 year 
12-month OS: 85.9% 24-month OS: 85.9% 
Desilets [26] (2021) RWS 67 CRT→D 147  — 12-month OS: 92.5% 24-month OS: 72.8% 44 At least 1 dose 
Bryant [21] (2022) RWS — CRT→D 312 cCRT — — — — — 6 months 
9 months 
1 year 
Taugner [34] (2021) RWS 67.6 CRT→D 22 — — 12-month PFS: 59.1% 24-month PFS: 54.5% — — 1 year 
12-month OS: 100% 24-month OS: 81.8% 
Jung [40] (2020) RWS 65.9 (36–77) CRT→D 21 cCRT — — — 17 1 year 
Bruni [44] (2021) RWS 66 (40–82) CRT→D 155 cCRT (58.8%) sCRT (41.2%) 54 12-month PFS: 65.2% 24-month PFS: 52.9% 66 At least 1 dose 
12-month OS: 87.7% 24-month OS: 79.4% 
Vrankar [17] (2021) RWS 63 (36–73) CRT→D 85 cCRT (63.5%) sCRT (36.5%) 12 12-month PFS: 70.6% 24-month PFS: 45.9% 15 — 1 year 
12-month OS: 85.9% 24-month OS: 68.2% 
Chu [20] (2020) RWS 64 (52–74) CRT→D 31 cCRT — 12-month PFS: 54.8% — — At least 1 dose 
Faehling [23] (2020) RWS 62.4 (34–82) CRT→D 126 cCRT (96.8%) sCRT (3.2%) 54 12-month PFS: 55.6% 24-month PFS: 46.8% 19 11 At least 1 dose 
12-month OS: 78.6% 24-month OS: 65.9% 
Taugner [43] (2021) RWS 67.6 (43.8–78.4) CRT→D 26 cCRT (96%) sCRT (4%) 12-month PFS: 65.4% 24-month PFS: 50.0% 12 At least 1 dose 
12-month OS: 100% 24-month OS: 76.9% 
Wang [25] (2021) RWS 63 (32–86) CRT→D 61 cCRT — 12-month PFS: 55.7% 24-month PFS: 42.6% 11 At least 1 dose 
12 month OS: 93,4% 24-month OS: 78.7% 
LeClair [42] (2021) RWS 69.8 CRT→D 83 — 33 — — 21 At least 1 dose 
Mayahara [35] (2022) RWS 72 (48–85) CRT→D 56 cCRT 19 12-month PFS: 49.2% — 50 1 year 
12-month OS: 75.4% 
Wass [24] (2022) RWS — CRT→D 78  — — — 22 — 1 year 
Tsukita [31] (2021) RWS 70 (43–86) CRT→D 87 cCRT — 12-month PFS: 70.1% 24-month PFS: 55.2% 76 At least 1 dose 
Shaverdian [39] (2020) RWS 66 (49–86) CRT→D 62 cCRT — — — — 1 year 
Landman [22] (2021) RWS 66.5 (48.8–85.1) CRT→D 39 — 15 12-month PFS: 48.7% 24-month PFS: 43.6% — 1 year 
12-month OS: 79.5% 24-month OS: 69.2% 
Bryant [37] (2022) RWS 69 (64–72) CRT→D 1,006 cCRT 312 12-month PFS: 61.8% 24-month PFS: 42.7% — — At least 1 dose 
12-month OS: 78.9% 24-month OS: 61.9% 
Hassanzadeh [30] (2020) RWS 68 (37–84) CRT→D 34 — — 12-month PFS: 50.0% — — 1 year 
12-month OS: 85.3% 
Miura [16] (2020) RWS 72 (51–80) CRT→D 41 cCRT — — 25 At least 1 dose 
Offin [18] (2020) RWS 66 (49–86) CRT→D 62 cCRT 22 12-month PFS: 64.5% — 12 1 year 
12-month OS: 85.5% 
Araki [36] (2022) RWS 70 (35–89) CRT→D 76 cCRT — 12-month PFS: 60.5% 24-month PFS: 52.6% 66 33 At least 1 dose 
12-month OS: 92.1% 24-month OS: 75.0% 
Harada [27] (2022) RWS 65.5 (43–77) CRT→D 26 cCRT 12-month PFS: 51.8% — 26 At least 1 dose 
12-month OS: 100% 
Sugimoto [38] (2022) RWS 69 (49–80) CRT→D 35 cCRT 14 12-month PFS: 51.4% — — At least 1 dose 
Jain [28] (2020) RWS 66 CRT→D 28 cCRT (96%) sCRT (4%) — — — At least 1 dose 
PACIFIC [][6Clinical trial 63.0 CRT→D 476 cCRT — 12-month PFS: 55.7% 24-month PFS: 45.0% 183 22 1 year 
12-month OS: 83.2% 24-month OS: 66.4% 
LUN-14-17.9 [14Clinical trial 66.0 (45.0–84.0) CRT→P 92 cCRT 40 12-month PFS: 61.2% 24-month PFS: 46.3% 18 1 year 
12-month OS: 81.1% 24-month OS: 62.0% 
TORG1937 [33Clinical trial 65.0 (42.0–75.0) CRT→D 47 cCRT — 12-month PFS: 74.5% — — 1 year 
12-month OS: 97.9% 
GEMSTONE-301[][29Clinical trial 61 (56–65) CRT→S 255 cCRT (66%) sCRT (34%) — 12-month PFS: 45.5% 24-month PFS: 34.9% 57 13 2 years 
12-month OS: 90.2% 24-month OS: 80.0% 
PACIFIC-6 [8Clinical trial 68.0 (39–85) CRT→D 117 sCRT — 12-month PFS: 49.6% 24-month OS: 70.1% 36 2 years 
12-month OS: 83.8% 
LUN-16-08.1 [13Clinical trial 62 CRT→N 54 cCRT — — 24-month OS: 75.9% — 6 months 
LUN-16-08.1 [13Clinical trial 61 CRT→N + I 51 cCRT — — 24-month OS: 82.4% — 6 months 
COAST [19Clinical trial 66.0 (46–81) CRT→D 67 cCRT — 12-month PFS: 34.3% — 23 1 year 
KEYNOTE-799 [47Clinical trial — CRT+P 112 cCRT — — 24-month PFS: 55.4% — 1 year 
24-month OS: 64.3% 
AFT-16 [12Clinical trial 63.9 (38.1–86.5) A→CRT 64 cCRT — 12-month PFS: 65.6% — — — — 
NCT02621398 [32Clinical trial 69.5 (53.0–85.0) CRT→P 21 cCRT — — — — 
ETOP NICOLAS [46Clinical trial 62 CRT+N 80 — 16 — — 34 1 year 
Author (year)Study typeYearsInterventionPatients, ncCRT or sCRTNumber of immunetherapy completion in 1 year, n1‐year treatment effect2‐year treatment effectPneumonitis, n≥ Grade 3 pneumonitis, nDuration of immunotherapy
Sankar [41] (2022) RWS 69 (64–72) CRT→D 1,006 cCRT 314 12-month PFS: 57.1% 24-month PFS: 42.7% — — At least 1 dose 
