Major Pathologic Response Rate Research Articles

Immuno-based conversion therapy for survival in initially unresectable locally advanced or oligometastatic gastric cancer: A retrospective real-world study with multi-omics analysis.

e16109 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) have shown certain effectiveness in resectable gastric cancer (GC), but the efficacy of conversion ICIs in initially unresectable locally advanced or oligometastatic GC is unclear, particularly regarding efficacy prediction and drug resistance mechanisms through multi-omics analysis. Methods: This is a single-arm, retrospective real-world study to evaluate the efficacy of ICI-containing neoadjuvant/conversion treatment for patients with unresectable locally advanced or oligometastatic GC. Primary endpoints included complete pathological response (pCR) rate, major pathological response (MPR) rate, and R0 resection rate. Secondary endpoints were overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and safety. Exploratory endpoint was the correlation between tumor genetic characteristics and treatment efficacy. Results: Of the 73 included patients, including 64.4% stage cIVa and 10.9% cIVb, 60 (82.2%) underwent radical surgery after conversion combination treatment. The pCR and MPR rates were 28.6% (95% CI 17.1–40.0%), 42.9% (95% CI 30.3–55.4%), with median DFS/PFS at 30.9 (95% CI 16.0-NA) and mOS at 41.3 (95% CI 23.9-NA) months. The stage IV patients achieved 76.4% R0 resection rate, 24.4% pCR rate, and 40.0% MPR rate, with significantly longer OS for R0 patients versus non-R0 ones (HR: 0.22, 95% CI 0.07-0.70, P = 0.0002), and 1-year OS rate 95.2% vs. 64.2%, the 2-year OS rates 71.1% vs. 9.2%, respectively. Even the mOS of stage IV nonMPR patients are significantly prolonged than that of nonR0 ones, indicating that the implementation of R0 surgery was more crucial than MPR. For stage IV patients of R0-MPR, R0-nonMPR and nonR0, the the 3-year OS rates were 85.0%, 51.3%, and near 0, respectively. Subgroup analysis identified significant correlations between pathological responses and pathological type, PD-L1 expression, and tumor mutational burden. The toxicity and post-surgery complications were manageable. Multi-omics analysis revealed that KMT2D mutations were associated with improved clinical outcomes and enhanced immune responses, while tumor cytochrome P450 was linked to treatment resistance. Additionally, an efficacy-predictive model PEMIT was established using an 8-gene panel and was confirmed to surpass common biomarkers such as PD-L1, tumor mutational burden, and mismatch repair status. Conclusions: ICIs-based neoadjuvant/conversion therapy demonstrated promising survival benefits and acceptable safety profiles for patients with unresectable locally advanced and oligometastatic GC, providing a valuable treatment option for this population. Multi-omics findings uncovered mechanisms of drug resistance and provided potential efficacy-related biomarkers.

Immuno-based conversion therapy for survival in initially unresectable locally advanced or oligometastatic gastric cancer: A retrospective real-world study with multi-omics analysis.

e16109 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) have shown certain effectiveness in resectable gastric cancer (GC), but the efficacy of conversion ICIs in initially unresectable locally advanced or oligometastatic GC is unclear, particularly regarding efficacy prediction and drug resistance mechanisms through multi-omics analysis. Methods: This is a single-arm, retrospective real-world study to evaluate the efficacy of ICI-containing neoadjuvant/conversion treatment for patients with unresectable locally advanced or oligometastatic GC. Primary endpoints included complete pathological response (pCR) rate, major pathological response (MPR) rate, and R0 resection rate. Secondary endpoints were overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and safety. Exploratory endpoint was the correlation between tumor genetic characteristics and treatment efficacy. Results: Of the 73 included patients, including 64.4% stage cIVa and 10.9% cIVb, 60 (82.2%) underwent radical surgery after conversion combination treatment. The pCR and MPR rates were 28.6% (95% CI 17.1–40.0%), 42.9% (95% CI 30.3–55.4%), with median DFS/PFS at 30.9 (95% CI 16.0-NA) and mOS at 41.3 (95% CI 23.9-NA) months. The stage IV patients achieved 76.4% R0 resection rate, 24.4% pCR rate, and 40.0% MPR rate, with significantly longer OS for R0 patients versus non-R0 ones (HR: 0.22, 95% CI 0.07-0.70, P = 0.0002), and 1-year OS rate 95.2% vs. 64.2%, the 2-year OS rates 71.1% vs. 9.2%, respectively. Even the mOS of stage IV nonMPR patients are significantly prolonged than that of nonR0 ones, indicating that the implementation of R0 surgery was more crucial than MPR. For stage IV patients of R0-MPR, R0-nonMPR and nonR0, the the 3-year OS rates were 85.0%, 51.3%, and near 0, respectively. Subgroup analysis identified significant correlations between pathological responses and pathological type, PD-L1 expression, and tumor mutational burden. The toxicity and post-surgery complications were manageable. Multi-omics analysis revealed that KMT2D mutations were associated with improved clinical outcomes and enhanced immune responses, while tumor cytochrome P450 was linked to treatment resistance. Additionally, an efficacy-predictive model PEMIT was established using an 8-gene panel and was confirmed to surpass common biomarkers such as PD-L1, tumor mutational burden, and mismatch repair status. Conclusions: ICIs-based neoadjuvant/conversion therapy demonstrated promising survival benefits and acceptable safety profiles for patients with unresectable locally advanced and oligometastatic GC, providing a valuable treatment option for this population. Multi-omics findings uncovered mechanisms of drug resistance and provided potential efficacy-related biomarkers.

Biomarker analysis and updated clinical outcomes: Neoadjuvant systemic treatment (NST) with nivolumab (nivo) and relatlimab (rela) in surgically resectable melanoma.

