Median Progression-free Survival Time Research Articles

Recurrence benefit from supramarginal resection in brain metastases of lung adenocarcinoma

BackgroundThere is growing evidence that brain metastases (BM) have no well-defined boundaries and that conventional microsurgical circumferential dissection of BM is often inadequate to prevent local tumor recurrence. Previous studies have suggested that supramarginal resection can significantly improve local tumor control. We retrospectively analyzed the local tumor control in a series of patients with BM from lung adenocarcinoma. MethodsWe retrospectively analyzed 48 patients with BM for lung adenocarcinoma in Shenzhen Second People’s Hospital from May 2015 to May 2020. 26 resected lesions were located in eloquent areas and underwent standard gross total resection (GTR group); 22 resected lesions were located in ineloquent areas, after standard gross total resection, the periphery was expanded and resected by 5 mm (MTR group). The postoperative tumor recurrence was compared between the two groups. ResultsDuring the follow-up period, the local recurrence rates in the GTR group and the MTR group were 61.5% and 27.3% (p = 0.022), respectively. Within 6 months after surgery, the local recurrence rates in the GTR group and the MTR group were 42.3% and 13.6% (p = 0.029), respectively. Within 12 months after surgery, the local recurrence rates in the GTR group and the MTR group were 57.7% and 22.7% (p = 0.014), respectively. The median progression-free survival time after surgery was 7.0 months (95% CI 4.0–10.0 months) in the GTR group and 14.0 months (95% CI 11.4–16.6 months) in the MTR group (Log-Rank p = 0.008). Compared with the MTR group, the HR of local recurrence in the GTR group was 3.74 (95% CI 1.38–10.39, p = 0.010). Cox multivariable analysis showed no other factors associated with local recurrence except for the surgical method (p = 0.012). ConclusionsOn the basis of conventional surgical total resection, expanded peripheral resection of 5 mm around the brain metastases of lung adenocarcinoma can significantly reduce the local recurrence rate and prolongs the progression-free survival time.

Activity of combination trametinib/navitoclax in patients with RAS-mutated gynecologic (GYN) cancers in a Phase 1/2 study (LBA 12)

<b>Objectives:</b> Preclinical data suggest that concurrent MEK and BCLxL inhibition can be synergistic. Mechanistically, inhibition of RAS signaling upregulates BIM, "priming" cells for apoptosis with BCLxL inhibition. A Phase 1 trial of the MEK inhibitor trametinib with the BCLxL inhibitor navitoclax was conducted to establish the recommended phase 2 dose (RP2D) and activity in select <i>RAS</i>-mutated tumors. We report the activity of this combination in patients (pts) with <i>RAS</i>-mutated GYN cancers. <b>Methods:</b> Pts with <i>RAS</i>-mutated GYN cancers were enrolled at the Dana-Farber Cancer Institute and Massachusetts General Hospital. Pts had RECIST 1.1 measurable disease and had progressed after at least one prior line of systemic chemotherapy. Eligible pts had cancers with activating mutations affecting codons 12, 13, 61, or 146 in <i>KRAS</i> or <i>NRAS</i>. Pts received combination trametinib and navitoclax either in dose escalation (7 pts) or in a dose expansion (24 pts) at the RP2D of navitoclax 250mg days 1-28 and trametinib 2mg days 1-14, following a lead-in cycle of navitoclax 150mg days 1-7 and 250mg days 8-28 with trametinib 2mg days 1-14 in 28-day cycles. <b>Results:</b> Between 1-22-2015 and 9-21-2021, 31 pts with GYN cancers (15 ovarian, 10 endometrial, 5 cervical, 1 mullerian) were enrolled. Data cutoff was 11-1-2021. Median follow-up is 4.9 mos. The median number of prior lines was 3 (range 1-7). Overall, 6 pts (19.4%; CI 7.5-37.5%) had a confirmed response. These included 3 ovarian cancers (1 low grade serous, 1 mucinous, 1 endometrioid), 1 endometrial (adenocarcinoma NOS), 1 cervical (mixed adenocarcinoma and neuroendocrine tumor), and 1 mullerian cancer (endometrioid). 9 pts stopped treatment before their disease was re-evaluated, and 1 pt's post baseline scan was deemed nonevaluable. Among 21 pts with at least one evaluable restaging scan, the response rate was 28.6% (95% CI 11.3-52.2%). Figure 1 shows the waterfall plot of best responses in these 21 pts. Median PFS time was 3.9 mos (95% CI 3.7-13.4) and 6-mo PFS was 37.7% (95% CI 17.5-57.9). In the 6 pts with response, the median duration for response was 9.5 mos (range 3.9-27.6). The most frequently observed adverse events included LFT changes, thrombocytopenia, diarrhea, nausea, and rash. <b>Conclusions:</b> Combined MEK and BCLxL inhibition with trametinib and navitoclax had clinical activity in pts with <i>RAS</i>-mutated GYN cancers, with a response rate in all pts of 19.4%. Among pts with at least one evaluable reassessment, the response rate was 28.6%. Further studies of combined MEK and BCLxL inhibition in pts with RAS-activated GYN cancers are warranted.Fig. 1

Comparison of the Efficacy and Safety of Transarterial Chemoembolization with or without Lenvatinib for Unresectable Hepatocellular Carcinoma: A Retrospective Propensity Score-Matched Analysis.