12-month OS: 77.0% 24-month OS: 61.9% 
Kishi [45] (2022) RWS 70 (64–75) CRT→D 136 cCRT 60 12-month PFS: 57.4% 24-month PFS: 40.4% — — At least 1 dose 
12-month OS: 88.2% 24-month OS: 69.1% 
Saad [15] (2022) RWS 67 (40–82) CRT→D 71 cCRT 39 12-month PFS: 83.1% 24-month PFS: 83.1% — — 1 year 
12-month OS: 85.9% 24-month OS: 85.9% 
Desilets [26] (2021) RWS 67 CRT→D 147  — 12-month OS: 92.5% 24-month OS: 72.8% 44 At least 1 dose 
Bryant [21] (2022) RWS — CRT→D 312 cCRT — — — — — 6 months 
9 months 
1 year 
Taugner [34] (2021) RWS 67.6 CRT→D 22 — — 12-month PFS: 59.1% 24-month PFS: 54.5% — — 1 year 
12-month OS: 100% 24-month OS: 81.8% 
Jung [40] (2020) RWS 65.9 (36–77) CRT→D 21 cCRT — — — 17 1 year 
Bruni [44] (2021) RWS 66 (40–82) CRT→D 155 cCRT (58.8%) sCRT (41.2%) 54 12-month PFS: 65.2% 24-month PFS: 52.9% 66 At least 1 dose 
12-month OS: 87.7% 24-month OS: 79.4% 
Vrankar [17] (2021) RWS 63 (36–73) CRT→D 85 cCRT (63.5%) sCRT (36.5%) 12 12-month PFS: 70.6% 24-month PFS: 45.9% 15 — 1 year 
12-month OS: 85.9% 24-month OS: 68.2% 
Chu [20] (2020) RWS 64 (52–74) CRT→D 31 cCRT — 12-month PFS: 54.8% — — At least 1 dose 
Faehling [23] (2020) RWS 62.4 (34–82) CRT→D 126 cCRT (96.8%) sCRT (3.2%) 54 12-month PFS: 55.6% 24-month PFS: 46.8% 19 11 At least 1 dose 
12-month OS: 78.6% 24-month OS: 65.9% 
Taugner [43] (2021) RWS 67.6 (43.8–78.4) CRT→D 26 cCRT (96%) sCRT (4%) 12-month PFS: 65.4% 24-month PFS: 50.0% 12 At least 1 dose 
12-month OS: 100% 24-month OS: 76.9% 
Wang [25] (2021) RWS 63 (32–86) CRT→D 61 cCRT — 12-month PFS: 55.7% 24-month PFS: 42.6% 11 At least 1 dose 
12 month OS: 93,4% 24-month OS: 78.7% 
LeClair [42] (2021) RWS 69.8 CRT→D 83 — 33 — — 21 At least 1 dose 
Mayahara [35] (2022) RWS 72 (48–85) CRT→D 56 cCRT 19 12-month PFS: 49.2% — 50 1 year 
12-month OS: 75.4% 
Wass [24] (2022) RWS — CRT→D 78  — — — 22 — 1 year 
Tsukita [31] (2021) RWS 70 (43–86) CRT→D 87 cCRT — 12-month PFS: 70.1% 24-month PFS: 55.2% 76 At least 1 dose 
Shaverdian [39] (2020) RWS 66 (49–86) CRT→D 62 cCRT — — — — 1 year 
Landman [22] (2021) RWS 66.5 (48.8–85.1) CRT→D 39 — 15 12-month PFS: 48.7% 24-month PFS: 43.6% — 1 year 
12-month OS: 79.5% 24-month OS: 69.2% 
Bryant [37] (2022) RWS 69 (64–72) CRT→D 1,006 cCRT 312 12-month PFS: 61.8% 24-month PFS: 42.7% — — At least 1 dose 
12-month OS: 78.9% 24-month OS: 61.9% 
Hassanzadeh [30] (2020) RWS 68 (37–84) CRT→D 34 — — 12-month PFS: 50.0% — — 1 year 
12-month OS: 85.3% 
Miura [16] (2020) RWS 72 (51–80) CRT→D 41 cCRT — — 25 At least 1 dose 
Offin [18] (2020) RWS 66 (49–86) CRT→D 62 cCRT 22 12-month PFS: 64.5% — 12 1 year 
12-month OS: 85.5% 
Araki [36] (2022) RWS 70 (35–89) CRT→D 76 cCRT — 12-month PFS: 60.5% 24-month PFS: 52.6% 66 33 At least 1 dose 
12-month OS: 92.1% 24-month OS: 75.0% 
Harada [27] (2022) RWS 65.5 (43–77) CRT→D 26 cCRT 12-month PFS: 51.8% — 26 At least 1 dose 
12-month OS: 100% 
Sugimoto [38] (2022) RWS 69 (49–80) CRT→D 35 cCRT 14 12-month PFS: 51.4% — — At least 1 dose 
Jain [28] (2020) RWS 66 CRT→D 28 cCRT (96%) sCRT (4%) — — — At least 1 dose 
PACIFIC [][6Clinical trial 63.0 CRT→D 476 cCRT — 12-month PFS: 55.7% 24-month PFS: 45.0% 183 22 1 year 
12-month OS: 83.2% 24-month OS: 66.4% 
LUN-14-17.9 [14Clinical trial 66.0 (45.0–84.0) CRT→P 92 cCRT 40 12-month PFS: 61.2% 24-month PFS: 46.3% 18 1 year 
12-month OS: 81.1% 24-month OS: 62.0% 
TORG1937 [33Clinical trial 65.0 (42.0–75.0) CRT→D 47 cCRT — 12-month PFS: 74.5% — — 1 year 
12-month OS: 97.9% 
GEMSTONE-301[][29Clinical trial 61 (56–65) CRT→S 255 cCRT (66%) sCRT (34%) — 12-month PFS: 45.5% 24-month PFS: 34.9% 57 13 2 years 
12-month OS: 90.2% 24-month OS: 80.0% 
PACIFIC-6 [8Clinical trial 68.0 (39–85) CRT→D 117 sCRT — 12-month PFS: 49.6% 24-month OS: 70.1% 36 2 years 
12-month OS: 83.8% 
LUN-16-08.1 [13Clinical trial 62 CRT→N 54 cCRT — — 24-month OS: 75.9% — 6 months 
LUN-16-08.1 [13Clinical trial 61 CRT→N + I 51 cCRT — — 24-month OS: 82.4% — 6 months 
COAST [19Clinical trial 66.0 (46–81) CRT→D 67 cCRT — 12-month PFS: 34.3% — 23 1 year 
KEYNOTE-799 [47Clinical trial — CRT+P 112 cCRT — — 24-month PFS: 55.4% — 1 year 
24-month OS: 64.3% 
AFT-16 [12Clinical trial 63.9 (38.1–86.5) A→CRT 64 cCRT — 12-month PFS: 65.6% — — — — 
NCT02621398 [32Clinical trial 69.5 (53.0–85.0) CRT→P 21 cCRT — — — — 
ETOP NICOLAS [46Clinical trial 62 CRT+N 80 — 16 — — 34 1 year 

