Consolidative nivolumab versus observation in unresectable stage III non-small cell lung cancer patients following neoadjuvant nivolumab plus chemotherapy and concurrent chemoradiotherapy (CA209-7AL): a randomized clinical trial

8008 Background: Enhancing clinical outcomes in resectable non-small cell lung cancer (NSCLC) has been associated with neoadjuvant or perioperative administration of nivolumab. However, the efficacy and safety of consolidation nivolumab versus observation following neoadjuvant chemotherapy plus nivolumab, hypofractionated radiotherapy and concurrent chemotherapy (hypo-CCRT) in patients with unresectable stage III NSCLC remain underexplored. Methods: Conducted as a randomized, multi-center, phase 2 trial in patients with unresectable stage IIIA-C NSCLC, this study enrolled individuals aged 18 to 75 with an ECOG performance status of 0 or 1. Neoadjuvant therapy consisted of docetaxel, cisplatin, and nivolumab (360mg every 3 weeks for 2 cycles), followed by hypo-CCRT. Patients without disease progression or G2+ pneumonitis after hypo-CCRT were randomly assigned to receive nivolumab (360 mg every 3 weeks for up to 12 months) or undergo observation. Randomization factors included age, sex, smoking history, and EGFR mutation status. The primary endpoint was progression-free survival (PFS) from randomization, with preplanned analysis results reported herein. The trial is registered with ClinicalTrials.gov, NCT04085250. Results: Between Dec 3rd, 2019, and Aug 18th, 2023, 264 patients underwent neoadjuvant therapy, 242 received hypo-CCRT, and 172 were randomly assigned to nivolumab consolidation (n = 86) or observation (n = 86) post hypo-CCRT. At the January 31, 2024, data cutoff, the median follow-up for all randomized patients was 22.8 months. Nivolumab consolidation exhibited significantly longer PFS compared to observation (median not reached vs. 12.2 months [95% CI 6.2-18.1]; hazard ratio 0.49 [95% CI 0.31-0.79], p = 0.002). The 12-month and 18-month PFS rates were 72.6% and 64.8% in the consolidation group, contrasting with 52.5% and 42.3% in the observation group. Grade 3-4 nonhematological adverse events occurred in 14.0% (37/264) during neoadjuvant therapy and hypo-CCRT. Following randomization, grade 3-5 adverse events occurred in 7.0% (6/86) with consolidation (G3 pneumonitis, 2.3%; G5 pneumonitis, 1.2%; G3 proximal bronchial tree toxicity, 3.5%) and 4.6% (4/86) with observation (G3 pneumonitis, 2.3%; G3 proximal bronchial tree toxicity, 2.3%). Conclusions: Consolidation with nivolumab after neoadjuvant chemotherapy plus nivolumab and hypo-CCRT demonstrates effectiveness and tolerability for patients with unresectable stage III NSCLC. Extended follow-up is essential for confirming these findings. Clinical trial information: NCT04085250 .

Systematic Review of Neoadjuvant Immunotherapy for Patients With Non–Small Cell Lung Cancer

Chemotherapy + PD-1/PD-L1 Blockade Should Be the Preferred Option in the Neoadjuvant Therapy of NSCLC

SY13-03: Neoadjuvant immunotherapy for operable non-small cell lung cancer: Lessons learned and current challenges

Patients with locally advanced non-small cell lung cancer (LA-NSCLC) usually bear high tumor burden and are not tolerated well to concurrent chemoradiation therapy (CRT) followed by consolidation immunotherapy. We investigated the feasibility of chemoimmunotherapy as induction therapy before CRT for LA-NSCLC. We retrospectively analyzed data from 91 patients with unresectable stage III NSCLC treated with either induction chemoimmunotherapy or chemotherapy before CRT. Tumor responses, survival statistics, and toxic effects were compared. The dosimetric parameters of the RT protocol were evaluated. The primary endpoint was progression-free survival (PFS). The overall response (ORR), the depth of response (DpR) were accessed at the end of CRT (ORRinduc+CRT, DpRinduc+CRT) and induction therapy (ORRinduc, DpRinduc). The median PFS (mPFS) were significantly longer in the chemoimmunotherapy induction group (13.5 months vs. 11.2 months; HR, 0.56; 95% CI, 0.32-0.97; p=0.036). The ORRinduc+CRT, median DpRinduc+CRT (mDpRinduc+CRT) and mDpRinduc were significantly higher in the chemoimmunotherapy induction group (ORRinduc+CRT, 84.0% vs. 65.9%, p=0.044; mDpRinduc+CRT, 49.5% vs. 39.0%, p = 0.012; mDpRinduc, 38.5% vs. 28.0%, p=0.044). Incidence of treatment-related adverse events (AE) was similar between groups, with myelosuppression being the most common grade ≥ 3 AE. Regarding radiotherapy, adopting a mapping strategy with a 5-8 mm margin for clinical tumor volume resulted in decreased radiation doses to critical organs in the chemoimmunotherapy induction group. Chemoimmunotherapy induction therapy before CRT improves efficacy with comparable incidence of AEs compared to chemotherapy induction in LA-NSCLC patients. Further studies are warranted to validate these findings.

