Immunotherapy in unresectable stage III non-small-cell lung cancer: state of the art and novel therapeutic approaches

•Adjuvant immunotherapy has revolutionized the treatment of patients with locally advanced unresectable stage III NSCLC.•Novel treatment strategies in this setting are under development to further improve patient survival.•A deeper understanding of the interplay between immune system and tumor biology will lead to tailored treatment strategies.•Biomarker implementation is key for identifying the patients who will benefit the most from a specific treatment.•For improving survival outcomes, it is unlikely that a 'one fits all' model represents the solution. The standard of care for patients with stage III non-small-cell lung cancer (NSCLC) is concurrent chemoradiotherapy (CCRT) followed by 1 year of adjuvant durvalumab. Despite the survival benefit granted by immunotherapy in this setting, only 1/3 of patients are alive and disease free at 5 years. Novel treatment strategies are under development to improve patient outcomes in this setting: different anti-programmed cell death protein 1/programmed death-ligand 1 [anti-PD-(L)1] antibodies after CCRT, consolidation immunotherapy after sequential chemoradiotherapy, induction immunotherapy before CCRT and immunotherapy concurrent with CCRT and/or sequential chemoradiotherapy. Cross-trial comparison is particularly challenging in this setting due to the different timing of immunotherapy delivery and different patients' inclusion and exclusion criteria. In this review, we present the results of clinical trials investigating immune therapy in unresectable stage III NSCLC and discuss in-depth their biological rationale, their pitfalls and potential benefits. Particular emphasis is placed on the potential mechanisms of synergism between chemotherapy, radiation therapy and different monoclonal antibodies, and how this affects the tumor immune microenvironment. The designs and questions tackled by ongoing clinical trials are also discussed. Last, we address open questions and unmet clinical needs, such as the necessity for predictive biomarkers (e.g. radiomics and circulating tumor DNA). Identifying distinct subsets of patients to tailor anticancer treatment is a priority, especially in a heterogeneous disease such as stage III NSCLC. The standard of care for patients with stage III non-small-cell lung cancer (NSCLC) is concurrent chemoradiotherapy (CCRT) followed by 1 year of adjuvant durvalumab. Despite the survival benefit granted by immunotherapy in this setting, only 1/3 of patients are alive and disease free at 5 years. Novel treatment strategies are under development to improve patient outcomes in this setting: different anti-programmed cell death protein 1/programmed death-ligand 1 [anti-PD-(L)1] antibodies after CCRT, consolidation immunotherapy after sequential chemoradiotherapy, induction immunotherapy before CCRT and immunotherapy concurrent with CCRT and/or sequential chemoradiotherapy. Cross-trial comparison is particularly challenging in this setting due to the different timing of immunotherapy delivery and different patients' inclusion and exclusion criteria. In this review, we present the results of clinical trials investigating immune therapy in unresectable stage III NSCLC and discuss in-depth their biological rationale, their pitfalls and potential benefits. Particular emphasis is placed on the potential mechanisms of synergism between chemotherapy, radiation therapy and different monoclonal antibodies, and how this affects the tumor immune microenvironment. The designs and questions tackled by ongoing clinical trials are also discussed. Last, we address open questions and unmet clinical needs, such as the necessity for predictive biomarkers (e.g. radiomics and circulating tumor DNA). Identifying distinct subsets of patients to tailor anticancer treatment is a priority, especially in a heterogeneous disease such as stage III NSCLC. IntroductionStage III non-small-cell