BackgroundCombination of angiogenesis inhibitor may achieve better therapeutic synergistic efficacy, considering of tumor hypoxia and promoted angiogenesis after transarterial chemoembolization (TACE). This study aimed to compare the safety and efficacy of TACE plus lenvatinib (TACE-lenvatinib) with TACE alone for patients with unresectable hepatocellular carcinoma (HCC).MethodsBetween June 2019 and September 2021, a total of 215 patients diagnosed with unresectable HCC were retrospectively reviewed, including 53 patients who received TACE-lenvatinib and 162 patients who received TACE alone. The patient selection bias between the TACE-lenvatinib group and the TACE group was balanced by propensity score matching analysis at a 1:2 ratio. Progression-free survival (PFS), overall survival (OS) and tumor response were evaluated in the two groups.ResultsAfter propensity score matching analysis, 34 patients receiving TACE-lenvatinib and 68 patients receiving TACE alone were enrolled. The median PFS and OS times in the TACE-lenvatinib group were significantly greater than those in the TACE group (PFS: 8.3 months vs 4.6 months, P = 0.008; OS: 27.7 months vs 18.4 months, P = 0.043). The objective response rate (ORR) in the TACE-lenvatinib group was higher than that in the TACE alone group (64.1% vs 36.5%, P = 0.002). Univariate and multivariate analyses revealed that TACE-lenvatinib treatment was an independent favorable prognostic factor for both PFS and OS.ConclusionFor unresectable HCC patients, the TACE-lenvatinib appeared superior to TACE alone regarding tumor control, PFS, and OS. However, considering the limitations of this study, these results should be interpreted as preliminary and warrant further confirmation.

Short bevacizumab infusion as an effective and safe treatment for colorectal cancer.

Bevacizumab is a humanized monoclonal antibody that contains <10% murine protein. To prevent infusion-related hypersensitivity reactions (HSRs), the initial bevacizumab infusion is delivered for 90 min, the second for 60 min and subsequent doses for 30 min. Several previous studies have shown that short bevacizumab infusions are safe and do not result in severe HSRs in patients with colorectal, lung, ovarian and brain cancer. However, the efficacy of short bevacizumab infusions for colorectal cancer management remains unclear. Therefore, to investigate this issue, a prospective multicenter study was conducted using 23 patients enrolled between June 2017 and March 2019. The initial infusion of bevacizumab was for 30 min followed by a second infusion rate of 0.5 mg/kg/min (5 mg/kg over 10 min and 7.5 mg/kg over 15 min. The primary endpoint was progression-free survival (PFS). The overall response and disease control rates were 57 and 87%, respectively. The median PFS time was 306 days (interquartile range, 204-743 days). No HSRs were noted. Adverse events associated with bevacizumab included grade 4 small intestinal perforation and grade 3 stroke in 1 patient each. These results suggest that a short bevacizumab infusion regime comprising an initial infusion for 30 min followed by a second infusion at 0.5 mg/kg/min is safe and efficacious for the management of colorectal cancer.

Serum microRNA-4297 is a sex-specific predictive biomarker of glioma grade and prognosis.

BackgroundGliomas account for nearly 80% of brain cancers, tending to occur more frequently in men with adverse outcomes. Emerging microRNAs have been positioned as promising predictors for glioma's histological grade and prognosis. However, there have been few studies concerning the sex-biased impacts on the clinical approach for the potential microRNA-4297 (miR-4297).MethodsWe utilized GSE139031micro-RNAs profiling to analyze serum miR-4297 expression in glioma. A total of 114 newly diagnosed glioma patients at the First Affiliated Hospital of Fujian Medical University from January 2017 to February 2021 were recruited and prospectively followed up. The association of miR-4297 levels with glioma grade and prognosis was investigated. Luciferase reporter gene assays and genotype analyses were carried out to explore the potential mechanism of sexually dimorphic miR-4297 in glioma.ResultsSerum miR-4297 levels were notably down-regulated in glioma. Besides, serum miR-4297 levels were positively associated with the high grades, which were exclusively present for females. The positive correlations of miR-4297 with O6-methylguanine-DNA methyltransferase (MGMT) protein and mean platelet volume were also observed in females. IDH-mutant females had decreased miR-4297. Median PFS time for females with miR-4297 ≥ 1.392 was distinctly shorter than those with miR-4297 <1.392 (12.3 months vs. 42.89 months, p = 0.0289). Based on multivariate logistic regression, miR-4297-based equation model was established as FHGRS. AU-ROC analysis revealed FHGRS exhibited a robust performance in predicting high-grade glioma in females (p < 0.001), whereas there was no such relationship in males. Furthermore, the MGMT-3'UTR variant rs7896488 in the specific binding region of miR-4297 was correlated with prognosis.ConclusionOur study uncovers sex-dependent characterization of serum miR-4297 in predicting glioma grade and the relapse risk for female patients, which underscores the clinical benefits of sex-specific analysis in non-coding RNA research.

A Combination of Sorafenib, an Immune Checkpoint Inhibitor, TACE and Stereotactic Body Radiation Therapy versus Sorafenib and TACE in Advanced Hepatocellular Carcinoma Accompanied by Portal Vein Tumor Thrombus.

