6-month Progression-free Survival Research Articles

Durvalumab Plus Concurrent Radiotherapy for Treatment of Locally Advanced Non–Small Cell Lung Cancer

Administration of durvalumab after concurrent chemoradiotherapy is the standard treatment of unresectable, locally advanced non-small cell lung cancer (NSCLC); however, 20% to 30% of patients do not receive durvalumab because of adverse events (AEs) during concurrent chemoradiotherapy. In addition, radiotherapy and immunotherapy have a synergistic effect. To investigate the efficacy and safety of durvalumab immunotherapy plus concurrent radiotherapy followed by maintenance with durvalumab therapy for treatment of locally advanced NSCLC without chemotherapy. The multicenter, single-arm DOLPHIN (Phase II Study of Durvalumab [MEDI4736] Plus Concurrent Radiation Therapy in Advanced Localized NSCLC Patients) nonrandomized controlled trial was performed by 12 institutions in Japan from September 13, 2019, to May 31, 2022. Participants in the primary registration phase included 74 patients with programmed cell death ligand 1 (PD-L1)-positive, unresectable, locally advanced NSCLC. The current analyses were conducted from June 1, 2022, to October 31, 2022. Patients received radiotherapy (60 Gy) in combination with concurrent and maintenance durvalumab immunotherapy, 10 mg/kg every 2 weeks, for up to 1 year. The primary end point of the rate of 12-month progression-free survival (PFS), as assessed by an independent central review, was estimated using the Kaplan-Meier method and evaluated with 90% CIs calculated using the Greenwood formula. The key secondary end points were PFS, objective response rate, treatment completion rate, and AEs. Data from 35 patients (median [range] age, 72 [44-83] years; 31 [88.6%] men) were included in the full analysis set of the evaluable population. The 12-month PFS rate was 72.1% (90% CI, 59.1%-85.1%), and the median PFS was 25.6 months (95% CI, 13.1 months to not estimable) at a median follow-up of 22.8 months (range, 4.3-31.8 months). Scheduled radiation therapy was completed in 97.1% of patients. The confirmed objective response rate was 90.9% (95% CI, 75.7%-98.1%), and the treatment completion rate was 57.6% (95% CI, 39.2%-74.5%). Among 34 patients evaluated in the safety analysis set, AEs of grade 3 or 4 occurred in 18 patients (52.9%), and of grade 5 in 2 patients (5.9%). Pneumonitis or radiation pneumonitis of any grade occurred in 23 patients (67.6%), and of grades 3 or 4 in 4 patients (11.8%). Findings from this phase 2 nonrandomized controlled trial indicate that durvalumab immunotherapy combined with curative radiotherapy for patients with PD-L1-positive, unresectable, locally advanced NSCLC is a promising treatment with tolerable AEs and is appropriate as a study treatment for phase 3 clinical trials. Japan Registry of Clinical Trials ID: jRCT2080224763.

Triplet maintenance therapy of olaparib, pembrolizumab and bevacizumab in women with BRCA wild-type, platinum-sensitive recurrent ovarian cancer: the multicenter, single-arm phase II study OPEB-01/APGOT-OV4

In this multicenter, open-label, single-arm, Phase II study with Simon two-stage optimum design (NCT04361370), we investigate the efficacy and safety of triplet maintenance (olaparib, pembrolizumab, bevacizumab) in patients with platinum-sensitive recurrent ovarian cancer who are wild-type for BRCA 1/2. A total of 44 patients were enrolled, and the median follow-up duration was 22.9 months (interquartile range: 17.4–24.7). The primary outcome was 6-months progression-free survival (PFS), which was 88.6% (95% confidence interval [CI] 75.4–96.2), meeting the pre-specified primary endpoint. The secondary outcomes reported here include median PFS, 12-months PFS, and overall survival and safety. The median PFS was 22.4 months (20.4–∞), with a 12-months PFS rate of 84.0% (95% CI 69.3–92.0). The median overall survival was 28.6 months (27.3–∞). The combination demonstrated tolerable toxicity with manageable side effects. Other secondary outcomes include time-to-progression, time to subsequent treatment, time to second treatment and PFS2; however, this data is not reported, as treatment is still ongoing in a majority of patients. Exploratory analysis shows that patients who were homologous recombination deficiency-positive or had a programmed death-ligand 1 combined positive score ≥1 showed a favorable response (P = 0.043 and P < 0.001, respectively). Thus, triplet maintenance shows durable efficacy with tolerable safety in patients with platinum-sensitive recurrence.

