Neoadjuvant Treatment Research Articles

Pathologic Response to Neoadjuvant Cetuximab, Platinum, and Taxane in Locally Advanced HNSCC.

Palbociclib plus letrozole versus weekly paclitaxel, both in combination with trastuzumab plus pertuzumab, as neoadjuvant treatment for patients with HR+/HER2+ early breast cancer: primary results from the randomized phase II TOUCH trial (IBCSG 55-17).

Rectal-sparing strategies for locally advanced rectal cancer are gaining interest owing to favorable oncological results and reduced impact on functional outcomes. In patients managed with watch-and-wait or local excision after neoadjuvant chemoradiotherapy (nCRT), local regrowth occurs in approximately 15-30% of cases. Total mesorectal excision (TME) is the standard treatment for regrowth; however, local excision (LE) may be considered in selected cases to preserve rectal function. This narrative review evaluates clinical and oncological outcomes of patients undergoing LE for suspected regrowth. A narrative review of the literature was conducted using databases and search terms including "rectal cancer," "rectal sparing," and "local regrowth." Five retrospective studies were identified, encompassing a total of 159 patients. Treatment protocols, neoadjuvant regimens, and follow-up strategies varied across the studies. Histopathological findings revealed ypT ≥ 2 in 45.3% of cases. Reported overall survival (OS) was consistently above 94.5%, while 2-year locoregional recurrence-free survival ranged from 74% to 85%. Systemic recurrence occurred in 9.1% of patients. LE was associated with shorter operative time, reduced blood loss, and lower rates of Clavien-Dindo ≥ 3 complications. Local excision for regrowth may represent a feasible alternative to radical surgery in selected patients, particularly within specialized centers and under strict surveillance protocols. Further prospective studies are warranted to validate its long-term oncologic safety and functional outcomes.

Esophageal cancer has a low 5-year survival rate despite treatments. scRNA-seq and MR offer insights into neoadjuvant treatment efficacy for precision medicine. Three post-neoadjuvant treatment datasets underwent QC for Seurat analysis. Marker genes identified cell subsets. MR analyzed eQTL data from GWAS cohorts for causal links. Single-cell and MR-derived genes intersected to reveal PLTP in CD4⁺T cells. Single-cell analysis of 16 samples found 40,198 genes and 120,102 cells. CD4⁺T cell numbers differed significantly between groups after therapy. Differentially expressed genes were immune-related. Pseudotime and cell-cell communication varied. PLTP, linked to esophageal cancer, co-expressed with genes involved in cell cycle processes. The study highlights CD4⁺T cells' predictive role in therapy efficacy via scRNA-seq and MR. PLTP emerges as a key gene, offering new precision medicine strategies for esophageal cancer.