Simple SummaryPortal vein tumor thrombosis (PVTT) is the commonest type of macrovascular invasion in hepatocellular carcinoma (HCC), while the effectiveness of treatments for HCC with PVTT remains unsatisfactory. The present study aimed to assess the effectiveness of the combination treatment of sorafenib, an immune checkpoint inhibitor, transcatheter arterial chemoembolization and stereotactic body radiation therapy in patients with advanced HCC and PVTT. We confirmed that the combination therapy yielded better survival data than the combined administration of sorafenib and transcatheter arterial chemoembolization in patients with advanced HCC and PVTT. Especially, this combination therapy could serve as a downstaging strategy to provide the chance of radical surgery for the patients with advanced HCC.Background: This study compared the effectiveness of the combined administration of sorafenib, an immune checkpoint inhibitor, transcatheter arterial chemoembolization (TACE), and stereotactic body radiation therapy (SBRT) (SITS group) vs. sorafenib combined with TACE (ST group) in treating and downstaging advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Methods: The present study included patients with advanced HCC and PVTT treated with one of the above combination therapies. The downstaging rate, objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) were assessed. Results: Sixty-two patients were analyzed. The ORR was elevated in the SITS group compared with the ST group (p = 0.036), but no differences were found in DCR (p = 0.067). The survival analysis revealed higher PFS (p = 0.015) and OS (p = 0.013) in the SITS group, with median PFS and OS times of 10.4 and 13.8 months, respectively. Ten patients displayed successful downstaging and underwent surgery in the SITS group, vs. none in the ST group. The prognosis was better in surgically treated patients compared with the non-surgery subgroup, based on PFS (p < 0.001) and OS (p = 0.003). Despite a markedly higher rate of AEs in the SITS group (p = 0.020), including two severe AEs, the SITS combination therapy had an acceptable safety profile. Conclusion: The SITS combination therapy yields higher PFS and OS than the combined administration of sorafenib and TACE in patients with advanced HCC and PVTT, especially as a downstaging strategy before surgery.

Continuing maintenance temozolomide therapy beyond 12cycles confers no clinical benefit over discontinuation at 12cycles in patients with IDH1/2-wildtype glioblastoma.

The optimal duration of maintenance temozolomide therapy is controversial. We aimed to examine the clinical benefits of continuing temozolomide therapy beyond 12cycles in patients with glioblastoma. We included 41 patients with isocitrate dehydrogenase 1/2-wildtype glioblastoma, who received 12 or more cycles of temozolomide therapy between June 2006 and December 2019. We evaluated the outcome between 16 patients who continued temozolomide therapy beyond 12cycles up to 24cycles (≥13cycles group) and 25 patients wherein temozolomide therapy was discontinued at 12cycles (12cycles group). The median progression-free survival and survival time after completing 12cycles (residual progression-free survival and residual overall survival) did not differ between the 12cycles group and ≥13cycles group (residual progression-free survival: 11.3 vs. 9.2months, P=0.61, residual overall survival: 25.7 vs. 30.2months, P=0.76). Multivariate analysis including temozolomide therapy beyond 12cycles, age at 12cycles, Karnofsky performance status at 12cycles, residual tumor at 12cycles, maintenance therapy regimen and O-6-methylguanine deoxyribonucleic acid methyltransferase promoter methylation status revealed that extended temozolomide therapy beyond 12cycles was not correlated with residual progression-free survival and residual overall survival (P=0.80 and P=0.41, respectively) but Karnofsky performance status at 12cycles ≥80 was significantly associated with increased residual overall survival (P=0.0012). Continuing temozolomide beyond 12cycles confers no clinical benefit over the discontinuation of temozolomide at 12cycles. Karnofsky performance status at 12cycles ≥80 may serve as a novel predictive factor for long-term survival.

Efficacy of the VIT (vincristine, irinotecan and temozolomide) regimen in adults with metastatic Ewing sarcoma

The goal of the research was to investigate if a combination of vincristine, irinotecan and temozolomide (VIT) could benefit adult patients with metastatic Ewing sarcoma who had already been heavily pretreated. Metastatic Ewing sarcoma patients had their data retrospectively analyzed. The patients' clinical, radiological and therapeutic data were recorded. Survival analyzes were performed with these data. The study enlisted the participation of sixteen patients. The average age was 25 years old (range: 20–42). The lung was the most prevalent metastatic location (81.3%). Patients had received at least two distinct chemotherapy combinations (87.5%) and palliative radiotherapy (37.5%) before receiving the (VIT) combination. The Median progression-free survival time was found as 3.4 (95% CI, 1.8–4.9) months. Five patients (31.3%) experienced a partial response, while the remaining patients (68.7%) had progressing disease. Thirteen individuals (81.3%) had grade 1–2 adverse events, whereas five (31.3%) had grade 3–4 adverse events. Hematological complications were the most common side effects (87.5%). Median overall survival was calculated as 5.6 (95% CI, 3.6–7.5) months in the patients after the beginning of VIT regimen. We demonstrated the efficacy of the VIT regimen in adult patients with metastatic Ewing sarcoma in this research. In these extensively pretreated patients, toxicities were a concern. Metastatic Ewing sarcoma patients have few treatment choices. In patients who have had a good performance status, VIT regimen may be considered for disease control.

Dacarbazine in the management of metastatic melanoma in the era of immune checkpoint therapy: a valid option or obsolete?