lung cancer (NSCLC) accounts for approximately one-third of newly diagnosed NSCLC cases.1Amin M.B. Edge S. Greene F. et al.AJCC Cancer Staging Manual.8th ed. Springer, Cham. American Joint Commission on Cancer, Cham, Switzerland2017Crossref Google Scholar Stage III comprises a heterogeneous group of patients, for whom dedicated discussion within an experienced multidisciplinary team is mandatory. Even if the definition of unresectability (technical and oncological) may vary between centers, some patients with stage IIIA and very selected ones with stage IIIB-N2 can benefit from surgical multimodality treatment.2Postmus P.E. Kerr K.M. Oudkerk M. 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: iv1-iv21Abstract Full Text Full Text PDF PubMed Scopus (885) Google Scholar They were discussed in our previous review.3Vansteenkiste J. Wauters E. Reymen B. Ackermann C.J. Peters S. De Ruysscher D. Current status of immune checkpoint inhibition in early-stage NSCLC.Ann Oncol. 2019; 30: 1244-1253Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar In light of the results of the CheckMate-816 study, chemo-immunotherapy, if approved by health authorities, is now the preferred neoadjuvant therapy in patients with resectable stage III-N2 NSCLC.4Forde P.M. Spicer J. Lu S. et al.Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (41) Google Scholar This approach should not be used to convert upfront unresectable stage III NSCLC to a resectable NSCLC, however, since surgical resectability should be determined at the time of initial diagnosis in a dedicated multidisciplinary tumor board.The majority of patients with stage III, however, have 'unresectable stage III'. In case of good performance status (PS), their standard of care (SoC) is concurrent chemoradiotherapy (CCRT) completed by 1 year of adjuvant durvalumab.2Postmus P.E. Kerr K.M. Oudkerk M. 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: iv1-iv21Abstract Full Text Full Text PDF PubMed Scopus (885) Google Scholar,5Antonia S.J. Villegas A. Daniel D. et al.Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer.N Engl J Med. 2017; 377: 1919-1929Crossref PubMed Scopus (2256) Google Scholar In the PACIFIC trial, adjuvant durvalumab after CCRT improved median overall survival (OS) compared with placebo {47.5 versus 29.1 months [hazard ratio (HR) = 0.68]}. Only 1/3 of patients receiving adjuvant durvalumab, however, is alive and disease free at 5 years.6Antonia S.J. Villegas A. Daniel D. et al.Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.N Engl J Med. 2018; 379: 2342-2350Crossref PubMed Scopus (1455) Google Scholar,7Spigel D.R. Faivre-Finn C. Gray J.E. 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: 1301-1311Crossref PubMed Scopus (44) Google Scholar Retrospective series showed that only half of the patients with stage III NSCLC are treated with radical intent in daily practice, and of those receiving CRT, only 2/3 are treated with CCRT whereas 1/3 received sequential chemoradiotherapy (SCRT).8Eichkorn T. Bozorgmehr F. Regnery S. et al.Consolidation immunotherapy after platinum-based chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer—cross-sectional study of eligibility and administration rates.Front Oncol. 2020; 10586449Crossref Scopus (4) Google Scholar, 9Ronden M.I. Bahce I. Claessens N.J.M. et al.The impact of the availability of immunotherapy on patterns of care in stage III NSCLC: a Dutch Multicenter Analysis.JTO Clin Res Rep. 2021; 2100195PubMed Google Scholar, 10Evers J. de Jaeger K. Hendriks L.E.L. et al.Trends and variations in treatment of stage I-III non-small cell lung cancer from 2008 to 2018: a nationwide population-based study from the Netherlands.Lung Cancer. 2021; 155: 103-113Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Furthermore, not all the patients treated with CCRT are eligible for adjuvant durvalumab due to residual toxicity, impaired PS, disease progression and, in the European Union, a programmed death-ligand 1 (PD-L1) level <1%.8Eichkorn T. Bozorgmehr F. Regnery S. et al.Consolidation immunotherapy after platinum-based chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer—cross-sectional study of eligibility and administration rates.Front Oncol. 