RWS, real-world study; PFS, progression-free survival; OS, overall survival; CRT, chemoradiotherapy; cCRT, concurrent chemoradiotherapy; sCRT, sequential chemoradiotherapy; A, atezolizumab; D, durvalumab; I, ipilimumab; N, nivolumab; P, pembrolizumab.

Risk of Bias

In our analysis, 2 clinical trials were eligible to be evaluated using the Cochrane bias risk assessment tool. These 2 studies were considered to have a low risk of bias (online suppl. Fig. S1; for all online suppl. material, see https://doi.org/10.1159/000534376). An additional 31 studies (8 two-arm studies and 23 single-arm studies) assessed the risk of bias using the MINORS scale (online suppl. Table S1). In our study, only meeting abstracts were retrieved in 5 studies, and we did not conduct bias risk assessment for them due to the small content.

Analysis of Therapeutic Efficacy

Our study analyzed the efficacy of CRT combined with immunotherapy in patients with NSCLC. The efficacy analysis included PFS and OS rates at 12 and 24 months. The pooled 12-month PFS and 12-month OS rates were 59.7% (95% CI, 56.3–63.1%) and 87.1% (95% CI, 84.3–89.7%), respectively (online suppl. Fig. S2A, B). Egger’s test suggested no significant publication bias in 12-month PFS and 12-month OS rate (p = 0.805 and p = 0.159, respectively). In clinical trials, pooled 12-month PFS and 12-month OS rates were 57.8% (95% CI, 49.0–66.6%) and 87.6% (95% CI, 81.5–93.8), respectively (online suppl. Fig. S2C, D). Egger’s test suggested no significant publication bias in 12-month PFS and 12-month OS rate (p = 0.479 and p = 0.753, respectively). In real-world studies, the pooled 12-month PFS and 12-month OS rates were 60.7% (95% CI, 57.2–64.2%) and 87.1% (95% CI, 83.7–90.1%), respectively (online suppl. Fig. S2E, F). Egger’s test suggested no significant publication bias in 12-month PFS rate (p = 0.975) and significant publication bias in 12-month OS rate (p = 0.014).

The pooled 24-month PFS and 24-month OS rates were 48.1% (95% CI, 43.5–52.7%) and 71.3% (95% CI, 67.3–75.2%), respectively (Fig. 2a, b). Egger’s test suggested that there was no significant publication bias in 24-month PFS rate (p = 0.150), and there was significant publication bias in 24-month OS rate (p = 0.024). In clinical trials, the pooled 24-month PFS and 24-month OS rates were 42.8% (95% CI, 34.8–50.9%) and 69.8% (95% CI, 62.3–77.3%), respectively (Fig. 2c, d). Egger’s test suggested no significant publication bias in 24-month PFS and 24-month OS rates (p = 0.914 and p = 0.774, respectively). In real-world studies, the pooled 24-month PFS and 24-month OS rates were 50.1% (95% CI, 44.3–55.9%) and 72.1% (95% CI, 67.2–76.9%), respectively (Fig. 2e, f). Egger’s test suggested that there was no significant publication bias in 24-month PFS rate (p = 0.142), and there was significant publication bias in 24-month OS rate (p = 0.004).

Fig. 2.

Pooled analysis of long-term efficacy. a Pooled 24-month PFS rate. b Pooled 24-month OS rate. c Pooled 24-month PFS rate of clinical trials. d Pooled 24-month OS rate of clinical trials. e Pooled 24-month PFS rate of real-world studies. f Pooled 24-month OS rate of real-world studies.

Fig. 2.

Pooled analysis of long-term efficacy. a Pooled 24-month PFS rate. b Pooled 24-month OS rate. c Pooled 24-month PFS rate of clinical trials. d Pooled 24-month OS rate of clinical trials. e Pooled 24-month PFS rate of real-world studies. f Pooled 24-month OS rate of real-world studies.

Close modal

In our study, we extracted the HR from the survival analysis of the included two-arm study and compared the therapeutic effects of consolidation immunotherapy after CRT versus no immunotherapy (online suppl. Table S2). Our data suggest that consolidation immunotherapy after CRT improves outcomes in patients with stage III NSCLC (PFS: HR: 0.60, 95% CI, 0.55–0.60; OS: HR: 0.59, 95% CI, 0.53–0.66) (Fig. 3a, b). In other subgroup analyses, we compared the impact of duration of consolidation immunotherapy after CRT on efficacy in clinical trials. The 12-month OS rates with 1 year and 2 years of immune consolidation were 87.7% (95% CI, 76.8–98.7%) and 88.7% (95% CI, 85.5–91.9%), respectively (Fig. 3c). Our data showed that duration of immunotherapy had no significant effect on 12-month OS (p = 0.867) (Fig. 3c). However, our data showed that duration of immunotherapy had significant effect on 24-month OS (p = 0.002) (Fig. 3d). 24-month OS rates with 1 year and 2 years of immune consolidation were 60.7% (95% CI, 51.0–70.3%) and 77.4% (95% CI, 73.2–81.7%), respectively (Fig. 3d).

Fig. 3.

Subgroup analysis of efficacy. a Pooled HR of PFS survival analysis. b Pooled HR of OS survival analysis. c Pooled 12-month OS rate of 1 year of immunotherapy versus 2 years of immunotherapy. d Pooled 24-month OS rate of 1 year of immunotherapy versus 2 years of immunotherapy. e 24-month PFS rate of the median time from CRT immune consolidation ≤42 days versus >42 days. f 24-month OS rate of the median time from CRT immune consolidation ≤42 days.

