Pathological Response Research Articles

A phenocopy signature of TP53 loss predicts response to chemotherapy

In preclinical studies, p53 loss of function impacts chemotherapy response, but this has not been consistently validated clinically. We trained a TP53-loss phenocopy gene expression signature from pan-cancer clinical samples in the TCGA. In vitro, the TP53-loss phenocopy signature predicted chemotherapy response across cancer types. In a clinical dataset of 3003 breast cancer samples treated with neoadjuvant chemotherapy, the TP53-loss phenocopy samples were 56% more likely to have a pathologic complete response (pCR), with a significant association between TP53-loss phenocopy and pCR in both ER positive and ER negative tumors. In an independent clinical validation in the I-SPY2 trial (N = 987), we confirmed the association with neoadjuvant chemotherapy pCR and found higher rates of chemoimmunotherapy response in TP53-loss phenocopy tumors compared to non-TP53-loss phenocopy tumors (64% vs. 28%). The TP53-loss phenocopy signature predicts chemotherapy response across cancer types in vitro, and in a proof-of-concept clinical validation is associated with neoadjuvant chemotherapy response across multiple clinical breast cancer cohorts.

Pathological response following neoadjuvant immune checkpoint inhibitors in patients with hepatocellular carcinoma: a cross-trial, patient-level analysis

Neoadjuvant use of immune checkpoint inhibitors (ICIs) before liver resection results in pathological tumour regression in patients with hepatocellular carcinoma. We aimed to describe the characteristics of pathological responses after preoperative ICI therapy for hepatocellular carcinoma and to evaluate the association between the depth of tumour regression and relapse-free survival. In this cross-trial, patient-level analysis, we performed a pooled analysis of data from patients with hepatocellular carcinoma receiving ICI therapy before liver resection as part of a global collaborative consortium (NeoHCC) of five phase 1 and 2 clinical trials and standardised observational protocols conducted in 12 tertiary referral centres across the USA, UK, and Taiwan. Eligible patients were adults (aged ≥18 years) diagnosed with hepatocellular carcinoma by tissue core biopsy before treatment initiation, a Liver Imaging Reporting and Data System score of 5 on imaging, or both, with an Eastern Cooperative Oncology Group performance status score of 0-1, and no extrahepatic spread or previous ICI treatment. Pathological response was measured as the percentage of non-viable tumour in the resected surgical specimen, with major pathological response corresponding to at least 70% tumour regression and pathological complete response corresponding to 100% tumour regression. We correlated pathological response with radiological overall response using RECIST criteria (version 1.1) and relapse-free survival, and evaluated the threshold of tumour regression that could be optimally associated with relapse-free survival. At data cutoff on Jan 31, 2024, 111 patients were included in the study, of whom data on pathological response were available for 104 (94%) patients. Patients received treatment from Oct 5, 2017, to Nov 15, 2023, mostly ICI combinations (76 [69%]), for a median of 1·4 months (IQR 0·7-2·9). 87 (78%) patients were men and 24 (22%) were women. Most patients had underlying viral chronic liver disease (73 [66%]) and Barcelona Clinic Liver Cancer stage A hepatocellular carcinoma (61 [55%]), without portal vein thrombosis (87 [78%]). We observed major pathological response in 33 (32%) patients and pathological complete response in 19 (18%) patients. Radiological overall response was associated with major pathological response, with 23 (74%) of 31 patients with radiological response showing major pathological response compared with ten (14%) of 73 patients without radiological response (p<0·0001). However, ten (30%) of 33 major pathological responses were not predicted by radiological response. After a median follow-up of 27·2 months (95% CI 22·3-32·1), median relapse-free survival for the whole cohort was 43·6 months (95% CI 28·3-not evaluable). Relapse-free survival was significantly longer in patients with major pathological response than in those who did not have a major pathological response (not reached [95% CI not evaluable-not evaluable] vs 28·3 months [12·8-43·8]; hazard ratio 0·26 [0·10-0·66]; p=0·0024) and in patients with pathological complete response than in those who did not have a pathological complete response (NR [95% CI not evaluable-not evaluable] vs 32·8 months [15·0-50·5]; 0·19 [0·05-0·78]; p=0·010). Unbiased recursive partitioning of the cohort for the risk of relapse, death, or both identified a threshold of 90% as the optimal cutoff of pathological tumour regression to predict improved relapse-free survival. The extent of tumour regression following neoadjuvant ICI therapy could identify patients with improved relapse-free survival following liver resection. The threshold of at least 90% tumour regression should be validated for its surrogate role for relapse-free survival in phase 3 randomised controlled trials. None.