BackgroundThis study evaluates the long-term anorectal function and rectal toxicity in rectal cancer patients who achieved a clinical complete response (cCR) to total neoadjuvant treatment (TNT) and were managed with a watch-and-wait (W&W) approach. While oncological outcomes have been favorable, functional outcomes warrant further investigation. Additionally, this research identifies clinical risk factors of anorectal dysfunction post-treatment.MethodsThis was a single-center, cross-sectional study. Rectal cancer patients who underwent TNT followed by W&W between December 2014 and November 2020 were recruited. A minimum 2-year follow-up with no disease progression was required. The study took the form of semi-structured interviews. Multiple scales for evaluation were used, including the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale, the Late Effects of Normal Tissues/Subjective Objective Management Analytic (LENT/SOMA) system, the Wexner score, the Low Anterior Resection Syndrome (LARS) score and the Memorial Sloan Kettering Cancer Center Bowel Function Instrument (MSKCC BFI). Univariate analysis and multi-factor Logistic regression were used to identify the risk factors for anorectal dysfunction.ResultsOut of 70 patients with a median follow-up of 43 months, less than half experienced grade I (28/70, 40.0%) or II (1/70, 1.4%) late rectal toxicity according to the RTOG/EORTC criteria, with no cases of more severe toxicity. The prevalence of fecal urgency was the most significant symptom reported (42/70, 60.0%). The median LARS score was 16 [interquartile ranges (IQR) 4–25]; 17.1% (12/70) of patients had minor LARS and 15.7% (11/70) had major LARS. The median Wexner score was 2 (IQR 0–3). The median MSKCC BFI total score was 82.5 (IQR 77–86). Smoking history was an independent risk factor for long-term anorectal dysfunction [odds ratio (OR) 6.562, 95% confidence interval (CI) 1.561–27.590].ConclusionMost rectal cancer patients under a W&W strategy after TNT sustain acceptable anorectal function, though fecal urgency remains a common issue. Smoking history emerged as a significant risk factor for anorectal dysfunction. Larger prospective studies focusing on bowel function are needed.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13014-025-02732-6.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and remains a leading cause of cancer-related mortality, particularly among younger men. Approximately one-third of colorectal cancers occur in the rectum. For patients with locally advanced rectal cancer, neoadjuvant therapy is considered the standard treatment approach. Despite advances in therapeutic approaches, improvements in the 5-year survival rate have been modest. Accurate assessment of tumor response to neoadjuvant therapy (NAT) is critical for guiding subsequent treatment strategies, especially when considering eligibility for non-operative management (NOM). Common evaluation methods include digital rectal examination (DRE), magnetic resonance imaging (MRI), and high-definition flexible endoscopy (HDFE). Tumor regression grading (TRG) systems-both histopathological (pTRG) and MRI-based (mrTRG)-are valuable tools for quantifying treatment response and predicting long-term outcomes. However, resistance to NAT remains a significant clinical challenge and is driven by a complex interplay of molecular mechanisms. Genetic factors, such as RAS mutations, have been linked to resistance to chemoradiotherapy (CRT), while tumors exhibiting microsatellite instability (MSI-high) tend to respond poorly to CRT but may show favorable outcomes with immune checkpoint inhibitors. Epigenetic pathways, including dysregulation of Wnt/β-catenin and PI3K/AKT signaling, along with alterations in DNA damage repair mechanisms, further influence CRT sensitivity. The tumor microenvironment also plays a pivotal role in modulating therapy response. Elements such as immune cell infiltration, hypoxia, angiogenesis, and the presence of cancer-associated fibroblasts (CAFs) contribute to a pro-resistance landscape. Moreover, emerging evidence suggests that gut microbiota composition-particularly an enrichment of Bacteroides species-is associated with diminished response to NAT. Understanding these multifaceted biological interactions is essential for developing personalized and more effective therapeutic strategies, with the goal of enhancing response to NAT and ultimately improving clinical outcomes in patients with rectal cancer.

Background: Pathological complete response (pCR) following neoadjuvant therapy (NAT) is a key surrogate marker for long-term outcomes in HER2-positive breast cancer. Identifying clinical and biological predictors of pCR, including systemic inflammatory and nutritional markers such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), neutrophil-to-albumin ratio (NAR), C-reactive protein-to-albumin ratio (CAR), systemic immune-inflammation index (SII), and prognostic nutritional index (PNI), may help refine treatment strategies and improve patient outcomes. Methods: We retrospectively analyzed 174 patients with stage II–III HER2-positive breast cancer who received neoadjuvant anti-HER2-based regimens at multiple centers between 2010 and 2025. Demographic, clinicopathological, and laboratory data were collected, and inflammatory and nutritional indices (NLR, PLR, LMR, NAR, CAR, SII, PNI) were calculated. Predictors of pCR were evaluated using univariate and multivariate logistic regression analyses. Results: Overall, 49% of patients achieved pCR. In multivariate analysis, independent predictors of pCR were hormone receptor negativity, smaller tumor size, HER2 IHC 3+ expression, dual HER2 blockade, and a higher prognostic nutritional index (PNI ≥ 55). In contrast, systemic inflammatory indices such as NLR, PLR, LMR, NAR, CAR, and SII were not significantly associated with pCR. Conclusions: This multicenter real-world study demonstrates that conventional inflammatory markers have limited predictive value, whereas the PNI emerges as a simple and practical biomarker reflecting nutritional and immune status. Integrating PNI with clinicopathological factors may enhance risk stratification and help guide individualized neoadjuvant treatment strategies in HER2-positive breast cancer.