Despite the dramatic improvement in both overall survival (OS) and progression-free survival (PFS) in patients with metastatic melanoma treated with immune checkpoint inhibitors, up to 60% will develop treatment resistance and 50% will die from their disease. Therefore, although dacarbazine is no longer a mainstay of modern melanoma management, we examined the extent to, and in which context, it may still play a role. A retrospective analysis of electronic medical records of patients who had received dacarbazine treatment between October 2014 and October 2021, following innate or acquired resistance to immune checkpoint inhibitors, was performed to determine PFS and OS and examine tolerability. Nine patients with locally advanced ( n = 1) or metastatic melanoma ( n = 8) were identified (average age: 74 years, 4 males and 5 females). The number of cycles of dacarbazine ranged from 2 to 45 (mean = 12). One-third of patients developed a complete ( n = 2) or partial ( n = 1) response, two-thirds did not respond to treatment. The median PFS time was 90 days. Common adverse events included blood dyscrasias; one patient developed a grade 3 hepatitis, although it was unclear if this was due to the chemotherapy or the preceding combined immunotherapy. Dacarbazine may still be a valid option in the setting of treatment for refractory, relapsed, or progressive disease. Future studies should focus on the immunomodulatory effects of dacarbazine on the tumor microenvironment, which could be harnessed to potentially restore sensitivity to immune checkpoint-based therapy.

Survival analysis of 80 elderly patients with esophageal squamous cell carcinoma receiving definitive concurrent chemoradiotherapy with S-1

PurposeThis single-center retrospective study aimed to observe survival and prognosis of elderly patients with esophageal cancer receiving radical radiotherapy combined with S1 chemotherapy, and to preliminarily explore whether hematologic indicators or inflammatory indicators before radiotherapy are prognostic factors. Material and methodsWe retrospectively collected data of 80 elderly patients with esophageal cancer who had received radical concurrent chemoradiotherapy from January 2015 to July 2018. The patients were older than 70 years. Radiation therapy was delivered with intensity-modulated irradiation therapy (IMRT) or volumetric modulated arc therapy (VMAT), while the chemotherapy regimen was S1 alone. Toxicities were evaluated in accordance with the criteria of the Radiation Therapy Oncology Group. Baseline hematologic basic nutritional indicators, such as hemoglobin (HGB), albumin (ALB), and prealbumin (PAB), along with inflammatory indicators, such as the ratio of neutrophils to lymphocytes (NLR), the ratio of platelets to lymphocytes (PLR), were collected to preliminarily analyze their relationship with progression and survival. ResultsThe median follow-up time was 39 months (range 30–65 months). The median overall survival and progression-free survival times were 24 and 17 months, respectively. The 1-, 2-, and 3-year overall survival rates were 76.5%, 48.1%, and 31.3%, respectively. The 1-, 2-, and 3-year progression-free survival rates were 57.5%, 37.8%, and 29.4%, respectively. T stage, clinical staging, and lesion region were independent prognostic factors for OS. No significant associations with prognosis were observed either for baseline hematologic or for inflammatory indicators (all P>0.05). The rates of esophagitis (grade 2 and above) and hematologic toxicity were 60% and 45%, respectively. ConclusionOral S-1 combined with definitive concurrent radiotherapy for elderly patients with esophageal cancer has a significant survival benefit. The toxicities are well tolerated. It seems that prognosis does not correlate with baseline hematologic nutritional indicators and inflammatory indicators.

Transarterial chemoembolization combined with lenvatinib versus transarterial chemoembolization combined with sorafenib for unresectable hepatocellular carcinoma: Acomparative retrospective study.

Tyrosine kinase inhibitors target transarterial chemoembolization (TACE)-mediated vascular endothelial growth factor to inhibit tumor revascularization and to slow tumor progression. The present study aimed to compare the clinical outcomes of TACE combined with lenvatinib (TACE-lenvatinib) and TACE combined with sorafenib (TACE-sorafenib) in patients with unresectable hepatocellular carcinoma (HCC). The clinical data of patients diagnosed with unresectable HCC who received TACE-lenvatinib or TACE-sorafenib between January 2018 and April 2021 were retrospectively reviewed. The tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated and compared between the two groups. A total of 112 patients were enrolled and classified into the TACE-lenvatinib group (n=53) and the TACE-sorafenib group (n=59). The objective response rates of patients in the TACE-lenvatinib and TACE-sorafenib groups were 54.7% and 44.1%, respectively (p=0.260), and the disease control rates (DCRs) were 81.1% and 61.0% (p=0.020). The median PFS time was significantly longer in the TACE-lenvatinib group than in the TACE-sorafenib group (10.7 vs. 6.0months; p=0.002). The median OS time between the TACE-lenvatinib and TACE-sorafenib groups also showed a significant difference (30.5 vs. 20.5months, p=0.018). All treatment-related AEs and grade 3/4 AEs were comparable between the two groups (p>0.05). Compared to TACE-sorafenib, TACE-lenvatinib was associated with better DCR, PFS and OS outcomes in patients with unresectable HCC. In subgroups of Barcelona Clinic Liver Cancer B stage or TACE-refractory patients, TACE-lenvatinib also showed a trend of superiority.

Cabazitaxel versus docetaxel for treatment of metastatic castrate refractory prostate cancer.