Fig. 3.

Subgroup analysis of efficacy. a Pooled HR of PFS survival analysis. b Pooled HR of OS survival analysis. c Pooled 12-month OS rate of 1 year of immunotherapy versus 2 years of immunotherapy. d Pooled 24-month OS rate of 1 year of immunotherapy versus 2 years of immunotherapy. e 24-month PFS rate of the median time from CRT immune consolidation ≤42 days versus >42 days. f 24-month OS rate of the median time from CRT immune consolidation ≤42 days.

Close modal

In the real world, we analyzed the effect of when to start immune consolidation after CRT on treatment outcomes. The 24-month PFS rate of immune consolidation within median 42 days after CRT and after median 42 days were 52.4% (95% CI, 43.6–61.2%) and 48.2% (42.9–53.5%), respectively (Fig. 3e). And the 24-month OS rate of immune consolidation within median 42 days after CRT and after median 42 days were 74.8% (95% CI, 69.6–79.9%) and 75.2% (69.3–81.1%), respectively (Fig. 3f). The data showed that initiation of immunotherapy longer than 42 days did not affect 24-month PFS (p = 0.420) or 24-month OS (p = 0.919) (Fig. 3e, f). In addition, we further analyzed and compared the influence of the expression level of PD-L1 on CRT combined with immunotherapy. The 12-month PFS and 12-month OS rates were 46.1% (95% CI, 40.3–51.9%) and 78.1% (95% CI, 73.1–82.7%) in the PD-L1 < 1% subgroup, respectively (Fig. S3A, B). The 12-month PFS and 12-month OS rates of the PD-L1 ≥1% subgroup were 58.0% (95% CI, 51.3–64.8%) and 89.1% (95% CI, 82.0–94.7%), respectively (Fig. S3A, B). The data showed that patients with high PD-L1 expression had significant benefits in 12-month PFS (p = 0.009) and 12-month OS (p = 0.011) (Fig. S3A, B). Finally, we performed subgroup analysis based on neutrophil/lymphocyte ratio (NLR). The results showed that the 12-month PFS rate in the low NLR group was higher than that in the high NLR group (73.8%; 95% CI, 66.1–81.5% vs. 59.1%; 95% CI, 49.7–68.5%; p = 0.018) (Fig. S3C).

1-Year Completion Rate of Immunotherapy

In real-world studies, 17 studies detailed completion rates of immune consolidation at 1 year after CRT. No studies have described 2-year completion rates for immunotherapy. All 17 studies used durvalumab immunotherapy, and 1,050 of the 3,125 patients completed 1-year immunotherapy. The 1-year completion rate of durvalumab consolidation after CRT was 35.6% (95% CI, 31.3–39.8%) (Fig. 4a). Egger’s test suggested that there was no significant publication bias in the 1-year completion rate of durvalumab consolidation therapy after CRT (p = 0.222).

Fig. 4.

Pooled analysis of completion rate of durvalumab consolidation in the real world and subgroup analysis. a 1-year completion rate of durvalumab consolidation. b 1-year completion rate of durvalumab consolidation of median age >65 versus median age <65.

Fig. 4.

Pooled analysis of completion rate of durvalumab consolidation in the real world and subgroup analysis. a 1-year completion rate of durvalumab consolidation. b 1-year completion rate of durvalumab consolidation of median age >65 versus median age <65.

Close modal

To analyze the factors influencing the 1-year completion rate of durvalumab consolidation therapy, we divided the median age >65 years and the median age <65 years into two subgroups. The results showed that the 1-year completion rate of the subgroup with median age <65 was higher than that of the subgroup with median age >65 (45.0%; 95% CI, 38.3–51.7% vs. 33.9%; 95% CI, 29.6–38.3%; p = 0.007) (Fig. 4b). In addition, we compared 1-year completion rates between studies using carboplatin in most patients and studies using cisplatin in most patients. The results showed that platinum-based chemotherapy drugs had no significant effect on the 1-year completion rates (33.7%; 95% CI, 27.8–39.5% vs. 36.9%; 95% CI, 23.8–49.9%; p = 0.660) (online suppl. Fig. S3D).

Safety Analysis of CRT Combined with Immunotherapy

The most studied adverse event in both real-world and clinical studies is pneumonitis. Because other adverse events were not systematically analyzed in each study, we did not analyze adverse events other than pneumonitis. The pooled incidence of pneumonitis for all grades was 41.7% (95% CI, 31.9–51.9%) (Fig. 5a). Egger’s test indicated no significant publication bias (p = 0.835). In real-world studies, the incidence of pneumonitis for all grades was 46.5% (95% CI, 31.1–62.3%) (Fig. 5c). In clinical trials, the incidence of pneumonitis for all grades was 31.3% (95% CI, 22.8–39.8%) (Fig. 5d). Egger’s test suggested that there was no significant publication bias in the pooled incidence of pneumonitis in both real-world studies and clinical trials (p = 0.783, p = 0.985). The pooled incidence of ≥ grade 3 pneumonitis was 6.7% (95% CI, 5.0–8.5%) (Fig. 5b). Egger’s test suggested a significant publication bias (p = 0.001). In real-world studies, the pooled incidence of ≥ grade 3 pneumonitis was 7.0% (95% CI, 4.1–10.0%) (Fig. 5e). In clinical trials, the pooled incidence of ≥ grade 3 pneumonitis was 6.0% (95% CI, 4.6–7.4%) (Fig. 5f). Egger’s test suggested that there was significant publication bias in the pooled incidence of ≥ grade 3 pneumonitis in both real-world studies and clinical trials (p = 0.0.005, p = 0.002).

Fig. 5.

Pooled analysis of pneumonitis. a Pooled rate of pneumonitis of any grade. b Pooled rate of ≥ grade 3 pneumonitis. c Pooled rate of pneumonitis of any grade in real-world studies. d Pooled rate of pneumonitis of any grade in clinical trials. e Pooled rate of ≥ grade 3 pneumonitis in real-world studies. f Pooled rate of ≥ grade 3 pneumonitis in clinical trials.

Fig. 5.

Pooled analysis of pneumonitis. a Pooled rate of pneumonitis of any grade. b Pooled rate of ≥ grade 3 pneumonitis. c Pooled rate of pneumonitis of any grade in real-world studies. d Pooled rate of pneumonitis of any grade in clinical trials. e Pooled rate of ≥ grade 3 pneumonitis in real-world studies. f Pooled rate of ≥ grade 3 pneumonitis in clinical trials.