e20569 Background: The study aimed to investigate the efficacy of integrating Thymosin into concurrent chemoradiotherapy (CCRT) and consolidative immunotherapy in unresectable locally advanced non-small cell lung cancer (LA-NSCLC). Methods: Ninety-one stage IIIA-IIIC LA-NSCLC patients enrolled from Jan 1, 2020, to Oct 31, 2022 were analyzed retrospectively. All patients received CCRT (total irradiation dose of 60Gy and weekly concurrent docetaxel and cisplatin) and consolidative immunotherapy (Nivolumab/Tislelizumab). Thymosin α1 (1.6 mg) was administered once a week from the start of treatment till 2 months after CCRT or till the last prescription of consolidative immunotherapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints included the overall survival (OS) and toxicity. Results: There were 31 patients who received Thymosin α1 till the last prescription of consolidative immunotherapy, 40 patients received Thymosin α1 till 2 months after CCRT and 20 patients without the administration of Thymosin α1. The median follow-up time was 28.3 months (range 8.2~31.6 months). The median PFS was 26.1 months in Thymosin α1+consolidative immunotherapy group, 15.3 months in Thymosin α1+CCRT group and 12.6 months in control group (P = 0.116). The median OS was not reached in Thymosin α1+consolidative immunotherapy group, 26 months in Thymosin α1+CCRT group and 16.5 months in control group (P = 0.046). The median courses of consolidative immunotherapy were 8 Thymosin α1+consolidative immunotherapy group, 6 in Thymosin α1+CCRT group and 3 in control group (P = 0.060). There were higher ≥grade 3 acute lymphopenia (62.3%) and acute grade 2 pneumonitis (8.0%) in the control group. The long-term use of Thymosin α1 was also found to be related to the lower level of IL-6(P = 0.048), CD 16+NK cells and CD56+NK cells (P = 0.043). Conclusions: The integration of Thymosin α1 into CCRT and consolidative immunotherapy could yield synergistic effect in LA-NSCLC patients. The combination might contribute to prolonged use of consolidative immunotherapy and survival benefit.

e17509 Background: Locally advanced and advanced cervical cancer (CC), characterized by extensive local invasion and potential distant metastasis, present substantial clinical challenges. Although concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced CC, a considerable proportion (23%-34%) of treated pts experienced recurrence or subsequent metastasis. Recently, neoadjuvant therapy (NAT) has been proposed to increase the radiosensitivity and decreases the fraction of hypoxic cells. Particularly, immunotherapy (IO)-based NAT has shown high activity in treating CC. Moreover, IO plus CRT has shown promise in enhancing both local control and systemic response. Hence, we analyzed the efficacy and safety of IO-based NAT followed by CCRT for locally advanced and advanced CC in a real-world setting. Methods: This study retrospectively analyzed data from pts with locally advanced and advanced CC who underwent IO-based NAT followed by CCRT at Shengjing Hospital of China Medical University from January 2022 to January 2024. Outcome measures included complete response (CR), partial response (PR), objective response rate (ORR), progression free survival (PFS), and safety. Tumor responses after neoadjuvant or CCRT therapy were evaluated using RECIST v1.1 and PFS was analyzed with the Kaplan-Meir method. Safety was assessed by adverse events (AEs) referring to CTCAEs v 5.0. Results: A total of 20 pts (median age 57 years, range, 39-72) were included in this analysis, with 15% at stage IIIB, 60% at IIIC, 10% at IVA, and 15% at IVB. Eight (40%) pts received 1 cycle of neoadjuvant IO, 8 (40%) received 1-4 cycles of neoadjuvant IO + chemotherapy, and 4 (20%) received 2 cycles of neoadjuvant IO + bevacizumab (Bev) + chemotherapy. After NAT, all 20 pts received CCRT. In the overall population, ORR after NAT was 55% (11/20), with 5% CR and 50% PR. Regarding different IO-based NAT regimens, objective responses were achieved in 1 of 8 (12.5%) pts receiving neoadjuvant IO, 6 of 8 (75%) pts receiving neoadjuvant IO + chemotherapy, and 4 of 4 (100%) pts receiving neoadjuvant IO + Bev + chemotherapy. After CCRT, 6 (30%) pts had a CR and 7 (35%) pts had a PR, resulting in an ORR of 65.0%. At a median follow-up of 14.9 months, the median PFS was not reached, with a 12-month and 24-month PFS rates of 68% and 56%, respectively. The most common treatment-related AEs during NAT were white blood cell count decreased (50%) and neutrophil count decreased. Conclusions: IO-based NAT followed by CCRT were effective and well-tolerated for pts with locally advanced and advanced CC. This treatment modalities may provide a potential therapeutic strategy for locally advanced and advanced CC.