2020; 10586449Crossref Scopus (4) Google Scholar,11Sakaguchi T. Ito K. Furuhashi K. et al.Patients with unresectable stage III non-small cell lung cancer eligible to receive consolidation therapy with durvalumab in clinical practice based on PACIFIC study criteria.Respir Investig. 2019; 57: 466-471Crossref PubMed Scopus (24) Google Scholar,12Senan S. Brade A. Wang L.-H. et al.PROCLAIM: randomized phase III trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer.J Clin Oncol. 2016; 34: 953-962Crossref PubMed Scopus (294) Google Scholar For patients not cured with, or not eligible for adjuvant durvalumab, new treatments are urgently needed. Conversely, ∼20% of patients are already cured after CCRT and do not need adjuvant durvalumab; identifying those patients would avoid unnecessary durvalumab-related toxicities and societal costs.12Senan S. Brade A. Wang L.-H. et al.PROCLAIM: randomized phase III trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer.J Clin Oncol. 2016; 34: 953-962Crossref PubMed Scopus (294) Google Scholar,13De Ruysscher D. van Baardwijk A. Wanders R. et al.Individualized accelerated isotoxic concurrent chemo-radiotherapy for stage III non-small cell lung cancer: 5-year results of a prospective study.Radiother Oncol. 2019; 135: 141-146Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar In this review, we present the results of clinical trials investigating immune therapy in unresectable stage III NSCLC, highlighting their pitfalls and potential benefits from a clinical and from a mechanistic point-of-view. The designs and questions tackled by ongoing clinical trials are also discussed. Last, we address open questions and unmet clinical needs, such as the necessity for predictive biomarkers.Current state of the art—adjuvant durvalumabIn the phase III PACIFIC trial, 709 patients were randomized (2 : 1) to receive either adjuvant durvalumab or placebo every 2 weeks for up to 12 months after the completion of CCRT [≥2 cycles of platinum-based chemotherapy and 54-66 Gray (Gy) radiotherapy]. The addition of durvalumab resulted in long-term benefit, with 5-year OS and progression-free survival (PFS) rates of 42.9% (versus 33.4% in the placebo arm), and 33.1% (versus 19.0%), respectively.7Spigel D.R. Faivre-Finn C. Gray J.E. 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: 1301-1311Crossref PubMed Scopus (44) Google Scholar The survival benefit was irrespective of PD-L1 expression level (patients were stratified for PD-L1 expression <25% versus ≥25%). The addition of durvalumab did not seem to result in excessive toxicity; 30% of the patients experienced all-cause grade ≥3 adverse events (AEs) (versus 26% in the placebo arm).5Antonia S.J. Villegas A. Daniel D. et al.Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer.N Engl J Med. 2017; 377: 1919-1929Crossref PubMed Scopus (2256) Google ScholarThe results of the PACIFIC trial were confirmed in the international, retrospective PACIFIC-R study (n = 1399), enrolling patients who received at least one cycle of durvalumab as part of an AstraZeneca-initiated Expanded Access Program (EAP). In some countries, SCRT was also allowed. The median PFS—counted from the first dose of durvalumab—was 21.7 months [95% confidence interval (CI) 19.2-24.5 months] in the full population, 23.7 months (95% CI 20.1-25.8 months) in patients treated with CCRT (77%) and 19.4 months (95% CI 12.4-25.3 months) in patients treated with SCRT (14%). The survival curves of PACIFIC-R resemble the ones of PACIFIC suggesting a similar plateau and long-term benefit, even for patients treated with SCRT.14Girard N. Smit H.J.M. Sibille A. et al.1171MO PACIFIC-R real-world study: Treatment duration and interim analysis of progression-free survival in unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy.Ann Oncol. 