Developed Disease Progression Research Articles

Penpulimab plus gemcitabine in combination with cisplatin or anlotinib as first-line treatment for metastatic nasopharyngeal carcinoma (M NPC): A phase II study.

e18032 Background: Cisplatin (P)-based combination regimen is the backbone in the first-line treatment of M NPC while the toxicity limited its usage. This study investigated the efficacy and safety of penpulimab (an anti-programmed death-1 antibody) plus gemcitabine (G) in combination with cisplatin (P) or anlotinib (a multikinase inhibitor) as first-line treatment of these pts. Methods: This is a multicenter, three cohorts, randomized, phase II study (NCT04736810). Pts with histologically confirmed regional or distant M NPC who had measurable lesions per RECIST 1.1 and received no systemic treatment for metastatic lesions were enrolled. Other inclusion criteria included 18-75 years old and ECOG PS 0-1. Pts in cohort A, B and C were given G + P + penpulimab + anlotinib; G + P + penpulimab or G + penpulimab + anlotinib, respectively. G (1000mg/m2, d1, d8) and P (80mg/m2, d1) were given intravenously for 4 to 6 cycles, 3 weeks per cycle. Penpulimab (200mg, d1) and anlotinib (12mg, qd, d1-14) were given intravenously and orally respectively until confirmed disease progression, or unacceptable toxicities, or up to 2 years, whichever occurred firstly. Pts who developed disease progression but still had clinical benefit could receive penpulimab and anlotinib continuously based on the decision of physicians. The primary endpoint was objective response rate (ORR). Here we report the preliminary results of this study. Results: Between March 2021 and September 2021, 17 pts were randomly assigned to cohort A (n = 5), B (n = 5) or C (n = 7), and the median age was 52, 49 and 52 years old, respectively. Nearly half (7/17, 41.2%) had liver metastasis and the majority (5/7, 71.4%) was in the cohort C. At the data cutoff date on January 17, 2022, the median treatment cycles were 6, 8, 8 across three cohorts. All pts received tumor response and the confirmed ORR was 80.0%, 80.0% and 100%. The details of tumor response were summered in followed table. Notably, in cohort C, 1 pts achieved confirmed complete response (CR) and all others had confirmed partial response (PR). Replacement of cisplatin with anlotinib seemed to show better safety profile that ≥ grade 3 adverse events (AEs) occurred in 6 pts (85.7%) in cohort A, 5 (100%) in cohort B while only 4 (57.1%) in group C. Moreover, the overall incidence of serious AEs was 28.6%, 20%, 14.3% across three cohorts. The most common ≥ grade 3 AEs were white blood cell decreased and neutrophil count decreased. Conclusions: This preliminary analysis indicated that penpulimab plus gemcitabine and anlotinib had promising efficacy and favorable tolerance profile as first-line treatment for M NPC. Further investigate is ongoing. Clinical trial information: NCT04736810. [Table: see text]

The Selective Personalized Radio-immunotherapy for Locally Advanced NSCLC Trial (SPRINT): Initial results.

8510 Background: Standard therapy for unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiotherapy followed by adjuvant durvalumab. We performed a prospective trial testing sequential pembrolizumab and risk-adapted radiotherapy without chemotherapy for biomarker-selected LA-NSCLC patients. Methods: Patients with stage III NSCLC or unresectable stage II NSCLC, ECOG performance status 0-1, and no contraindications to protocol-specified therapy were eligible for this trial. Subjects with PD-L1 tumor proportion score (TPS) ≥ 50% underwent baseline FDG-PET/CT, received three cycles of induction pembrolizumab (200 mg, every 21 days), underwent restaging FDG-PET/CT, received risk-adapted thoracic radiotherapy (55 Gy delivered to tumors or lymph nodes with metabolic tumor volume exceeding 20 cc and 48 Gy delivered to smaller lesions, all in 20 daily fractions), and then received up to 13 cycles of additional pembrolizumab. The primary study endpoint was one-year progression-free survival (PFS). Here we report response rates following induction pembrolizumab, PFS and overall survival (OS) rates, and adverse event rates (CTCAE v. 4.03). Results: Twenty-five subjects with PD-L1 TPS ≥ 50% from three institutions were enrolled between August 2018 and November 2021. Median age was 71 (interquartile range [IQR] 62 to 77). One subject had stage II disease, 13 had stage IIIA disease, nine had stage IIIB disease, and two had stage IIIC disease. Median PD-L1 TPS was 75% (IQR 60 to 80%). Two subjects (8%) developed disease progression during induction pembrolizumab, and two subjects discontinued pembrolizumab after one infusion due to immune-related adverse events. Using RECIST 1.1 criteria, 12 subjects (48%) exhibited a partial (n = 11) or complete (n = 1) response following induction pembrolizumab on CT. Using PERCIST criteria, 12 subjects (48%) exhibited a partial response following induction pembrolizumab on PET. Four subjects had responses on PET but not on CT, and four had responses on CT but not on PET. With a median follow-up duration of 13 months, the actuarial 1-year PFS rate is 74%, and the actuarial 1-year OS rate is 95%. Grade 3 adverse events have been limited to single cases of anemia, arthritis, diarrhea, esophagitis, and pneumonitis, and no grade 4-5 adverse events have occurred. Exploratory analyses suggest that response to induction pembrolizumab on PET predicts efficacy of this treatment approach, with a 1-year PFS rate of 100% for responders, compared to 61% for non-responders (logrank p = 0.007). Conclusions: Treatment with pembrolizumab and risk-adapted radiotherapy is a promising treatment approach for LA-NSCLC patients with PD-L1 TPS ≥ 50%. Response on PET following induction pembrolizumab may be useful for identifying patients who can be treated successfully without chemotherapy. Clinical trial information: NCT03523702.