Close modal

In clinical trials, we analyzed whether the use of anti-PD-1 or PD-L1 drugs affected the incidence of full-grade pneumonitis. The results showed that there was no significant difference in full-grade pneumonitis induced by anti-PD-1 or PD-L1 immune drugs (31.3%; 95% CI, 14.8–47.9% vs. 31.3%; 95% CI, 22.4–40.3%; p = 0.999) (online suppl. Fig. S4A). Compared with PD-L1 inhibitors, anti-PD-1 treatment had a higher incidence of ≥ grade 3 pneumonitis (8.2%; 95% CI, 5.3–11.0% vs. 5.0%; 95% CI, 3.6–6.4%; p = 0.048) (online suppl. Fig. S4B). In addition, we analyzed the incidence of ≥ grade 3 pneumonitis at 1 year of immunotherapy and 2 years of immunotherapy. The incidence of pneumonitis after 1 year of immunotherapy is 4.8 (95% CI, 3.1–6.5%). The incidence of pneumonitis after 2 years of immunotherapy is 5.1 (95% CI, 2.9–7.3%) (online suppl. Fig. S4C). Our study showed that prolonged immunotherapy had no significant effect on the incidence of ≥ grade 3 pneumonia (p = 0.832) (online suppl. Fig. S4).

Prior to the PACIFIC trial, the standard treatment for patients with inoperable locally advanced NSCLC was concurrent CRT [48, 49]. After recurrence of the disease, further treatment measures are taken. Although many explorations have been made in both maintenance therapy and intensive therapy, the results are not satisfactory [49]. This limitation was improved until PACIFIC trial found that durvalumab consolidation therapy after concurrent CRT could improve patient prognosis [4]. And a lot of clinical data also confirmed this result. Two meta-analyses pooled these data and analyzed the efficacy and safety of CRT combined with immunotherapy in patients with unresectable stage III NSCLC [7, 50]. In the meta-analysis of Nan Bi [7], the safety and short-term efficacy of durvalumab in real-world studies were consistent with those of the PACIFIC trial.

However, the duration of immune consolidation and the efficacy and safety of different immune agents remain unclear. Our meta-analysis provided an overview of existing clinical trials and real-world data on the use of CRT in combination with immunotherapy in stage III NSCLC. In terms of efficacy, our meta-analysis extended the PFS rate and OS rate to 24 months on the basis of Nan Bi [7]. In addition, our study also provides a quantitative pooled analysis of the completion rate and pneumonitis incidence of this cutting-edge therapy.

In the clinical trials that we included, we concluded that the combined 12-month PFS and 12-month OS rates were 57.8% and 87.6%, and the combined 24-month PFS and 24-month OS rates were 42.8% and 69.8%, respectively. This is similar to what happens in real-world studies. Our study provided further evidence that long-term efficacy in consolidating durvalumab in stage III NSCLC patients in real-world studies is similar to data from clinical trials. In the analysis of the incidence of pneumonitis, the incidence of pneumonitis and ≥ grade 3 pneumonitis in clinical trials was 31.2% and 6.0%, respectively. In real-world studies, the incidence of pneumonitis and grade ≥3 pneumonitis was 46.5% and 7.0%, respectively. In the analysis of efficacy, there is a high degree of similarity between real-world studies and clinical trial data. However, adverse reactions are also factors that must be considered in practical drug use. The incidence of all-grade pneumonitis in real-world studies was higher than in clinical trials. This may be because the criteria for enrolling patients in clinical trials are more stringent. For example, patients enrolled in clinical trials had lower EGOC scores. Elderly and frail patients, who account for the majority of NSCLC cases worldwide, are often excluded from registries [51]. However, the incidence of grade ≥3 pneumonitis in real-world studies was similar to that in clinical trials. This makes it possible in the real world that most patients will not end treatment because of high-grade pneumonitis. In conclusion, CRT combined with immunotherapy has good practicability in the real world.

PACIFIC trial refers to immune consolidation therapy for 1 year after concurrent CRT. This has led some researchers to study the effect of 2 years of immune consolidation on treatment outcomes. In clinical trials, our meta-analysis found that the 24-month OS rate at 2 years of immune consolidation was 77.4%, which was greater than the 24-month OS rate at 1 year of immune consolidation (60.7%). Moreover, the incidence of ≥ grade 3 pneumonitis was similar between the two groups (1 year: 4.8%, 95% CI, 3.1–6.5% vs. 2 years: 5.1%, 95% CI, 2.9–7.3%; p = 0.832). Therefore, our study demonstrates that 2 years of immunotherapy after CRT is better than 1 year in cases of similar incidence of high-grade pneumonitis. However, there are few existing studies of immunotherapy at 2 years, and more real-world studies and clinical trials are needed to confirm the optimal length of immunotherapy.

Some elderly patients may not be able to tolerate longer treatment because of their poor foundation. Therefore, age is also a factor influencing survival benefits. In the meta-analysis of Nan Bi, the incidence of pneumonitis in the median age >65 years subgroup was higher than that in the median age <65 years subgroup. This may cause some patients >65 years of age to discontinue treatment. In our meta-analysis, we also analyzed the 1-year completion rate of immunotherapy in patients. The 1-year completion rate of durvalumab consolidation following CRT in real-world studies was 35.6%. Further analysis found that completion rates were significantly higher in the median age <65 subgroup than in the median age >65 subgroup (45.0% vs. 33.9%; p = 0.007). These results suggest that the duration of immunotherapy is associated with a higher incidence of pneumonitis in older patients. In addition, as shown in our analysis above, shortened immunotherapy duration reduces the outcome in patients with stage III NSCLC. A real-world study found similar results. In a real-world study by Bryant et al. [21], 9 and 12 months of concurrent CRT followed by durvalumab consolidation had similar survival benefits and were superior to 6 months of immune consolidation. In conclusion, the high incidence of pneumonia in elderly patients will decrease the continuation of immunotherapy in the world, which further reduces the survival benefits of elderly patients.

In the analysis of efficacy, our meta-analysis also conducted other subgroup analyses. As for the influence of PD-L1 expression on the efficacy, our study confirmed that the subgroup with negative PD-L1 expression had a lower survival rate than the group with high PD-L1 expression. In addition, the proportion of NLR in peripheral blood is also an influencing factor. In a retrospective study, Diem et al. [52] included 52 patients with metastatic NSCLC who received nivolumab. Studies have shown that increased NLR before treatment is associated with shorter OS and PFS, and the NLR can be used as a prognostic marker for patients with NSCLC treated with nivolumab. In our meta-analysis, the low NLR subgroup had a higher 12-month PFS rate than the high NLR group.