ObjectivesTo assess cabazitaxel versus docetaxel re‐challenge for the treatment of metastatic castrate refractory prostate cancer (CRPC) patients previously treated with docetaxel at inception of primary hormone therapy.Patients and MethodsThe CANTATA trial was a prospective, two‐arm, open‐label, phase II study conducted in eight UK centres. Patients over the age of 18, with histologically proven, metastatic prostate cancer who had been previously treated with up to 6 cycles of docetaxel as part of the STAMPEDE trial (or treated with the same drug outside of the trial at primary diagnosis) and had a performance status (PS) of 0–2, were eligible. Patients who progressed during primary treatment with docetaxel or had received prior systemic chemotherapy were excluded. Cabazitaxel (25 mg/m2) or docetaxel (75 mg/m2) was administered via intravenous infusion every 3 weeks with oral prednisolone (10 mg) for up to 10 cycles, until disease progression, death or unacceptable toxicity. The primary outcome was clinical progression‐free survival (PFS) as defined by either date of pain progression, date of a cancer‐related skeletal‐related event, or date of death from any cause. Analyses were by intention to treat. EudraCT number: 2012‐003835‐40ResultsBetween 7 March 2013 and 4 January 2016, 15 patients with a median age of 70 years (range 54–76) were recruited; seven received cabazitaxel, eight docetaxel. The study was halted due to slow accrual. The median clinical PFS time in the cabazitaxel group was 6.2 months compared with 8.4 for the docetaxel group (95% confidence intervals were not reached due to the small number of patients). A total of 13 serious adverse events were reported.ConclusionDue to the low number of patients recruited, meaningful comparisons could not be made. However, toxicity was in line with known outcomes for these agents, demonstrating it is feasible and safe to deliver chemotherapy to men relapsing with CRPC after upfront chemotherapy.

Abstract 1025: Phase Ib trial single-arm efficacy estimates via comparison to a historical clinical trial synthetic control arm

Abstract Background: Innovations in data science and trial design have catalyzed novel clinical research methods which may inform the future success of new experimental therapies more efficiently than previously believed. To guide development of the novel immune agent GEN-1, we compared endpoints experienced by patients from a recent neoadjuvant single-arm phase Ib study of GEN-1 plus standard chemotherapy to those of similar historical clinical trial patients in receipt of standard chemotherapy alone. Methods: To compare safety and efficacy endpoints following first-line neoadjuvant weekly GEN-1 immunotherapy and carboplatin and paclitaxel to standard first-line neoadjuvant carboplatin and paclitaxel in women with advanced ovarian cancer, we first applied key OVATION-1 trial (NCT02480374) inclusion and exclusion criteria to the Medidata Enterprise Data Store (MEDS) data to identify candidate historical clinical trial patients for comparison. We standardized and integrated patient-level MEDS data (N=41) from distinct phase I-III trials (enrollment years 2015-2016) with patient-level OVATION-1 data (N=18). Standard propensity score methods were used to identify MEDS patients who appeared similar to OVATION-1 patients to create a synthetic control arm (SCA). Results: Fifteen OVATION-1 patients (15/18, 83%) were matched to 15 (37%, 15/41) MEDS historical trial control patients. Matching attenuated pre-existing differences in attributes between the OVATION-1 and MEDS patients. The median progression-free survival time was not reached by the OVATION-1 group and was 15.8 months for the SCA. The hazard of progression for the OVATION-1 group relative to the SCA was 0.53 (95% CI 0.16, 1.73). Fourteen of 15 OVATION-1 patients (93.3%) and 15 of the SCA patients (100%, 15/15) had at least one MedDRA toxicity. Compared to SCA patients, OVATION-1 patients had a slightly higher incidence in nausea (OVATION-1 73.3%; SCA 53.3%), fatigue (OVATION-1 73.3%; SCA 33.3%), anorexia (OVATION-1 46.7%; SCA 13.3%), chills (OVATION-1 26.7%; SCA 6.7%), and infusion-related reaction (OVATION-1 26.7%; SCA 0%). Conclusions: The comparison of patient endpoints from a single-arm phase Ib trial to a historical clinical trial SCA provided informative and relatively reliable estimates of efficacy endpoints which were used to inform GEN-1’s expected effect study size in the phase II setting. This information led to a decrease in the number of planned patients for the subsequent randomized phase II trial. More broadly, this approach supports the ability of historical clinical trial patient comparisons to inform drug development via trial design, something which may further increase the scientific value of early phase trials. Citation Format: Xiang Yin, Ruthanna Davi, Elizabeth B. Lamont, Premal H. Thaker, William H. Bradley, Charles A. Leath, Kathleen M. Moore, Khursheed Anwer, Lauren Musso, Nicholas Borys. Phase Ib trial single-arm efficacy estimates via comparison to a historical clinical trial synthetic control arm [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1025.

Early administration of durvalumab after chemoradiotherapy increased risk of pneumonitis in patients with locally advanced non-small cell lung cancer.