2021; 32: S939-S940Abstract Full Text Full Text PDF Google Scholar The EAP mandated, however, that patients fulfilled specific eligibility criteria, thus the results are probably comparable only to fit patients in daily clinical practice.New studies evaluating immunotherapy for unresectable stage III NSCLCSeveral studies are evaluating new strategies to improve survival: different anti-programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] antibodies after CCRT, consolidation immunotherapy after SCRT, induction immunotherapy before CCRT and immunotherapy concurrent with CCRT and/or SCRT. Cross-trial comparison is particularly challenging in this setting due to the different timing of immunotherapy delivery—before or after CCRT—and the consequent different starting point of PFS and OS assessment, and the difference in patient exclusion criteria. Moreover, within the same approach, windows of accrual were sometimes different (Figure 1). Trials with results available (Table 1) as well as ongoing trials (Table 2) are discussed below.Table 1RCTs completed or with preliminary data available in unresectable stage III NSCLCStudy name (Registry number)Study designExperimental arm(s)Treatment durationControl arm(Target) accrualPrimary End PointResultsConsolidation immunotherapy after CCRT or SCRTPACIFIC (NCT02125461)Randomized (2 : 1) phase IIIDurvalumab 10 mg/kg i.v. Q2W (after CCRT)1 YearPlacebo709PFS, OSmPFS = 17.2 versus 5.6 months (HR = 0.51; 95% CI 0.41-0.63) mOS = 47.5 versus 29.1 months (HR = 0.68; 99% CI 0.47-0.9)PACIFIC-R (NCT03798535)RetrospectiveDurvalumab 10 mg/kg i.v. Q2W (after CCRT/SCRT)1 YearSingle arm1399PFS, OSmPFS = 21.7 months (95% CI, 19.2-24.5 months)—interim analysisLUN 14-179 (NCT02343952)Phase IIPembrolizumab 200 mg i.v. Q3W (after CCRT)1 YearSingle arm93mTMDDmTMDD = 30.7 months (95% CI 18.7 months-NR)mPFS = 18.7 months (95% CI 12.4-33.8 months)GEMSTONE-301 (NCT03728556)Randomized (2 : 1) phase IIISugemalimab 1200 mg i.v. Q3W (after CCRT/SCRT)2 YearsPlacebo381mPFSmPFS = 9 months versus 5.8 months (HR 0.64; 95% CI 0.48-0.85; P = 0.0026)—interim analysisPACIFIC-6 (NCT03693300)Phase IIDurvalumab (after SCRT)1 YearPlacebo120% AEs grade ≥3mPFS = 10.9 months (95% CI 7.3-15.6 months)Concurrent immunotherapy with CCRTNICOLAS (NCT02434081)Phase IICCRT + nivolumab 360 mg Q3W → nivolumab 480 mg i.v. Q4W1 YearSingle arm79Safety1 year PFS = 53.5% (95% CI 39.9% to 60.1%)DETERRED (NCT02525757)Phase IICCRT + atezolizumab → atezolizumab 1200 mg i.v. Q3W1 YearSingle arm52% of AEs ≥3AEs grade ≥3 = 80%; irAEs grade ≥3 = 20% mPFS = 13.2 months—interim analysisKEYNOTE-799 (NCT03631784)Phase IICCRT + pembrolizumab → pembrolizumab 200 mg i.v. Q3W1 YearSingle arm216ORRORR = 70.5% (95% CI ≈60% to 80%)1 Year PFS ≈68% mPFS 30.6 months for cohort A (95% CI 16.6 months-NR) NR for cohort B (95% CI 20.6 months-NR)Induction immunotherapy followed by CRTAFT-16 (NCT03102242)Phase IIAtezolizumab 1200 mg i.v. Q3W × 4 cycles → CCRT → atezolizumab1 YearSingle arm64DCR at 12 weeksmPFS = 23.7 months (95% CI 13.2 months-NR)—interim analysisDoublet checkpoint inhibitionCOAST (NCT03822351)Randomized (1 : 1 : 1) phase IICCRT → durvalumab 1500 mg i.v. + oleclumab 300 mg i.v. Q4W (arm A)CCRT → durvalumab 1500 mg i.v. Q4W + monalizumab 750 mg i.v. Q2W (arm B)1 YearCCRT → durvalumab 1500 mg i.v. Q4W (arm C)189ORRORR = 30.0% (95% CI 18.8% to 43.2%) in arm A, 35.5% (95% CI 23.7% to 48.7%) in arm B, 17.9% (95% CI 9.6% to 29.2%) in arm C mPFS = NR (10.4 months-NR) (arm A), 15.1 months (95% CI 13.6 months-NR) arm B, 6.3 months (95% CI 3.7-11.2 months)—interim analysisBTCRC-LUN 16-081 (NCT03285321)Randomized (1 : 1) phase IICCRT → nivolumab 3 mg/kg Q4W + ipilimumab 1 mg/kg Q6W6 MonthsCCRT → nivolumab 480 mg Q4W10818 months PFSmPFS = 25.8 months (95% CI 16.5 months-NR) in the nivolumab arm and 25.4 months (95% CI 18.6 months-NR) in the nivolumab/ipilimumab armAEs, adverse events; CCRT, concurrent chemoradiotherapy; CI, confidence