Fumarate hydratase-deficient renal cell carcinoma: The real-world experience at Dana-Farber Cancer Institute and Moores Cancer Center.

e16522 Background: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare and aggressive tumor with limited clinical trials dedicated to therapeutics for this disease. This retrospective study aimed to report a multi-center experience in the systemic treatment of FH-deficient RCC. Methods: The medical records of patients undergoing systemic therapy for advanced or metastatic FH-deficient RCC at Dana-Farber Cancer Institute and Moores Cancer Center were reviewed from 2012 to 2021. Demographic, histologic, molecular, and survival parameters were collected. Response was assessed using RECIST 1.1 criteria. A confirmative initial diagnosis of FH-RCC was made utilizing FH/2SC immunohistochemistry (n = 12) and/or the presence of an FH mutation (n = 6). The primary endpoint of this study was to characterize patients with FH-deficient RCC in the modern era. Results: 18 patients were included; median age at diagnosis was 45 (interquartile range [IQR]: 40-55) years. All patients had a Karnofsky Performance Status (KPS) ≥ 80. Among 14 patients with evaluable IMDC criteria, 1 (7.4%) had favorable-risk disease, while 10 (71.4%) and 3 (21.4%) had intermediate- and poor-risk disease, respectively. Tumors at diagnosis were stage III (n = 6, 33.3%), and IV (n = 12, 66.7%). Median time from diagnosis to the start of systemic therapy was 2.8 months. Six types of regimens were given as first-line therapy (Table). Fourteen patients (78%) developed disease progression on frontline therapy and received subsequent therapy; two patients, initially treated with an mTOR inhibitor and combined vascular endothelial growth factor (VEGF) inhibitor and immune checkpoint inhibitor (ICI), are off therapy and still under surveillance with no recurrence to date; one patient passed away while on frontline therapy; and one patient has limited follow-up. For a median follow-up of 22 months (IQR:6.4-49), the 18-month-overall survival estimate was 81% (95% confidence interval [CI]: 53%-94%) and median progression-free survival (PFS) was 6.7 months (95%CI: 5.0-17.0). Conclusions: This study shows considerable heterogeneity in the treatment for FH deficient-RCC, with disparate clinical outcomes. Dedicated trials and guidelines on the management of FH-deficient RCC are needed.[Table: see text]

Outcomes of Patients with EGFR-Mutant Advanced NSCLC in a Developing Country in Southeast Asia.

BackgroundAlthough first- and second-generation EGFR TKIs are considered first-line treatment in EGFRm+ NSCLC, most patients develop resistance and progress, commonly, EGFR T790M mutation. The third-generation EGFR-TKI has demonstrated efficacy in patients with progressive disease harboring the T790M mutation and in the first-line setting, bypassing this mode of resistance. The primary objectives of this study are to describe the proportion of EGFRm+ NSCLC patients treated with first-, second- and third-generation EGFR TKIs, and cytotoxic chemotherapy in the first-line setting, and the time on treatment for each category. Secondary objectives are to determine the dropout rate, the rates for T790M mutation testing at disease progression and the type of subsequent treatment.MethodsThis multicenter retrospective study utilized data from the Malaysian Lung Cancer Registry that actively registers all lung cancer patients ≥18 years, with primary lung cancer confirmed histologically or cytologically. All patients diagnosed with advanced stages (ie stages IIIB, IIIC and IV) EGFRm+ NSCLC from 1st of January 2015 to 31st December 2019 were included.ResultsOf 406 patients with EGFRm+ NCSLC, 351 were treated. Types of first-line treatment were as follows: EGFR-TKIs (first generation – 54.1%, second generation – 25.6% and third-generation – 12.5%) and chemotherapy (7.7%). The median time of treatment for each generation of EGFR-TKI was 12 months, 12 months and 24 months, and 2 months for chemotherapy. The dropout rate was 28.7% (n = 101). Nearly half (49.4%) of patients who were on first- or second-generation EGFR-TKI had further genetic testing via liquid or tissue biopsies upon disease progression. About 24.9% of those who developed disease progression after first- or second-generation EGFR TKI were started on a third-generation EGFR TKI.ConclusionIn the real-world, the management of EGFRm+ advanced NSCLC patients in an Asian cost-restrictive setting may adversely affect the choice of first-line therapy, time on each line of treatment and subsequently the overall survival of patients.

