Clinical Tumor Response Research Articles

INNV-12. CUTANEOUS TOXICITIES OF MITOGEN-ACTIVATED PROTEIN KINASE INHIBITORS IN CHILDREN AND YOUNG ADULTS WITH NEUROFIBROMATOSIS-1

Abstract BACKGROUND Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. Cutaneous adverse events (CAEs) are common and may hinder patients’ abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1. METHODS We reviewed institutional medical records of patients under 30 years with a diagnosis of “NF1,” “NF2,” or “other neurofibromatoses” on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response. RESULTS The median age of 40 patients with NF1 was 14 years old. Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%) (Table 1). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%) (Figure 1). Twenty-three out of the 28 cases of acneiform eruption were in post-pubertal patients (82.1%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi (Table 2). There was no significant association between CAE presence and tumor response (p=0.39). CONCLUSIONS MEK inhibitors have been demonstrated as a valuable treatment, but CAEs complicate the ability to stay on the treatment. Most patients in our cohort developed a CAE, demonstrating its prevalence in this population. Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.

Pathological responses of primary tumor and lymph nodes in non-small cell lung cancer after neoadjuvant chemoimmunotherapy: a retrospective real-world study.

In patients with non-small cell lung cancer (NSCLC) receiving neoadjuvant chemoimmunotherapy (NCIT), inconsistent pathological responses between the tumor and lymph nodes (LNs) are often observed. There has been limited evidence comparing the different responses of tumors and LNs in those patients. This retrospective real-world analysis intended to evaluate the clinical and pathological response of primary tumors and LNs, and the long-term outcomes in NSCLC patients after NCIT. We included resectable NSCLC patients who had received neoadjuvant therapy and had available clinicopathological records. The progression-free survival (PFS) and overall survival (OS) outcomes were analyzed using survival analysis. In total, 204 patients were included in the final analysis. Patients were predominantly male (85.8%) and ever-smokers (66.2%), with a median age of 63 years. No significant difference was observed in intraoperative bleeding (P=0.51 and P=0.54) and operation time (P=0.57 and P=0.58) between the major pathologic response (MPR) and pathological complete response (pCR) group, respectively. Patients who were male (pCR, P=0.01; MPR, P=0.004), with squamous cell carcinoma (SCC) (pCR, P=0.02; MPR, P=0.001), and overall response rate (ORR) (pCR, P<0.001; MPR, P<0.001) demonstrated significantly higher rates of pCR and MPR. The median follow-up time for all patients in this study was 23 months. Patients with MPR (P=0.004) and pCR (P=0.02) experienced prolonged PFS, but not OS (MPR, P=0.08; pCR, P=0.15). In terms of yield pathological tumor MPR (ypTMPR) and yield pathological LNs stage (ypN), Kaplan-Meier analyses demonstrated that there was a better PFS for the ypTMPR(+)/ypN(0) group, followed by ypTMPR(-)/ypN(0), ypTMPR(+)/ypN(0), and ypTMPR(-)/ypN(1+2) (P=0.01). The average PFS time was 35.7, 31.7, 29.4, and 28.7 months, respectively. After achieving MPR, the probability of local recurrence or distant metastasis was 7.3%, 25%, 23.5%, and 23.7%, respectively. In this real-world study, the combination of tumor and LNs responses was significantly associated with prognosis, and we demonstrated that ypTMPR(+)/ypN(0) group had a better prognosis, followed by ypTMPR(-)/ypN(0), ypTMPR(+)/ypN(0), and ypTMPR(-)/ypN(1+2). We advocate for ypTMPR(+)/ypN(0) status as a better surrogate of PFS in resectable NSCLC patients after NCIT.

Hepatic artery infusion pump (HAIP) therapy in combination with targeted delivery of IL-12 for patients with metastatic colorectal cancer or intrahepatic cholangiocarcinoma: a phase II trial protocol.

Treatment of advanced liver tumors remains challenging. Although immune checkpoint inhibition has revolutionized treatment for many cancers, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. Investigation into additional immunomodulatory therapies for these cancers is needed. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with robust anti-tumor activity, but systemic adverse effects largely terminated therapeutic development of recombinant human IL-12 (rhIL-12). PDS01ADC is a novel human monoclonal antibody (NHS76) conjugated to two IL-12 heterodimers with established safety in phase I trials. The NHS76 antibody specifically targets histone/DNA complexes which are accessible only in regions of cell death and this antibody has been shown to accumulate locally in tumors. Patients with unresectable metastatic colorectal cancer (mCRC) or unresectable intrahepatic cholangiocarcinoma (ICC) will receive synchronization of subcutaneous PDS01ADC with floxuridine delivered via a hepatic artery infusion pump (HAIP). The primary outcome measured in this study will be overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes measured in this study will include hepatic and non-hepatic progression-free survival (PFS), overall survival, and safety of PDS01ADC combination therapy with HAIP. Poor clinical response of these liver tumors to immunotherapy is likely due to various factors, including poor immune infiltrate into the tumor and immunosuppression by the tumor microenvironment. By exploiting the tumor cell death induced by HAIP locoregional therapy in combination with systemic chemotherapy, PDS01ADC is poised to modulate the tumor immune microenvironment to improve outcomes for patients undergoing HAIP therapy. ClinicalTrials.gov (ID NCT05286814 version 2023-10-18); https://clinicaltrials.gov/study/NCT05286814?term=NCT05286814&rank=1.