The success of the PACIFIC trial has allowed researchers to explore the efficacy or safety of different immune agents in combination with CRT in stage III NSCLC. Such as anti-PD-1 or anti-PD-L1 combined with CRT [29, 32, 46, 53]. However, security is an important consideration. We found that the incidence of ≥ grade 3 pneumonitis in clinical trials was higher with anti-PD-1 treatment than with anti-PD-L1 treatment (8.2% vs. 5.0%; p = 0.048), which is consistent with the systematic review and meta-analysis by Adithya Balasubramanian et al. [50]. The following mechanisms may account for this finding. Studies have shown that PD-1 inhibitors can mediate an increase in RGMb-PD-L2 interaction, which may disrupt the immune tolerance of lung tissue by increasing the intense clonal amplification of T cells residing in the lungs and then lead to the development of pneumonitis [54]. This suggests that the use of anti-PD-L1 drugs in elderly patients may reduce the incidence of pneumonia and increase the duration of immunotherapy, thereby improving the efficacy. This also proves that durvalumab has good practicability in treating elderly stage III NSCLC patients in the real world. However, other than durvalumab, there are limited existing real-world studies on the use of anti-PD-L1. However, beyond durvalumab, there are limited existing real-world studies on the use of anti-PD-L1. Therefore, the safety of two immunotherapy drugs cannot be compared in real-world studies.

Building on the success of the PACIFIC trial, researchers are also exploring other combination treatments. PACIFIC trial is consolidation immunotherapy followed by concurrent CRT. The multicenter phase III randomized controlled trial PACIFIC-5 trial (NCT03706690) is evaluating the efficacy and toxicity of durvalumab after concurrent CRT or sequential CRT. Ross et al. [12] are refining data on the efficacy and safety of CRT after immunotherapy with atezolizumab. The researchers also explored the use of multiple agents for consolidation after CRT. Clinical trials by Herbst et al. [19] demonstrated that the addition of the new drug oleclumab or monalizumab to durvalumab provided an additional clinical benefit compared to durvalumab alone in unresectable stage III NSCLC patients without disease progression after CRT. In addition, Durm et al. [55] also conducted a study of chemotherapy followed by double immunotherapy for stage III NSCLC. In this study, the nivolumab plus ipilimumab group demonstrated improved survival compared with nivolumab alone after CRT. But it also raises the risk of pneumonitis.

Finally, our study had several limitations. (a) Most of our studies are real-world studies, which makes some analyses highly heterogeneous. (b) Of the clinical trials we included, most studies could only be retrieved in abstract or conference format, thus not obtaining complete data and reliable assessment of them. This reflects the relative lack of data currently available in this area. (c) While we would like to perform subgroup analyses for sex, smoking status, radiotherapy dose, chemotherapy regimen, and mutant gene status, the current data do not support such an analysis. This reflects the relative dearth of data currently available in this area. (d) Most of the studies included in our meta-analysis were single-arm studies, and comparisons between subgroups lacked statistical significance. Due to the limitations of this study, it is hoped to design and implement large-sample, multicenter randomized controlled trials to obtain more reliable conclusions and guide clinical practice.

In conclusion, our study on the basis of Nan Bi’s study confirmed that long-term survival of real-world CRT combined with immunotherapy was similar to that of clinical trials. Moreover, the rates of high-grade pneumonia were similar. In addition, our study shows that the duration of immunotherapy improves survival benefits in patients with similar rates of pneumonia. The duration of immunotherapy is shortened in older patients due to their lower 1-year completion rate of immunotherapy, which reduces the survival benefit of combination between CRT and immunotherapy in older patients. In addition, more trial results are needed to validate the efficacy and safety of different immunotherapy administration sequences. Many trials are underway to evaluate further mature randomized data on the effectiveness and safety of these strategies. We will also update our meta-analysis in real time.

The authors appreciate the Ethics Committee of Shandong Provincial Qianfoshan Hospital, Shandong First Medical University.

Ethical approval and consent were not required as this study was based on publicly available data.

The authors declare that they have no conflicts of interest.

This study was funded by the National Natural Science Foundation of China (No. 81803043) and Shandong Natural Science Foundation [ZR2021LSW023, ZR2021QH356, and ZR2022QH351].

Conception and design: Jiandong Zhang, Pingping Hu, and Guodong Deng; writing, review, and/or revision of the manuscript and acquisition of data: Yang Li and Guodong Deng; and study supervision: Ning Liang, Pingping Hu, Deguo Xu, and Fengjun Liu. Pingping Hu, Yan Zhang, Lili Qiao, Yingying Zhang, Jian Xie, Hui Luo, Fei Wang, and Fangjie Chen have read and approved the final manuscript.

Additional Information

Yang Li and Guodong Deng contributed equally to this work.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.