PROOF 301: A multicenter, open-label, randomized, phase 3 trial of infigratinib versus gemcitabine plus cisplatin in patients with advanced cholangiocarcinoma with an FGFR2 gene fusion/rearrangement.

TPS4171 Background: First-line treatment options are limited for patients with advanced cholangiocarcinoma (CCA). Genetic alterations in the fibroblast growth factor receptor ( FGFR) gene play an important role in CCA. FGFR gene fusions/rearrangements are present in 10–16% of intrahepatic CCA and may predict tumor sensitivity to FGFR inhibitors. Infigratinib (BGJ398) is a potent, orally bioavailable, selective, ATP-competitive, small-molecule tyrosine kinase inhibitor of FGFRs that showed promising clinical activity and a manageable adverse event profile in a phase 2 study in patients with previously treated, unresectable locally advanced/metastatic CCA with an FGFR2 gene fusion/rearrangement. The multicenter, open-label, randomized, controlled phase 3 PROOF 301 trial is evaluating infigratinib vs standard-of-care gemcitabine + cisplatin as first-line treatment for patients with advanced/metastatic or inoperable CCA with an FGFR2 gene fusion/rearrangement. Methods: Approximately 300 patients ≥18 years of age with histologically or cytologically confirmed, advanced/metastatic or inoperable CCA with an FGFR2 gene fusion/rearrangement (confirmed by central laboratory) are randomized 2:1 to oral infigratinib 125 mg once daily for the first 21 days of a 28-day treatment cycle vs intravenous standard gemcitabine (1000 mg/m2) + cisplatin (25 mg/m2) on days 1 and 8 of a 21-day cycle. Randomization will be stratified by unresectable locally advanced vs metastatic disease, geographic region, prior neoadjuvant/adjuvant treatment vs none, and receipt of up to 1 cycle of gemcitabine-based chemotherapy for unresectable locally advanced/metastatic disease prior to randomization vs none. Treatment will continue until confirmed progressive disease by blinded independent central review (BICR), intolerance, withdrawal of informed consent, or death. Patients on the gemcitabine + cisplatin arm who develop disease progression, confirmed by BICR, can cross-over to receive infigratinib. The primary endpoint is progression-free survival (PFS, RECIST v1.1), confirmed by BICR. Secondary endpoints include overall survival, PFS (investigator determined), overall response rate, best overall response, disease control rate, duration of response (BICR and investigator determined), and the type, frequency, and severity of adverse events (AEs) and serious AEs. PFS after subsequent therapy (PFS2), quality of life, pharmacokinetics and other exploratory genetic alterations/biomarkers will also be evaluated. Trial enrollment is ongoing in the US, EU, and APAC (including Australia). The Data Monitoring Committee last reviewed the trial in December 2021. Clinical trial information: NCT03773302.

A phase 1b adaptive androgen deprivation therapy trial in metastatic castration sensitive prostate cancer.

5075 Background: Despite early utilization of new hormonal agents (NHA, abiraterone, enzalutamide and apalutamide) in metastatic castration sensitive prostate cancer (mCSPC), increasingly more men are dying from prostate cancer. While continued development of new drugs is needed, we propose improved survival of metastatic prostate cancer can be obtained through tumor evolution informed treatment strategies. Compared to the conventional treat until progression paradigm, our previous study (NCT02415621) in metastatic castration resistant prostate cancer reported that on and off abiraterone therapy adapted to individual’s PSA response dynamics can provide better cancer control with less abiraterone usage (Zhang et al, Nat Commun. 2017). Here we present the first interim analysis of our adpative therapy trial in mCSPC with a median follow up of 21 months. Methods: Men with asymptomatic mCSPC and no liver metastasis were enrolled after achieved > 75% PSA decline with 12 - 16 weeks of luteinizing hormone-releasing hormone (LHRH) analog, and 8 - 12 weeks of NHA. Both treatments were stopped after enrollment. PSA and testosterone levels were measured every 6 weeks, CT and bone scan were performed every 18 weeks while on study. Treatment will be restarted if subjects develop PSA or radiographic progression per prostate cancer working group 3 criteria. If the testosterone level (T) is > 100 ng/dl, LHRH analog will be restarted. If the T is between 50 and 100 ng/dl, NHA will be restarted. If the T is below 50, combined therapy with LHRH analog and NHA will be restarted. Treatment will be discontinued after achieving 50% or more PSA decline. For patients who restarted therapy for radiographic progression, partial response or stable disease needs to be documented on the post treatment scans along with PSA response prior to stopping therapy. The primary objective is feasibility, which is measured by percentage of patients who remain on study without on treatment disease progression at 12 months from first dose of LHRH analog for mCSPC. Results: 16 evaluable patients were enrolled between April 2019 and June 2021. Five of the 16 patients had high risk mCSPC based on the LATITUDE trial criteria. The median follow up was 21 months at the data cut off in January 2022. Only one patient was off study due to imaging progression at 27.6 months from first dose of LHRH analog for mCSPC. Three of the 16 patients developed on treatment PSA progression at month 12.3 and 15.2, and 20.5. Given none of the first 14 enrolled patients developed disease progression at 12 months, the study has already met its primary objective of feasibility. Conclusions: It is feasible to use individual’s PSA response and testosterone level to guide intermittent therapy with LHRH analog and NHA in mCSPC. The study is ongoing to collect data on secondary endpoints of median time to PSA progression and median time to radiographic progression. Clinical trial information: NCT 03511196.