Efficacy and safety of immune checkpoint inhibitors in Proficient Mismatch Repair (pMMR)/ Non-Microsatellite Instability-High (non-MSI-H) metastatic colorectal cancer: a study based on 39 cohorts incorporating 1723 patients

PurposeThis study was designed to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs)-based therapy in proficient mismatch repair (pMMR)/non-microsatellite instability-high (non-MSI-H) metastatic colorectal cancer (mCRC).MethodsElectronic databases were screened to identify relevant trials. The primary endpoints were pooled objective response rate (ORR) and disease control rate (DCR). Stratified analysis was accomplished on ICIs-based regimens, treatment lines and RAS status.ResultsTotally, 1723 mCRC patients from 39 cohorts were included. The pooled ORR, DCR, 12-month overall survival (OS) rate and 6-month progression-free survival (PFS) rate of ICIs-based therapy in pMMR/non-MSI-H mCRC were 8.5% (95% CI: 4.4%-13.5%), 48.2% (95% CI: 37.8%-58.6%), 52.3% (95% CI: 46.4%-58.1%) and 32.8% (95% CI: 23.5%-42.7%) respectively. As a whole, no significantly differences were shown between ICIs-based and non-ICIs-based therapy for pMMR/non-MSI-H mCRC in terms of both PFS (HR = 1.0, 95% CI: 0.9–1.1, P = 0.91) and OS (HR = 1.0, 95% CI: 0.9–1.2, P = 0.51). It was worth noting that the addition of ICIs to anti-vascular endothelial growth factor (VEGF) agent plus chemotherapy displayed excellent efficacy in pMMR/non-MSI-H mCRC (ORR = 42.4%, 95% CI: 10.0%-78.6%; DCR = 92.0%, 95% CI: 68.3%-100.0%; 12-month OS rate = 71.4%, 95% CI: 50.0%-89.1%; 6-month PFS rate = 55.2%, 95% CI: 24.8%-83.8%; and PFS (compared with non-ICIs-based therapy): HR = 0.9, 95% CI: 0.8–1.0, P = 0.02), especially served as first-line therapy (ORR = 74.2%, 95% CI: 61.4%-85.4%; DCR = 98.7%, 95% CI: 92.0%-100.0%); and without additional treatment related adverse events (TRAEs) were observed.ConclusionsICIs-based combination therapy, especially the addition of ICIs to first-line anti-VEGF agent plus chemotherapy, is promising in pMMR/non-MSI-H mCRC with good efficacy and controllable toxicity.

First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: a single-arm, single-centre, phase 2 trial

The addition of nivolumab to chemotherapy improves survival in patients with advanced oesophagogastric (oesophageal, gastric, or gastro-oesophageal junction) adenocarcinoma; however, outcomes remain poor. We assessed the safety and activity of regorafenib in combination with nivolumab and chemotherapy in the first-line treatment of advanced oesophagogastric adenocarcinoma. This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with previously untreated, HER2-negative, metastatic oesophagogastric adenocarcinoma was done at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients had measurable disease or non-measurable disease that was evaluable (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received FOLFOX chemotherapy (fluorouracil [400 mg/m2 bolus followed by 2400 mg/m2 over 48 h], leucovorin [400 mg/m2], and oxaliplatin [85 mg/m2]) and nivolumab (240 mg) intravenously on days 1 and 15, and oral regorafenib (80 mg) on days 1-21 of a 28-day cycle. Treatment was continued until disease progression (defined by RECIST version 1.1), unacceptable toxicity, or withdrawal of consent. The primary endpoint was 6-month progression-free survival in the per-protocol population (ie, all participants who received a dose of all study treatments). The regimen would be considered worthy of further investigation if at least 24 of 35 patients were progression free at 6 months. Safety was assessed in all participants who received at least one dose of any study treatment. This trial is registered with ClinicalTrials.gov, NCT04757363, and is now complete. Between Feb 11, 2021, and May 4, 2022, 39 patients were enrolled, received at least one dose of study drug, and were included in safety analyses. 35 patients were evaluable for 6-month progression-free survival. Median age was 57 years (IQR 52-66), nine (26%) patients were women, 26 (74%) were men, 28 (80%) were White, and seven (20%) were Asian. At data cutoff (March 3, 2023), median follow-up was 18·1 months (IQR 12·7-20·4). The primary endpoint was reached, with 25 (71%; 95% CI 54-85) of 35 patients progression free at 6 months. Nine (26%) of 35 patients had disease progression and one (3%) patient died; the death was unrelated to treatment. The most common adverse event of any grade was fatigue (36 [92%] of 39). The most common grade 3 or 4 adverse events were decreased neutrophil count (18 [46%]), hypertension (six [15%]), dry skin, pruritus, or rash (five [13%]), and anaemia (four [10%]). Serious treatment-related adverse events occurred in ten (26%) patients, which were acute kidney injury (three [8%]), hepatotoxicity (two [5%]), sepsis (two [5%]), dry skin, pruritus, or rash (one [3%]), nausea (one [3%]), and gastric perforation (one [3%]). There were no treatment-related deaths. Regorafenib can be safely combined with nivolumab and chemotherapy and showed promising activity in HER2-negative metastatic oesophagogastric cancer. A randomised, phase 3 clinical trial is planned. Bristol Myers Squibb, Bayer and National Institutes of Health/National Cancer Institute.