ESORES-Trial: Surgery as needed versus surgery on principle in patients with postneoadjuvant clinical complete tumor response of esophageal cancer.

TPS4185 Background: A substantial fraction of patients with esophageal cancer (EC) shows post-neoadjuvant pathological complete response (pCR). Principal esophagectomy after neoadjuvant treatment is the standard of care for all patients. Active surveillance (AS) and surgery as needed may be a treatment alternative for patients with clinical complete response (cCR). Methods: ESORES is a multicenter randomized controlled parallel-group non-inferiority trial. Patients are randomized either to surgery on principle and subsequent follow-up (Arm B) or clinical response evaluation (CRE) and surgery as needed (Arm A). CRE consists of esophagogastroscopy with deep biopsies (EGD), endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) of suspicious lymph nodes, and F18-FDG-PET CT. In case of residual tumor (non-CR) after CRE, treatment is surgery. Patients with cCR will proceed with AS and surgery only if local regrowth occurs. AS comprises EGD, EUS-FNA and CT-Thorax/Abdomen at 3/6/9/12/18/24 months and yearly thereafter. A sample size of 670 patients is needed to demonstrate non-inferiority of Arm A vs. Arm B with regard to overall survival (OS) at a one-sided significance level of 5%, choosing a hazard ratio of 1.325 as non-inferiority margin which corresponds to a difference in 3-year OS rates of 8%. Superiority with regard to quality of life will be evaluated hierarchically only after non-inferiority with respect to OS has been shown. Key inclusion criteria: histologically verified EC, TNM stage ycT0-3 ycN0 ycM0, completion of neoadjuvant chemotherapy (nCT) or chemoradiation (nCRT) (irrespective of specific protocol), no visible lymphatic or distant metastasis in routine postneoadjuvant CT. Key exclusion criteria: postneoadjuvant dysphagia and/or esophageal obstruction, tumors of the cervical esophagus, tumors with direct proximity to the membranous part of the central airways (if regrowth is suspected to evoke locally irresectable ryT4b-stage), TNM stage cT4/ycT4 and/or cM1/ycM1, tumor progression during/after nCT/nCRT, and nCRT with &gt;50 Gy radiation dose. Primary endpoints (hierarchically tested): 1) OS, 2) EORTC QLQ C30 global quality of life subscale. Secondary endpoints: Efficacy: long term tumor control, disease free survival, distant metastasis/local recurrence/regional recurrence; quality of life: EORTC QLQ C30, QLQ OES18, fear of progression: FoP-Q-12, surgery-free survival time in Arm A, patients’ satisfaction: EORTC OUT-PATSAT7; economic impact: days and costs of hospitalization; Safety: Interventional Safety: 3-Year-Comprehensive Complication Index, Oncological Safety (diagnostic accuracy of CRE, resection status (R0/R1/R2), irresectable regrowth during AS). Enrollment of patients started on January 30th, 2024. Clinical trial information: DRKS00032613 .

Clinical and Pathologic Tumor Response Following Response-guided Neoadjuvant Chemotherapy for Locally-advanced Breast Cancer in a Tertiary Hospital Breast Center in the Philippines

Clinical and Pathologic Tumor Response Following Response-guided Neoadjuvant Chemotherapy for Locally-advanced Breast Cancer in a Tertiary Hospital Breast Center in the Philippines

A single-arm phase II study of platinum doublet induction chemotherapy combined with toripalimab for driver gene-negative advanced NSCLC.