Neoadjuvant immunotherapy for resectable stage III melanoma has demonstrated promising outcomes in recent trials, prompting a change in clinical practice in many countries. Although therapeutic lymph node dissection (TLND) remains the standard of care after neoadjuvant treatment, a less invasive index lymph node (ILN)-guided approach has been proposed. The global melanoma community's acceptance of neoadjuvant immunotherapy and the need for TLND or ILN after this remains unclear. A two-stage international survey was conducted among melanoma experts between May 2023 and January 2025. Respondents were asked about their familiarity with neoadjuvant trials, current practices, and opinions on ILN versus TLND before and after publication of the NADINA trial. The response rates were 50% (118/237) in the first survey and 62% (148/237) in the second survey. In the second survey, 74% of the respondents considered neoadjuvant therapy the standard of care, and support for ILN-guided surgery rose from 27 to 40% between the surveys. However, 54% still favored a phase 3 randomized controlled trial before changing the clinical practice guidelines, and only 27% believed the current data were sufficient for adoption of ILN as standard. Key barriers included concerns about oncologic safety, pathologic standardization, and patient selection. The current evidence supports the use of neoadjuvant immunotherapy as the standard of care for stage III melanoma. However, widespread clinical adoption of ILN-guided surgical de-escalation remains limited. A multicenter phase 3 trial (MSLT-3), launching in 2025, is expected to provide important data to guide future practice.

Metastatic disease traditionally classifies gastric cancer as stage M1, precluding surgical intervention and enrolling patients in palliative treatment protocols. This principle holds regardless of the number, the location, and the quantity of metastatic sites. "Oligometastatic disease" is an intermediate state between localized and widely spread gastric cancer. Locoregional treatments may offer long survival or even cure in highly selected cases. There are no evidence-based guidelines for the appropriate management of this clinical entity. Tailored strategic techniques are required to incorporate surgical treatment, when applicable, into the management protocols of these patients. The surgical approach (following neoadjuvant treatment) aiming at R0 resection of neoplasms that are technically or oncologically unresectable, or only borderline resectable at initial evaluation is defined as "conversion therapy". The surgical approach aims at locoregional control of the disease, radical resection of all cancer sites, adequate lymph node cleansing and uncomplicated anastomosis. Disease progression is a clear indication of palliative treatment. In this article, we aim to provide an extensive literature search about current status of oligometastatic gastric disease multimodal treatment. Given the malignancy potential of gastric cancer, the decision for an operative approach should be made with strict criteria by experienced surgeons and rational oncologists.

Outcomes with neoadjuvant osimertinib and/or chemotherapy in patients with EGFR-mutant resectable non-small cell lung cancers.

Intraductal Carcinoma Predicts Poor Response to Neoadjuvant Therapy in High-risk Prostate Cancer: A Retrospective Analysis of a Prospective Trial