9587 Background: NST with immune checkpoint blockade (ICB) improves clinical outcomes over upfront surgery followed by adjuvant treatment (tx) in patients (pts) with stage III, surgically resectable melanoma. The NST platform also provides an opportunity for deep translational analysis to identify baseline (BL) biomarkers predicting pathologic response and to gain insights into resistance. BL biomarkers, including gene expression signatures (GES) such as IFN-γ/ tumor mutational burden, tumor infiltrating lymphocytes, and presence of tertiary lymphoid structures, have been associated with pathologic response to NST with anti-PD1 and/or anti-CTLA4 antibodies. These studies have not evaluated the newest ICB combination, nivo (anti-PD1) + rela (anti-LAG3), which achieved a major pathologic response rate (MPR) (≤10% viable tumor) of 63% in a Ph II study (NCT02519322). Here we report GES analysis from BL and longitudinal tumor tissues obtained on this study and correlations with outcomes. Methods: Longitudinal tissue was collected from 30 pts treated on the clinical trial and available RNA analyzed using the NanoString nCounter PanCancer IO360 panel. Clinical outcomes, including recurrence and event-free survival, were also updated with longer follow-up. Pts were grouped into MPR and non- major pathologic responders (non MPR). Normalization, differential expression / GES evaluation was performed using nSolver Advanced Analysis software. Differential expression is fit on a per signatures basis using a linear model for analysis. P-values were adjusted within each analysis and on the grouping variable level difference t-test using the Benjamini and Yekutieli False Discovery Rate adjustment to account for correlations amongst the tests. BL analysis was grouped based on pathologic response, MPR vs non-MPR. Results: Of the 30 pts (median follow up 44 months), 53 RNA samples from 26 patients (9 NR and 17 R) were included in the full analysis. Immune GES with significantly higher (adjusted p< 0.05) differences at BL in MPR vs non-MPR included: B cells, CD45, CD-8+ T cells, TIGIT, IDO1, and IFN-γ. Significantly higher B7-H3 GES at BL was associated with non MPR. Additional analyses (i.e., cell population changes over time) and association with event outcomes are underway. Conclusions: To our knowledge, this is the first longitudinal RNA analysis reported from pts treated with nivo+rela. BL immune features associated with major pathologic response include higher GES of B cells, CD45+ cells, CD8 T cells, and increased expression of TIGIT, IDO and IFN-y. Additionally, higher B7-H3 in non MPR pts may indicate a clinically actionable strategy for further evaluation. Ongoing analyses of longitudinal samples and correlations with clinical outcomes are underway and will be presented. Clinical trial information: NCT02519322 .

Neoadjuvant serplulimab in combination with concurrent chemoradiotherapy for locally advanced, resectable esophagogastric junction adenocarcinoma.

e16103 Background: Surgery combined with perioperative therapy was recommended as standard treatment for patients with locally advanced esophagogastric junction (EGJ) adenocarcinoma, but the survival rate was still poor. Immunotherapy has shown antitumor activity and an acceptable safety profile in advanced EGJ cancer. The aim of this study was to evaluate the efficacy and safety of neoadjuvant Serplulimab combined with concurrent chemoradiotherapy in previously untreated locally advanced resectable EGJ adenocarcinoma. Methods: Eligible patients with resectable EGJ(Siewert Type II and Type III, Siewert classification 2000)adenocarcinoma stage cT3-4 or N+ were enrolled. Patients received neoadjuvant Serplulimab (300mg on day 1) plus SOX(oxaliplatin at 130mg/㎡on day 1; TS1 40-60mg two times per day on D1-D14, Q3W) in first cycle, followed by Serplulimab (300mg on day 1) combined with concurrent chemoradiotherapy (Reduced SOX regimen: oxaliplatin at 100mg/㎡on day 1, TS1 40-60mg two times per day on D1-D14, Q3W; Radiotherapy dose:45Gy in 25f) in second and third cycle. The patient finished the preoperative treatment and rested for 6-8 weeks for surgery. The primary endpoint was pathological complete response (pCR) rate. Secondary endpoints were major pathological response(MPR) rate, R0 resection rate, objective response rate(ORR), disease-free survival(DFS), overall survival(OS), and toxicity. Results: From March 8, 2023 to January 31,2024,15 patients were enrolled. Nine patients completed neoadjuvant therapy. Eight of these patients underwent radical surgical resection. One out of nine achieved a confirmed pathological complete response (pCR) after three cycles of neoadjuvant treatment. Additionally, two out of nine patients achieved major pathological response(MPR). So, the pCR rate was 11.1%, and the MPR rate was 22.2%. The Tumor and Lymph Nodes downstaging rates are 62.5% and 87.5%, respectively. The median DFS and OS were not reached. In terms of safety, fifteen patients who received at least one cycle of neoadjuvant therapy were included. The most common treatment-related adverse events(TRAE) across all grades were nausea/vomiting(6/15), anorexia(5/15), thrombocytopenia(4/15), and fatigue(4/15). Four patients (26.7%) had grade≥3 adverse events during preoperative therapy, with thrombocytopenia(3/15) and hepatic veno-occlusive disease(1/15). Immune-related adverse reactions(irAE) included myositis(1/15) and rash(1/15), both were grade 1. No grade 4 or higher TRAEs were observed. Conclusions: Initial benefits were demonstrated when using Serplulimab with concurrent chemoradiotherapy for the treatment of locally advanced, resectable EGJ adenocarcinoma patients. The efficacy and safety of Serplulimab with chemoradiotherapy will be further investigated in this trial later. Clinical trial information: NCT05918419 .