Optimal Sequence for Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: An Evidence-Based Review.

Historically, multimodal therapeutic strategies involving preoperative chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (CT) have been employed to treat locally advanced rectal cancer (LARC). Total Neoadjuvant Therapy (TNT) is showing promise in improving outcomes. Despite its benefits, the optimal sequencing within TNT-whether induction chemotherapy should precede or follow chemoradiotherapy-remains a critical question. This study endeavors to explore the effects of different TNT sequencing strategies on patient outcomes, including tumor downstaging, pathological response, organ preservation, and the balance between efficacy and tolerability. Our methodology entailed a comprehensive literature review conducted on Medline, focusing on recent research, including retrospective studies, systematic reviews, and clinical trials. The review emphasized the comparison of induction chemotherapy versus consolidation chemotherapy within TNT regimens, assessing outcomes such as pathological response, organ preservation rates, and adverse effects. To ensure the selection of appropriate and high-quality studies, specific inclusion and exclusion criteria were applied. The analysis revealed that induction chemotherapy might lead to decreased adherence to subsequent chemoradiotherapy while offering an early intervention against micrometastasis and potentially improving overall chemotherapy compliance. Conversely, consolidation chemotherapy has been associated with higher pathological complete response (pCR) rates and improved tolerability, indicating its potential for patients requiring local symptom relief or those eligible for a nonoperative management approach. Comparative studies like CAO/ARO/AIO-12 and the OPRA trials have significantly contributed to our understanding, suggesting that while both strategies have distinct advantages, the choice between induction and consolidation chemotherapy should be tailored based on individual patient profiles and tumor characteristics. This narrative review underscores the importance of a nuanced approach to TNT sequencing in locally advanced rectal cancer, highlighting the need for further research to refine treatment strategies.

Concordance of whole slide imaging and conventional light microscopy for assessment of pathologic response following neoadjuvant therapy for lung cancer

Pathologic response is an endpoint in many ongoing clinical trials for neoadjuvant regimens, including immune checkpoint blockade and chemotherapy. Whole slide scanning of glass slides generates high resolution digital images and allows for remote review and potential measurement with image analysis tools, but concordance of pathologic response assessment on digital scans compared to glass slides has yet to be evaluated. Such a validation goes beyond previous concordance studies which focused on establishing surgical pathology diagnoses, as it requires quantitative assessment of tumor, necrosis, and regression. Further, as pathologic response assessment is being used as an endpoint, such concordance studies have regulatory implications. The purpose of this study was two fold: firstly, to determine the concordance between pathologic response assessed on glass slides and on digital scans; and secondly, to determine if pathologists benefited from using measurement tools when determining pathologic response. To that end, H&E-stained glass slides from 64 non-small cell lung carcinoma specimens were visually assessed for percent residual viable tumor (%RVT). The sensitivity and specificity for digital vs. glass reads of complete pathologic response (pCR, 0% RVT) and major pathologic response (MPR, ≤10% RVT) were all >95%. When %RVT was considered as a continuous variable, intraclass correlation coefficient of digital vs. glass reads was 0.94. The visual assessments of pathologic response were supported by pathologist annotations of residual tumor and tumor bed areas. In a separate subset of H&E-stained glass slides, several measurement approaches to quantifying %RVT were performed. Pathologist estimates strongly reflected measured %RVT. This study demonstrates the high level of concordance between glass slides evaluated using light microscopy and digital whole slide images for pathologic response assessments. Pathologists did not require measurement tools to generate robust %RVT values from slide annotations. These findings have broad implications for improving clinical workflows and multisite clinical trials.