e20565 Background: PD-1/PD-L1 inhibitors combined with platinum doublet chemotherapy have become the standard first-line treatment for driver gene-negative advanced non-small cell lung cancer (NSCLC). However, not all patients can benefit from this treatment. Previous studies have shown that induction chemotherapy can reduce tumor burden, induce tumor immunogenic cell death, and improve the tumor immune microenvironment. Therefore, effective induction chemotherapy may enhance the efficacy of PD-1/PD-L1 immunotherapy. This single-arm, phase II clinical trial aims to evaluate the efficacy and safety of induction chemotherapy followed by immunotherapy (Toripalimab: PD-1 inhibitor) in treatment of driver gene-negative advanced NSCLC. Methods: Eligible patients received platinum doublet chemotherapy for 2-4 cycles (pemetrexed + platinum for adenocarcinoma; paclitaxel or gemcitabine + platinum for squamous cell carcinoma). patients who achieved tumor response (CR/PR/SD) received Toripalimab (240mg Q3W) for 2 years or until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS), which was defined as the duration from the initiation of induced chemotherapy to either tumor progression or death from any cause,and the secondary endpoints were toxicity, overall survival (OS), and clinical tumor response including objective response (defined as complete [CR] or partial response [PR]) and disease control (defined as CR, PR, or stable disease [SD]) during the course of combination treatment with Toripalimab following induction chemotherapy. Results: During the period from February 2020 through October 2023, a total of 19 qualified patients were enrolled in the study. As of December 31. 2023,the median follow-up was 22,9 months (range,15.9 to 30 months).11 patients (57.9%) experienced PFS events and 7 (36.8%) died, mOS were not reached. mPFS was 7.9 mo (95% CI,4.8-15.0months).12-month and 18-month PFS rate were 43% and 35%, respectively. One patient has not received tumor response assessment. Among the remaining 18 pts, 10 patients had a PR,5 patients had SD, and 3 patients had PD. The ORR and DCR were 55.6% and 83.3% respectively.42.1% (8/19) pts experienced immune-related adverse events(irAEs), included immune-related pneumonia (21.1%), rash (10.5%), hypothyroidism (10.5%). 2 pts experienced ≥3 grade irAEs, including grade 3 rash and grade 4 immune-related thrombocytopenia. Conclusions: Induction chemotherapy combined with Toripalimab achieved impressive 12-month and 18-month PFS rates in pts with driver gene-negative advanced NSCLC, along with manageable toxicities. These findings demonstrate the potential of induction chemotherapy could enhance the efficacy of immunotherapy. Clinical trial information: NCT04613804 .

Abstract PO1-28-07: Neoadjuvant docetaxel plus cisplatin versus docetaxel plus doxorubicin and cyclophosphamide in early-stage triple-negative breast cancer (HNBC-001): results from a multicenter, randomized controlled, open-label phase II trial

Abstract Background: Adding platinum to anthracycline- and taxane-based neoadjuvant chemotherapy has improved pathological complete response (pCR) in patients with triple-negative breast cancer (TNBC). However, the efficacy of combining docetaxel and platinum without anthracycline remains controversial. Methods: The HNBC-001 trial was a randomized, phase 2 controlled, and open-label investigation carried out in China at 6 hospitals. The participants who were aged 18–70 years, were histologically confirmed for TNBC clinical stage II–III, suitable for potentially curative surgery, and had an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1 were selected for this trial. Participants were randomly categorized into two equal groups; those who received docetaxel plus cisplatin (75 mg/m2, respectively) and those who received docetaxel plus doxorubicin and cyclophosphamide (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2). These regimens were given every 3 weeks for 6 cycles. Randomization was stratified by tumor size and nodal status. The primary endpoint was the number of individuals achieving a pCR (ypT0/is ypN0). The trial was registered with chictr.org (number ChiCTR-1800019501). Results: Between November 28, 2018, and June 11, 2022, 212 patients were selected (n=106/treatment). The number of individuals who achieved pCR after docetaxel plus cisplatin treatment was 51.9%, and that of those who attained pCR after docetaxel plus doxorubicin and cyclophosphamide was 35.8% (P=0.019). After 21 months of median follow-up [interquartile range (IQR), 13 to 33], 11 of 106 patients (10.4%) in the docetaxel plus cisplatin group and 14 of 106 patients (13.2%) in the docetaxel plus doxorubicin and cyclophosphamide group had event-free survival (EFS) events [95% confidence interval (CI) =0.360 to 1.783, hazard ratio (HR) =0.801, P=0.585]. The incidence of grade 3 or 4 events was similar in both groups [57 (54%) vs. 51 (48%)]. However, no treatment-associated deaths were identified. Conclusions: In stage II to III TNBC, the docetaxel plus cisplatin regimen achieved higher pCR rates than docetaxel plus doxorubicin and cyclophosphamide, with a manageable toxicity profile. Consistent with the literature, the docetaxel plus cisplatin regimen demonstrated a favorable risk-to-benefit profile and could serve as an optimal neoadjuvant chemotherapy option for patients with high-risk TNBC. table 1: Patient characteristics figure 1: Study endpoints Error bars denote 95% CIs based on normal approximation. p values were calculated from the Chi-square test. (A) Frequency of patients who achieved a pathological complete response per treatment group (primary endpoint). (B) Frequency of patients who achieved a clinical breast tumour response per treatment group, assessed by serial MRI scans after completion of neoadjuvant treatment. (C) Frequency of patients who achieved a minimal residual disease (residual cancer burden class 0 or 1). (D) Frequency of patients who received breast-conservation surgery. table 2: Treatment-emergent adverse events Citation Format: Dechuang Jiao, Jianghua Qiao, Chengzheng Wang, Juntao Li, Xianfu Sun, Zhenduo Lu, Chongjian Zhang, Lianfang Li, Min Yan, Yueqing Feng, Yong Zhou, Miao Deng, Xinlan Liu, Mingde Ma, Haiquan Jia, Qingxin Xia, Xiuchun Chen, Zhenzhen Liu. Neoadjuvant docetaxel plus cisplatin versus docetaxel plus doxorubicin and cyclophosphamide in early-stage triple-negative breast cancer (HNBC-001): results from a multicenter, randomized controlled, open-label phase II trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-28-07.