Neoadjuvant serplulimab in combination with concurrent chemoradiotherapy for locally advanced, resectable esophagogastric junction adenocarcinoma.

e16103 Background: Surgery combined with perioperative therapy was recommended as standard treatment for patients with locally advanced esophagogastric junction (EGJ) adenocarcinoma, but the survival rate was still poor. Immunotherapy has shown antitumor activity and an acceptable safety profile in advanced EGJ cancer. The aim of this study was to evaluate the efficacy and safety of neoadjuvant Serplulimab combined with concurrent chemoradiotherapy in previously untreated locally advanced resectable EGJ adenocarcinoma. Methods: Eligible patients with resectable EGJ(Siewert Type II and Type III, Siewert classification 2000)adenocarcinoma stage cT3-4 or N+ were enrolled. Patients received neoadjuvant Serplulimab (300mg on day 1) plus SOX(oxaliplatin at 130mg/㎡on day 1; TS1 40-60mg two times per day on D1-D14, Q3W) in first cycle, followed by Serplulimab (300mg on day 1) combined with concurrent chemoradiotherapy (Reduced SOX regimen: oxaliplatin at 100mg/㎡on day 1, TS1 40-60mg two times per day on D1-D14, Q3W; Radiotherapy dose:45Gy in 25f) in second and third cycle. The patient finished the preoperative treatment and rested for 6-8 weeks for surgery. The primary endpoint was pathological complete response (pCR) rate. Secondary endpoints were major pathological response(MPR) rate, R0 resection rate, objective response rate(ORR), disease-free survival(DFS), overall survival(OS), and toxicity. Results: From March 8, 2023 to January 31,2024,15 patients were enrolled. Nine patients completed neoadjuvant therapy. Eight of these patients underwent radical surgical resection. One out of nine achieved a confirmed pathological complete response (pCR) after three cycles of neoadjuvant treatment. Additionally, two out of nine patients achieved major pathological response(MPR). So, the pCR rate was 11.1%, and the MPR rate was 22.2%. The Tumor and Lymph Nodes downstaging rates are 62.5% and 87.5%, respectively. The median DFS and OS were not reached. In terms of safety, fifteen patients who received at least one cycle of neoadjuvant therapy were included. The most common treatment-related adverse events(TRAE) across all grades were nausea/vomiting(6/15), anorexia(5/15), thrombocytopenia(4/15), and fatigue(4/15). Four patients (26.7%) had grade≥3 adverse events during preoperative therapy, with thrombocytopenia(3/15) and hepatic veno-occlusive disease(1/15). Immune-related adverse reactions(irAE) included myositis(1/15) and rash(1/15), both were grade 1. No grade 4 or higher TRAEs were observed. Conclusions: Initial benefits were demonstrated when using Serplulimab with concurrent chemoradiotherapy for the treatment of locally advanced, resectable EGJ adenocarcinoma patients. The efficacy and safety of Serplulimab with chemoradiotherapy will be further investigated in this trial later. Clinical trial information: NCT05918419 .

Preoperative nivolumab plus SOX in patients with locally advanced gastric or gastro-esophageal junction cancer: A phase 2, single-arm trial.

4074 Background: Preoperative chemotherapy has been widely recommended in patients with locally advanced gastric or gastro-esophageal junction cancer (GC/GEJC), and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. We conducted a single-arm phase II trial (Stimulate-01) to evaluate the efficacy and safe of the anti-PD-1 antibody nivolumab plus SOX regimen in patients with locally advanced GC/GEJC and to explore the biomarker associated with therapy response. Methods: Patients with locally advanced GC/GEJC (cT3-4N+M0) were enrolled and received either 3 preoperative and 3 postoperative cycles of nivolumab (360 mg, IV, d1, Q21d) plus SOX regimen (oxaliplatin 130 mg/m2, IV, d1 with oral S-1 40-60mg, bid, d1-d14, Q21d) therapy, followed by 11 cycles of nivolumab monotherapy. The primary endpoint was the pathological complete response (pCR) rate, while the major pathological response rate (mPR), 3-year-DFS and 3-year-OS as the second endpoint. This clinical trial was registered at Clinicaltrial.gov (NCT05739045). In addition, tissue sample before and after treatment from patients were performed scRNA-seq. Results: Forty-six patients were enrolled from November 2022 to March 2023, with a median age of 66 years (range, 34-74), and 38 were male. The pCR rate was 28.26% [95% confidence interval (CI), 15.2%-41.3%], and the major pathologic response (mPR) [tumor regression grade (TRG)0/1] rate was 41.3% (95% CI, 27.1%-55.5%). All the patients underwent R0 resection. The mPR rate in patients with PD-L1 CPS ≥5 and patients with PD-L1 CPS<5 was 42.86% vs 38.89% ( P= 0.790). In addition, This clinical study period spans from epidemic control to full liberalization in China. The mPR rate in patients infected with COVID-19 was 44.44% (12/27), while the mPR rate in patients who have not been infected with COVID-19 was 36.84% (7/19) ( P=0.146). There were no severe complications or death related to the surgery. The scRNA-seq data revealed that the composition of MHC-II (HLA-DRA, HLA-DPA1, HLA-DRB1, HLA-DPB1 and HLA-DQB1) were significantly over-expressed in cancer cell of treatment-sensitive patients (TRG0/1) compared to that of treatment-insensitive patients (TRG2/3). Then the MHC-II expression in pre-treatment biopsy samples from 240 GC patients who received preoperative immunotherapy plus chemotherapy were performed by immunohistochemistry. The results showed that the mPR rate in patients with MHC-II IHC ≥2 and patients with MHC-II IHC<2 was 58.87% (83/141) vs 21.21% (21/99) ( P<0.001). Conclusions: Nivolumab plus SOX as neoadjuvant therapy showed an encouraging pCR rate, mPR rate, and manageable safety. The long-term efficacy of this combination of regimens will be continued to follow up. In addition, the MHC-II expression may be a potential biomarker for predicting the effectiveness of immunotherapy combined with chemotherapy for GC/GEJC. Clinical trial information: NCT05739045 .

A phase 2 study of de-escalation in resectable, locally advanced cutaneous squamous cell carcinoma (cSCC) with the use of neoadjuvant pembrolizumab: De-Squamate.