Improved Event-Free Survival After Complete or Major Pathologic Response in Patients With Resectable NSCLC Treated With Neoadjuvant Chemoimmunotherapy Regardless of Adjuvant Treatment: A Systematic Review and Individual Patient Data Meta-Analysis

IntroductionNeoadjuvant chemoimmunotherapy has reshaped the treatment landscape for resectable NSCLC, yet the prognostic significance of pathologic response remains unclear. We conducted a systematic review and individual patient data (IPD) meta-analysis to evaluate the impact of achieving pathologic complete response (pCR) or major pathologic response (MPR) on event-free survival (EFS) and assessed the influence of adjuvant immunotherapy. MethodsWe performed an IPD meta-analysis of prospective clinical trials on neoadjuvant or perioperative anti–programmed death-ligand 1 in combination with platinum-based chemotherapy in patients with resectable NSCLC. The IPD was extracted from Kaplan-Meier curves for pCR and/or MPR from the included studies. Survival outcomes were compared between patients achieving pCR or MPR and those who did not, considering both intention-to-treat and resected populations. ResultsAchieving pCR or MPR was associated with improved EFS in the intention-to-treat population (pCR, hazard ratio = 0.13; MPR, hazard ratio = 0.18, respectively) with a 24 months EFS rate of 94% and 88% for patients who achieved pCR and MPR, respectively. Independently from pCR status, patients who were treated in an experimental arm that included adjuvant immunotherapy had similar EFS. ConclusionsOur study reported a strong EFS improvement in patients who achieved either pCR or MPR after neoadjuvant chemoimmunotherapy. The use of adjuvant immunotherapy after tumor resection was not associated with improved EFS.

Tumor-infiltrating lymphocytes in necrotic tumors after melanoma neoadjuvant anti-PD1 therapy correlate with pathological response and recurrence-free survival.

Neoadjuvant anti-PD1 therapy in melanoma may increase tumor-infiltrating lymphocytes (TILs), and more TILs are associated with better treatment response. A major pathological response (MPR) in melanoma after neoadjuvant anti-PD1 therapy usually comprises tumor necrosis and fibrosis. The role of TILs in necrotic tumor necrosis (nTILs) has not been explored. We performed CD3 and CD8 immunohistochemical stains on 41 melanomas with geographic necrosis. 14 were immunotherapy-naïve, and 27 had been treated with one dose of neoadjuvant anti-PD-1 in two clinical trials. CD3+ and CD8+ nTILs were graded as absent/minimal or moderate/brisk. The percentage of necrotic areas in the tumor bed before and after treatment was quantified. Endpoints were MPR and 5-year recurrence-free survival (RFS). In the immunotherapy-naïve cohort, 3/14 (21%) specimens had moderate/brisk CD3+, and 2/14 (14%) had moderate/brisk CD8+ nTILs. In the treated cohort, 16/27 (59%) specimens had moderate/brisk CD3+, and 15/27 (56%) had moderate/brisk CD8+ nTILs, higher than the naïve cohort (CD3, p=0.046; CD8, p=0.018). Tumor necrosis was significantly increased after anti-PD1 therapy (p=0.007). In the treated cohort, moderate/brisk CD3+ and CD8+ nTILs correlated with MPR (p=0.042, p=0.019, respectively). Treated patients with moderate/brisk CD3+ nTILs had higher 5-year RFS than those with absent/minimal nTILs (69% versus 0%; p=0.006). This persisted on multivariate analysis (HR 0.16, 95% CI 0.03-0.84, p=0.03), adjusted for pathologic response, which was borderline significant (HR 0.26, 95% CI 0.07-1.01, p=0.051). CD3+ and CD8+ nTILs are associated with pathological response and 5-year RFS in melanoma patients after neoadjuvant anti-PD1 therapy.

Neoadjuvant atezolizumab plus bevacizumab prior liver transplantation for hepatocellular carcinoma☆