Characteristics of cytokine profiles of peripheral blood in patients with melanoma receiving checkpoint inhibitor therapy with disease progression.

e21509 Background: The limited range of patients clinically responding to checkpoint inhibitor therapy (CIT) is of interest and requires studying the immunological mechanisms underlying this phenomenon. It also remains to be decided or better clarified which biomarkers should be considered when selecting patients for immunotherapy. The purpose of this study was to evaluate some parameters of the cytokine profiles of peripheral blood in melanoma patients receiving CIT with the disease progression. Methods: The study included 11 patients aged 47-82 years with advanced melanoma. CIT (nivolumab 3 mg/kg once every 14 days or 240 mg once every 14 days) continued until the appearance of reliable signs of the disease progression (in combination with symptomatic deterioration of the patient's condition). The levels of cytokines (TNF-α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-γ) in the blood serum of patients were determined by ELISA before treatment, after 4 and after 8 injections. The results were expressed as specific content (units/mg). Results: All patients developed disease progression after immunotherapy. CIT was accompanied by different changes most pronounce after the 8th CIT cycle. Levels of IL-1β, IFN-γ, IL-10 and α-TNF exceeded the values before CIT by 118%, 131%, 84% and 20%, respectively (5.2 [4.37; 6.1] versus 2.0 [0.44;4], p≤0.041, 3.9 [3.7;4.5] vs. 1.7 [0.5;3.5], p≤0.021, 6.5 [5.8 ;8.2] vs. 3.5 [3.2;5.4], p≤0.04; 4.1 [3.9;4.9] vs. 3.4 [3.2;3.9] pg/ml, p≤0.047). Levels of IL-6, on the contrary, decreased by the 8th CIT cycle by 32%: 5.1 [3.5; 6.1] versus 7.5 [6.2; 22.3] pg/ml, p≤ 0.045. Levels of IL-2 and IL-8 did not change. Conclusions: The revealed significant increase in levels of IL-1β, IFN-γ, IL-10 and α-TNF, as well as the IL-6 decrease, may indicate certain features of the cytokine profile of melanoma patients during the treatment, which may affect the imbalance of regulatory molecules and contribute to the disease progression.

Tumor mutation burden (TMB) and Notch1 gene alteration are associated with short disease-free survival in early laryngocarcinoma.

e18049 Background: Patients with early-stage laryngocarcinoma, even stage T1-2N0, are at substantial risk of relapse and death. Molecular alterations are thought to be associated with the immune microenvironment in the tumor and to have an important role in predicting the prognosis. In this study, we explored the distinct features of molecular alterations and immune-related gene expression and examined the relationship between molecular alterations and prognosis. Methods: A total of 42 stage T1-2N0 laryngocarcinoma patients were enrolled, no patients received chemotherapy or immunotherapy before surgery, tissue samples from radical operation were collected. Of these, 23 cases developed disease progression within 24 months after operation [shorter disease-free survival (shorter DFS)], while others 19 cases showed longer DFS over 24 months (longer DFS). Distinct features of molecular alterations and immune-related gene expression in Formalin-fixed paraffin-embedded (FFPE) samples through using DNA sequencing and an immune oncology panel RNA sequencing platform were performed. Results: A total of 293 mutations were detected within 42 patients, the median number of mutations in the short-DFS group was higher than that in the long-DFS group (9.0 vs. 5.2; P = 0.045). No correlation between mutation type and DFS was found. TMB-high (Top 25%) was associated with worse DFS (TMB-L: Not reached, TMB-H: 11.5 months, p = 0.036; HR, 2.4; 95% CI 1.05 to 5.48). Among 522 cancer-related genes, alterations in 51 genes were detected. TP53 (33/42, 79%) was the most common mutation gene in the entire cohort. Mutations of LRP1B (30.4% vs 5.3%, p = 0.039) and Notch1 (21.7% vs 0%, p = 0.030) were significantly occurred in the short-DFS group, patients with Notch1 mutation had a significantly shorter DFS period (P = 0.0012). Univariate and multivariate analysis showed that high TMB and Notch1 mutation were independent prognostic factors in DFS. Conclusions: In early-stage laryngocarcinoma, Notch1 mutation and high TMB were associated in patients with short-DFS, indicating the potential prognostic biomarkers and therapeutic molecular targets for early-stage laryngocarcinoma.

Predictors of Outcome after (Chemo)Radiotherapy for Node-Positive Oropharyngeal Cancer: The Role of Functional MRI.