9514 Background: Neoadjuvant anti-Programmed Death therapy has shown a 64% complete or major pathological response rate in patients (pts) with resected stage II-IV(M0) cSCC. The De-Squamate study (NCT05025813) evaluated the feasibility of a risk adapted surgical de-escalation approach guided by clinical, radiological and pathological response in resectable cSCC pts of all sites receiving neoadjuvant pembrolizumab. Methods: This multi-centre, open-labelled, non-randomised, single-arm phase 2 study evaluated the response of neoadjuvant Pembrolizumab for 4 cycles administered IV 200mg Q3W in immunocompetent pts with Stage II-IV (M0) resectable cSCC. Pts underwent CT/MRI and 18F-FDG-PET imaging at baseline and following completion of neoadjuvant pembrolizumab. In those with a complete metabolic response, mapping biopsies of target site(s) were performed and if negative for residual SCC (clinical complete response [CCR]), surgery and post operative radiation therapy (PORT) were omitted. Patients with clinical or radiological residual disease/ positive mapping biopsy underwent surgical resection. PORT was de-escalated if there was a pathological complete response (PCR - no residual tumour cells) or major pathological response (MPR - less than or equal to 10% viable tumour cells). Pts proceeded to 13 cycles of maintenance Pembrolizumab. The primary endpoint was the combined rate of PCR, MPR and CCR following neoadjuvant Pembrolizumab and secondary endpoint includes treatment de-escalation and safety. Results: All 27 patients were enrolled and received a minimum of 2 cycles of neoadjuvant Pembrolizumab. The primary endpoint was observed in 17 patients (63%, 95% CI: 42-80), comprised of PCR (15%), MPR (0%) and CCR (48%). De-escalation of both surgery and PORT was achieved in 48% and a further 15% avoided PORT alone. With a minimum follow up of 6 months, no pts with PCR/MPR/CCR recurred. Investigator assessed treatment-related adverse events ≥ grade 3 was seen in 2 patients (7%). Conclusions: Pembrolizumab led to a high rate of PCR and CCR in resectable cSCC. The de-squamate study design effectively selected pts for surgical and PORT de-escalation and demonstrated a sustained response in this cohort. Clinical trial information: NCT05025813 .

Neoadjuvant chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine for locally advanced esophageal squamous cell carcinoma: A prospective phase II trial.

4087 Background: Surgery-based combination therapy is the current primary treatment for nonmetastatic esophageal squamous cell carcinoma (ESCC). An increasing number of results indicate that neoadjuvant chemotherapy alone might be a choice for perioperative treatment. Previously, a retrospective study we conducted showed that neoadjuvant chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine (referred to as the APCC regimen) for locally advanced ESCC had achieved promising results. To further confirm the efficacy of this regimen, we conducted this prospective phase II clinical study. Methods: Patients (pts) with locally advanced ESCC (cT2N+M0, cT3-4aNanyM0) received preoperative chemotherapy with the APCC regimen (albumin-bound paclitaxel 125 mg/m2 iv, day 1/8, cisplatin 60 mg/m2 iv day 1, and capecitabine 1750 mg/m2 po bid day 1-14, repeated every 21 days for 4 cycles). The primary endpoint was pathological complete response (pCR), and the secondary endpoints were major pathological response (MPR), the R0 resection rate, disease free survival (DFS), overall survival (OS), and safety. Results: A total of 82 pts were enrolled and all received 4 cycles of preoperative APCC regimen. Of the 80 (97.6%) pts who underwent surgery, the R0 resection rate was 100%, pCR was observed in 23 (28.7%) pts and 50 (62.5%) pts had an MPR. Postoperative pathology revealed that 42 (52.5%) pts had stage I (ypT0-2N0M0). The most common grade 3/4 adverse events of chemotherapy included neutropenia (25%), leukopenia (14.5%), nausea (7.5%) and peripheral neurotoxicity (5.5%). No neoadjuvant chemotherapy related, or perioperative death occurred. As of December 1, 2023, with a median follow-up time of 36.8 months, 16(19.5%) patients had recurrent disease, among which 8 (8.5%) pts had local recurrence, 10 (12.2%) pts had distant metastasis. The 3-year DFS rate was 79.4%. As of the last follow-up, eight pts died, and the 3-year survival rate was 88.8%. Conclusions: The results meet our initial aim that preoperative chemotherapy with albumin-bound paclitaxel, cisplatin and capecitabine is highly active and resulted in a considerable pCR and MPR rate with promising 3-year survival rate in pts with locally advanced ESCC, while well-tolerated. This triplet regimen could be another effective neoadjuvant treatment strategy for locally advanced ESCC. Clinical trial information: NCT04390958 .

Analysis of neoadjuvant nivolumab and ipilimumab for clinical stage III melanoma using the SWOG S1801 event-free survival definition.

e21563 Background: Perioperative pembrolizumab to advanced melanoma, as shown SWOG S1801 trial, was associated with a longer event-free survival (EFS) than those who received adjuvant pembrolizumab (EFS at 2y: 72% vs 49%, respectively). EFS, as defined in this trial, encompasses important factors related to neoadjuvant therapy in clinical practice. So far, there is no data of EFS rate for melanoma patients(pts.) treated with neoadjuvant nivolumab and ipilimumab, which is associated with more response rate but also more toxicity. Methods: We conducted a retrospective analysis of pts. with clinical stage III melanoma treated with neoadjuvant nivolumab 3mg/kg + ipilimumab 1 mg/kg (N3+I1) for two cycles followed by surgery and adjuvant therapy at AC Camargo Cancer Center. We applied the SWOG S1801 EFS definition (which includes inability to receive surgery, to start adjuvant therapy, melanoma recurrence and death) to this cohort. Results: Between Jan 2019 and Jan 2024, 37 pts. with clinical stage III melanoma treated with neoadjuvant N3+I1 were identified. Gender: 25 males (67%), median age (years): 58 (range: 31-78), BRAFV600 mut: 25(67%), Stage AJCC 8th edition: IIIB = 23 (62%), IIIC = 12 (32%), IIID = 2(6%). G3/G4 immune-related adverse events (irAE): 11 patients (30%). Two out 37 pts. did not complete the programmed neoadjuvant cycles due to toxicity (1 = colitis, 1 = myositis). Three pts. (8%) were unable to receive surgery: irAE = 1, metastatic disease = 2. All pts. who underwent surgery (n = 35) achieved R0 resection and started adjuvant therapy within 84-days after the procedure. Major pathological response (MPR) = 23 pts(66%) and non-MPR = 12 pts.(34%). There were 4 melanoma relapses after starting adjuvant therapy (11%). The total number of events was 7 (19%). In a median follow-up of 16.1 months(range:13.9-25), the landmark analysis of EFS at 2 years was 73% (95%CI, 49 to 87). Relapse-free survival(RFS) for MPR at 2 years: 96%. Conclusions: Neoadjuvant N3+I1 seems to have similar EFS compared to SWOG S1801, but numerically more MPR rate and fewer events of progression, relapse and/or death. [Table: see text]

Induction therapy with PD-1 antibody combined with platinum-based doublet chemotherapy for locally-advanced non-small cell lung cancer: A randomised controlled, open-label, phase 2 trial.