Aim of this study is to evaluate the prognostic role of nodal parameter in early stage pathologically patients with N0 who underwent lobectomy and lymphadenectomy. Clinical and pathological characteristics of patients who underwent anatomical lung resection from 1/01/2010 to 31/12/2019 were reviewed and retrospectively analyzed. GGO and part-solid tumors, MIA, AIS, more than 5cm in size, with nodal and/or distant metastases, or receiving neoadjuvant treatment were excluded. Operatory and pathological report were reviewed to collect data on lymphadenectomy. The primary end-point was disease-free survival (DFS), calculated from surgery to recurrence appearance. Clinical/pathological characteristics and nodal parameters were associate to DFS using Kaplan-Meier curves. The log-rank test was used to assess differences between subgroups. A multivariable model was built using Cox-regression analysis, including variable resulting significant (p value<0.05), at univariable analysis. The final analysis was conducted on 487 patients. Most patients presented stage I tumor (82.4%). The mean number of resected nodes (#RN), resected N1 (#RN1) nodes, and resected N2 nodes (#RN2) resulted 9.5±8.0, 3.4±4.3, and 5.9±4.4. The mean number of total resected stations (#RS), N1 resected stations (#RSN1), and N2 resected stations (#RSN2) resulted 2.5±1.6, 1±0.8, and 1.5±1.2, respectively. During a mean follow-up of 43±28months, a recurrence occurred in 137 (28.1%) patients. At univariable analysis, age<70years (p=0.025), N1 lymphadenectomy (p=0.019), #RSN1≥3 (p=0.001), #RN≥10 (p=0.019), #RN1≥3 (p<0.001), node sampling with more than 3 resected nodes (p=0.049), at least 3 stations with 3 N1 nodes resected (p=0.013), at least 3 stations resected with 10 lymphnodes, and 3N1 lymphnodes (p=0.020) significantly correlated with improved DFS. Multivariable analysis confirmed as independent prognostic factor #RN1≥3 (p=0.017; HR 1.782; and 95% CI: 1.107-2.867). Patients with #RN1≥3 presented a 5-years DFS of 76.3% versus 57.8% of patients with #RN1<3 (p=0.001). Hilar lymphadenectomy seems to significantly correlate with disease-free survival in patients with pN0NSCLC and should be better defined in lymphadenectomy guidelines.

Colorectal cancer is a significant global health burden, with locally advanced colon cancer (LACC) comprising up to 20% of cases and associated with high rates of local recurrence and distant metastases. Although neoadjuvant chemotherapy (NAC) is well established in several gastrointestinal malignancies, its role in LACC and locally recurrent colon cancer remains debated. This study aimed to assess the perceptions and current practices of colorectal surgeons in Australia and New Zealand regarding the use of neoadjuvant therapies in these settings. A structured 16-question online survey was distributed via Qualtrics to 275 colorectal surgeons affiliated with the Colorectal Surgical Society of Australia and New Zealand (CSSANZ). The survey included demographic questions and 13 clinical scenarios addressing the management of LACC and locally recurrent colon cancer without distant metastases. Responses were collected over 1 month, with one reminder sent at 2 weeks. Data were analyzed using Microsoft Excel, and responses were presented as percentages with bar graphs illustrating management preferences. Ninety-seven surgeons (35.3% response rate) completed the survey; 86% were based in Australia and 70% had more than 5 years of consulting experience. Overall, 57% of respondents had previously employed neoadjuvant chemotherapy ± radiotherapy for non-metastatic LACC. In T4N0 disease, 54.3% opted for upfront resection, while 46% favored neoadjuvant strategies (29.4% chemotherapy and 16.3% chemoradiotherapy). For T4N1/2 disease, 63.5% preferred neoadjuvant therapy. Management varied in more complex scenarios: in obstructing cecal cancers with retroperitoneal invasion, 75% favored upfront resection; in non-obstructing transverse colon cancers invading the liver and sigmoid cancers with bladder invasion, decisions were split between upfront surgery and neoadjuvant treatment. For locally recurrent cancers, the majority preferred upfront surgery in non-T4 cases (68.5%), whereas over half (56.5%) opted for neoadjuvant therapy for T4 recurrent disease, particularly when vascular structures were involved. The survey reveals a paradigm shift among colorectal surgeons in Australia and New Zealand toward incorporating neoadjuvant therapies for managing LACC and locally recurrent colon cancer. While upfront resection remains standard of care, there is increasing adoption of neoadjuvant strategies to downstage tumors and potentially improve oncological outcomes. Further high-quality evidence and randomized controlled trials are warranted to refine patient selection and optimize treatment protocols in these challenging clinical scenarios.