Abstract CT065: Modakafusp alfa shows intratumoral immune pharmacodynamics (PD) in a subset of patients (pts) in a phase 1b study in advanced/metastatic solid tumors

Abstract Background: Modakafusp alfa (moda), a novel immunocytokine, is an innate immune enhancer comprising an anti-CD38 IgG4 antibody fused to 2 attenuated interferon (IFN) α2b molecules. Moda is being evaluated in phase 1/2 trials for multiple myeloma and in a phase 1/2 trial in solid tumors. Here, we present PD data in tumor biopsies and peripheral blood (PB) from the phase 1/2 study of moda as monotherapy in pts with advanced/metastatic solid tumors (NCT04157517). Methods: A total of 21 pts were treated with moda 0.1-1.5 mg/kg every 3 weeks. Tumor biopsy samples were collected at screening and on cycle 2, day 2 (C2D2). Biopsies were evaluated by multiplex immunofluorescence (using a Multiomyx platform) and RNASeq. PB samples were collected pre-dose on C1D1 and at timepoints after treatment. PB samples were evaluated by CyTOF to assess PD changes in immune cells. Results: No clinical tumor responses (partial or better) were observed in the 21 pts. Analysis of tumor biopsies revealed two subgroups defined by differences in upregulation of CD38 expression after moda treatment, with differential intratumoral PD changes. The CD38 gene has IFN response elements within its promoter region. Thus, correlation of tumor PD with changes in CD38 expression is of interest because, along with being a target of moda, an increase in CD38 expression may indicate drug activity in the tumor microenvironment. Interestingly, in the subset of pts in whom an increase in the percentage of CD38+ lymphocytes in response to moda was reported, there were also increases in CD8 and CD4 T cell activation, (%CD69) as well as CD8 T cell cytotoxic function (%GzB). Additionally, moda led to increase in CD14+CD16+ intermediate monocytes, indicating an enhanced myeloid response in several pts, and minimal changes in FoxP3+ Tregs regardless of changes in CD38 expression. Moda treatment led to an increase in activated and cytolytic natural killer (NK) and CD8 T cells in all pts. This was accompanied by increased NK and CD8 T cell proliferation (%Ki67) in PB, without sustained increase in exhaustion markers. CD4 T cells were also activated in response to moda and there was no increase in circulating FoxP3+ Tregs. Enhanced myeloid cell response, measured by increased proliferation of monocytes and dendritic cells, along with upregulation of costimulatory molecules, were also seen. Importantly, immune PD changes in the PB were seen in most pts and there were no immune PD differences identified between the two patient subsets defined in the biopsy analysis. Conclusion: PD biomarker data from this phase 1/2 trial in pts with advanced solid tumors demonstrated that moda enhances innate and adaptive immune activation in PB and within tumors. The presence of a differential intratumoral PD response in a subset of pts with elevated CD38+ cells highlights that tumor intrinsic factors may play a role in driving moda’s activity in tumors. Citation Format: Gurpanna Saggu, Janet L. Markman, Min Young Lee, Faith Dunbar, Adarsh Joshi, Shining Wang, Sabrina Collins. Modakafusp alfa shows intratumoral immune pharmacodynamics (PD) in a subset of patients (pts) in a phase 1b study in advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT065.

Abstract CT021: Preliminary clinical results of a therapeutic cancer vaccine PDC*lung01 in combination with anti-PD-1 in patients (pts) with stage IV NSCLC