interval; DCR, disease control rate; HR, hazard ratio; irAEs, immune related adverse events; i.v., intravenous; mOS, median overall survival; mPFS, median progression free survival; mTMDD, median time to metastatic disease/death; NR, not reached; NSCLC, non-small-cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PS, performance status; Q2W, every 2 weeks; Q3W, every 3 weeks; Q4W, every 4 weeks; RCTs, randomized, controlled trials; SCRT, sequential chemoradiotherapy. Open table in a new tab Table 2Ongoing phase II/III RCTs with immuno-(chemoRT) in unresectable stage III NSCLCRegistry numberStudy designPopulationExperimental armControl armTarget accrualPrimary endpointConsolidation immunotherapy after CRT (concurrent or sequential) if not PDNCT03379441Phase II, randomized (1 : 1)CCRT/SCRTPembrolizumab 200 mg Q3W i.v. up to 2 yearsFollow-up126OSNCT03728556Phase III RCT (1 : 1)CCRT/SCRTCS1001 (anti PDL-L1) up to 2 yearsPlacebo381PFSNCT04325763Phase III RCT (1 : 1 : 1)CCRT/SCRTArm A: TQB2450 (anti-PD-L1) + anlotinibArm B: TQB2450 (anti-PD-L1)Placebo315PFSNCT03706690 (PACIFIC 5)Phase III RCT (1 : 1)CCRT/SCRTDurvalumab 1500 mg i.v. Q4W until PDPlacebo400PFSConcurrent immunotherapy with CCRTNCT03519971 (PACIFIC-2)Phase III RCT (1 : 1)All comersCCRT + durvalumab → durvalumab up to 1 yearCCRT + placebo → placebo327PFSNCT04092283Phase III RCT (1 : 1)All comersCCRT + durvalumab → durvalumab up to 1 yearCCRT + placebo → durvalumab660OSNCT04380636 (KEYLYNK-012)Phase III RCT (1 : 1 : 1)All comersCCRT + pembrolizumab → pembrolizumabCCRT + pembrolizumab → pembrolizumab + olaparib (up to 1 year)CCRT → durvalumab870PFS, OSNCT04085250Phase II, randomized (1 : 1)All comersCT + nivolumab (2 cycles) → CCRT + nivolumab (1 cycle) → nivolumab up to 1 yearCT + nivolumab (2 cycles) → CCRT + nivolumab (1 cycle) → FU264PFSNCT03840902Phase III RCT (1 : 1)All comersCCRT + M7824 (bintrafusp alpha) → M7824 up to 1 yearCCRT → durvalumab350PFSNCT04765709 (BRIDGE trial)Phase IIPts not eligible for radical CCRT due to large tumorsCT + durvalumab → durvalumab + RT → durvalumab up to 2 yearsNone65PFSInduction immunotherapyNCT04776447 (APOLO)Phase IIAll comersAtezolizumab + CT (3 cycles q21) → CCRT (5 weeks) → atezolizumab up to 1 yearNone51PFSNCT04364048Phase IIAll comersDurvalumab → CCRT → durvalumab to 1 yearNone54PFSNCT04230408 (PACIFIC BRAZIL)Phase IIAll comersDurvalumab 1500 mg q21 days + CT (2 cycles) → CCRT + durvalumab → durvalumab up to 1 yearNone48PFSNCT05128630 (DEDALUS)Phase IIAll comersCT + durvalumab → RT +durvalumab → durvalumab up to 1 yearNone45SafetyDoublet checkpoint inhibitionNCT04513925 (Skyscraper-03)Phase III RCT (1 : 1)Not progressive after CCRTCCRT → atezolizumab 1680 mg i.v. + tiragolumab 840 mg i.v. Q4W up to 1 yearCCRT → durvalumab800PFSNCT04026412 (Checkmate 73L)Phase III RCT (1 : 1 : 1)All comersCCRT + nivolumab 360 mg Q3W → nivolumab 360 mg Q3W + ipilimumabCCRT + nivolumab 360 mg Q3W → nivolumabCCRT → durvalumab888PFS, OSNCT05221840 (Checkmate-9)Phase III RCT (1 : 1 : 1)Not progressive after CCRTCCRT → durvalumab 1500 mg i.v. + oleclumab 300 mg i.v. Q4W (arm A)CCRT → durvalumab 1500 mg i.v. Q4W + monalizumab 750 mg i.v. Q2W (arm B)CCRT → durvalumab999NCT04905316 (CHORUS)Phase IIAll comersCCRT + canakinumab → canakinumab + durvalumabnone32PFSDe-escalation strategiesNCT03523702 (SPRINT)Non-randomized phase IIPD-L1 ≥50%Pembrolizumab 200 mg Q3W IV (3 cycles) → RT (60 Gy) → pembrolizumab up to 1 yearCCRT → durvalumab (patients with PD-L1 <50%)63PFSNCT04249362Phase IIPS 0-2TRT → durvalumab up to 1 yearNone150SafetyjRCTs031190070Phase IIPS of 2 and/or >74 yearsRT (60 Gy) + carboplatin daily → durvalumabNone95PFSNCT04351256 (TRADE-hypo)Randomized phase II (1 : 1)PS 2 or PS 1 and CCI ≥1 and/or ≥70 yearsRT (20 × 2.75 Gy) + durvalumab up to 1 yearRT (60 Gy/30) + durvalumab88Safety, ORRNCT04003246Phase IIAll comersTRT (60 Gy) + durvalumab → durvalumab up to 1 yearNone50PFSNCT03999710Phase IIAll comersTRT (60 Gy) + durvalumab 1500 mg i.v. Q4W → durvalumab up