8044 Background: Chemoradiotherpay plus immunotherapy is recommended for unresectable locally-advanced non-small cell lung cancer (NSCLC) based on PACIFIC trial. However, it is unclear whether surgery can provide survival benefit for patients with tumors initially unresectable transformed into resectable ones after chemoimmunotherapy. This trial aims to investigate the efficacy and safety of the therapeutic regimen of chemoimmunotherapy plus surgery or radiotherapy. Methods: Patients with unresectable stage IIIB-IIIC NSCLC were enrolled to receive 4 cycles (q21d) of PD-1 antibody (Serplulimab, 4.5mg/kg) and platinum-based doublet chemotherapy. After the induction therapy, those with disease downstaged to IIIA or lower stage and resectable were randomized to receive radical surgery or radiotherapy with a ratio of 1:1, and those with stage IIIB or higher stage or unresectable disease after induction therapy were then treated by oncologists. Primary endpoint was event-free survival (EFS). Secondary endpoints included objective response rate (ORR), major pathologic response (MPR), pathologic complete response (pCR), progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), R0 rate of resection, severe adverse event (SAE) rate, and health related quality of life (HRQol). Preliminary short-term results were collected. Results: One hundred patients will be enrolled as planned, and a total of 82 patients were enrolled by the data cutoff date (January 6, 2024). Fifty-four and 28 patients were diagnosed with stage IIIB and IIIC disease, respectively. The percentage of squamous carcinomas, adenocarcinomas, and NSCLCs not otherwise specified were 68.3% (56/82), 15.9% (13/82), and 15.9% (13/82), respectively. ORR in 73 evaluable patients was 74.0% (54/73). Twenty-six of them are still in induction therapy phase, and the other 47 and 9 patients received 4 cycles and 1-3 cycles of induction therapy, respectively. Thirty-one patients had downstaged and resectable disease after 4 cycles of induction therapy, and 26 of them were randomized to arm A (n = 13) and arm B (n = 13), and 5 refused randomization (3 received surgery). One patient received surgery after 2 cycles of induction therapy. In 56 patients finished 1-4 cycles of induction therapy, the rate of conversion to resectability was 57.1% (32/56). In total, 17 patients received surgery, and the MPR and pCR rate in 16 evaluable patients were 62.5% (10/16) and 31.3% (5/16), respectively. The grade 3-5 adverse event rate in 56 patients finished induction therapy was 50.0% (28/56). One patient died of immune-related pneumonia. Conclusions: Induction therapy with PD-1 antibody (Serplulimab) and chemotherapy could transform half of unresectable stage IIIB-IIIC NSCLC into resectable, and the efficacy and safety were satisfactory. Clinical trial information: NCT05766800 .

PD-1 blockade plus chemotherapy followed by concurrent SBRT with SIB as preoperative therapy for patients with potentially resectable pancreatic cancer: A single-arm phase 2 study.

e16312 Background: Pancreatic cancer has 10% low rate of early diagnosis and resection due to its insidious onset and poor prognosis. We aimed to assess the safety and efficacy of a new mode of preoperative therapy for patients with Potentially Resectable Pancreatic Cancer. Methods: This is a single arm clinical trial (NCT05634564). Gemcitabine (1000 mg/m2) and nabpaclitaxel (125 mg/m2; AG) were administered to patients with LAPC or BRPC on days 1 and 8, along with tislelizumab (200 mg) on day 1 intravenously (IV) every three weeks. Concurrently, the patients underwent stereotactic body radiotherapy (SBRT) with simultaneous integrated boost (SIB)during the third cycle of treatment. Surgical intervention was reassessed after four cycles of treatment. Objective response rate (ORR) was the primary endpoint and Disease control rate (DCR), R0 resection rate, median overall survival (mOS), median progression free survival (mPFS) rate, time to progression (TTP) and safety were analyzed as secondary endpoints. Results: Between May 2020 and April 2023, 62 patients with LAPC or BRPC were enrolled. Until the last follow-up time (January 30, 2024) ,56 of them included in the intention-to-treat (ITT) analysis who completed at least three cycles of tislelizumab plus AG and underwent concurrent radiotherapy. The median age in intention-to-treat analysis was 65 years. 25 patients had a best response of partial response, the ORR was 44.6%, DCR was 100%. Thirty-one patients met the criteria for surgical resection after treatment, 9 of whom refused surgery and continued conservative treatment. 22 patients underwent resection, and the R0 resection rate was 95.45%. Two of the 22 resected patients achieved pathologic complete response (pCR) and five patients achieved major pathological response (MPR). The pathologic complete response rate was 9.10% and significant pathological response rate was 31.82%. The TTP was 19.38 months (95% CI: 12.8%-27.9%), and the mOS was 21.32 months (95% CI:15.9%-NR). The 12-months PFS rate and 12-months OS rate were 59.9% (95% CI:45.2%-71.8%) and 74.4% (95% CI:59.9%-84.3%), respectively. Grade 5 adverse events were not observed. The most common grade 3-4 hematological and non-hematological toxicities were leukopenia (17.9%), neutropenia (16.1%), anemia (8.9%), thrombocytopenia (7.1%), rash: dermatitis (7.1%), Peripheral neuropathy (3.6%). Conclusions: Anti-PD-1 inhibitor tislelizumab plus AG chemotherapy followed by concurrent SBRT with SIB significantly prolonged mPFS rate, as well as R0 resection rate of surgical patients, and also improved the major pathological response rate. Clinical trial information: NCT05634564 .

The safety and efficacy of neoadjuvant immunochemotherapy following laparoscopic gastrectomy for gastric cancer: a multicenter Real-world clinical study.