Abstract Background PDC*lung01 (IMP) is a therapeutic cancer vaccine based on an irradiated plasmacytoid dendritic cell line loaded with HLA-A*02:01-restricted peptides (NY-ESO-1, MAGE-A3, MAGE-A4, Multi-MAGE-A, MUC1, Survivin and Melan-A), able to prime and expand peptide-specific CD8+ T cells in vitro and in vivo, and is synergistic with anti-PD-1. Methods In this phase I/II study, HLA-A*02 positive NSCLC pts were enrolled in 4 cohorts: resected stage II/IIIA in adjuvant setting treated with low dose (A1) or high dose (A2) of IMP following SOC; or untreated stage IV NSCLC with measurable disease, PD-L1≥50% and no targetable driver mutation, treated with low dose (B1) or high dose (B2) of IMP in combination to pembrolizumab 200mg q3w, continuously. IMP was simultaneously administered by SC and IV route weekly for 6 consecutive doses. Objective response rate (ORR) and progression-free survival (PFS) were assessed in cohort B2. We report herein preliminary efficacy results of the first 21 pts analysed when the 19th evaluable patient reached the 9-months PFS and the safety of 38 pts. Results Out of 21, 19 pts receiving at least 5 doses of IMP and having 1 post-baseline radiological evaluation were evaluated. The median follow-up was 12.5 months. The best objective response (BOR) included 12 PR (63.2%) and 7 SD (36.8%) with ORR of 63.2% (80% CI 45.9% - 78.2%) and a disease control rate (DCR) of 94.7%. The 9mPFS according to the Kaplan-Meier estimate was 52.1% (80% CI 36.5% - 65.56%). The mPFS was 10.9 months. The median duration of response was 9.49 months. An antigen-specific CD8+ T-cell response was induced against the lung antigens of the IMP in 68.4% of pts. Immune responses with remarkable expanded anti-tumor CD8+ T-cells were observed both in PR and SD. More immune response results will be available in the final analysis of the 45 pts of cohort B2. Treatment-related AEs (TRAEs) were mostly Grade 1-2. Only 1 severe TRAE occurred, a Grade 4 allergic infusion-related reaction, leading to IMP discontinuation. Thirteen pts experienced a serious AE, of which 3 were considered causally related to the IMP. Conclusions The BOR, ORR, DCR, PFS, duration of response and safety of PDC*lung01 in combination with anti-PD-1 showed encouraging signals suggesting that this combination may provide a clinical meaningful tumour response in stage IV NSCLC population with a mild safety profile. Interestingly, the immune response observed confirms the mechanism of action of the IMP in relation to clinical activity. Citation Format: Willemijn Theelen, Maurice Perol, Kristof Cuppens, Ingel Demedts, Frank Borm, Bonne Biesma, Els Wauters, Benoit Colinet, Eva-Lotte Buchmeier, Friederike Althoff, Elvire Pons-Tostivint, Charlotte Van de Kerkhove, Denis Moro-Sibilot, Anne Sibille, Sofie Derijcke, Marcin Skrzypski, Joel Plumas, Beatrice De Vos, Channa Debruyne, Frederique Cantero, Stefanie Adriaenssens, Florence Renard, Johan Vansteenkiste. Preliminary clinical results of a therapeutic cancer vaccine PDC*lung01 in combination with anti-PD-1 in patients (pts) with stage IV NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT021.

Long-term response to MEK inhibitor monotherapy in a patient with papillary thyroid carcinoma harboring BRAF V600E mutation.

Solid tumors harboring mutations in the Braf gene (BRAF) are currently treated by combination Braf/MEK inhibitor therapy, and there is an extensive literature on patient response rates. Alternatively, few studies have documented the clinical response of BRAF mutation-positive solid tumors to MEK inhibitor monotherapy. We report the case of a 57-year-old female diagnosed with papillary thyroid carcinoma and progressive lung metastases initially treated by total thyroidectomy and subsequent thyroid-stimulating hormone suppression therapy. Next-generation sequencing revealed that the tumor harbored a BRAF V600E mutation, and the patient was enrolled in a clinical study of the oral MEK1/2 inhibitor binimetinib. Shortly after starting treatment, the patient experienced pneumothorax due to rapid regression of lung metastases, and computed tomography after 6 months of binimetinib treatment revealed a partial sustained response. One year later, the dose was reduced because of an acneiform rash. After 5 years of binimetinib treatment, lung metastases had regrown, and treatment was switched to the oral multikinase inhibitor lenvatinib. This case demonstrates the potential of MEK inhibitor monotherapy as an alternative treatment for BRAF mutation-positive papillary thyroid carcinoma.

Platelet-to-lymphocyte ratio predicts tumor response and survival of patients with hepatocellular carcinoma undergoing immunotherapies

BackgroundLymphocyte-related factors were associated with survival outcome of different types of cancers. Nevertheless, the association between lymphocytes-related factors and tumor response of immunotherapy remains unclear. MethodsThis is a retrospective study. Eligible participants included patients with unresectable or advanced hepatocellular carcinoma (HCC) who underwent immunotherapy as their first-line treatment. Radiological assessment of tumor response adhered to RECIST 1.1 and HCC-specific modified RECIST (mRECIST) criteria. Univariate and multivariate logistic analyses were employed to analyze clinical factors associated with tumor response. Kaplan-Meier survivial analysis were employed to compare progression‐free survival (PFS) and overall survival (OS) across different clinical factors. Furthermore, patients who received treatment with either a combination of bevacizumab and anti-PD-1(L1) antibody (Beva group) or tyrosine-kinase inhibitor (TKI) and anti-PD-1 antibody (TKI group) were examined to explore the relation between clinical factors and tumor response. ResultsA total of 208 patients were enrolled in this study. The median PFS and OS were 9.84 months and 24.44 months,respectively. An independent factor associated with a more favorable tumor response to immunotherapy was identified when PLR<100. Patients with PLR<100 had longer PFS than other patients, while OS showed no significant difference. Further analysis revealed that PLR exhibited superior prognostic value in patients of the Beva group as compared to those in the TKI group. ConclusionsThere exisits an association between PLR and tumor response as well as survival outcomes in patients receiving immunotherapy, particularly those treated with the combination of bevacizumab and anti-PD-1.