The optimal management of oestrogen receptor (ER)-low HER2-negative breast cancer (BC) is unclear. We surveyed current approaches of UK clinicians in ER-low BC, and also present outcomes of ER-low early BC at single centre. Survey: We conducted an anonymised online survey of clinicians treating BC in the UK between 6May and 5June 2024. Participants were presented with clinical scenarios of ER-low (Allred ER3/ER4) BC with multiple-choice and free-text questions. Clinical audit: Patients diagnosed with stageI-III, ER2-4 HER2-negative BC undergoing neoadjuvant treatment (chemotherapy vs. chemo-immunotherapy) from 1January 2017 to 31December 2023 were included. Clinical data was collected retrospectively at Barts Health NHS Trust, London, UK. The primary endpoint was pathological complete response (pCR). Survey: Of 72 survey respondents, 40% recommended neoadjuvant chemo-immunotherapy for ER3 disease vs. 10% for ER4 disease; 57% recommended adjuvant endocrine therapy for ER3 disease, and 90% for ER4 disease. In the advanced setting 75% recommended chemo-immunotherapy for PD-L1-positive ER3 disease with 7% recommending CDK4/6 inhibitors. For PDL1-positive ER4 disease, these percentages were 32% and 51% respectively. In PDL1-negative disease, chemotherapy rates were 81% for ER3 and 36% for ER4 disease. Clinical audit: Sixty-six patients receiving neoadjuvant treatment were included, with 29 belonging to the ER2, 30 belonging to the ER3 and 7 belonging to the ER4 groups respectively; 33% received neoadjuvant chemo-immunotherapy. pCR rate was 61%, with no association with ER score for chemotherapy (p = 0.319) and chemo-immunotherapy (p = 0.603). There is marked variation in approach to ER-low in the UK. The audit data suggests treating ER-low BC as triple-negative BC.

Rectal cancer has become a significant health concern in current years, but there are very effective current neo-adjuvant treatment modalities which can result in the complete disappearance of the disease without surgery, which is often associated with severe post-surgical sequelae. Therefore, a significant effort has been made to identify the subset of patients who can avoid surgery and to investigate the long-term oncologic and functional results associated with the Non-Operative Management of such a disease.

Background and Objectives: To evaluate the prognostic value of the Clinical–Pathologic Stage–Estrogen receptor status and Grade (CPS+EG) staging system, which combines clinical staging, pathological staging, oestrogen receptor (ER) status, and tumour grade in predicting survival outcomes in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving neoadjuvant therapy (NACT). Materials and Methods: A retrospective review was performed on 245 female breast cancer patients who received anti-HER2 therapy alongside NACT at the Medical Oncology Department of Kartal Dr Lütfi Kırdar City Hospital, University of Health Sciences, from April 2012 to June 2024. The CPS+EG score was calculated using the MD Anderson Cancer Centre neoadjuvant treatment response calculator. Patients were categorised into two groups based on their CPS+EG score < 3 and ≥3. The primary outcomes assessed were disease-free survival (DFS) and overall survival (OS). Kaplan–Meier and log-rank tests were utilised for time-to-event analysis; Cox regression was used for multivariate analysis. A significance level of ≤0.05 was considered. Results: The median age of the patient cohort was 51 years (range: 27–82 years). Among these patients, 183 (74.6%) had a CPS+EG score less than 3, while 62 (25.3%) exhibited a score of 3 or higher. The median follow-up duration was 37.6 months. The pathological complete response (pCR) rate across the entire cohort was 51.8%. Specifically, the pCR rate was 56.3% in the group with CPS+EG scores below 3, and 38.7% in those with scores of 3 or higher (p = 0.017). Patients with CPS+EG scores less than 3 demonstrated superior overall survival (OS), which reached statistical significance in univariate analysis. Multivariate analysis identified the CPS+EG score as an independent prognostic factor for both overall survival and disease-free survival (DFS), with hazard ratios of 0.048 (95% CI: 0.004–0.577, p = 0.017) and 0.35 (95% CI: 0.14–0.86, p = 0.023), respectively. Conclusions: The CPS+EG score is an independent and practical prognostic marker, particularly for overall survival, in patients with HER2-positive breast cancer who have received neoadjuvant therapy. Patients with a CPS+EG score < 3 have higher pCR rates and survival rates. When used in conjunction with pCR, it can improve risk categorisation and contribute to the individualisation of adjuvant strategies in the post-neoadjuvant period. Due to its ease of calculation and lack of additional costs, this score can be instrumental in clinical practice for identifying high-risk patients. Our findings support the integration of the CPS+EG score into routine clinical decision-making processes, although prospective validation studies are necessary.