Background & AimsThe combination of atezolizumab and bevacizumab offers a novel approach to immunomodulation, showing efficacy as a primary treatment in advanced hepatocellular carcinoma (HCC). Concerns about graft safety and rejection have limited its exploration in the neoadjuvant setting of liver transplantation (LT).This study investigates the clinical efficacy and the safety profile related to the pre-transplant administration of atezolizumab and bevacizumab for HCC. MethodsProspective assessment of 17 patients with HCC treated with neoadjuvant preoperative atezolizumab and bevacizumab prior to LT for HCC, obtained from December 2020 and December 2023 at seven Western transplant centers. ResultsAmong the 17 patients with HCC included in the study, 16 (94.1%) had a tumor burden outside of Milan Criteria (MC). Neoadjuvant loco-regional therapies along with the administration of atezolizumab plus bevacizumab (median:5 months; discontinued at least 4 weeks prior LT), achieved an ORR 94% (Complete response: 59%), downstaging to within MC (82%) and a pathological response at explant examination of 88%. Grade 3-4 TRAE accounted for 17.6% of cases and were manageable. During the 25 months median follow-up period, 2 cases of mild (RAI ≤ 4), biopsy-proven rejection were reported but no instances of severe allograft rejection or graft loss. The 1-year and 3-year post-LT survival rates were 94.2% and 88.2%, respectively. ConclusionsThis study highlights the favorable oncological and survival outcomes from a multicentric cohort of HCC patients treated with atezolizumab and bevacizumab in the pre-LT setting. This immune-based combination was safe in terms of TRAE, and absence of severe post-transplant rejection or graft loss. These preliminary results could pave the way for expanding transplant eligibility criteria in patients at more advanced HCC stages. Impact and Implications•The combination of atezolizumab and bevacizumab in the neoadjuvant setting prior to liver transplantation for hepatocellular carcinoma (HCC) has been limitedly explored despite its potential to enhance anti-tumor response and downstaging due to raising concerns about its safety profile.•Among 17 patients who underwent successful liver transplantation following neoadjuvant atezolizumab/bevacizumab, 82% achieved downstaging to within MC, 94% radiological objective response and 88% pathology response, without drop-outs due to TRAEs or graft loss.•The neoadjuvant combination of atezolizumab plus bevacizumab prior liver transplantation in HCC shows an encouraging safety profile and stands out as a promising pre-transplant optimization treatment adjunct, leading to improved oncological outcomes

A Meta-Analysis of Efficacy and Safety of Neoadjuvant Immunotherapy Plus Chemotherapy for Resectable Non-Small Cell Lung Cancer.

Neoadjuvant immunotherapy plus chemotherapy has ushered in a new era for surgical treatment for patients with NSCLC. This study aimed to examine the efficacy and safety of neoadjuvant immunotherapy plus chemotherapy in NSCLC. Eligible studies were identified from PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and conference meeting abstracts. The endpoints included major pathological response (MPR), complete pathological response (pCR), surgical resection rate, R0 resection, treatment-related adverse events (TRAEs), severe adverse events (SAEs), surgical complications, treatment discontinuation, surgical delay, and treatment-related death. Stata 18 software was used for statistical analysis, and p < 0.05 was considered statistically significant. Twenty-two studies including a total of 1108 patients were eligible for this study. Among the patients who received neoadjuvant immunotherapy plus chemotherapy, the pooled MPR rate was 51% (95% CI [0.44-0.58]), and pCR rate was 34% (95% CI [0.28-0.40]). The pooled surgical resection rate was 85% (95% CI [0.81-0.89]), and the pooled R0 rate was 94% (95% CI [0.91-0.96]). The pooled rate of pathological tumor downstaging was 84% (95% CI [0.79-0.88]), and the pooled rate of pathological nodal downstaging was 38% (95% CI [0.23-0.57]). During the treatment of neoadjuvant immunotherapy plus chemotherapy with or without surgery, the pooled rate of TRAEs (any grade) was 84% (95% CI [0.73-0.91]), and the pooled rate of SAEs was 29% (95% CI [0.21-0.38]). Surgical complications pooled rate was 25% (95% CI [0.14-0.41]). The pooled rate of treatment discontinuation (11%, 95% CI [0.09-0.13]), surgical delay (3%, 95% CI [0.02-0.05]), and treatment-related death (2%, 95% CI [0.02-0.03]) were conducted. Neoadjuvant immunotherapy plus chemotherapy provides a high pathological response, surgical resection rate, R0 resection rate, and pathological downstage rate and has a low risk of increasing the incidence of SAEs, surgical complications, treatment discontinuation, surgical delay, and treatment-related death. The validation of prospective and large sample studies is needed to confirm this conclusion.

RESIDUAL MICROCALCIFICATIONS AFTER NEOADJUVANT SYSTEMIC THERAPY FOR EARLY BREAST CANCER: IMPLICATIONS FOR SURGICAL PLANNING AND LONG-TERM OUTCOMES

Residual microcalcifications on mammograms after neoadjuvant chemotherapy (NACT) pose a challenge in surgical decision-making. This single-centre retrospective review of all patients who had NACT for breast cancer over five years, evaluated the relationship between pathological complete response and residual microcalcifications, controlling for tumour size, nodal stage, grade, and receptor status, as well as the impact of residual microcalcifications on recurrence and survival. There was no significant association between pathological complete response (pCR) and residual microcalcifications (p=0.763). We computed hazard ratios (HR) for Time-to-recurrence (TTR) and overall survival (OS) which were both not significant, with HR=2.599, [0.290, 23.264], p=0.393 and HR=1.362 [0.123, 15.062], p=0.801 respectively. The predictive and prognostic significance of residual microcalcifications remains to be proven. The surgical excision of these lesions should be considered based on individual patient risk.