Durvalumab (Durva) administration after chemoradiation therapy (CRT) in locally advanced non-small-cell lung cancer (NSCLC) is the standard of care, associated with relatively prolonged progression-free (PFS) and overall survival. However, pneumonitis occurs in 73.6% of Japanese patients. This retrospective study aimed to identify factors associated with Durva efficacy and safety, specifically, the risk of pneumonitis. This study included data from 26 consecutive patients with locally advanced NSCLC who underwent CRT followed by Durva. The rates of adverse events and PFS were examined. The median PFS time was 15.6 months (95% confidence interval [CI]: 8.7-not available). Patients developed pneumonitis of grade 1, 2, 3, and 4 at the rate of 62%, 27%, 12%, and 0%, respectively. The median PFS time was 6.4 months for patients with programmed death ligand 1 (PD-L1) expression level of<50% and not reached for patients with PD-L1 expression level of ≥50% (hazard ratio [HR], 0.19; 95% CI: 0.04-0.89), which was significantly prolonged. The cumulative incidence of pneumonitis grade 2 or above was significantly higher when the time between the last day of thoracic radiotherapy (TRT) and the start of Durva therapy was within 14 days compared to >14 days (HR: 0.19; 95% CI: 0.06-0.59). This association was statistically significant in multivariate analysis. The initiation of Durva therapy within 14 days after TRT may increase the risk of pneumonitis grade 2 or above. Careful observation and suitable treatment are recommended.

Decrease in estimated glomerular filtration rates in non-small cell lung cancer patients treated with crizotinib.

Crizotinib is a tyrosine kinase inhibitor used in patients with non-small cell lung cancer, and there are uncertainties about its effect on kidney function. In this study, it was aimed to document the possible adverse effect of the drug on kidney functions. The estimated glomerular filtration rates (eGFRs) of the patients were calculated by creatinine-based Chronic Kidney Disease Epidemiology Collaboration and compared by months using the paired samples t-test. Kaplan-Meier survival method was used for progression-free survival and overall survival (OS) analysis. Twenty-six patients who received crizotinib were included in the study, and the median progression-free survival time with crizotinib was 14.2 months and the median OS time was 27.4 months. There was a significant reduction of eGFR after the 1st month of crizotinib treatment when compared to the rate before treatment initiation (P < 0.001). The eGFR values at the end of the 1st month and the 2nd month of treatment and the 2nd and 3rd months of treatment were statistically similar (P = 0.086, P = 0.663; respectively). This decrease in eGFR values was reversible, and there was no difference detected between pretreatment and posttreatment discontinuation (P = 0.100). A reversible decrease in renal functions was detected in patients using crizotinib. When the literature data are examined, it is thought that the reason for this decrease may be related to the increase in renal inflammation or a pseudo decrease due to the decrease in creatinine excretion. When evaluating renal functions in these patients, using noncreatine-based (iothalamate, etc.) calculations can give more accurate results.

Association of Driver Oncogene Variations With Outcomes in Patients With Locally Advanced Non–Small Cell Lung Cancer Treated With Chemoradiation and Consolidative Durvalumab

Consolidative durvalumab after definitive chemoradiation for unresectable locally advanced non-small cell lung cancer (NSCLC) can significantly improve progression-free survival (PFS) and overall survival (OS), as shown in the PACIFIC trial. However, whether patients with driver variations derive equal benefit from this regimen remains unclear. To compare outcomes of patients with locally advanced NSCLC with and without driver variations treated with the PACIFIC regimen. This cohort study examined 104 patients with unresectable locally advanced NSCLC with mutational profiling treated at a tertiary cancer center with definitive chemoradiation and consolidative durvalumab from June 2017 through May 2020. Patients with recurrent disease or those receiving postoperative therapy were excluded. Outcomes were analyzed with Kaplan-Meier and multivariate regression analyses. Patients were grouped according to the presence of non-KRAS driver variations (EGFR exon 19 deletion, EGFR exon 20 insertion, EGFR exon 21 mutation [L858R], ERBB2 exon 20 insertion, EML4-ALK fusion, MET exon 14 skipping, NTRK2 fusion), KRAS driver variations, or no driver variations. The primary outcomes were PFS, OS, and second progression-free survival (PFS2) times. The 104 patients had a median (IQR) age of 65.1 (9.8) years, with 55 females (53%) and 85 former or current smokers (88%). There were 43 patients (41%) with driver variations with a median PFS time of 8.4 months vs 40.1 months for patients without driver variations (hazard ratio [HR], 2.75; 95% CI, 1.64-4.62; log-rank P < .001). Both patients with non-KRAS and KRAS driver variations had worse PFS. No difference in OS was found between patients with and without driver variations (log rank P = .24). Among the 63 patients who developed progressive disease, those with non-KRAS driver variations had a median PFS2 time of 13.7 months vs 4.4 months for all other patients (HR, 0.37; 95% CI, 0.21-0.64; log-rank P = .001). Rates of overall grade 2 toxic effects or higher did not differ by driver mutation status. In this cohort study, driver variations in patients with unresectable locally advanced NSCLC were associated with significantly shorter PFS time after definitive chemoradiation and consolidative durvalumab. These findings suggest the need to consider additional or alternative treatment options to the PACIFIC regimen for patients with driver variations.