Induction Immunotherapy vs. Consolidation Immunotherapy for Unresectable Stage III NSCLC

Introduction The outcome of high-risk stage III melanoma patients was poor with a 5-year overall survival (OS) rate of <50%. Adjuvant ipilimumab (IPI) improved the relapse-free survival (RFS) and OS, and adjuvant anti-PD-1 improved the RFS further. Preclinical data suggested that neoadjuvant therapy may be more effective than adjuvant therapy due to broader immune activation. The OpACIN trial compared neoadjuvant IPI plus nivolumab (NIVO) versus adjuvant IPI plus NIVO, while the subsequent OpACIN-neo trial tested three different dosing schedules of neoadjuvant IPI plus NIVO only. Neoadjuvant IPI plus NIVO induced high pathologic response rates of 74-78%. Here, we present the 36- and 18-months RFS update of the OpACIN and OpACIN-neo trial, respectively. Methods The phase 1b OpACIN trial randomized 20 stage IIIB/IIIC melanoma patients to receive either 4 cycles of adjuvant IPI 3 mg/kg plus NIVO 1 mg/kg or 2 cycles of neoadjuvant IPI plus NIVO at the same dose followed by 2 cycles adjuvant IPI plus NIVO. In the OpACIN-neo trial, 86 patients were randomized to 2 cycles neoadjuvant in arm A: 2x IPI 3 mg/kg plus NIVO 1 mg/kg q3w (n=30), arm B: 2x IPI 1 mg/kg plus NIVO 3 mg/kg q3w (n=30), and arm C: 2x IPI 3 mg/kg q3w followed immediately by 2x NIVO 3 mg/kg q3w (n=26). Pathologic response was defined as <50% viable tumor cells and centrally reviewed by a blinded pathologist. RFS rates were estimated using the Kaplan-Meier method. Results After a median follow-up of 36 months for the OpACIN and 18 months for the OpACIN-neo trial, only 1 of 71 patients (1.4%) with a pathologic response on neoadjuvant therapy had relapsed, versus 15 of 23 patients (65.2%) without a pathologic response. The estimated 3-year RFS rate for the neoadjuvant arm was 80% (95% CI: 59%-100%) versus 60% (95% CI: 36%-100%) for the adjuvant arm in the OpACIN trial. The median RFS was not reached in any of the arms within the OpACIN-neo trial. Estimated 18-months RFS rate was 85% (95% CI: 78%-93%) for all patients; for arm A 90% (95% CI: 80%-100%), for arm B 82% (95% CI: 70%-98%) and for arm C 83% (95% CI: 70%-100%). Translational analyses showed that tumor mutational burden and interferon-γ gene expression score at baseline, both separate and combined, can function as predictors of response. Conclusions OpACIN showed for the first time a potential benefit of neoadjuvant versus adjuvant immunotherapy, while OpACIN-neo confirmed the high pathologic response rates which can be achieved by neoadjuvant IPI plus NIVO. Both trials argue for pathologic response as a surrogate markers for RFS. Clinical trial information: NCT02437279, NCT02977052 Citation Format: Christian U. Blank, Judith M. Versluis, Elisa A. Rozeman, Alexander M. Menzies, Irene L. Reijers, Oscar Krijgsman, Esmée P. Hoefsmit, Bart A. van de Wiel, Karolina Sikorska, Carolien Bierman, Petros Dimitriadis, Maria Gonzalez, Annegien Broeks, Ron M. Kerkhoven, Andrew J. Spillane, John B. Haanen, Winan J. van Houdt, Robyn P. Saw, Hanna Eriksson, Alexander C. van Akkooi, Richard A. Scolyer, Ton N. Schumacher, Georgina V. Long. 36-months and 18-months relapse-free survival after (neo)adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma patients - update of the OpACIN and OpACIN-neo trials [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3412.