The safety and efficacy of neoadjuvant immunochemotherapy (nICT) for locally advanced gastric cancer (LAGC) remain controversial. Patients with LAGC who received either nICT or neoadjuvant chemotherapy (nCT) at 3 tertiary referral teaching hospitals in China between January 2016 and October 2022 were analysed. After propensity-score matching (PSM), comparing the radiological response, pathological response rate, perioperative outcomes, and early recurrence between the two groups. After PSM, 585 patients were included, with 195 and 390 patients comprising the nICT and nCT groups, respectively. The nICT group exhibited a higher objective response rate (79.5% versus [vs.] 59.0%; P<0.001), pathological complete response rate (14.36% vs. 6.41%; P=0.002) and major pathological response rate (39.49% vs. 26.15%; P=0.001) compared with the nCT group. The incidence of surgical complications (17.44% vs. 16.15%, P=0.694) and proportion of perioperative textbook outcomes (80.0% vs. 81.0%; P=0.767) were similar in both groups. The nICT group had a significantly lower proportion of early recurrence than the nCT group (29.7% vs. 40.8%; P=0.047). Furthermore, the multivariable logistic analysis revealed that immunotherapy was an independent protective factor against early recurrence (odds ratio 0.62 [95% CI 0.41-0.92]; P=0.018). No significant difference was found in neoadjuvant therapy drug toxicity between the two groups (51.79% vs. 45.38%; P=0.143). Compared with nCT, nICT is safe and effective, which significantly enhanced objective and pathological response rates, and reduced the risk for early recurrence among patients with LAGC. Clinical Trials.gov.

Clinical factors and major pathological response after neoadjuvant chemoimmunotherapy in potentially resectable lung squamous cell carcinoma.

Major pathological response (MPR) helps evaluate the prognosis of patients with lung squamous cell carcinoma (LUSC). However, the clinical factors that affect the achievement of MPR after neoadjuvant chemoimmunotherapy (NCIO) in patients with LUSC remain unclear. This study aimed to explore the clinical factors affecting the MPR after NCIO in patients with potentially resectable LUSC. This retrospective study included patients with stage IIB-IIIC LUSC who underwent surgical resection after receiving NCIO at a center between March 2020 and November 2022. In addition to the postoperative pathological remission rate, sex, age, body mass index (BMI), smoking history, TNM stage, hematological and imaging test results, and other indicators were examined before NCIO. According to the pathological response rate of the surgically removed tumor tissue, the patients were split into MPR and non-MPR groups. In total, 91 LUSC patients who met the study's eligibility criteria were enrolled: 32 (35%) patients in the non-MPR group and 59 (65%) in the MPR group, which included 43 cases of pathological complete remission (pCR). Pre-treatment lymphocyte level (LY) (odds ratio [OR] =5.997), tumor burden (OR=0.958), N classification (OR=15.915), radiographic response (OR=11.590), pulmonary atelectasis (OR=5.413), and PD-L1 expression (OR=1.028) were independently associated with MPR (all P < 0.05). Based on these six independent predictors, we developed a nomogram model of prediction having an area under the curve (AUC) of 0.914 that is simple to apply clinically to predict the MPR. The MPR group showed greater disease-free survival (DFS) than the non-MPR group, according to the survival analysis (P < 0.001). The MPR rate of NCIO for potentially resectable LUSC was 65%. LY, tumor burden, N classification, radiographic response, pulmonary atelectasis, and PD-L1 expression in patients with LUSC before NCIO were the independent and ideal predictors of MPR. The developed nomogram demonstrated a good degree of accuracy and resilience in predicting the MPR following NCIO, indicating that it is a useful tool for assuring customized therapy for patients with possibly resectable LUSC.

Phase Ⅱ clinical trial of PD-1 inhibitor combined with chemotherapy for locally advanced resectable oral squamous cell carcinoma

Objective: To explore the effectiveness and safety of programmed death 1(PD-1) inhibitory combined with chemotherapy as a neoadjuvant therapy for locally advanced resectable oral squamous cell carcinoma. Methods: This study was a randomized controlled phase Ⅱ trial. Patients recruited from Tianjin Medical University Cancer Institute and Hospital from July 2021 to February 2023 were randomly divided into two groups in a 1∶1 ratio: the experimental group (Toripalimab combined with albumin paclitaxel and cisplatin) and the control group (albumin paclitaxel and cisplatin); patients in both groups underwent three cycles of neoadjuvant therapy. After completion of neoadjuvant therapy, patients were evaluated and subsequent surgical treatment was performed. According to the completion of treatment, the analysis was conducted on both the full analysis set and the protocol set. The effectiveness and safety of treatments were evaluated. SPSS 20.0 software was used for statistical analysis. Results: A total of 41 cases with oral cancer were enrolled, including 26 males and 15 females, aged between 34 and 74 years old. There were 23 cases in the experimental group and 18 cases in the control group. A total of 23 cases completed neoadjuvant therapy and surgery according to the protocol. Experimental group and control group showed respectively the complete response rates of 1/19 and 0/17, the partial response rates of 13/19 and 8/17, the stage-down rates of 4/19 and 3/17, the pathologic complete response rate of 8/14 and 2/9, with no statistically significant differences in individual rates between two groups (P>0.05). The major pathological response rate of 13/14 in experimental group was higher than that of 2/9 in control group (P<0.05). The incidence of grade 3-4 adverse reactions related to treatment was low in both groups (4/23 vs. 3/18, χ2=0.13, P=0.72), and the most common serious adverse reactions in the experimental group were granulocyte deficiency and electrolyte disorder. There were no adverse reactions that affected subsequent surgical treatment or caused death, and the safety and tolerability were good. The median follow-up time was 15 months, and the one-year disease-free survival rate of the experimental group was higher than that of control group (92.86% vs. 77.78%, χ2=0.62, P=0.42), with a relative decrease of 87% in the risk of disease progression or death (P=0.029). For patients with programmed death-ligand 1(PD-L1) protein expression combined positive score≥20, the experimental group showed higher major pathological response rate than control group (5/5 vs. 0/4, P=0.03). Conclusion: The neoadjuvant therapy of immunotherapy combined with chemotherapy can improve the pathological remission of oral squamous cell carcinoma and the long-term survival benefits and the prognosis of patients.