Impact of delays in neoadjuvant chemotherapy initiation on pathologic complete response among patients with HER2-positive or triple negative breast cancer.

102 Background: Pathologic complete response (pCR) is used as a surrogate endpoint for overall survival (OS) in high-risk early-stage breast cancer (BC). pCR rates vary according to BC molecular subtype and have the highest association with OS in triple negative BC (TNBC) and HER2-positive (HER2+) BC. In these subgroups, neoadjuvant chemotherapy (NACT) is often the standard of care. We evaluated the association of delays in NACT initiation (NACTI) with pCR. Methods: We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis cT2+ or lymph node positive HER2+ or TNBC between 1/1/2010 – 12/31/2020, who were treated with NACT within 180 days of BC diagnosis. Time to chemotherapy (TTC) was recorded in days. Patients were categorized by receptor status. We used AJCC 7 th and 8 th edition T and N staging to define pCR (pT0 or pTis and pN0 or pN0I-). Delay was defined as TTC &gt; 60 days. Multivariable logistic regression, adjusted for demographic, socioeconomic and tumor characteristics, was used to calculate odds of pCR associated with delays. A sensitivity analysis defining delay &gt;30 and &gt;90 days was also conducted. Results: We identified 105,352 eligible patients, 73% were White, 19% were Black, 3% were Asian, and 4% were Other/Unknown. Median age at diagnosis was 52 years (range 18-90), median TTC was 32 days (range 0-180). There were 56,868 patients with HER2+ BC and 48,484 with TNBC; 9% of patients were delayed &gt; 60 days in each group. Among all HER2+ patients, 39.1% achieved a pCR: 35.0% with delay compared to 39.5% without delay. Among TNBC patients, 30% achieved a pCR: 25% with delay compared to 31% without delay (p &lt; 0.0001 for all). In multivariable analysis, patients with HER2+ disease (OR 0.85, 95%CI 0.79-0.92) and TNBC (OR 0.80, 95%CI 0.73-0.87) were less likely to achieve pCR if delayed &gt; 60 days. In a sensitivity analysis, delay &gt; 30 days was associated with lower likelihood of achieving pCR for all and delay &gt; 90 days was associated with lower likelihood for TNBC (Table). Conclusions: Delays in NACTI &gt;60 days among patients with HER2+ and TNBC BC was an independent predictor of not achieving pCR. Given the known association between socioeconomic factors and delays to initiation of treatment, interventions aimed at reducing delays may reduce disparities in BC outcomes. Future studies to identify causes of delays and the downstream impact are needed to ultimately develop interventions that mitigate these effects among patients with HER2+ or TNBC, where pCR rates are associated with OS. Association of pCR in patients who experience NACTI delay using multivariable logistic regression* n(complete case) = 77,690. Subgroup &gt;30-day Delay in NACTIOR (95% CI) &gt;60-day Delay in NACTIOR (95% CI) &gt;90-day Delay in NACTIOR (95% CI) HER2+n =41,672 0.91 (0.87-0.95) 0.85 (0.79-0.92) 0.93 (0.80-1.07) TNBCn = 36,018 0.87 (0.83-0.92) 0.80 (0.73-0.87) 0.78 (0.65-0.92) *Adjusted for demographic, socioeconomic and tumor characteristics.

Predicting Pathologic Complete Response in Locally Advanced Rectal Cancer with [68Ga]Ga-FAPI-04 PET, [18F]FDG PET, and Contrast-Enhanced MRI: Lesion-to-Lesion Comparison with Pathology.