1.
Postmus PE, Kerr KM, Oudkerk M, Senan S, Waller DA, Vansteenkiste J, et al. Early and locally advanced Non-Small-Cell Lung Cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(Suppl l_4):iv1–iv21.
2.
Eberhardt WE, De Ruysscher D, Weder W, Le Péchoux C, De Leyn P, Hoffmann H, et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. Ann Oncol. 2015;26(8):1573–88.
3.
Curran WJJr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103(19):1452–60.
4.
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919–29.
5.
Faivre-Finn C, Vicente D, Kurata T, Planchard D, Paz-Ares L, Vansteenkiste JF, et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC-an update from the PACIFIC trial. J Thorac Oncol. 2021;16(5):860–7.
6.
Spigel DR, Faivre-Finn C, Gray JE, Vicente D, Planchard D, Paz-Ares L, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol. 2022;40(12):1301–11.
7.
Wang Y, Zhang T, Huang Y, Li W, Zhao J, Yang Y, et al. Real-world safety and efficacy of consolidation durvalumab after chemoradiation therapy for stage III non-small cell lung cancer: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys. 2022;112(5):1154–64.
8.
Garassino MC, Mazieres J, Reck M, Chouaid C, Bischoff H, Reinmuth N, et al. Durvalumab after sequential chemoradiotherapy in stage III, unresectable NSCLC: the phase 2 PACIFIC-6 trial. J Thorac Oncol. 2022;17(12):1415–27.
9.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj. 2021;372:n71.
10.
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. Bmj. 2011;343:d5928.
11.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5.
12.
Ross HJ, Kozono DE, Urbanic JJ, Williams TM, DuFrane C, Bara I, et al. AFT-16: phase II trial of neoadjuvant and adjuvant atezolizumab and chemoradiation (CRT) for stage III Non-Small Cell Lung Cancer (NSCLC). J Clin Oncol. 2021;39(15_Suppl l):8513.
13.
Jun S, Shukla N, Durm GA, Hui AB, Cao S, Kunder C, et al. Analysis of circulating tumor DNA in the phase 2 BTCRC LUN 16-081 trial of consolidation nivolumab with or without ipilimumab after chemoradiation in stage III non–small cell lung cancer. J Clin Oncol. 2022;40(16_Suppl l):8534.
14.
Shukla NA, Althouse S, Meyer Z, Hanna N, Durm G. Association of immune-related adverse events and efficacy outcomes with consolidation pembrolizumab after chemoradiation in patients with inoperable stage III non-small-cell lung cancer. Clin Lung Cancer. 2021;22(4):274–81.
15.
Saad A, Goldstein J, Appel S, Daher S, Urban D, Onn A, et al. Chemoradiation followed by adjuvant durvalumab in stage III non-small cell lung cancer: real-world comparison of treatment outcomes to historical controls treated with chemoradiation alone. Thorac Cancer. 2022;13(12):1763–71.
16.
Miura Y, Mouri A, Kaira K, Yamaguchi O, Shiono A, Hashimoto K, et al. Chemoradiotherapy followed by durvalumab in patients with unresectable advanced non-small cell lung cancer: management of adverse events. Thorac Cancer. 2020;11(5):1280–7.
17.
Vrankar M, Stanic K, Jelercic S, Ciric E, Vodusek AL, But-Hadzic J. Clinical outcomes in stage III non-small cell lung cancer patients treated with durvalumab after sequential or concurrent platinum-based chemoradiotherapy: single institute experience. Radiol Oncol. 2021;55(4):482–90.
18.
Offin M, Shaverdian N, Rimner A, Lobaugh S, Shepherd AF, Simone CB2nd, et al. Clinical outcomes, local-regional control and the role for metastasis-directed therapies in stage III non-small cell lung cancers treated with chemoradiation and durvalumab. Radiother Oncol. 2020;149:205–11.
19.
Herbst RS, Majem M, Barlesi F, Carcereny E, Chu Q, Monnet I, et al. COAST: an open-label, phase II, multidrug platform study of durvalumab alone or in combination with oleclumab or monalizumab in patients with unresectable, stage III non-small-cell lung cancer. J Clin Oncol. 2022;40(29):3383–93.
20.
Chu CH, Chiu TH, Wang CC, Chang WC, Huang AC, Liu CY, et al. Consolidation treatment of durvalumab after chemoradiation in real-world patients with stage III unresectable non-small cell lung cancer. Thorac Cancer. 2020;11(6):1541–9.
21.
Bryant AK, Sankar K, Zhao L, Strohbehn GW, Elliott D, Moghanaki D, et al. De-escalating adjuvant durvalumab treatment duration in stage III non-small cell lung cancer. Eur J Cancer. 2022;171:55–63.
22.
Landman Y, Jacobi O, Kurman N, Yariv O, Peretz I, Rotem O, et al. Durvalumab after concurrent chemotherapy and high-dose radiotherapy for locally advanced non-small cell lung cancer. Oncoimmunology. 2021;10(1):1959979.
23.
Faehling M, Schumann C, Christopoulos P, Hoffknecht P, Alt J, Horn M, et al. Durvalumab after definitive chemoradiotherapy in locally advanced unresectable Non-Small Cell Lung Cancer (NSCLC): real-world data on survival and safety from the German Expanded-Access Program (EAP). Lung Cancer. 2020;150:114–22.
24.
Wass R, Hochmair M, Kaiser B, Grambozov B, Feurstein P, Weiß G, et al. Durvalumab after sequential high dose chemoradiotherapy versus Standard Of Care (SoC) for stage III NSCLC: a Bi-centric trospective comparison focusing on pulmonary toxicity. Cancers. 2022;14(13):3226.
25.
Wang CC, Chiu LC, Ju JS, Lin YC, Fang YF, Yang CT, et al. Durvalumab as consolidation therapy in post-concurrent chemoradiation (CCRT) in unresectable stage III non-small cell lung cancer patients: a multicenter observational study. Vaccines. 2021;9(10):1122.
26.
Desilets A, Blanc-Durand F, Lau S, Hakozaki T, Kitadai R, Malo J, et al. Durvalumab therapy following chemoradiation compared with a historical cohort treated with chemoradiation alone in patients with stage III non-small cell lung cancer: a real-world multicentre study. Eur J Cancer. 2021;142:83–91.
27.
Harada D, Shimonishi A, Saeki K, Ninomiya T, Kanzaki H, Nagasaki K, et al. Early administration of durvalumab after chemoradiotherapy increased risk of pneumonitis in patients with locally advanced non-small cell lung cancer. Asia Pac J Clin Oncol. 2023;19(2):e111–7.
28.
Jain P, Murray P, Clarke K, Franks K, Teo M, Saha A, et al. Early experience of maintenance durvalumab post chemoradiation (CRT) in stage III Non-Small Cell Lung Cancer (NSCLC) across West Yorkshire network: from Expanded Access Programme (EAP) to routine clinical use. Lung Cancer. 2020;139:S46.
29.
Zhou Q, Chen M, Wu G, Chang JH, Jiang O, Cui JW, et al. GEMSTONE-301: a phase III clinical trial of CS1001 as consolidation therapy in patients with locally advanced/unresectable (stage III) Non-Small Cell Lung Cancer (NSCLC) who did not have disease progression after prior concurrent/sequential chemoradiotherapy. Transl Lung Cancer Res. 2020;9(5):2008–15.