to 1 yearNone53PFSCCI, Charlson comorbidity index; CCRT, concurrent chemoradiotherapy; CRT, chemoradiotherapy; CT, chemotherapy; FU, follow-up; Gy, Gray; i.v., intravenous; NSCLC, non-small-cell lung cancer; OS, overall survival; PD, progressive disease; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PS, performance status; Q2W, every 2 weeks; Q3W, every 3 weeks; Q4W, every 4 weeks; Q6W, every 6 weeks; RCT, randomized, controlled trial; SC, subcutaneous; SCRT, sequential chemoradiotherapy; TRT, thoracic radiotherapy.Studies in resectable stage III, studies enrolling patients with driver mutations and other studies NOT evaluating immunotherapy are not included in the present table.If not otherwise specified, only patients with Eastern Cooperative Oncology Group PS 0-1 are eligible in the clinical trial.Studies already presented in Table 1 are not included in this table.If not otherwise specified, immunotherapy dosages are the following: durvalumab 1500 mg i.v. Q4W; pembrolizumab 200 mg i.v. Q3W; tiragolumab 840 mg i.v. Q4W; atezolizumab 1680 mg i.v. Q4W; CS1001 monoclonal antibody 1200 mg i.v. Q3W; TQB2450 1200 mg i.v. Q3W; M7824 (bintrafusp alpha) 1200 mg i.v. Q2W; ipilimumab 1 mg/kg Q6W; nivolumab 480 mg Q4W; canakinumab 200 mg s.c. Q3W → 200 mg i.v. Q4W. Open table in a new tab Consolidation immune therapy after concurrent or sequential CRTAdjuvant single agent immunotherapyThe single-arm phase II LUN 14-179 trial (n = 93) evaluated 1 year of adjuvant pembrolizumab after CCRT in patients with unresectable NSCLC and met its primary endpoint: time to metastatic disease or death was 30.7 months [95% CI 18.7 months-not reached (NR)]. The median PFS was 18.7 months (95% CI 12.4-33.8 months) and the median OS was 35.8 months (95% CI 24.2 months-NR). The estimated 1-, 2-, and 3-year survival rates were 81.2%, 62.0% and 48.5%, respectively.15Durm G.A. Jabbour S.K. Althouse S.K. 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: 4353-4361Crossref PubMed Scopus (0) Google Scholar The first data about efficacy of consolidation immunotherapy after SCRT were presented in the phase III randomized, controlled trial (RCT) GEMSTONE-301 (n = 381). Patients who had not progressed after either CCRT or SCRT were randomized (2 : 1) to receive consolidation sugemalimab—a fully human anti-PD-L1 immunoglobulin G4 (IgG4)—or placebo, up to 24 months. At the pre-planned interim analysis, carried out with a median follow-up of 14 months, median PFS was 9.0 months in the sugemalimab arm compared with 5.8 months in the placebo group (HR 0.64; 95% CI 0.48-0.85; P = 0.0026) and 1-year PFS was 45% (versus 25%). PFS benefit was observed in both the SCRT (median PFS 8.1 versus 4.1 months, HR 0.59) and CCRT groups (median PFS 10.5 versus 6.4 months, HR 0.66).16Zhou Q. Chen M. Jiang O. et al.Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial.Lancet Oncol. 2022; 23: 209-219Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar In the single-arm phase II open label PACIFIC-6 trial, 120 patients with Eastern Cooperative Oncology Group PS ≤ 2 received adjuvant durvalumab (up to 2 years versus 1 year in PACIFIC), if they did not have progressive disease (PD) after SCRT. The primary endpoint was safety, defined as the incidence of treatment-related AEs (TRAEs) grade ≥3. Overall, 18.8% of patients developed a grade ≥3 AE and 10% of the patients discontinued treatment due to pneumonitis (any grade). Median PFS and median OS were, respectively, 10.9 months (95% CI 7.3-15.6 months) and 25 months (95% CI 25 months-NR). One-year survival was 84.1% (95% CI 75.6% to 89.9%). The reason to use SCRT instead of CCRT (e.g. PS, radiation field, logistics, comorbidities) was not provided for these patients. It should be noted that only 2.6% of the patients enrolled in the study had a PS = 2.17Garassino M.C. Mazieres J. Reck M. et al.108MO Safety and efficacy outcomes with durvalumab after sequential chemoradiotherapy (sCRT) in stage III, unresectable NSCLC (PACIFIC-6).Ann Oncol. 