Simple SummaryProstate cancer is the second most common malignancy among men, and the number of new cases is projected to increase substantially in the coming years. To assess the current state of knowledge on the economic burden of this disease, we conducted a literature review that included 31 studies. Our analysis focused on estimates of direct costs—such as treatment, adjuvant and neoadjuvant therapies, and supportive and palliative care—as well as indirect costs. However, the vast majority of studies addressed direct costs only, highlighting a clear gap in the literature. This accentuates the need for further comprehensive reviews and the development of standardized methodologies to enable reliable comparisons across studies.Background: Prostate cancer is the second most common malignant cancer among men, and according to the predictions, the estimated number of new cases will substantially grow in the coming years. Therefore, the costs of the disease will increase as well. Methods: We conducted a literature review of the state of knowledge about the costs of treatment and the economic burden of prostate cancer. The vast majority of studies were focused on direct costs only, which clearly shows the literature gap. Results: We focused on the estimates of direct costs, i.e., treatment of prostate cancer, adjuvant and neoadjuvant treatment, and supportive and palliative care, and indirect costs. Cost-effectiveness analyses indicated that docetaxel combined with androgen deprivation therapy (ADT) was the most cost-effective strategy for metastatic hormone-sensitive prostate cancer (incremental cost-effectiveness ratio (ICER): USD 13,647). In contrast, novel therapies such as PARP inhibitors and whole-genome-sequencing-guided treatments were not cost-effective unless drug prices were reduced by 47–70%. In the United States, 5-year cumulative treatment costs ranged from USD 48,000 for conservative management to over USD 91,000 for radiotherapy, while out-of-pocket expenses averaged AUD 1172 in Australia. Indirect costs were also considerable, with Slovakia reporting an increase in sick leave costs from EUR 1.2 million in 2014 to EUR 2.1 million in 2022. Conclusions: Metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer were the most frequent categories for various treatment cost evaluations. A few specific combinations of drugs were cost-effective only under the condition of dropping the unit prices of a medication. Further summarizing, reviewing, and developing a methodology for standardized comparisons are needed.

Treatment paradigms for patients with locally recurrent rectal cancer (LRRC) have shifted from palliative approaches to multimodal curative-intent treatment in selected patients. This retrospective cohort study evaluates survival outcomes following curative-intent treatment in patients with LRRC. All consecutive patients with LRRC undergoing curative-intent treatment at a tertiary referral center between 2014 and 2024 were retrospectively analyzed (n=147). Overall survival (OS), local re-recurrence-free survival (LRFS), metastasis-free survival (MFS), and prognostic factors were analyzed using Kaplan-Meier and Cox regression analyses. 147 patients underwent neoadjuvant treatment with curative intent at baseline. After response assessment, 117/147 (80%) patients continued curative therapy, which consisted of 109/117 (93%) patients undergoing surgery and a highly selected group of 8/117 (7%) patients monitored with a watch-and-wait strategy. For the remaining 30/147 patients (20%), treatment intent changed from curative to palliative. Median OS was 54months with a 5-year OS of 47%. For patients treated with an overall curative intent (n=117), median OS was 63months with a 5-year OS of 58%. Clear resection margins, achieved in 76% of surgical cases, was a prognostic factor for OS and LRFS: 5-year OS was 66% for R0-resections and 33% for R1-resections (p<0.001), and 3-year RFS was 69% for R0-resections and 50% for R1-resections (p<0.001). Among the watch-and-wait group, 5/8 patients remained alive and disease-free (median follow-up 14months (IQR 9-16)). This single-center retrospective cohort study demonstrates reasonably good oncological outcomes following curative-intent LRRC treatment. Further investigation of watch-and-wait strategies in highly selected patients is warranted.