Efficacy and safety of anlotinib plus XELOX regimen as first-line therapy for mCRC: a single-arm, multicenter, phase II study (ALTER-C-001).

Anlotinib showed encouraging anti-tumor activity in metastatic colorectal cancer (mCRC). This study was designed to assess the efficacy and safety of anlotinib plus XELOX as first-line therapy in mCRC patients. Eligible patients aged ≥18 with mCRC were enrolled in this multicenter, single-arm, phase II, exploratory study. Patients received at least 6 cycles of anlotinib, oxaliplatin, and capecitabine as initial therapy. Subsequently, patients received anlotinib monotherapy as maintenance therapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Thirty-one patients were included between December 2019 and March 2022. The median follow-up was 17.5 (95% CI, 3.0-17.5) months. The median PFS was 8.3 (95% CI, 6.3-10.0) months, with 6- and 12-month PFS rates of 82.3% (95% CI, 59.2%-93.0%) and 18.9% (95% CI, 4.8%-40.1%), respectively. Fifteen (48.4%) achieved partial response for an ORR of 48.4% (95% CI, 30.2%-66.9%). The disease control rate was 71.0% (95% CI, 52.0%-85.8%) due to 7 (22.6%) stable diseases. The median duration of response was 6.0 (95% CI, 3.6-8.0) months and 1 patient had the longest ongoing response of 17.3 months. Of 24 patients with evaluable imaging, 23 (74.2%) obtained tumor shrinkage. The median PFS (11.0 vs. 6.9 months) and ORR (66.7% vs. 60.0%) for patients with RAS/BRAF wild-type were numerically better than those with mutation. Three patients are still ongoing treatment. The grade 3 or more treatment-emergent adverse events (TEAEs) were mainly hypertension (12.9%) and decreased neutrophil count (12.9%). Four (12.9%) had serious TEAEs, primarily including abdominal pain and incomplete intestinal obstruction. Anlotinib plus XELOX as first-line therapy in patients with mCRC showed anti-tumor activity and safety profile, which is worth further investigation. chictr.org.cn, identifier ChiCTR1900028417.

Orelabrutinib for the treatment of relapsed or refractory marginal zone lymphoma: A phase 2, multicenter, open-label study.

Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton's tyrosine kinase inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic profiles were evaluated as secondary outcome measures. A total of 111 patients were enrolled, of which 90 patients had MZL confirmed by central pathology review, who were mainly with extra-nodal MZL of mucosa-associated lymphoid tissue (MALT, 46.7%) and nodal MZL (35.6%). The majority had late-stage disease, with stage IV accounting for 75.6%. After a median follow-up duration of 24.3 months, the IRC-assessed ORR was 58.9% (95% confidence interval [CI], 48.0-69.2), with rates of complete response and partial response being 11.1% and 47.8%, respectively. The IRC-assessed median duration of response was 34.3 months, and the IRC-assessed median progression-free survival (PFS) was not reached with a 12-month PFS rate of 82.8% (95% CI, 72.6-89.5). The rate of overall survival at 12 months was 91.0% (95% CI, 82.8-95.4). Common all-grade treatment-related adverse events (TRAEs) included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), blood present in urine (16.2%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL.

Evaluation of prevalence and outcomes of serial tyrosine kinase inhibitor use in pediatric patients with advanced solid tumors.