The aim of the study was to evaluate the toxicity and efficacy of 62 patients with locally advanced nasopharyngeal carcinoma (NPC) (stage III, IVA, IVB) treated by three different modalities. Cisplatin was given weekly 35 mg/m(2)/day or every 3 weeks 100 mg/m(2)/day during radiotherapy (RT) in all patients. Patients were classified into following three groups: The patients in the group 1 (n=23) were treated only with concurrent chemoradiotherapy (CCRT). In the group 2 (n=15), before the CCRT, neoadjuvant chemotherapy, consisting of intravenous cisplatin and docetaxel on day 1, every 3 weeks treatment cycles was administered. In the group 3 (n=24), adjuvant chemotherapy, consisting of cisplatin on day 1 and 5-fluorouracil on day 1 to 5 every 3 weeks was used after CCRT. Three arms were treated with the same RT technique and dose. There was no difference for age, sex, and stage among the groups. Radiotherapy was administered in planned dose for all patients. A total of 82% patients completed planned chemotherapy concurrent with RT. The treatment related adverse effects were mild or moderate in intensity. There was no statistical difference between the groups regarding the treatment responses. Complete response rate of RT was 73.9%, 86.7%, and 87.5%, respectively. Median progression free survival (PFS) and overall survival (OS) were 13, 12, 9 months and 22, 20, 15 months for groups 1, 2, 3, respectively. No difference was observed in median OS and PFS among three groups. In our study, the efficacy and toxicity of neoadjuvant and/or adjuvant chemotherapy with CCRT and CCRT alone were found similar.

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.

Comparison of Neoadjuvant Chemotherapy Plus Concurrent Chemoradiotherapy vs. Concurrent Chemoradiotherapy Alone in Locally Advanced Cervical Cancer Under 2018FIGO Staging Correction

Objective To compare the effectiveness of concurrent chemoradiotherapy and sequential chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC).Methods From March 2002 to October 2012,121 patients with stage Ⅲ NSCLC in Peking Union Medical College Hospital were enrolled into concurrent chemoradiotherapy group and sequential chemoradiotherapy group.Objective response rate (ORR),overall survival (OS),and progression-free survival (PFS) were compared between two groups.Enumeration data were analyzed by Chi-Square test,the mean of samples by t-test,and OS and PFS by Kaplan-Meier test.Results Among 121 patients with stage Ⅲ NSCLC,66 patients received concurrent chemoradiotherapy and 55 patients received sequential chemoradiotherapy.The median OS and PFS of the whole group were 23.1 and 10.7 months.In concurrent chemoradiotherapy group and sequential chemoradiotherapy group,ORR was 45.5％ and 16.4％,the disease control rate (DCR) was 84.8％ and 61.8％,the median OS was 33.4 and 19.7 months,and the median PFS was 12.7 and 9.8 months,there were significant differences between two groups (x2 =10.128,P ＜0.05).In concurrent chemoradiotherapy group,ten patients received surgery after chemoradiotherapy.The median OS and PFS did not arrival.Conclusions Compared with sequential chemoradiotherapy,concurrent chemoradiotherapy can significantly increase the ORR,DCR,OS,and PFS for patients with locally advanced NSCLC.Surgery after concurrent chemoradiotherapy may prolong the survival in carefully selected patients. Key words: Locally advanced non-small cell lung cancer; Concurrent chemoradiotherapy; Sequential chemoradiotherapy