Cutaneous toxicities of mitogen-activated protein kinase inhibitors in children and young adults with neurofibromatosis-1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. However, cutaneous adverse events (CAEs) are common and may hinder patients' abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1. We reviewed institutional medical records of patients under 30 years with a diagnosis of "NF1," "NF2," or "other neurofibromatoses" on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response. Our cohort consisted of 40 patients with NF1 (median age, 14 years). Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi. There was no significant association between CAE presence and tumor response (p = 0.39). Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.

Organ Preservation and Survival by Clinical Response Grade in Patients With Rectal Cancer Treated With Total Neoadjuvant Therapy

Assessing clinical tumor response following completion of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer is paramount to select patients for watch-and-wait treatment. To assess organ preservation (OP) and oncologic outcomes according to clinical tumor response grade. This was secondary analysis of the Organ Preservation in Patients with Rectal Adenocarcinoma trial, a phase 2, nonblinded, multicenter, randomized clinical trial. Randomization occurred between April 2014 and March 2020. Eligible participants included patients with stage II or III rectal adenocarcinoma. Data analysis occurred from March 2022 to July 2023. Patients were randomized to induction chemotherapy followed by chemoradiation or chemoradiation followed by consolidation chemotherapy. Tumor response was assessed 8 (±4) weeks after TNT by digital rectal examination and endoscopy and categorized by clinical tumor response grade. A 3-tier grading schema that stratifies clinical tumor response into clinical complete response (CCR), near complete response (NCR), and incomplete clinical response (ICR) was devised to maximize patient eligibility for OP. OP and survival rates by clinical tumor response grade were analyzed using the Kaplan-Meier method and log-rank test. There were 304 eligible patients, including 125 patients with a CCR (median [IQR] age, 60.6 [50.4-68.0] years; 76 male [60.8%]), 114 with an NCR (median [IQR] age, 57.6 [49.1-67.9] years; 80 male [70.2%]), and 65 with an ICR (median [IQR] age, 55.5 [47.7-64.2] years; 41 male [63.1%]) based on endoscopic imaging. Age, sex, tumor distance from the anal verge, pathological tumor classification, and clinical nodal classification were similar among the clinical tumor response grades. Median (IQR) follow-up for patients with OP was 4.09 (2.99-4.93) years. The 3-year probability of OP was 77% (95% CI, 70%-85%) for patients with a CCR and 40% (95% CI, 32%-51%) for patients with an NCR (P < .001). Clinical tumor response grade was associated with disease-free survival, local recurrence-free survival, distant metastasis-free survival, and overall survival. In this secondary analysis of a randomized clinical trial, most patients with a CCR after TNT achieved OP, with few developing tumor regrowth. Although the probability of tumor regrowth was higher for patients with an NCR compared with patients with a CCR, a significant proportion of patients achieved OP. These findings suggest the 3-tier grading schema can be used to estimate recurrence and survival outcomes in patients with locally advanced rectal cancer who receive TNT. ClinicalTrials.gov Identifier: NCT02008656.

Epidermal Growth Factor Receptor Exon 19 Deletion Subtypes Do Not Influence Survival Outcomes Following First-line Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitors in Advanced Nonsmall Cell Lung Cancer Patients

Abstract Background: Several deletion and insertion subtypes occur in exon 19 of the epidermal growth factor receptor (EGFR) gene, collectively called exon 19 deletions (del19), and are one of the common EGFR mutations in nonsmall cell lung cancer (NSCLC). Previous studies have shown that del19 subtypes might influence the response to tyrosine kinase inhibitors (TKIs), but their findings have been inconsistent. Therefore, this study aimed to evaluate the impact of del19 subtypes in an Asian population and provide additional evidence on this issue. Materials and Methods: NSCLC patients treated at Chang Gung Medical Hospitals between 2011 and 2018 were retrospectively reviewed. Their clinicopathological characteristics, clinical tumor response, progression-free survival (PFS), and overall survival (OS) were collected. PFS was evaluated among different del19 subtypes and EGFR-TKIs. Results: This study included 164 patients with NSCLC carrying an EGFR del19 mutation who had detailed information about their del19 subtype and were treated with frontline EGFR-TKIs (39 with afatinib and 125 with gefitinib/erlotinib). In this cohort, del19 subtypes did not influence PFS and OS based on different classifications, including start codon of deletion, the number of deleted nucleotides, or pure deletion versus mixed deletion/insertion/substitution. In addition, afatinib generally showed better PFS than gefitinib/erlotinib, particularly and significantly for patients with the p. E746_A750 mutation, a common 15 nucleotide deletion, or a pure deletion without insertion/substitution. Conclusion: In this study, del19 subtypes did not influence PFS and OS with EGFR-TKIs. Afatinib showed better activity than first-generation TKIs and should be preferred for patients with del19 mutations.

Clinical Tools for Rectal Cancer Response Assessment following Neoadjuvant Treatment in the Era of Organ Preservation.