Simple SummaryWe have conducted a prospective study on patients with locally advanced oropharyngeal cancer who are candidates for concomitant radio-chemotherapy; we considered their anamnestic findings, tumor characteristics and evaluated the role of innovative radiological features, particularly the magnetic resonance imaging (MRI) biomarkers. Our aim was to identify those elements correlated with worse tumor control. Diffusion-weighted (DWI) imaging and dynamic contrast–enhanced (DCE) can help identify hypoxic regions in head and neck cancer which are known to be more resistant to the effects of radiation. A better understanding of these factors may help us improve our knowledge on tumor behavior and thus provide a more tailored treatment in patients that respond poorly.The prognosis of a subset of patients with locally advanced oropharyngeal cancer (LA-OPC) is still poor despite improvements in patient selection and treatment. Identifying specific patient- and tumor-related factors can help to select those patients who need intensified treatment. We aimed to assess the role of historical risk factors and novel magnetic resonance imaging (MRI) biomarkers in predicting outcomes in these patients. Patients diagnosed with LA-OPC were studied with diffusion-weighted imaging (DWI) and dynamic-contrast enhanced MRI at baseline and at the 10th radiotherapy (RT) fraction. Clinical information was collected as well. The endpoint of the study was the development of disease progression, locally or distantly. Of the 97 patients enrolled, 68 were eligible for analysis. Disease progression was recorded in 21 patients (11 had loco-regional progression, 10 developed distant metastases). We found a correlation between N diameter and disease control (p = 0.02); features such as p16 status and extranodal extension only showed a trend towards statistical significance. Among perfusion MRI features, higher median values of Kep both in primary tumor (T, p = 0.016) and lymph node (N, p = 0.003) and lower median values of ve (p = 0.018 in T, p = 0.004 in N) correlated with better disease control. Kep P90 and N diameter were identified by MRMR algorithm as the best predictors of outcome. In conclusion, the association of non-invasive MRI biomarkers and patients and tumor characteristics may help in predicting disease behavior and patient outcomes in order to ensure a more customized treatment.

Efficacy of different sequential patterns after crizotinib progression in advanced anaplastic lymphoma kinase-positive non-small cell lung cancer.

BackgroundThe efficacy difference between the second‐ and third‐generation of anaplastic lymphoma kinase‐tyrosine kinase inhibitors (ALK‐TKIs) after crizotinib failure in advanced ALK‐positive non–small cell lung cancer (NSCLC) has not been clarified. This study evaluates the efficacy of different sequential patterns after crizotinib progression.MethodsData of patients who met the study criteria were retrospectively analyzed. The Kaplan–Meier method was used to draw survival curves, log‐rank method was used to compare the differences between groups, and Cox multivariate analysis was used to evaluate the significance of influencing factors.ResultsA total of 128 patients developed disease progression after crizotinib. The overall survival (OS) of 57 patients in the sequential second‐generation ALK‐TKIs group was significantly longer than that of 65 patients with other systemic treatment (58.5 months vs. 33.0 months, p < 0.001); The OS of the direct sequential lorlatinib group was significantly longer than the second‐generation ALK‐TKIs group (114.0 months vs. 58.5 months, p = 0.020). Similarly, of the 48 patients who developed disease progression after first‐ and second‐generation ALK‐TKIs treatment, 16 patients with sequential lorlatinib had significantly longer OS than the others (62.0 months vs. 43.0 months, p = 0.014). The progression‐free survival (PFS) of second‐line and third‐ or later‐line lorlatinib were statistically different (20.0 months vs. 5.5 months, p = 0.011).ConclusionsThe application of next‐generation ALK‐TKIs after crizotinib progression significantly prolonged survival, whereas direct sequencing lorlatinib seemed advantageous. Similarly, lorlatinib also prolonged survival in patients with first‐ and second‐generation ALK‐TKIs failure.

Immune checkpoint inhibitor therapy for recurrent meningiomas: a retrospective chart review.

Meningiomas that progress despite surgery and radiotherapy represent an unmet medical need. Expression of PD-1 and PDL-1 has been demonstrated in meningiomas and is proportional to tumor grade, suggesting a potential role for anti-PD-1/anti-PDL-1 inhibitor therapy. We explored the potential role of immunotherapy for recurrent meningiomas by describing progression-free survival (PFS) and overall survival (OS) in a single-center patient sample. This is a retrospective chart review of patients with meningioma who were treated with PD-1 inhibitors at UPMC Hillman Cancer Center. Any patient over age 18 who received immunotherapy was included in this study. Patients received treatment until development of disease progression, intolerable toxicities or adverse events, death, or oncologist decision. Serial radiographic assessments were made every 3-6months. Between January 2015 and November 2021, eight patients received anti-PD-1 therapy. All patients underwent tumor resection and radiosurgery, and four patients received prior systemic therapy. Six out of eight patients experienced symptomatic perilesional edema and three patients experienced exacerbation of seizures. Median PFS was 7months (95% CI 1-24) and median OS was 1.75years (95% CI 1.5-4.0). In patients with positive PD-1/PD-L1 expression, median PFS was 2years and median OS was 3years. Anti-PD-1 therapy was associated with a manageable safety profile in patients with recurrent meningiomas. Patients with WHO Grade III tumors and positive PD-1/PD-L1 expression were noted to have increased PFS and OS, suggesting a potential role for immunotherapy in these patients, but further studies are needed to investigate this in a larger patient population.