Multitargeted tyrosine kinase inhibitors (mTKIs) are increasingly utilized in the treatment of pediatric sarcomas and other solid tumors. It is unknown whether serial treatment with multiple TKIs provides a benefit and which patients are most likely to benefit from mTKI rechallenge. We performed a retrospective cohort study of pediatric cancer patients who received serial mTKI therapy off-study between 2007 and 2020 as either monotherapy or combination therapy. We report patient characteristics, clinical outcomes, dosing patterns, and treatment-associated toxicity. The study cohort included 25 patients. The overall prevalence of serial mTKI therapy among all patients treated for sarcoma at our institution was 3.7%, and the response rate to second mTKI was 9%. Median 6-month progression-free survival (PFS) and overall survival (OS) from start of second mTKI were 42.1% (95% CI: 20.4%-62.5%) and 79.1% (95% CI: 57.0%-90.8%), respectively. Patients who had received 4months or more (n=11) of therapy with first mTKI had significantly longer PFS versus those who received less than 4months (n=11; p=.001). Thirty-three percent of patients discontinued second mTKI due to toxicity. Six (40%) of 15 patients who discontinued the first mTKI due to progression had either a partial response or stable disease on the second mTKI. We observed a low response rate to mTKI rechallenge. However, we identified patients who had been treated with first mTKI for ≥4months as more likely to have prolonged stable disease with second mTKI. Several patients had a response or stable disease on the second mTKI despite having progressed on the first mTKI. Though toxicity was common, only a minority of patients discontinued the second mTKI due to toxicity.

Chemotherapy following immune checkpoint inhibitors in recurrent or metastatic head and neck squamous cell carcinoma: clinical effectiveness and influence of inflammatory and nutritional factors

ObjectiveThis study aimed to evaluate the clinical effectiveness of chemotherapy following immune checkpoint inhibitors (ICI). The association between inflammatory and nutritional factors and prognosis has also been investigated.MethodsWe retrospectively reviewed the medical records of recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC) patients who received chemotherapy following ICI therapy. The response rate and survival after chemotherapy, and nutritional and inflammatory factors, were examined.ResultsThe ICI before chemotherapy was nivolumab in 36 patients (70.6%) and pembrolizumab in 15 patients (29.4%). The chemotherapy regimens consisted of PTX in 32 patients (62.7%), PTX + Cmab in 9 (17.6%), and S1 in 10 (19.6%). The median overall survival (OS) was 20 months (95% CI 12–25), the estimated 12-month OS rate was 63.3%, the median progression-free survival (PFS) was 5 months (CI 4–6), and the 12-month PFS estimate was 8.9%. Univariate analysis significantly correlated Neutrophil-to-Lymphocyte Ratio (NLR), platelet-to-lymphocyte ratio (PLR), controlling nutritional status score (CONUT), and prognostic nutrition index (PNI) with OS and PFS. Additionally, these factors were significantly correlated with OS and PFS in the log-rank tests.ConclusionsChemotherapy following ICI is highly effective. There were no significant differences in the chemotherapy regimens. Inflammatory and nutritional factors may associate with patient prognosis after chemotherapy.

Clinical outcomes of liposomal irinotecan in advanced pancreatic adenocarcinoma patients previously treated with conventional irinotecan-based chemotherapy: a real-world study.

The efficacy of combination chemotherapy beyond the first-line setting remains modest in patients with advanced pancreatic adenocarcinoma (PAC). Evidence from recent clinical studies has shown that liposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) resulted in survival benefits in patients with advanced pancreatic adenocarcinoma (APAC) after progression on gemcitabine-based treatment. However, the survival benefits of nal-IRI in the third and later lines, in which limited options are available, have yet to be extensively studied. Also, some studies have shown conflicting results regarding the impact of prior treatment with conventional IRI on patient outcomes following treatment with nal-IRI. Therefore, this real-world study aimed to evaluate the efficacy and safety of nal-IRI plus 5FU-LV in advanced PAC patients who progressed on conventional IRI-containing regimens. A retrospective chart review was conducted between November 2016 to December 2022 on 30 patients diagnosed with advanced PAC who completed at least one cycle of nal-IRI plus 5-FU- LV and were previously treated with conventional IRI. Data regarding survival outcomes were retrieved. Thirty patients met the inclusion criteria. Overall, 76.7% of the patients received at least two lines of therapy prior to nal-IRI. The median overall duration of nal-IRI treatment was 2.0 months (IQR: 1.3 - 3.9 months). One patient (3.3%) had a partial response, and seven patients (23.3%) had stable disease as their best response. The median progression-free survival (PFS) was 1.9 months (95% CI 1.6 - 2.0) and the 6-month PFS rate was 20.0%. The median overall survival (OS) was 5.0 months (95% CI 3.4 - 7.0), and the 6-month OS rate was 36.7%. An interval between conventional IRI and nal-IRI ≥5.5 months was significantly associated with prolonged OS of 10.2 months (95% CI 3.3 - 12.1) versus 4.3 months (95% CI 2.1 - 5.9; p =0.003). Ten patients (33.3%) experienced grade 3 adverse events, most commonly nausea, fatigue, diarrhea, and non-neutropenic fever. Nal-IRI plus 5FU/LV had modest survival benefits and an acceptable safety profile in patients with prior conventional IRI. A longer interval between conventional IRI and nal-IRI was associated with increased survival outcomes.