Down-regulated HHLA2 enhances neoadjuvant immunotherapy efficacy in patients with non-small cell lung cancer (NSCLC) with chronic obstructive pulmonary disease (COPD)

BackgroundEmerging data suggested a favorable outcome in advanced non-small cell lung cancer (NSCLC) with chronic obstructive pulmonary disease (COPD) patients treated by immunotherapy. The objective of this study was to investigate the effectiveness of neoadjuvant immunotherapy among NSCLC with COPD versus NSCLC without COPD and explore the potential mechanistic links.Patients and methodsPatients with NSCLC receiving neoadjuvant immunotherapy and surgery at Shanghai Pulmonary Hospital between November 2020 and January 2023 were reviewed. The assessment of neoadjuvant immunotherapy’s effectiveness was conducted based on the major pathologic response (MPR). The gene expression profile was investigated by RNA sequencing data. Immune cell proportions were examined using flow cytometry. The association between gene expression, immune cells, and pathologic response was validated by immunohistochemistry and single-cell data.ResultsA total of 230 NSCLC patients who received neoadjuvant immunotherapy were analyzed, including 60 (26.1%) with COPD. Multivariate logistic regression demonstrated that COPD was a predictor for MPR after neoadjuvant immunotherapy [odds ratio (OR), 2.490; 95% confidence interval (CI), 1.295–4.912; P = 0.007]. NSCLC with COPD showed a down-regulation of HERV–H LTR-associating protein 2 (HHLA2), which was an immune checkpoint molecule, and the HHLA2low group demonstrated the enrichment of CD8+CD103+ tissue-resident memory T cells (TRM) compared to the HHLA2high group (11.9% vs. 4.2%, P = 0.013). Single-cell analysis revealed TRM enrichment in the MPR group. Similarly, NSCLC with COPD exhibited a higher proportion of CD8+CD103+TRM compared to NSCLC without COPD (11.9% vs. 4.6%, P = 0.040).ConclusionsThe study identified NSCLC with COPD as a favorable lung cancer type for neoadjuvant immunotherapy, offering a new perspective on the multimodality treatment of this patient population. Down-regulated HHLA2 in NSCLC with COPD might improve the MPR rate to neoadjuvant immunotherapy owing to the enrichment of CD8+CD103+TRM.Trial registrationApproval for the collection and utilization of clinical samples was granted by the Ethics Committee of Shanghai Pulmonary Hospital (Approval number: K23-228).

Combination of EGFR-TKI and Chemotherapy Versus EGFR-TKI Monotherapy as Neoadjuvant Treatment of Stage III-N2 EGFR-Mutant Non-Small Cell Lung Cancer.

The efficacy of neoadjuvant treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) monotherapy in patients with stage III-N2 EGFR-mutant remains unsatisfactory. This study explored the potential benefits of combining first-generation EGFR-TKI with chemotherapy as a neoadjuvant treatment for patients with stage III-N2 EGFR-mutant non-small cell lung cancer (NSCLC). The medical records of patients with III-N2 EGFR-mutant NSCLC who received neoadjuvant therapy with EGFR-TKI at Shanghai Chest Hospital from October 2011 to October 2022 were retrospectively reviewed. Patients with stage III-N2 EGFR-mutant NSCLC who received first-generation TKI combined with chemotherapy as neoadjuvant treatment were included in the combination group, and those who received EGFR-TKI monotherapy were included in the monotherapy group. The study assessed the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, disease-free survival (DFS), overall survival (OS), downstaging rates of pathologic lymph nodes (from stage N2 to N1 or N0), major pathologic response (MPR) rate, pathological complete response (PCR) rate, and safety. A total of 74631 patients with EGFR-mutant NSCLC were screened, and 60 patients were included, 7 of whom did not undergo surgery after neoadjuvant targeted therapy. Of the remaining 53 patients, 15 received first-generation EGFR-TKI combined with chemotherapy as neoadjuvant treatment, and 38 received EGFR-TKI monotherapy. The median follow-up time was 44.12 months. The ORR was 50.0% (9/18) in the combination group and 40.5% (17/42) in the monotherapy group (P = .495). The MPR rate was 20.0% (3/15) and 10.5% (4/38) in the combination and monotherapy groups, respectively (P = .359). No patients achieved PCR in the combination group, while 3 (7.89%) attained PCR in the monotherapy group. The 2 groups did not differ in N2 downstaging rate (P = .459). The median DFS was not reached in the combination group, while it was 23.6 months (95% CI: 8.16-39.02) in the monotherapy group (P = .832). Adverse events observed were consistent with those commonly associated with the 2 treatments. Combination therapy with first-generation EGFR-TKI and chemotherapy could be considered a neoadjuvant treatment option for patients with stage III-N2 EGFR-mutant NSCLC, exhibiting acceptable toxicity. However, regarding short-term efficacy, combination therapy did not demonstrate superiority over EGFR-TKI monotherapy. Long-term follow-up is warranted for a more accurate assessment of the DFS and OS.