Local tumor response evaluation following neoadjuvant treatment(s) in rectal adenocarcinoma requires a multi-modality approach including physical and endoscopic evaluations, rectal protocoled MRI, and cross-sectional imaging. Clinical tumor response exists on a spectrum from complete clinical response (cCR), defined as the absence of clinical evidence of residual tumor, to near-complete response (nCR), which assumes a significant reduction in tumor burden but with increased uncertainty of residual microscopic disease, to incomplete clinical response (iCR), which incorporates all responses less than nCR that is not progressive disease. This article aims to review the clinical tools currently routinely available to evaluate treatment response and offers a potential management approach based on the extent of local tumor response.

The dynamics of circulating tumour DNA (ctDNA) during treatment reflects tumour response in advanced melanoma patients.

Despite the introduction of targeted (BRAFi/MEKi) and immune checkpoint inhibitors (ICIs) has significantly reduced the recurrence rate and improved the overall survival (OS) of patients with Stage III and IV melanoma, only a percentage will benefit of durable disease control. The aim of this study was to examine whether the levels of circulating tumour DNA (ctDNA) in plasma of advanced melanoma patients undergoing BRAFi/MEKi or ICIs vary according to the patients' survival outcomes (i.e. progression-free survival (PFS) and OS) and disease progression. Plasma samples of Stage III-IV melanoma patients were collected at baseline (treatment initiation) and thereafter every 3 months. Circulating BRAFV600E/K and NRASQ61R/K mutations were analysed through droplet digital PCR (ddPCR, Bio-Rad) in a total of 177 plasma samples from 48 melanoma patients (19 Stage III, 29 Stage IV). Baseline ctDNA concentration was significantly associated with OS (HR = 1.003, 95% CI = 1.000-1.006, p = 0.043) and PFS (HR = 1.004, 95% CI = 1.000-1.007, p = 0.029) independent of clinical-prognostic confounders. For each unit increase in the ∆ctDNA (concentration difference between the last follow-up and baseline) there was a 24% increased risk of disease progression, irrespective of treatment type and stage at diagnosis (OR = 1.24, 95% CI = 1.03-1.49, p = 0.020, AUC = 0.93). Patients with reduction of ctDNA level from baseline to the last follow-up had longer OS (HR = 0.14; 95% CI = 0.05-0.44, p = 0.001) and PFS (HR = 0.08; 95% CI = 0.03-0.27, p < 0.0001) compared to patients with increased ctDNA, including adjustment for confounding factors. Our findings suggest that variation of ctDNA over time during melanoma treatment reflects the clinical outcome and tumour response to therapy and might be helpful in clinical monitoring.

Significance of neutrophil to lymphocyte ratio as a predictor of outcome in head and neck cancer treated with definitive chemoradiation.

The role of host immune system in carcinogenesis and response to treatment is increasingly studied, including predictive potential of circulating neutrophils and lymphocytes. The objective of the study was to evaluate the prognostic value of pre- and post-treatment neutrophil-to-lymphocyte (NLR) for treatment outcome in patients diagnosed with squamous cell carcinoma of head and neck (HNSCC) treated with definitive chemoradiation. Electronic medical records of patients were evaluated and NLR was calculated. Cox regression was used to assess the impact of selected variables on overall survival (OS), disease specific survival (DSS), progression free survival (PFS) and distant failure free survival (DFFS). Logistic regression was used to estimate odds ratios of complete response with NLR. 317 patients' records were included in the study. Increases in both pre-and post-NLR were associated with decreased OS in univariable analysis [hazard ratio (HR): 2.26 (1.25-4.07), p = 0.0068 and HR: 1.57 (1.03-2.37), p = 0.035 respectively). Post-NLR remained significant for OS in multivariable analysis [HR: 1.93 (1.22-3.1), p = 0.005] as well as for unfavorable DSS [HR: 2.31 (1.22-4.4), p = 0.01]. Pre-treatment NLR and nodal status correlated with shorter DFFS in multivariable analysis [HR 4.1 (1.14-14), p = 0.03 and HR 5.3: (1.62-18), p = 0.0062, respectively]. Strong correlation of increased both pre- and post-NLR with probability of clinical tumor response (CR) was found [odds ratio (OR): 0.23 (0.08-0.6), p = 0.003, and OR: 0.39 (0.2-0.8), p = 0.01 respectively]. NLR evaluated before and post treatment was a strong predictor of unfavorable treatment outcome and can be used for risk evaluation and clinical decision about treatment and post-treatment surveillance.

Genomic landscape of locally advanced rectal adenocarcinoma: Comparison between before and after neoadjuvant chemoradiation and effects of genetic biomarkers on clinical outcomes and tumor response.