30.
Hassanzadeh C, Sita T, Savoor R, Samson PP, Bradley J, Gentile M, et al. Implications of pneumonitis after chemoradiation and durvalumab for locally advanced non-small cell lung cancer. J Thorac Dis. 2020;12(11):6690–700.
31.
Tsukita Y, Yamamoto T, Mayahara H, Hata A, Takeda Y, Nakayama H, et al. Intensity-modulated radiation therapy with concurrent chemotherapy followed by durvalumab for stage III non-small cell lung cancer: a multi-center retrospective study. Radiother Oncol. 2021;160:266–72.
32.
Jabbour SK, Berman AT, Decker RH, Lin Y, Feigenberg SJ, Gettinger SN, et al. Phase 1 trial of pembrolizumab administered concurrently with chemoradiotherapy for locally advanced non-small cell lung cancer: a nonrandomized controlled trial. JAMA Oncol. 2020;6(6):848–55.
33.
Nakamichi S, Kubota K, Misumi T, Murakami S, Kondo T, Okamoto I, et al. A phase II study of durvalumab (MEDI4736) immediately after completion of chemoradiotherapy in unresectable stage III non–small cell lung cancer: TORG1937 (DATE study). J Clin Oncol. 2022;40(16_Suppl l):8536.
34.
Taugner J, Käsmann L, Karin M, Eze C, Flörsch B, Guggenberger J, et al. Planning target volume as a predictor of disease progression in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy and concurrent and/or sequential immune checkpoint inhibition. Invest New Drugs. 2022;40(1):163–71.
35.
Mayahara H, Uehara K, Harada A, Kitatani K, Yabuuchi T, Miyazaki S, et al. Predicting factors of symptomatic radiation pneumonitis induced by durvalumab following concurrent chemoradiotherapy in locally advanced non-small cell lung cancer. Radiat Oncol. 2022;17(1):7.
36.
Araki T, Tateishi K, Komatsu M, Sonehara K, Wasamoto S, Koyama S, et al. Predictive value of post-treatment C-reactive protein-to-albumin ratio in locally advanced non-small cell lung cancer patients receiving durvalumab after chemoradiotherapy. Thorac Cancer. 2022;13(14):2031–40.
37.
Bryant AK, Sankar K, Strohbehn GW, Zhao L, Daniel V, Elliott D, et al. Prognostic and predictive role of PD-L1 expression in stage III non-small cell lung cancer treated with definitive chemoradiation and adjuvant durvalumab. Int J Radiat Oncol Biol Phys. 2022;113(4):752–8.
38.
Sugimoto T, Fujimoto D, Sato Y, Tamiya M, Yokoi T, Taniguchi Y, et al. Prospective multicenter cohort study of durvalumab for patients with unresectable stage III non-small cell lung cancer and grade 1 radiation pneumonitis. Lung Cancer. 2022;171:3–8.
39.
Shaverdian N, Thor M, Shepherd AF, Offin MD, Jackson A, Wu AJ, et al. Radiation pneumonitis in lung cancer patients treated with chemoradiation plus durvalumab. Cancer Med. 2020;9(13):4622–31.
40.
Jung HA, Noh JM, Sun JM, Lee SH, Ahn JS, Ahn MJ, et al. Real world data of durvalumab consolidation after chemoradiotherapy in stage III non-small-cell lung cancer. Lung Cancer. 2020;146:23–9.
41.
Sankar K, Bryant AK, Strohbehn GW, Zhao L, Elliott D, Moghanaki D, et al. Real world outcomes versus clinical trial results of durvalumab maintenance in veterans with stage III non-small cell lung cancer. Cancers. 2022;14(3):614.
42.
LeClair JN, Merl MY, Cohenuram M, Luon D. Real-world incidence of pneumonitis in patients receiving durvalumab. Clin Lung Cancer. 2022;23(1):34–42.
43.
Taugner J, Käsmann L, Eze C, Rühle A, Tufman A, Reinmuth N, et al. Real-world prospective analysis of treatment patterns in durvalumab maintenance after chemoradiotherapy in unresectable, locally advanced NSCLC patients. Invest New Drugs. 2021;39(4):1189–96.
44.
Bruni A, Scotti V, Borghetti P, Vagge S, Cozzi S, D'Angelo E, et al. A real-world, multicenter, observational retrospective study of durvalumab after concomitant or sequential chemoradiation for unresectable stage III non-small cell lung cancer. Front Oncol. 2021;11:744956.
45.
Kishi N, Matsuo Y, Shintani T, Ogura M, Mitsuyoshi T, Araki N, et al. Recurrence patterns and progression-free survival after chemoradiotherapy with or without consolidation durvalumab for stage III non-small cell lung cancer. J Radiat Res. 2022;64(1):142–53.
46.
Peters S, Felip E, Dafni U, Belka C, Guckenberger M, Irigoyen A, et al. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-The ETOP NICOLAS trial. Lung Cancer. 2019;133:83–7.
47.
Reck M, Lee KH, Frost N, Breder VV, Kowalski D, Levchenko E, et al. Two-year update from KEYNOTE-799: pembrolizumab plus Concurrent Chemoradiation Therapy (cCRT) for unresectable, locally advanced, stage III NSCLC. J Clin Oncol. 2022;40(16_Suppl l):8508.
48.
Miller M, Hanna N. Advances in systemic therapy for non-small cell lung cancer. Bmj. 2021;375:n2363.
49.
Zeng J, Bowen SR. Treatment intensification in locally advanced/unresectable NSCLC through combined modality treatment and precision dose escalation. Semin Radiat Oncol. 2021;31(2):105–11.
50.
Balasubramanian A, Onggo J, Gunjur A, John T, Parakh S. Immune checkpoint inhibition with chemoradiotherapy in stage III non-small-cell lung cancer: a systematic review and meta-analysis of safety results. Clin Lung Cancer. 2021;22(2):74–82.
51.
Califano R, Gomes F, Ackermann CJ, Rafee S, Tsakonas G, Ekman S. Immune checkpoint blockade for non-small cell lung cancer: what is the role in the special populations?Eur J Cancer. 2020;125:1–11.
52.
Diem S, Schmid S, Krapf M, Flatz L, Born D, Jochum W, et al. Neutrophil-to-Lymphocyte Ratio (NLR) and Platelet-to-Lymphocyte Ratio (PLR) as prognostic markers in patients with Non-Small Cell Lung Cancer (NSCLC) treated with nivolumab. Lung Cancer. 2017;111:176–81.
53.
Durm GA, Jabbour SK, Althouse SK, Liu Z, Sadiq AA, Zon RT, et al. A phase 2 trial of consolidation pembrolizumab following concurrent chemoradiation for patients with unresectable stage III non-small cell lung cancer: hoosier Cancer Research Network LUN 14-179. Cancer. 2020;126(19):4353–61.
54.
Xiao Y, Yu S, Zhu B, Bedoret D, Bu X, Francisco LM, et al. RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med. 2014;211(5):943–59.
55.
Yan M, Durm GA, Mamdani H, Ernani V, Jabbour SK, Naidoo J, et al. Consolidation nivolumab/ipilimumab versus nivolumab following concurrent chemoradiation in patients with unresectable stage III NSCLC: a planned interim safety analysis from the BTCRC LUN 16-081 trial. J Clin Oncol. 2020;38(15_Suppl l):9010.