2022; 33: S81-S82Abstract Full Text Full Text PDF Google Scholar Usually patients with PS 0/1 are fit enough to receive CCRT; reasons for receiving SCRT instead of CCRT should be elucidated, since patients receiving SCRT for logistic reasons and patients not fit enough for CCRT comprise two different populations, and it could be that they would derive a different benefit—and different AEs—from immunotherapy. Frailer patients are more prone to develop toxicities during CRT, and we can speculate that their immune system might be more severely impaired by CRT jeopardizing immunotherapy efficacy.18Vaes R.D.W. Reynders K. Sprooten J. et al.Identification of potential prognostic and predictive immunological biomarkers in patients with stage I and stage III non-small cell lung cancer (NSCLC): a prospective exploratory study.Cancers. 2021; 13: 6259Crossref PubMed Scopus (2) Google Scholar Based on the aforementioned trials and biological evidence, fit patients treated with SCRT might derive meaningful survival benefit from adjuvant immunotherapy, although data for patients with PS = 2 are largely lacking. Studies should be carried out in this patients' population, as well. A limitation of the design of the aforementioned trials—including the PACIFIC trial—is that they did not take into consideration the patients who progressed during CRT or who did not recover from CRT. This also precludes a comparison with survival data from trials evaluating immunotherapy concurrent with CRT.Adjuvant combination immunotherapyCombining monoclonal antibodies with complementary mechanisms of action represents another strategy to maximize immunotherapy potential benefit and to overcome resistance to anti-PD-(L)1 antibodies (Figure 2). Another potential major benefit of double checkpoint inhibition may be the chance of a long-lasting response, as seen in stage IV disease.19Motzer R.J. Tannir N.M. McDermott D.F. et al.Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.N Engl J Med. 2018; 378: 1277-1290Crossref PubMed Scopus (2229) Google Scholar, 20Larkin J. Chiarion-Sileni V. Gonzalez R. et al.Five-year survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med. 2019; 381: 1535-1546Crossref PubMed Scopus (1354) Google Scholar, 21Baas P. Scherpereel A. Nowak A.K. et al.First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.Lancet. 2021; 397: 375-386Abstract Full Text Full Text PDF PubMed Scopus (276) Google ScholarFigure 2Ipilimumab is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor, which favors the CD80/CD86–CD28 binding and T-cell activation. Pembrolizumab, nivolumab, sugemalimab, durvalumab and atezolizumab are anti-PD-(L)1 antibodies, which block the interaction between PD-L1 and PD-1. Tiragolumab inhibits the T-cell immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibition motif domain (TIGIT), which is expressed on T cells—CD8+, natural killer (NK) and T regulatory cells (Tregs). Monalizumab is an Ig targeting NKG2A receptors on NK and T cells. Oleclumab is an anti-CD73 monoclonal antibody, which promotes antitumor immunity by reducing adenosine levels. Canakinumab blocks IL-1β activity by blocking its interaction with the IL-1 receptor thus enhancing antitumor immune response. Bintrafusp alfa (M7824) is a bifunctional fusion protein targeting TGF-β and PD-L1.Show full captionAPC, antigen-presenting cells; IL-1, interleukin 1; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TGF-β, transforming growth factor-β.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Cytotoxic T-lymphocyte antigen 4 (CTLA-4) counteracts T-cell activation by inhibiting CD80/CD86 co-stimulation by antigen-presenting cells (APCs) in the tumor draining lymph nodes and within the tumor microenvironment (TME).22Seidel J.A. Otsuka A. Kabashima K. Anti-PD-1 and Anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations.Front Oncol. 2018; 8: 86Crossref PubMed Scopus (533) Google Scholar, 23Salvi S. Fontana V. 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