Abstract Purpose: Exploratory data suggest a benefit of an immune checkpoint inhibitor (ICI) monotherapy window in early triple-negative breast cancer (TNBC). The neoMono trial prospectively investigated whether the addition of an atezolizumab monotherapy window before neoadjuvant atezolizumab and chemotherapy improves pathologic complete remission (pCR) rates in early TNBC. Patients and Methods: neoMono is a phase 2 randomized multicenter trial that recruited patients with primary TNBC larger than 10 mm. Neoadjuvant treatment in both arms consisted of neoadjuvant atezolizumab and chemotherapy, with treatment in arm A preceded by atezolizumab monotherapy 2 weeks before combination therapy. This study used a Bayesian trial design. Results: A total of 359 patients were included. Overall, pCR rates in study arms A and B were similar (intention-to-treat population: 65.7% and 69.0%, respectively). In an exploratory analysis, pCR rates in PD-L1–positive tumors were 91.5% in arm A and 82.2% in arm B. The corresponding pCR rates in the PD-L1–negative group were 56.1% in arm A and 64.5% in arm B. In patients with low-risk TNBC (cT1c and cN0), pCR rates in the PD-L1–positive group were 100.0% in arm A and 90.0% in arm B, and the corresponding pCR rates in the PD-L1 (immune cell)–negative group were 65.9% and 76.3%, respectively. Conclusions: The neoMono trial demonstrated the highest pCR rates reported in a phase II/III trial in TNBC, particularly in the case of PD-L1 positivity. Although no significant impact of an ICI monotherapy window on the pCR rate in the unselected intention-to-treat population could be demonstrated, our data reinforce the use of combinations of neoadjuvant chemotherapy and ICI in this indication.

Abstract Background Immune checkpoint inhibitor treatment in non-small cell lung cancer (NSCLC) expands to early stages of disease. The neoadjuvant setting allows to investigate the mechanism-of-action of immune therapy using molecular imaging and tissue analysis. We investigated the safety and feasibility of programmed cell death ligand-1 (PD-L1) PET-imaging with 89Zr-labeled avelumab and neoadjuvant avelumab treatment in resectable NSCLC. Secondly, [89Zr]Zr-DFO-avelumab accumulation was correlated with features of the tumor immune microenvironment and pathological response. Methods This phase I-II study (NCT03514719) enrolled 20 patients with stage Ia-IIIa NSCLC who received 2 cycles of avelumab (10mg/kg Q2W) prior to surgery. In the imaging optimization part, [89Zr]Zr-DFO-avelumab PET was performed with protein doses of 2mg, 10mg or 50mg avelumab and imaging at day 2 and 4 post-injection. Subsequent patients were scanned with 10mg [89Zr]Zr-DFO-avelumab at day 4. Tracer-accumulation was correlated to PD-L1 expression and immune cell densities on pretreatment biopsies. Results [89Zr]Zr-DFO-avelumab PET/CT was successfully performed in 23/24 patients. 19/20 patients started neoadjuvant avelumab treatment, with no delays or conversions of surgical procedures. Six patients showed pathologic response, including two major pathologic responses. [89Zr]Zr-DFO-avelumab tumor-accumulation was not correlated to PD-L1 expression, but did correlate with regulatory T-cell density (r=0.72, p=0.030) and pathologic response (r=0.56, p=0.036); and was inversely correlated with CD303+ plasmacytoid dendritic cell density (r=-0.72, p=0.030). SUVpeak on baseline [18F]FDG-PET correlated with pretreatment PD-L1 expression but not with [89Zr]Zr-DFO-avelumab accumulation nor with pathologic response. Conclusion [89Zr]Zr-DFO-avelumab PET imaging is a safe and feasible approach in early-stage NSCLC. Higher [89Zr]Zr-DFO-avelumab tumor-accumulation at baseline strongly correlates with features of a suppressive tumor immune environment and response to neoadjuvant avelumab.