Survival analysis of different kinds of tyrosine kinase inhibitors in the treatment of patients with epidermal growth factor receptor mutated non-small cell lung cancer and leptomeningeal metastasis

Objective: To explore the prognosis of patients with leptomeningeal metastasis (LM) and epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC) treated with different kinds of tyrosine kinase inhibitors (TKIs). Methods: From January 2016 to June 2021, the clinicopathological data of 70 patients confirmed by histologically or cytologically EGFRm LM who received different types of TKIs in Cancer Hospital of Chinese Academy of Medical Sciences were retrospectively analyzed. According to treatment patterns, patients were divided into the first-and second-generation EGFR-TKIs treatment group and the third-generation EGFR-TKIs treatment group [Osimertinib 80 mg once a day], and the prognosis and prognostic factors (with Cox proportional hazards model) of patients in different treatment group were assessed. The next-generation sequencing (NGS) of paired samples of cerebrospinal fluid (CSF) and plasma from 64 patients at the time of LM diagnosis was performed simultaneously. Results: There were 20 males and 50 females in 70 EGFRm NSCLC patients with LM. The age ranged from 35 to 69 years, with a median age of 56 years. A total of 24 patients received the first-and second-generation EGFR-TKIs treatment, and 46 received the third-generation EGFR-TKIs treatment. Twenty-four patients developed disease progression on the first-and second EGFR-TKIs treatments, followed by treatment with the third-generation EGFR-TKIs (Osimertinib) in 12 cases, chemotherapy or anti-angiogenesis therapy in 4 cases, and the optimal supportive treatment in 8 cases. Among the 70 patients, 18 had partial response (PR), 48 had stable disease (SD), and 4 had progressive disease (PD). The objective response rate (ORR) and disease control rate (DCR) were 26% (18/70) and 94% (66/70), respectively. The median follow-up time was 16.5 months. The median progression-free survival (PFS) was 5.3 months(95%CI: 2.8-7.8)in the first-and second-generation EGFR-TKIs and 10.8 months (95%CI: 7.9-13.6) in the third-generation EGFR-TKIs, and the difference was statistically significant (P=0.019). The median overall survival (OS) was 14.9 months (95%CI: 9.7-20.0) and 15.7 months (95%CI: 13.3-18.1) in the two groups, respectively, but no statistical differences was observed (P=0.713). Univariate analysis showed that the PFS of patients with EGFRm LM were related to gender and different types of EGFR-TKIs (P˂0.05). Multivariate analysis demonstrated that male (HR=2.30, 95%CI: 1.31-4.03, P=0.004) and the first-and second-generation EGFR-TKIs (HR=2.03, 95%CI: 1.20-3.41, P=0.008) were independent risk factors for PFS in patients with EGFRm LM. The EGFR mutation was detected in 61 (95%) CSF and in 27 (42%) plasma samples. Conclusion: In EGFRm NSCLC patients with LM, the dose of Osimertinib 80 mg (once a day) has a significant PFS benefit compared with the first-and second-generation EGFR-TKIs.

Systemic and Radiation Therapy Approaches for Locally Advanced Non-Small-Cell Lung Cancer.

The treatment for locally advanced non-small-cell lung cancer has changed dramatically over the past several years, with consolidative immunotherapy after concurrent chemoradiation becoming the new standard of care. Five-year survival outcomes have substantially improved with this approach. Despite these advances, further improvements are needed as the majority of patients ultimately develop progression of disease. The next-generation immunotherapy trials are currently being conducted that include approaches such as concurrent immunotherapy and addition of other therapeutic agents in the concurrent and consolidative settings. Specific unmet needs continue to exist for patients who develop disease progression after concurrent chemoradiation and immunotherapy, as well as defining the best treatment for patients with driver mutations. Future directions also include refinement of radiation techniques to reduce toxicities as much as possible, as well as the use of circulating tumor DNA in the surveillance setting. The current scientific landscape shows promising approaches that may further improve outcomes for patients with locally advanced non-small-cell lung cancer.

Managing Resistance to Immune Checkpoint Inhibitors in Lung Cancer: Treatment and Novel Strategies.