Neoadjuvant therapy in patients with locally advanced rectal cancer (LARC) has achieved good pathologic complete response (pCR) rates, potentially eliminating the need for surgical intervention. This study investigated preoperative methods for predicting pCR after neoadjuvant short-course radiotherapy (SCRT) combined with immunochemotherapy. Methods: Treatment-naïve patients with histologically confirmed LARC were enrolled from February 2023 to July 2023. Before surgery, the patients received neoadjuvant SCRT followed by 2 cycles of capecitabine and oxaliplatin plus camrelizumab. 68Ga-labeled fibroblast activation protein inhibitor ([68Ga]Ga-FAPI-04) PET/MRI, [18F]FDG PET/CT, and contrast-enhanced MRI were performed before treatment initiation and before surgery in each patient. PET and MRI features and the size and number of lesions were also collected from each scan. Each parameter's sensitivity, specificity, and diagnostic cutoff were derived via receiver-operating-characteristic curve analysis. Results: Twenty eligible patients (13 men, 7 women; mean age, 60.2 y) were enrolled and completed the entire trial, and all patients had proficient mismatch repair or microsatellite-stable LARC. A postoperative pCR was achieved in 9 patients (45.0%). In the visual evaluation, both [68Ga]Ga-FAPI-04 PET/MRI and [18F]FDG PET/CT were limited to forecasting pCR. Contrast-enhanced MRI had a low sensitivity of 55.56% to predict pCR. In the quantitative evaluation, [68Ga]Ga-FAPI-04 change in SULpeak percentage, where SULpeak is SUVpeak standardized by lean body mass, had the largest area under the curve (0.929) with high specificity (sensitivity, 77.78%; specificity, 100.0%; cutoff, 63.92%). Conclusion: [68Ga]Ga-FAPI-04 PET/MRI is a promising imaging modality for predicting pCR after SCRT combined with immunochemotherapy. The SULpeak decrease exceeding 63.92% may provide valuable guidance in selecting patients who can forgo surgery after neoadjuvant therapy.

MA01.12 Survival Outcomes and Pathologic Response after Chemo-Immunotherapy in Resectable NSCLC: An Individual Patient Data Meta-Analysis

MA01.12 Survival Outcomes and Pathologic Response after Chemo-Immunotherapy in Resectable NSCLC: An Individual Patient Data Meta-Analysis

Perioperative chemoimmunotherapy induces strong immune responses and long-term survival in patients with HLA class I-deficient non-small cell lung cancer

BackgroundLoss of human leukocyte antigen (HLA) class I expression and loss of heterozygosity (LOH) are common events implicated in the primary resistance of non-small cell lung cancer (NSCLC) to immunotherapy....

CD8+ T cells infiltrating into tumors were controlled by immune status of pulmonary lymph nodes and correlated with non-small cell lung cancer (NSCLC) patients’ prognosis treated with chemoimmunotherapy

PurposeNeoadjuvant chemoimmunotherapy has the potential to reduce tumor burden, improve the pathological complete response (pCR) rate, and significantly prolong patients’ disease-free survival (DFS). However, the treatment’s effectiveness varies among NSCLC patients. The immunological mechanisms contributing to tumor regression still require further exploration and elucidation. MethodsThe immune status of patients’ local tumor microenvironment (TME) before and after neoadjuvant chemoimmunotherapy, their paired pulmonary lymph nodes (11th LNs) after therapy, including infiltrating immune cell densities and their correlations, were analyzed using multiplex immunofluorescence. ResultsFifty-six NSCLC patients undergoing neoadjuvant chemoimmunotherapy were enrolled and subsequently underwent surgical resection and pathological evaluation. Among these, 19 patients achieved a pCR, 6 patients exhibited a major pathological response (MPR), and 31 patients did not achieve MPR. There were no significant difference in the densities of CD8+ T cell, Treg and Dendritic cell (DC) in patients’ TME before neoadjuvant therapy (n = 26, P = 0.091, P = 0.753, P = 0.905, respectively), but after treament, these immune cells’ dynamics were significantly different between different response group. CD8+ T cell densities were increased in pCR gourp (P = 0.006), but not in non-pCR group (P = 0.389); the densities of Treg were increased in non-pCR gourp (P = 0.0004), but DC were significantly decreased in non-pCR gourp (P = 0.005). After surgery, the TME were also significantly different: patients achieving pCR typically demonstrated high densities of CD8+ T cell, DC and low densities of Tregs (P = 0.0001, P < 0.0001 and P = 0.0004). The immune status of 11th LNs also exhibited significant differences. DC densities were much higher in pCR patients, whereas Treg in the pCR group were significantly lower than those in the non-pCR group (P = 0.0008 and P = 0.003). Furthermore, the densities of DC in the TME showed a moderate positive correlation with DC in 11th LNs (P = 0.0002), while the densities of Tregs in the TME exhibited a moderate negative correlation with DC densities in 11th LNs (P = 0.03). Patients who had high densities of CD8+ T cell in the resection tissues and DC in the LNs, experienced longer DFS (P = 0.048 and P = 0.024). ConclusionImmune cells in both pulmonary LNs and the TME collectively influence the remodeling of the NSCLC patient’s TME, thus impacting treatment response and prognosis.