Total Neoadjuvant Therapy With PD-1 Blockade for High-Risk Proficient Mismatch Repair Rectal Cancer

Total neoadjuvant therapy (TNT) is the standard treatment for locally advanced rectal cancer, especially for patients with high-risk factors. However, the efficacy of TNT combined with immunotherapy for patients with proficient mismatch repair (pMMR) rectal cancer is unknown. To evaluate the safety and efficacy of TNT with induction chemoimmunotherapy followed by long-course chemoradiation in patients with high-risk, pMMR rectal cancer and to identify potential molecular biomarkers associated with treatment efficacy. This cohort study was a single-arm phase 2 trial conducted at Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, from June 2020 to October 2021. Biopsies and plasma were collected before treatment for whole-exome sequencing and cell-free DNA sequencing, respectively. Data were analyzed from May 2022 to September 2022. Participants received 3 cycles of induction oxaliplatin and capecitabine combined with camrelizumab and radiotherapy (50.6 Gy in 22 fractions) with concurrent capecitabine. Patients without disease progression received 2 cycles of consolidation oxaliplatin/capecitabine. The primary end point was pathologic complete response rate. Of 25 patients enrolled (19 men [76%]; 6 women [24%]; median [IQR] age, 58 [48-64] years), 22 patients (88%) completed the TNT schedule. The pathologic complete response rate was 33.3% (7/21). Twelve patients (48%) achieved clinical complete response, and 4 patients (16%) chose to watch and wait. R0 resection was achieved in 21 of 21 patients, and the major pathologic response rate was 38.1% (8/21). The most common adverse event was nausea (80%, 20/25); grade 3 toxic effects occurred in 9 of 25 patients (36%). Patients with tumor shrinkage of 50% or greater after induction oxaliplatin/capecitabine and camrelizumab or clinical complete response had higher percentages of LRP1B mutation. Mutation of LRP1B was associated with high tumor mutation burden and tumor neoantigen burden. Patients with high tumor mutation burden all benefited from therapy. This study found that TNT with induction chemoimmunotherapy followed by long-course chemoradiation was safe and effective for patients with high-risk rectal cancer with pMMR status. Longer follow-up and larger clinical studies are needed to validate this innovative regimen. There is also an urgent need to further validate the predictive value of LRP1B and discover other novel biomarkers with potential predictive value for rectal cancer.

A new, potential and safe neoadjuvant therapy strategy in epidermal growth factor receptor mutation-positive resectable non-small-cell lung cancer-targeted therapy: a retrospective study.

Studies of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in resectable non-small-cell lung cancer (NSCLC) have been conducted. The purpose of our study was to evaluate the benefits of osimertinib as neoadjuvant therapy for resectable EGFR-mutated NSCLC. This retrospective study evaluated patients with EGFR mutations in exon 19 or 21 who received targeted therapy with osimertinib (80 mg per day) before surgery between January 2019 and October 2023 in Henan Cancer Hospital. Twenty patients were evaluated, all of whom underwent surgery. The rate of R0 resection was 100% (20/20). The objective response rate was 80% (16/20), and the disease control rate was 95% (19/20). Postoperative pathological analysis showed a 25% (5/20) major pathological response rate and 15% (3/20) pathological complete response rate. In total, 25% (5/20) developed adverse events (AEs), and the rate of grades 3-4 AEs was 10% (2/20). One patient experienced a grade 3 skin rash, and 1 patient experienced grade 3 diarrhea. Osimertinib as neoadjuvant therapy for resectable EGFR-mutated NSCLC is safe and well tolerated. Osimertinib has the potential to improve the radical resection rate and prognosis.

Fruquintinib plus oxaliplatin combined with S-1 (SOX) as neoadjuvant therapy for locally advanced gastric cancer (GC) or gastro-oesophageal junction adenocarcinoma (GEJ): a multicentre, phase II, single-arm, open-label clinical trial (FRUTINEOGA) protocol

IntroductionCuring locally advanced gastric cancer (GC) or gastro-oesophageal junction adenocarcinoma (GEJ) with surgery alone is challenging. Neoadjuvant chemotherapy (NCT) has become the standard treatment for patients with locally advanced GC/GEJ,...

Efficacy and Safety of Preoperative Transcatheter Rectal Arterial Chemoembolisation in Patients with Locally Advanced Rectal Cancer: Results from a Prospective, Phase II PCAR Trial

AimsThe PCAR study aimed to assess the efficacy and safety of preoperative transcatheter rectal arterial chemoembolisation (TRACE) in patients with locally advanced rectal cancer (LARC). Materials and methodsThis was a single-centre, prospective, phase II trial conducted in China. Eligible patients were adults aged 18 years and older with histologically confirmed stage II or III rectal carcinoma and an Eastern Cooperative Oncology Group performance status of 0–1. Patients received TRACE with oxaliplatin, followed by radiotherapy with a cumulative dose of 45 Gy (1.8 Gy/time/day, five times a week for 5 weeks) and received oral S1 capsules twice daily (7 days a week for 4 weeks). Patients underwent total mesorectal excision 4–8 weeks after the completion of chemoradiotherapy, followed by mFOLFOX6 or CAPOX regimens for 4–6 months. The hypothesis of this study was that adding TRACE to preoperative neoadjuvant chemoradiotherapy would improve tumour regression and prognosis. The primary end point was the pathological complete response rate; secondary end points included the major pathological response rate, anal preservation rate, 5-year disease-free survival (DFS), 5-year overall survival and treatment-related adverse events. ResultsIn total, 111 LARC patients received TRACE and subsequent scheduled treatment plans. The pathological complete response and major pathological response rates were 20.72% and 48.65%, respectively. The 5-year DFS and 5-year overall survival were 61.89% (95% confidence interval 51.45–74.45) and 74.80% (95% confidence interval 65.05–86.01), respectively. Grade 3–4 toxicities were reported in 29 patients (26.13%). The postoperative complication rate was 21.62%, without serious surgical complications. Multivariate Cox regression analysis showed that ypN stage (hazard ratio = 4.242, 95% confidence interval 2.101–8.564, P = 0.00017) and perineural invasion (hazard ratio = 2.319, 95% confidence interval 1.058–5.084, P = 0.0487) were independent risk factors associated with DFS, whereas ypN stage (hazard ratio = 3.164, 95% confidence interval 1.347–7.432, P = 0.0101), perineural invasion (hazard ratio = 4.118, 95% confidence interval 1.664–10.188, P = 0.0134) and serum carbohydrate antigen 199 (CA199; hazard ratio = 4.142, 95% confidence interval 1.290–13.306, P = 0.0344) were independent predictors for overall survival. ConclusionThe current study provides evidence that adding TRACE to neoadjuvant chemoradiotherapy can improve the pathological remission rate in LARC patients with acceptable toxicity. Given its promising effectiveness and safe profile, incorporating TRACE into the standard treatment strategy for patients with LARC should be considered.