A proportion of patients with lung cancer experience long-term clinical benefit with immune checkpoint inhibitors (ICIs). However, most patients develop disease progression during treatment or after treatment discontinuation. Definitions of immune resistance are heterogeneous according to different clinical and biologic features. Primary resistance and acquired resistance, related to tumor-intrinsic and tumor-extrinsic mechanisms, are identified according to previous response patterns and timing of occurrence. The clinical resistance patterns determine differential clinical approaches. To date, several combination therapies are under development to delay or prevent the occurrence of resistance to ICIs, including the blockade of immune coinhibitory signals, the activation of those with costimulatory functions, the modulation of the tumor microenvironment, and the targeting T-cell priming. Tailoring the specific treatments with distinctive biologic resistance mechanisms would be ideal to improve the design and results of clinical trial. In this review, we reviewed the available evidence on immune resistance mechanisms, clinical definitions, and management of resistance to ICIs in lung cancer. We also reviewed data on novel strategies under investigation in this setting.

Phase Ib/II trial of Ibrutinib and Nivolumab in Patients with Advanced Refractory Renal Cell Carcinoma1

BACKGROUND: Although immune checkpoint inhibitor-based therapy has improved the outcomes of many patients with metastatic renal cell carcinoma (mRCC), most eventually develop disease progression. Newer agents that modulate immune response can possibly potentiate checkpoint inhibitor therapy. The ITK/ETK/BTK inhibitor ibrutinib has been reported to inhibit myeloid derived suppressor cells in preclinical models and to potentiate immunotherapy. We conducted an investigator-initiated trial of ibrutinib plus the PD1 inhibitor nivolumab in mRCC patients, particularly in those previously exposed to immune checkpoint inhibitors. METHODS: Eligible patients had mRCC of any histologic subtype, completed at least one line of prior systemic therapy which could have included prior immunotherapy, and had acceptable end-organ function with ECOG performance status of 0–2. Treatment consisted of nivolumab 240 mg intravenously every 2 weeks plus ibrutinib 560 mg (dose level 0) or 420 mg (dose level -1) orally once daily. Cycle length was 28 days. Dose limiting toxicity (DLT) was defined as any Grade 3 or higher adverse event (AE) attributable to therapy. After identification of the recommended phase 2 dose (RP2D), up to 19 patients were enrolled to an expansion cohort to further evaluate toxicities and any early evidence of efficacy. The primary endpoints of the trial were establishment of RP2D and progression-free survival (PFS). RESULTS: A total of 31 patients were enrolled, 6 to dose level 0, 7 (of which one was not evaluable for DLT) in dose level -1, and 18 in the expansion cohort. Median age was 60 years (range, 36–90), most had clear cell histology (n = 27; 87%), and most had prior immune checkpoint inhibitor therapy (n = 28; 90%). Three patients experienced one DLT each, all in dose level 0 (all Grade 3), namely elevated lipase, hypoalbuminemia, and nausea. No DLTs were seen in dose level –1 which was declared the RP2D. The most common Grade 3 or higher AEs include anemia (n = 5), lymphocyte count decrease (4), nausea (2), and hypotension (2). Of 28 patients evaluable for response, one patient (3.6%) had a complete response, 2 (7.1%) had a partial response, and 11 (39.2%) had stable disease, for an objective response rate of 10.7%(95%CI: 3.7%–27.2%) and a disease control rate of 50%(95%CI: 32.6%–67.4%). All responders had received prior immune checkpoint inhibitor therapy. Median PFS was 2.5 months (95%CI, 1.9 –4.8) while median OS was 9.1 months (95%CI, 6.6 –19.0). CONCLUSIONS: Ibrutinib at a dose of 420 mg orally once daily in combination with nivolumab 240 mg IV every 2 weeks is feasible and tolerable in mRCC patients. No unique immune-related AEs were observed. Anti-tumor activity was seen in patients previously exposed to PD-1 targeted therapy.

Prognostic Value of FDG PET/CT in Patients With Neuroendocrine Carcinoma of the Uterine Cervix.

We evaluated the prognostic value of metabolic parameters measured on pretreatment FDG PET/CT in patients with cervical neuroendocrine carcinomas (NECs). A total of 22 patients with cervical NECs who underwent pretreatment FDG PET/CT were retrospectively reviewed. The SUVmax, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary lesion were measured. The associations between prognostic factors and progression-free survival (PFS) and overall survival (OS) were investigated using the Kaplan-Meier method, log-rank test, and univariate and multivariate Cox proportional hazards model. Of the 22 patients, 12 developed disease progression, and 5 died during the follow-up period. Univariate analyses revealed that MTV, TLG, and the International Federation of Gynecology and Obstetrics stage were significantly associated with PFS (all P < 0.05), whereas SUVmax did not show a significant correlation with PFS. Kaplan-Meier survival curves revealed that patients with MTV >31.9 cm3 (log-rank, P < 0.001), TLG >154.3 (log-rank, P < 0.001), and higher International Federation of Gynecology and Obstetrics stage (log-rank, P = 0.026) had significantly shorter PFS. In the multivariate analyses, MTV (P = 0.017; hazard ratio [HR], 7.298; 95% confidence interval [CI], 1.427-37.316) and TLG (P = 0.003; HR, 15.175; 95% CI, 2.470-93.244) were independent prognostic factors, whereas for OS, the univariate analysis revealed that only TLG >154.3 showed statistical significance (P = 0.043; HR, 9.821; 95% CI, 1.080-89.290). Metabolic tumor volume and TLG on FDG PET/CT were the significant prognostic factors of PFS in patients with cervical NECs. Patients with high MTV and TLG had worse clinical outcomes. In addition, TLG may also be a predictor of OS.