Multiparametric MRI-Based Radiomics Signature with Machine Learning for Preoperative Prediction of Prognosis Stratification in Pediatric Medulloblastoma

Despite advances in risk-stratified treatment strategies for children with medulloblastoma (MB), the prognosis for MB with short-term recurrence is extremely poor, and there is still a lack of evaluation of short-term recurrence risk or short-term survival. This study aimed to construct and validate a radiomics model for predicting the outcome of MB based on preoperative multiparametric magnetic resonance images (MRIs) and to provide an objective for clinical decision-making. The clinical and imaging data of 64 patients with MB admitted to Shenzhen Children's Hospital from December 2012 to December 2021 and confirmed by pathology were retrospectively collected. According to the 18-month progression-free survival, the cases were classified into a good prognosis group and a poor prognosis group, and all cases were divided into training group (70%) and validation group (30%) randomly. Radiomics features were extracted from MRI of each child. The consistency test, t-test, and the least absolute shrinkage and selection operator were used for feature selection. The support vector machine (SVM) and receiver operator characteristic were used to evaluate the distinguishing ability of the selected features to the prognostic groups. RAD score was calculated based on the selected features. The clinical characteristics and RAD score were included in the multivariate logistic regression, and prediction models were constructed by screening out independent influences. The radiomics nomogram was constructed, and its clinical significance was evaluated. A total of 1930 radiomic features were extracted from the images of each patient, and 11 features were included in the construction of radiomics score after selected. The area under the curve (AUC) values of the SVM model in the training and validation groups were 0.946 and 0.797, respectively. The radiomics nomogram was constructed based on the training cohort, and the AUC values in the training group and the validation group were 0.926 and 0.835, respectively. The results of clinical decision curve analysis showed that a good net benefit could be obtained from the nomogram. The radiomics nomogram established based on MRI can be used as a noninvasive predictive tool to evaluate the prognosis of children with MB, which is expected to help neurosurgeons better conduct preoperative planning and patient follow-up management.

Impact of cumulative dose of brentuximab vedotin on outcomes of frontline therapy for advanced-stage Hodgkin lymphoma

AbstractIn the pivotal study ECHELON-1, brentuximab vedotin (BV), doxorubicin, vinblastine, and dacarbazine (A + AVD) demonstrated superior efficacy compared with bleomycin + AVD for the treatment of advanced-stage classic Hodgkin lymphoma (cHL). However, there are minimal available data regarding the frequency of dose reductions or omission of BV during curative therapy and the potential impact on patient outcomes. In a real-world analysis, we retrospectively reviewed the characteristics and outcomes of 179 patients with stage III or IV cHL treated with frontline A + AVD from January 2010 to April 2022. Treatment consisted of up to 1.2 mg/kg of BV and standard dose AVD IV on days 1 and 15 of each 28-day cycle for up to 6 cycles. At the time of treatment, the median patient age was 37 years, and a high-risk International Prognostic Score was observed in 46% of patients. Overall, 91% of patients received 6 cycles of AVD; 55% of patients did not receive the intended cumulative dose of BV (CDB); 28% of patients received two-thirds or less than the planned CDB. At a median follow-up time of 27.4 months (95% confidence interval [CI], 24.8-29), the median progression-free survival (PFS) was not reached, and the 12-month PFS was 90.3% (95% CI, 85.9-95.0). The impact of CDB on PFS was not significant (P = .15), nor was high CDB significantly associated with increased adverse events. In real-world experience, A + AVD is a highly effective treatment for patients with advanced-stage cHL, including for patients with prominent dose reductions of BV.