MEDB-38. Significance of CSF cytology and neurologic deterioration in relapsed medulloblastomas in the German HIT-REZ-97/-2005 Studies and the HIT-REZ-Register

BACKGROUND: Follow-up examinations are an essential part of the aftercare of patients with brain tumours. We investigated survival in relation to neurological impairment and positive CSF findings at first relapse/progression of medulloblastomas. METHODS: We collected data from patients with relapsed medulloblastoma from the German HIT-REZ studies (HIT-REZ-1997, HIT-REZ-2005, HIT-REZ-Register, n=342). Survival differences dependent on tumour cell-positive and -negative CSF cytology as well as on new onset or worsening of neurological impairment (i.e. headache, nausea/vomiting, ataxia, seizures and others) were analysed. RESULTS: 247 patients with a recurrent medulloblastoma were evaluable for CSF cytology at first relapse/progression (positive n=97, negative n=150). Patients with tumour cell-positive CSF results showed a significantly shorter median PFS and OS time compared to patients with negative CSF cytology [PFS: 9.1 (CI: 5.3-12.9) vs. 16.8 (CI: 13.8-19.8) months, plog rank test=0.001; OS: 14.4 (CI: 12.3-16.4) vs. 41.8 (CI: 33.3–50.4) months, plog rank test<0.001]. The shortest PFS and OS were observed in SHH-activated (n=18) and group 3 medulloblastomas (n=23) independently of CSF cytology result [median PFSSHH: 4.3 (CI:1.1-12.2), OSSHH: 6.3 (CI:1.1-18.7); PFSgroup3: 4.2 (CI:2.3-13.1), OSgroup3: 13.2 (CI:7.1-18.5) months]. For analysis of the impact of neurological deterioration on survival at first relapse, 249 Patients were evaluable. 105 patients with new or severely worsened neurological impairment at first relapse/progression displayed a significantly poorer PFS and OS time in comparison to 144 patients with unchanged or improved neurological symptoms [PFS: 8.2 (CI: 6.0-10.3) vs. 14.9 (CI: 12.0-17.9) months, plog rank test=0.001; OS: 15.1 (CI: 9.5-20.6) vs. 32.6 (CI: 26.2-38.4) months, plog rank test<0.001]. CONCLUSIONS: Patients with relapsed medulloblastoma show significantly worse survival (PFS and OS) in presence of positive CSF cytology or neurologic deterioration at relapse. These findings could be relevant for patient/parents counselling and treatment recommendations at relapse. Funded by the German Children Cancer Foundation

MEDB-58. Risk factors and risk prediction models for medulloblastoma recurrence

BACKGROUND: There is a clear need for systematic appraisal of models/factors predicting medulloblastoma recurrence because clinical decisions about adjuvant treatment are taken on the basis of such variables. METHODS： A total of 273 patients diagnosed with medulloblastoma were retrospectively analyzed. The pre-rediotherapy neutrophile-lymphocyte ratio (NLR) was calculated, and other clinical characteristics were collected such as genetic type , whether with dissemination, degree with excision. The Kaplan-Meier method was used for survival analysis. Cox regression models was used to identify independent prognostic factors. R software was used to develop a nomogram with all the independent prognostic factors included. The prognostic predictive ability of the nomogram was evaluated by Concordance-index (C-index), area under the curve (AUC), and calibration curve. RESULTS: The median median progression-free survival time was 63.8 months in overall cohort. Univariate and multivariate cox hazards regression analysis identified independent prognostic factors associated with the PFS of patients with medulloblastoma to include age, residual tumor volume ＞1.5cm3 after excision, NLR ＞4.5, whether with dissemination before RT, and whether the genetic type is group 3,which were integrated to establish a nomogram. The C-indexes of nomogram were 0.696 and 0.676 in the training and validation cohort, respectively. The AUC of predicting 3-years PFS showed satisfactory accuracy as well (Training cohort: AUC=0.696; Validation cohort: AUC=0.676). The calibration curve showed agreement between the ideal and predicted values. Kaplan-Meier curves based on the PFS showed significant differences between nomogram predictive low-, and high groups (P < 0.001). CONCLUSIONS: We found that pre-treatment NLR was an independent prognostic factor for recurrence or metastasis of medulloblastoma after treatment. In combination with NRL and clinical factors, nomogram has a good prediction of PFS in patients with medulloblastoma after radiotherapy. It has the potential to facilitate more precise risk stratification to guide personalized treatment of medulloblastoma.

Nedaplatin plus pemetrexed or cisplatin plus pemetrexed as first-line chemotherapy for EGFR/ALK-negative advanced lung adenocarcinoma (NACA): A multicenter, open-label, non-inferiority, randomized, phase III trial.