9096 Background: Nivolumab (NIV) is a Programmed-cell-Death-1 inhibitor approved as 2nd line treatment for metastatic Non-Small Cell Lung Cancer (NSCLC). NIV mainly targets T(CD8) cells, whose functions and trafficking are regulated by circadian clocks (Nobis et al. PNAS 2019), hence suggesting possible dosing time-dependent changes in NIV efficacy. Methods: Consecutive metastatic NSCLC patients (pts) received single agent NIV (240 mg iv q 2 weeks) at a single institution. NIV timing slots were randomly allocated for each course by the day hospital coordinator on a logistics basis and recorded. The median NIV timing and its intra-pt coefficient of variation (CVar) were computed over the whole treatment span. The study population was split into two NIV timing groups based upon the median value of the median treatment times of all the pts. CTCAE-toxicity rates were compared between groups with c2 or Fisher exact. Progression free survival (PFS) and overall survival (OS) were compared between both NIV timing groups with Log Rank. Results: From 9/2015 to 11/2020, the study accrued 95 stage 4 NSCLC pts (males, 83%; PS 0-1, 96%), aged 41-83 years (median, 67). Primary histological types were adenocarcinoma (55 pts, 58%), squamous cell carcinoma (37 pts, 39%) or unspecified (3 pts, 3%). The pts had a median of 4 metastatic sites, including bone (52% of the pts), pleura (41%), liver (25%), brain (24%) and adrenal gland (20%). A total of 1818 NIV courses were given as 2nd line for 72 pts (76%), or as 3rd or later line for 22 pts (23%). Median PFS and OS (months, mo.) were 3.9 mo. [95% CL, 2.1 – 5.8], and 14.0 mo. [9.5 – 18.4] respectively, for the 95 pts. The majority of NIV administrations occurred between 9:27 and 12:54 for 48 pts (‘morning’ group) and between 12:55 and 17:14 for 47 pts (‘afternoon’ group), with intra-pt NIV timing CVar ranging from 2% to 21% (median, 10%). Main pts characteristics were similar for both groups, except for fewer females (8% vs 26%) and younger age (median, 66 vs 69 years) in the ‘morning’ group compared to the ‘afternoon’ one. Grade 3-4 fatigue, anorexia or myalgias were less in the ‘morning’ group compared with the “afternoon’ one (6% vs 15%; 2% vs 6%; 0% vs 4%, respectively). Strikingly, median PFS [95% CI] were 11.3 mo. [5.5 - 17.1] for the ‘morning’ group as compared to 3.1 mo. [1.5 - 4.6] for the ‘afternoon’ one (p<0.001). Median OS were 34.2 mo. [15.1 - 53.3] for the ‘morning’ group vs 9.6 mo. [4.9 - 14.4] for the ‘afternoon’ group (p<0.001). Multivariate analyses identified NIV ‘morning’ timing and 2nd line administration, as significant independent predictors of longer PFS and OS. Conclusions: NIV was both less toxic and four times as effective following ‘morning’ as compared to ‘afternoon’ dosing in this study in Stage 4 NSCLC pts, possibly as a result of dosing time-dependent pharmacology. Translational and clinical nivolumab timing validation studies are needed, in order to optimize pts benefits from cancer immunotherapy.

7557 Background: Concurrent chemoradiotherapy (CRT) is standard treatment for stage III NSCLC, although the management of resectable patients (pts) remains controversial. We report an open-label phase I/II trial of the epidermal growth factor receptor inhibitor E added to perioperative CRT for resectable stage III NSCLC pts, followed by maintenance (m) E. Methods: Eligible pts had stage IIIA/B NSCLC, PS 0–1, and were resectable as determined by a thoracic surgeon. Pts received weekly P (50 mg/m2), and C (AUC 2) with daily oral E for 28 days concurrent with twice daily thoracic radiation (1.5 Gy/fraction) to 30 Gy, followed by restaging. Non-progressors underwent resection followed by the same CRT regimen and 2 years of mE (150mg). The primary endpoint of the phase I portion was the maximum tolerated dose (MTD) of E given with CRT; and for the phase II was safety and tolerability. Secondary endpoints were pathologic complete response (pCR) rate, pathologic downstaging of mediastinal nodes, progression free survival (PFS), and overall survival (OS). Results: 9 pts were enrolled in the phase I trial. The MTD of E was150mg, which was the phase II dose used. 25 pts were treated in the phase II component: median age 60, 92% stage IIIA, 64% female, 72% PS 0, 64% adenocarcinoma, and 16% never smokers. The median duration of mE was 5.5 months, with the most common reason for discontinuation being pt preference. There was no grade 4 toxicity. Grade 3 toxicity seen in >5% of pts: rash (12%), diarrhea (9%), nausea (9%), and encephalopathy (6%). The most common toxicities during mE: grade 1/2 diarrhea (72%), rash (61%), fatigue (56%), nausea (22%), and dry eyes (17%).1 pt (4%) had a pCR after neoadjuvant CRT, and 46% were downstaged to pN0–1 at surgery. At a median follow-up of 36.5 mos the median PFS is 41.8 mos (95% CI 9.3-not yet reached). The median OS has not been reached. 3 year survival is 69%. Pts downstaged to pN0–1 vs those with persistent pN2–3 had a median PFS of 41.8 vs 18.1 mos (p=0.11). Conclusions: Perioperative P, C, and E given concurrently with HFRT was well tolerated and showed promising efficacy, while compliance was poor with maintenance E. [Table: see text]