Final database lock results of the phase 2 cohort of lenvatinib + pembrolizumab for progressive disease after a PD-1/PD-L1-containing therapy in metastatic clear cell renal cell carcinoma

Abstract Background Lenvatinib + pembrolizumab is approved for the first-line treatment of advanced renal cell carcinoma (RCC). In the CLEAR trial, the combination showed statistically significant/clinically meaningful improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs sunitinib (Motzer R et al. NEJM. 2021). As immune checkpoint inhibitors (ICIs) have become standards of care as first-line treatment of RCC, an unmet need exists for patients who have disease progression after treatment with ICIs. A phase 1b/2 trial of lenvatinib + pembrolizumab was performed in multiple tumor types enrolling patients who had or had not received prior therapy; the primary analysis of the RCC cohort has been reported previously (Lee C-H et al. Lancet Oncol. 2021). Here, we report the final results of this RCC cohort with an additional 24 months of follow-up. Methods Eligible patients ≥18 years old with measurable disease were treated with lenvatinib 20 mg daily + pembrolizumab 200 mg once every 3 weeks. The primary endpoint (ORR at week 24 [ORRwk24] per immune-related [ir] RECIST by the investigators) has been previously reported (Lee C-H et al. Lancet Oncol. 2021). Secondary endpoints included ORR, duration of response (DOR), PFS (each by the investigators), OS and safety. In the analyses reported herein, efficacy data were grouped by prior therapy patients had received, including ICI-pretreated, treatment-naïve, and previously treated but ICI-naïve. Tumors were assessed by the investigators per irRECIST and RECIST v1.1 (modified to allow assessment of ≤10 target lesions [≤5 per organ]). Results 145 Patients were enrolled, of whom 105 were ICI-pretreated, 23 were treatment-naïve, and 17 were previously treated ICI-naïve. By the final database lock date (August 24, 2022), the median duration of follow-up for OS was 37.7 months (95% CI 35.2–42.7). Efficacy analyses included 104 ICI-pretreated patients and 22 treatment-naïve patients; 1 patient in either group was excluded as they were negative for clear cell disease. Per irRECIST by investigator assessment, ORR was 62.5% for ICI-pretreated patients (median DOR: 14.1 months), 77.3% for treatment-naïve patients (median DOR: 24.2 months), and 52.9% for previously treated ICI-naïve patients (median DOR: 9.0 months) (Table). Notably, 18-month PFS rates were 38.0% for ICI-pretreated patients, 70.5% for treatment-naïve patients, and 36.1% for previously treated ICI-naïve patients (Table). The median OS was 32.1 months for ICI-pretreated patients, 55.8 months for treatment-naïve patients, and 30.3 months for previously treated ICI-naïve patients; 24-month OS rates were &amp;gt;50% in all groups. Additional efficacy data are included in the Table. For those who had their dose of lenvatinib reduced (per recommended algorithms for standard adverse event [AE] management) the median time to first dose reduction was 2.10 months (range 0.1–16.6) for ICI-pretreated patients (n=75), 6.47 months (range 0.3–33.1) for treatment-naïve patients (n=18), and 2.89 months (range 1.0–12.5) for previously treated ICI-naïve patients (n=10). Overall, treatment-related (TR) AEs were reported in 99.3% of all 145 patients; grade ≥3 TRAEs were reported in 66.2%. The most common TRAE was diarrhea (n=88). Treatment-emergent, clinically significant (CS) AEs and AEs of special interest for pembrolizumab (AEOSIs) were reported in 95.2% and 55.9% of patients, respectively. Hypertension was the most common grade ≥3 CSAE (n=37), severe skin reactions were the most common grade ≥3 AEOSI (n=6). The median time to first onset of CSAEs was 0.64 months; the median time to first onset of AEOSIs was 2.07 months. Conclusions Lenvatinib + pembrolizumab demonstrated promising and durable antitumor activity with a manageable safety profile in patients with metastatic RCC, including in those who were ICI-pretreated. To our knowledge, this represents the largest cohort of ICI-pretreated patients with RCC prospectively treated in a clinical trial. CDMRP DOD Funding: no

Atezolizumab and paclitaxel as first line therapy in advanced triple-negative breast cancer patients included in the French early access program