EP.09B.03 Salvage Surgery Following Inductiontherapy for Advanced ALK-Positive NSCLC: Pathological Response and Surgical Outcomes

EP.09B.03 Salvage Surgery Following Inductiontherapy for Advanced ALK-Positive NSCLC: Pathological Response and Surgical Outcomes

Resection of colorectal liver metastases with second-line aflibercept plus FOLFIRI: Results from the RESECTION prospective French cohort

AimTo evaluate R0/R1 resection rate in patients with colorectal liver metastases (CLM) treated with aflibercept plus FOLFIRI after failure of a prior oxaliplatin-based regimen in daily clinical practice. MethodsThis French, multicentre, prospective, observational cohort (NCT05178745) included patients with CLM (alone or predominant; up to 5 lung nodules <2 cm allowed) initiating aflibercept/FOLFIRI every 2 weeks per physician choice. Primary endpoint was R0/R1 resection rate. Secondary endpoints included overall survival (OS), progression-free survival (PFS), radiological and pathological responses, and safety. ResultsA total of 137 patients (median age 65 years, RAS/BRAF mutant 57%/9%) were enrolled at 22 French sites. CLM (median 4) were synchronous in 82%, bilobar in 71% and located in liver only in 54%. Overall, 17% of patients had R0/R1 resection (21% for patients with liver-only disease). A major pathological response per Blazer score was observed in 55% of resected patients, along with significantly longer OS (median 34.8 vs 9.1 months, p<0.0001) and PFS (median 11.4 vs 4.9 months, p<0.0001) compared to non-resected patients. Post-operative complications occurred in 17% of patients (all Dindo-Clavien grade I-II) with no post-operative deaths. Overall, 34% had grade ≥3 adverse events, mainly general health deterioration and diarrhea. ConclusionsResults suggest that aflibercept plus FOLFIRI, after failure of a prior oxaliplatin-based regimen, allows R0/R1 resection of CLM in almost 20% of patients with a major pathological response in most cases and a median OS prolonged by more than 3-fold versus non-resected patients.

EP.06E.05 Is Diffusion-Weighted Imaging Able to Indicate Pathological Response in NSCLC after Neo-Adjuvant Immuno-Chemotherapy?

EP.06E.05 Is Diffusion-Weighted Imaging Able to Indicate Pathological Response in NSCLC after Neo-Adjuvant Immuno-Chemotherapy?

Neoadjuvant treatment with regorafenib and capecitabine combined with radiotherapy in locally advanced rectal cancer: a multicenter phase Ib trial (RECAP)–SAKK 41/16

BackgroundThe multi tyrosine kinase inhibitor regorafenib is active in metastatic colorectal cancer. Improvement in clinical outcome by adding regorafenib to long-course chemoradiotherapy (LcCRT) was investigated in molecularly undefined LARC. MethodsPatients with T3–4 and/or N+ but M0 rectal cancer were included. Neoadjuvant LcRCT consisted in capecitabine (C) 825mg/m2 d1–d38 and 28 fractions of 1.8Gy (50.4Gy). Regorafenib was added d1–14 and d22–35 in three dose escalation (DE) cohorts (40mg/80mg/120mg). The recommended dose (RD) was used for the expansion (EXP) cohort. Primary endpoints were dose-limiting toxicity (DLT) for DE and pathological response (near-complete regression [npCR] or complete regression [pCR]) for EXP. ResultsOverall, 25 patients were included. Two DLTs occurred at the regorafenib dose level of 120 mg, thereby establishing the RD at 80mg daily. Among the 19 patients who were treated at the RD, eight (42.1%; one-sided 80% confidence interval [CI] (lower bound): 30.7%; 95% CI: 20.3%–66.5%) reached the primary endpoint (five [26.3%] had npCR and three [15.8%] pCR). One additional patient received no surgery due to clinical complete response. All patients had R0 resections and clear circumferential margins. Postoperative complications occurred in six patients (35.3%). The most common grade ≥3 treatment-related adverse event in the EXP cohort was diarrhea (two patients). ConclusionAdding regorafenib 80mg to LcCRT in LARC resulted in both primary endpoints being met and yielded an expectedpathological response rate. Toxicity was manageable, and postoperative complications were as expected. Micro AbstractThe SAKK 41/16 study investigated the addition of regorafenib to the standard neoadjvuant chemoradiation with capecitabine. We could show expected pathological response rate and manageable toxicity at the recommended dose of regorafenib. Regorafenib may be potential partner for future trials investigating treatment intensification for high-risk locally advanced rectal cancer.