To explore genomic biomarkers in rectal cancer by performing whole-exome sequencing. Pre-chemoradiation (CRT) biopsy and post-CRT surgical specimens were obtained from 27 patients undergoing neoadjuvant CRT followed by definitive resection. Exomes were sequenced to a mean coverage of 30×. Somatic single-nucleotide variants (SNVs) and insertions/deletions (indels) were identified. Tumor mutational burden was defined as the number of SNVs or indels. Mutational signatures were extracted and fitted to COSMIC reference signatures. Tumor heterogeneity was quantified with a mutant-allele tumor heterogeneity (MATH) score. Genetic biomarkers and frequently occurred copy number alterations (CNAs) were compared between pre- and post-CRT specimens. Their associations with tumor regression grade (TRG) and clinical outcomes were explored. Top five mutated genes were APC, TP53, NF1, KRAS, and NOTCH1 for pre-CRT samples and APC, TP53, NF1, CREBBP, and ATM for post-CRT samples. Several gene mutations including RUNX1, EGFR, and TP53 in pre-CRT samples showed significant association with clinical outcomes, but not with TRG. However, no such association was found in post-CRT samples. Discordance of driver mutation status was found between pre- and post-CRT samples. In tumor mutational burden analysis, higher number of SNVs or indels was associated with worse treatment outcomes. Six single-base substitution (SBS) signatures identified were SBS1, SBS30, SBS29, SBS49, SBS3, and SBS44. The MATH score decreased after CRT on paired analysis. Less than half of CNAs frequent in post-CRT samples were present in pre-CRT samples. Pre- and post-CRT samples showed different genomic landscape. Potential genetic biomarkers of pre-CRT samples found in the current analysis call for external validation.

Endoscopic calcium electroporation for colorectal cancer: a phase I study.

Background and study aims Colorectal cancer is one of the most common malignancies, with approximately 20 % of patients having metastatic disease. Local symptoms from the tumor remain a common issue and affect quality of life. Electroporation is a method to permeabilize cell membranes with high-voltage pulses, allowing increased passage of otherwise poorly permeating substances such as calcium. The aim of this study was to determine the safety of calcium electroporation for advanced colorectal cancer. Patients and methods Six patients with inoperable rectal and sigmoid colon cancer were included, all presenting with local symptoms. Patients were offered endoscopic calcium electroporation and were followed up with endoscopy and computed tomography/magnetic resonance scans. Biopsies and blood samples were collected at baseline and at follow-up, 4, 8, and 12 weeks after treatment. Biopsies were examined for histological changes and immunohistochemically with CD3/CD8 and PD-L1. In addition, blood samples were examined for circulating cell-free DNA (cfDNA). Results A total of 10 procedures were performed and no serious adverse events occurred. Prior to inclusion, patients reported local symptoms, such as bleeding (N = 3), pain (N = 2), and stenosis (N = 5). Five of six patients reported symptom relief. In one patient, also receiving systemic chemotherapy, clinical complete response of primary tumor was seen. Immunohistochemistry found no significant changes in CD3 /CD8 levels or cfDNA levels after treatment. Conclusions This first study of calcium electroporation for colorectal tumors shows that calcium electroporation is a safe and feasible treatment modality for colorectal cancer. It can be performed as an outpatient treatment and may potentially be of great value for fragile patients with limited treatment options.

New method of modified chemoradiotherapy for cancer of the upper and middle ampullary rectum

The last decade is characterized by significant progress in the treatment of rectal cancer (reduction in the number of relapses to 5–6 % with the use of prolonged radiation therapy) before surgery. The greatest success has been achieved in the treatment of cancer of the lower ampulla of the rectum, when it is possible to develop a complete clinical response of the rectal tumor to chemoradiotherapy. Nevertheless, the requirement issues to improve the results of treatment of cancer of the upper and middle ampullar rectum with an increase in the survival of patients remain. Which makes it relevant to develop new methods, that increase the effectiveness of the treatment of rectal cancer.The method of modified chemoradiotherapy for cancer of the upper ampulla of the rectum was developed in our study. The method is as follows: at the first stage, one day before the start of radiation therapy, the patient undergoes superselective catheterization of the superior rectal artery through the radial or femoral artery, followed by regional administration of radiomodifying chemotherapy drugs: cisplatin 50 mg and fluorouracil 500 mg. In one day, patients begin to undergo a course of conformal remote large- fraction radiation therapy to the primary focus and metastasis pathways for 5 sessions with a single focal dose of 5 Gy to a total focal dose of 25 Gy using a low-energy linear accelerator. During the entire course of radiation therapy, fluorouracil 500 mg is administered daily intravenously for 30 minutes in 30 minutes before the session. Surgical intervention with the sampling of material for research is carried out 6–8 weeks after the radiation therapy is completed. To assess the effectiveness of the modified chemoradiotherapy, the stage of tumor regression was determined according to the RECIST scale, and the level of therapeutic pathomorphology of the tumor according to Dworak was determined during a morphological study of the rectal tumor removed during the operation.The developed method of modified chemoradiotherapy makes it possible to achieve regression of the rectal tumor in a short time, reduce the time and increase the effectiveness of treatment. The method of modified chemoradiotherapy is intended for patients with cancer of the upper and middle ampullar rectum T3-4N0-2M0, for whom radiation therapy is indicated as the first stage of treatment, after which resection of the rectum is performed in a standard volume.