Impact of docetaxel plus ramucirumab in a second-line setting after chemoimmunotherapy in patients with non-small-cell lung cancer: A retrospective study.

BackgroundChemoimmunotherapy has become a standard treatment option for patients with untreated advanced non‐small‐cell lung cancer (NSCLC). However, numerous patients with advanced NSCLC develop disease progression. Therefore, the selection of second‐line treatment after chemoimmunotherapy is crucial for improving clinical outcomes.MethodsOf 88 enrolled patients with advanced NSCLC who received chemoimmunotherapy, we retrospectively evaluated 33 who received second‐line chemotherapy after progression of chemoimmunotherapy at six centers in Japan. Among them, 18 patients received docetaxel plus ramucirumab and 15 patients received single‐agent chemotherapy.ResultsThe objective response rate in patients treated with docetaxel plus ramucirumab was significantly higher than that in patients treated with a single‐agent chemotherapy regimen (55.6% vs. 0%, p < 0.001). The median progression‐free survival (PFS) of patients who received docetaxel plus ramucirumab and single‐agent chemotherapy was 5.8 months and 5.0 months, respectively (log‐rank test p = 0.17). In the docetaxel plus ramucirumab regimen group, patients who responded to chemoimmunotherapy for ≥8.8 months had a significantly longer response to docetaxel plus ramucirumab than those who responded for <8.8 months (not reached vs. 4.1 months, log‐rank test p = 0.003). In contrast, in the single‐agent chemotherapy group, there was no significant difference in PFS between the ≥8.8‐ and <8.8‐month PFS groups with chemoimmunotherapy (5.0 vs. 1.6 months, log‐rank test p = 0.66).ConclusionOur retrospective observations suggest that the group with longer PFS with chemoimmunotherapy might be expected to benefit from docetaxel plus ramucirumab treatment in second‐line settings for patients with advanced NSCLC.

Concurrent Monitoring of Peripheral Blood Circulating Tumor DNA and Circulating Tumor Cells in Relapsed/Refractory Follicular Lymphoma Patients Post Axicabtagene Ciloleucel, a Single Center Experience

Concurrent Monitoring of Peripheral Blood Circulating Tumor DNA and Circulating Tumor Cells in Relapsed/Refractory Follicular Lymphoma Patients Post Axicabtagene Ciloleucel, a Single Center Experience

A Phase 1 Study of CFT7455, a Novel Degrader of IKZF1/3, in Multiple Myeloma and Non-Hodgkin Lymphoma

A Phase 1 Study of CFT7455, a Novel Degrader of IKZF1/3, in Multiple Myeloma and Non-Hodgkin Lymphoma

Disease Progression in Patients With Nontuberculous Mycobacterial Lung Disease of Nodular Bronchiectatic (NB) Pattern: The Roles of Cavitary NB and Soluble Programmed Death Protein-1.

In patients with nodular bronchiectatic (NB) nontuberculous mycobacterial lung disease (NTM-LD), risk factors for disease progression have not been clearly investigated. The roles of cavitary NB and soluble programmed death protein-1 (sPD-1), an immune-related biomarker, in the disease course of NB NTM-LD remain unknown. Patients with NB NTM-LD were enrolled from 2 medical centers in 2014-2020. We identified cavitary NB, measured sPD-1 levels, and analyzed factors associated with cavitary NB and predictors for disease progression of NB NTM-LD. Of 120 cases of NB NTM-LD, 87 (72.5%) were caused by Mycobacterium avium complex. sPD-1 levels were lower in 13 (10.8%) patients with cavitary NB than in noncavitary patients (P=.020). Over 1.41±1.43 years of follow-up, 12 (92.3%) patients in the cavitary and 66 (61.7%) in the noncavitary group developed disease progression (P=.032). In multivariable analysis, body mass index (BMI [kg/m2]; adjusted hazard ratio [aHR], .895 [95% confidence interval, .811-.988]), sputum smear grade (aHR, 1.247 [1.014-1.534]), cavitary NB (aHR, 2.008 [1.052-3.834]), and sPD-1 (per 10-pg/mL increase; aHR, .889 [.816-.967]) were predictive for disease progression. Notably, sPD-1 showed a dose-dependent association with disease progression (sPD-1 ≤23.5 pg/mL; aHR, 3.306 [1.664-6.567]; sPD-1: 23.6-53.7 pg/mL; aHR, 2.496 [1.390-4.483]) compared with the reference (sPD-1 >53.7 pg/mL). Patients with NB NTM-LD and low sPD-1, low BMI, high smear grade, and cavitary NB were at high risk for disease progression. sPD-1 was low in patients with cavitary NB phenotype and dose-responsively associated with disease progression.