9089 Background: Platinum-based chemotherapy is the backbone of treatment for advanced non-small cell lung cancer. Cisplatin has well-known side effects such as gastrointestinal reaction and fatigue, and nedaplatin was developed to be an alternative platinum with less toxicity. We aimed to compare nedaplatin plus pemetrexed was non-inferior to cisplatin plus pemetrexed as first-line chemotherapy for advanced EGFR/ALK-negative lung adenocarcinoma. Methods: We did an open-label, randomized, phase III trial at 15 centers in China. Advanced lung adenocarcinoma patients with EGFR/ALK-negative status were randomly assigned to receive nedaplatin 90 mg/m2 or cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 for 6 cycles as first-line treatment, and pemetrexed maintenance for those without progressive disease. The primary endpoint was progression-free survival (PFS), non-inferiority was shown if the upper limit of the 95% CI for the hazard ratio (HR) of PFS did not exceed 1.30. Secondary endpoints included objective response, overall survival and toxicity. This trial is registered with ClinicalTrials.gov, number NCT02607592. Results: Between Sep 2015 and May 2021, 218 patients were randomized to nedaplatin group (n = 111) or cisplatin group (n = 107). In the intention-to-treat population, median PFS time was 6.87 months (95%CI, 5.25 to 8.49) in the nedaplatin group and 5.53 months (95%CI, 4.57 to 6.50) in the cisplatin group, with a HR of 0.76 (95%CI, 0.56 to 1.03, p= 0.078). In the per-protocol population (nedaplatin group, n = 105; cisplatin group, n = 94), median PFS time was 6.87 months (95%CI, 5.36 to 8.37) and 5.20 months (95%CI, 4.03 to 6.37) respectively, with a HR of 0.76 (95%CI, 0.56 to 1.03, p= 0.082). Overall response rate was 41.9% in nedaplatin group and 26.6% in cisplatin group ( p= 0.026). A significantly higher frequency of any grade nausea and vomiting (51[53.68%] of 95 in the cisplatin group vs 30[28.04%] of 107 in the nedaplatin group, p&lt; 0.001), fatigue (37[38.95%] vs 27[25.23%], p= 0.037), and constipation (15[15.79%] vs 5[4.67%], p= 0.008) were reported in the cisplatin group compared with the nedaplatin group. Higher rate of grade 3/4 nausea and vomiting was observed in cisplatin group (10[10.53%] vs 0, p= 0.001). Patients in the nedaplatin group had higher frequency of thrombocytopenia but without statistical significance (any grade: 28[26.17%] of 107 in the nedaplatin group vs17[17.89%] of 95 in the cisplatin group, p= 0.158; grade 3/4: 8[7.48%] in the nedaplatin group vs 3[3.16%] in the cisplatin group, p= 0.177). Conclusions: Our findings show that nedaplatin plus pemetrexed is not inferior to cisplatin plus pemetrexed in progression-free survival, with less toxicities, which represents an alternative chemotherapy regimen for EGFR/ALK-negative advanced lung adenocarcinoma. Clinical trial information: NCT02607592.

A phase II study to evaluate the safety and efficacy of IMM-101 in combination with checkpoint inhibitors in patients with advanced melanoma: Final results of the IMM-101-015 trial.

9554 Background: IMM-101 is a suspension of heat-killed whole cell Mycobacterium obuense (NCTC 13365), which enhances the innate immune response and dendritic cell maturation. In animal models, it increases antigen specific responses and number of CD8+ CTL and CD4 + Th1 cells. The clinical studies with IMM-101 have shown promising efficacy signals in pancreatic cancer when combined with gemcitabine and in melanoma as adjunctive or single agent. Methods: IMM-101-015 is an open-label Phase 2a study to investigate the safety and efficacy of IMM-101 in combination with checkpoint inhibitors (CPIs) in patients (pts) with advanced melanoma who were either treatment-naive (cohort A), or whose disease had progressed during PD-1 blockade (cohort B). Pts with evaluable lesions, adequate performance status and organ function were eligible. Pts received 1.0 mg of IMM-101 every 2 weeks for the first 3 doses followed by a rest period of 4 weeks, then every 2 weeks for the next 3 doses, and thereafter every 4 weeks. Nivolumab was given every 2 or 4 weeks (dependent on Investigator choice). Pts in cohort B had the option to change to ipilimumab and IMM-101 if their disease continued to progress. Biopsies and blood samples were obtained at baseline and during treatment for assessment of tumor biomarkers and immune correlatives. The primary objectives of the study were to evaluate the overall response rate (ORR) after a maximum of 18 months of treatment by RECIST 1.1 and to assess the safety and tolerability of the combination of IMM-101 + CPIs. Results: Sixteen pts (11 Cohort A and 5 Cohort B) were treated between October 2018 and May 2021. The median age was 68.5 yrs (range 36-92) and 11 (69%) were male. The ECOG ps was 0 in 9 (56%) and 1 in 7 (44%) pts. Four (25%) had unresectable stage III melanoma and 12 (75%) stage IV. In Cohort A (3 stage III, 5 stage IV M1b and 3 M1c) 3 pts (27%) had an elevated baseline LDH, 6 (55%) a positive PD-L1 status and 3 (27%) a BRAF mutation. Pts in cohort A were on study for a median time of 8.5 months (range 1.5 - 19.1) and those in cohort B for 3.0 months (range 1.5 - 7.4). All pts were evaluated for response. The ORR was 73% (95% CI 39.03, 93.98) in cohort A whereas all pts in cohort B reported progressive disease. With respect to cohort A, 2 (18%) pts had CR, 6 (55%) PR and 1 (9%) SD. The median progression-free survival time was 10.2 months (95% CI 2.50, NE) with 41% of the pts progression-free at 18 months. The most frequent treatment emergent adverse events (TEAEs) were injection site reaction (63%), pruritus (44%), fatigue (38%), skin rash (25%), hypothyroidism (25%) and diarrhoea (19%). There were no grade 4 TEAEs. Grade 3 TEAEs occured in 10 patients (63%), mostly skin toxicity (19%) and lab abnormalities (13%). Conclusions: IMM-101 in combination with nivolumab is safe and shows encouraging antitumor activity in treatment-naive patients with advanced melanoma. Clinical trial information: NCT03711188.