Early outcomes of pre-operative short course radiotherapy with simultaneous integrated boost and response-adapted chemotherapy for advanced rectal cancer

Background and purposeLimited evidence exists for dose escalation in neoadjuvant short course radiotherapy (SCRT) for rectal cancer. With enhanced imaging and radiotherapy techniques over the past decades along with the valuable endpoint of pathological complete response (pCR), we believe SCRT with simultaneous integrated boost could potentially provide deeper pathological responses and improve local control. Methods and MaterialsBetween Jan-2020 to Dec 2022, Locoregional advanced rectal cancer patients that were treated with neoadjuvant SCRT with SIB up to 5.5-6Gy per fraction with 5 daily fractions followed by response adapted chemotherapy was retrospectively reviewed. pCR rates, R0 resection rates, tumour down staging, toxicities and early pattern of recurrence are reported. ResultsAmong the 76 patients, 67 (88%) were able to undergo curative intent surgery. R0 resection was achieved in 99% (n = 66) of patients with pCR rates of 28% (n = 19). 46% (n = 31) of patients had significant pathological down staging (ypT2N0) and 55% (n = 37) of patients had both T and N down staging. Most common grade 3 or above radiotherapy related side effects were proctitis, rectal pain and dermatitis found in 5% (n = 4), 3% (n = 2) and 3% (n = 2) of patients respectively. Grade 3 or above surgical complications were observed in 15% (n = 10) of patients. There was no treatment related deaths. With a median follow up of 27 months, only 6% (n = 4) had local recurrence after surgery. ConclusionNeoadjuvant short course radiotherapy with simultaneous boost for rectal cancer is feasible with no added toxicities. Patients who underwent surgery achieve a high R0 resection and pCR rates. Early data suggests low rates of locoregional recurrence. Further follow up and research is needed to validate and optimize the dose, method, and schedule of dose escalation.

A case of salvage surgery following chemoradiotherapy and durvalumab for initially unresectable superior sulcus tumor with N3 involvement

BackgroundDurvalumab after chemoradiation (PACIFIC regimen) provides favorable treatment outcomes for unresectable stage III non-small cell lung cancer (NSCLC). The feasibility of salvage surgery after the PACIFIC regimen has been reported in some studies; however, its efficacy remains unclear. We herein present the first case of salvage surgery after the PACIFIC regimen for a superior sulcus tumor with N3 involvement, in which a pathological complete response was achieved.Case presentationA 53-year-old man with a left superior sulcus tumor with N3 (# 1L, #4R) involvement (adenocarcinoma, clinical T3N3M0/IIIC) underwent concurrent chemoradiotherapy (2 cycles of cisplatin plus vinorelbine with 60 Gy radiotherapy) followed by durvalumab treatment for 1 year at a previous hospital. The PACIFIC regimen provided a significant primary tumor shrinkage (diameter 3.1 cm to 0.5 cm) with the disappearance of 18F-fluorodeoxyglucose uptake in all nodes. Six months after the end of the PACIFIC regimen, only the primary tumor showed enlargement (diameter 0.5 cm to 2.0 cm). Accordingly, local tumor recurrence was suspected. Salvage surgery (left upper lobectomy with combined chest wall resection [1st to 4th rib]) was performed. The histological examination revealed no viable tumor cells (ypT0N0M0). At 7 months after salvage surgery, the patient remains alive with no signs of tumor recurrence.ConclusionsThe present case suggests that salvage surgery may be feasible after the PACIFIC regimen for superior sulcus tumors. A long-term follow-up is essential to determine the efficacy of salvage surgery.