Following the results of the IMpassion130 trial, an early access program (EAP) was opened in France, allowing patients with PD-L1-positive advanced triple negative breast cancer (aTNBC) to receive a combination of paclitaxel and atezolizumab as first line therapy. This EAP was later discontinued when the IMpassion131 trial read out with negative results. We performed a retrospective multicentric analysis in patients who were prospectively enrolled in the French EAP. Efficacy and toxicity data were obtained on 64 patients treated from August 2019 to August 2020 in 10 French cancer centers. Median progression-free survival (PFS) and overall survival (OS) were 4.1 months (95% CI [3.0–5.8]) and 17.9 months (95% CI [12.4–NR]), respectively. The 6-months PFS rate was 28% (95% CI [16–40%]) (N = 18/64), while N = 33/64 patients (52%, 95% CI [38–63%]) experienced a tumor response. Exploratory subgroup analyses retrieved that corticosteroid use at inclusion in the EAP, before treatment initiation, was the only independent unfavorable prognostic factor for PFS (HR 2.7, 95% CI [1.3–5.6]). No new safety signal was observed. This real-life study, unique by its setting (EAP granted by anticipation and later withdrawn), suggests atezolizumab and paclitaxel has a limited efficacy in PD-L1-positive aTNBC, especially in patients receiving corticosteroids as comedication before treatment start.

Randomised phase II trial of trifluridine/tipiracil (FTD/TPI) plus ramucirumab (RAM) versus trifluridine/tipiracil for previously treated patients with advanced gastric or esophagogastric junction adenocarcinoma (RETRIEVE study, WJOG15822G)

BackgroundTrifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma.MethodsThis RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70.DiscussionThis study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer.Trial registrationjRCTs041220120.

Long-term Clinical Outcomes of Yttrium-90 Transarterial Radioembolization for Hepatocellular Carcinoma: A 5-Year Institutional Experience

To examine the clinical outcomes of yttrium-90 (Y90) transarterial radioembolization (TARE) for primary hepatocellular carcinoma (HCC) through the evaluation of a 5-year institutional experience. This retrospective study evaluated 88 consecutive patients with primary HCC receiving Y90 TARE treatment at an academic medical center from 2017 to 2021. Disease distribution was bilobar in 60.2% of patients with an average lesion diameter of 5.0±3.4cm and Barcelona Clinic Liver Cancer stage B or C in 77% of the participants. Clinical outcomes were elucidated by examination of complications, liver function tests, biochemical response, and radiographic response. Objective response ratio (ORR) and progression-free survival (PFS) were also calculated. The mean administered Y90 radiation dose was 127.8±20.2Gy. No significant complications or LFT elevations occurred post-therapy. Of the 73.9% of patients with α-fetoprotein-producing tumors, 67.8% experienced a complete or partial biochemical response 1 month post-treatment. The ORR was 83.3% on 6-month imaging and PFS was 9.6±8.5 months. Functional outcomes (Eastern Cooperative Oncology Group) were maintained or improved in 79.6% and 76.1% of patients by 6 months and 1 year post-treatment, respectively. The mean survival was 14.7±12.1 months. At 6 months post-treatment, 77.3% of patients were downstaged to or maintained Milan criteria, which was sustained for 74.4% and 70.0% of patients 1 year and 2 years after treatment, respectively. Y90-TARE is a safe and effective therapy for primary HCC. Enduring outcomes further act as a realistic bridge to liver transplantation, with a majority of patients maintaining Milan criteria and preserving their functional status long term.

A multicenter, phase II trial of GC1118, a novel anti-EGFR antibody, for recurrent glioblastoma patients with EGFR amplification.

We evaluated the therapeutic efficacy of GC1118, a novel anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in recurrent glioblastoma (GBM) patients with EGFR amplification. This study was a multicenter, open-label, single-arm phase II trial. Recurrent GBM patients with EGFR amplification were eligible: EGFR amplification was determined using fluorescence in situ hybridization analysis when a sample had both the EGFR/CEP7 ratio of ≥2 and a tight cluster EGFR signal in ≥10% of recorded cells. GC1118 was administered intravenously at a dose of 4 mg/kg once weekly. The primary endpoint was the 6-month progression-free survival rate (PFS6). Next-generation sequencing was performed to investigate the molecular biomarkers related to the response to GC1118. Between April 2018 and December 2020, 21 patients were enrolled in the study and received GC1118 treatment. Eighteen patients were eligible for efficacy analysis. The PFS6 was 5.6% (95% confidence interval, 0.3%-25.8%, Wilson method). The median progression-free survival was 1.7 months (range: 28 days-7.2 months) and median overall survival was 5.7 months (range: 2-22.0 months). GC1118 was well tolerated except skin toxicities. Skin rash was the most frequent adverse event and four patients experienced Grade 3 skin-related toxicity. Genomic analysis revealed that the immune-related signatures were upregulated in patients with tumor regression. This study did not meet the primary endpoint (PFS6); however, we found that immune signatures were significantly upregulated in the tumors with regression upon GC1118 therapy, which signifies the potential of immune-mediated antitumor efficacy of GC1118.

Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden

BackgroundPembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe...

Balancing Efficacy and Tolerability of First-Line Systemic Therapies for Advanced Hepatocellular Carcinoma: A Network Meta-Analysis

Background: Atezolizumab + bevacizumab represent the current standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, direct comparison with other combination treatments including immune checkpoint inhibitors (ICI) + tyrosine kinase inhibitors (TKIs) are lacking. Objectives: This network meta-analysis (NMA) aims to indirectly compare the efficacy and the safety of first-line systemic therapies for unresectable advanced HCC. Method: A literature search of MEDLINE, Embase, and SCOPUS databases was conducted up to October 31, 2022. Phase 3 randomized controlled trials (RCTs) testing TKIs, including sorafenib and lenvatinib, or ICIs reporting overall survival (OS) and progression-free survival (PFS) were included. Individual survival data were extracted from OS and PFS curves to calculate restricted mean survival time. A Bayesian NMA was performed to compare treatments in terms of efficacy (15- and 30-month OS, 6-month PFS) and safety, represented by grade ≥3 (severe) adverse events (SAEs). The incremental safety-effectiveness ratio as measure of net health benefit was calculated as the difference in SAE probability divided by survival difference between the 2 most effective treatments. Results: Nine RCTs enrolling 6,600 patients were included. Atezolizumab plus bevacizumab showed the highest probability (88%) of achieving the 30-month OS landmark. Lenvatinib showed a probability of 86% of achieving best PFS outcomes. ICI monotherapies ranked as most tolerable. Atezolizumab plus bevacizumab showed the best net health benefit for OS, compared to durvalumab plus tremelimumab. When evaluating the net health benefit for PFS, at a willingness-to-risk threshold of 10% of SAEs for life-month gained, atezolizumab plus bevacizumab was favoured in 78% of cases, while at threshold of 30% of SAEs for life-month gained, lenvatinib was favoured in 76% of cases. Conclusions: Atezolizumab plus bevacizumab is the best treatment in terms of net benefit and therefore it should be recommended as standard of care. Compared to atezolizumab plus bevacizumab, lenvatinib monotherapy had the best net benefit for PFS when physicians and patients are available to accept a higher risk of toxicity.

Advancements of ALK inhibition of non-small cell lung cancer: a literature review.

The therapeutic landscape for non-small cell lung cancer (NSCLC) has evolved considerably in the last few years. The targeted drugs and molecular diagnostics have been developed together at a fast pace. This narrative review explores the evolution of anaplastic lymphoma kinase (ALK) targeting therapies from discovering the ALK protein, molecular tests, present clinical trial data and future perspectives. Since the body of evidence on lung cancer is growing daily, most oncologists need time to implement data in their daily practice. We developed a narrative review to provide up-to-date help in the clinical decision-making of ALK-altered NSCLC patients. In 2022, the authors reviewed PubMed's published pivotal randomized Phase 3 trial results. The development of ALK inhibitors was a revolution that is still ongoing; second and third-generation ALK inhibitors provided more than 30 months of progression-free survival (PFS) and impressive "brain-control". Brigatinib provided a survival benefit for patients with baseline brain metastases (HR 0.43, 95% CI: 0.21-0.89), and Lorlatinib demonstrated intracranial response rates of 82%, with 71% of complete intracranial responses. Personalized medicine is the new paradigm, from performing broad genetic panels for diagnosis to individual targeted therapy or combinations of different targeted agents. In the future, performing broad molecular panels should be the standard of care in the front line and after each progression to detect arising resistance mechanisms. Longer PFS will substantially convert a deadly condition into an almost chronic disease in the following decades. Treatment sequencing will be the cornerstone for patient survival, and liquid biopsies may replace tissue biopsies.

Nivolumab and ipilimumab with concurrent stereotactic radiosurgery for intracranial metastases from non-small cell lung cancer: analysis of the safety cohort for non-randomized, open-label, phase I/II trial

BackgroundUp to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without surgery. There...