Efficacy and safety of trifluridine/tipiracil in older and younger patients with metastatic gastric or gastroesophageal junction cancer: subgroup analysis of a randomized phase 3 study (TAGS)

Background Trifluridine and tipiracil (FTD/TPI) demonstrated survival benefit vs placebo and manageable safety in previously treated patients with metastatic gastric/gastroesophageal junction cancer (mGC/GEJC) in the randomized, placebo-controlled, phase 3 TAGS study. This subgroup analysis of TAGS examined efficacy/safety outcomes by age. Methods In TAGS, patients with mGC/GEJC and ≥ 2 prior therapies were randomized (2:1) to receive FTD/TPI 35 mg/m2 or placebo, plus best supportive care. A preplanned subgroup analysis was performed to evaluate efficacy and safety outcomes in patients aged < 65, ≥ 65, and ≥ 75 years. Results Among 507 randomized patients (n = 337 FTD/TPI; n = 170 placebo), 55%, 45%, and 14% were aged < 65, ≥ 65, and ≥ 75 years, respectively. Overall survival hazard ratios for FTD/TPI vs placebo were 0.67 (95% CI 0.51–0.89), 0.73 (95% CI 0.52–1.02), and 0.67 (95% CI 0.33–1.37) in patients aged < 65, ≥ 65, and ≥ 75 years, respectively. Regardless of age, patients receiving FTD/TPI experienced improved progression-free survival and stayed longer on treatment than those receiving placebo. Among FTD/TPI-treated patients, frequencies of any-cause grade ≥ 3 adverse events (AEs) were similar across age subgroups (80% each), although grade ≥ 3 neutropenia was more frequent in older patients [40% (≥ 65 and ≥ 75 years); 29% (< 65 years)]; AE-related discontinuation rates did not increase with age [14% (< 65 years), 12% (≥ 65 years), and 12% (≥ 75 years)]. Conclusions The results of this subgroup analysis show the efficacy and tolerability of FTD/TPI treatment regardless of age in patients with mGC/GEJC who had received 2 or more prior treatments.

Avelumab first-line maintenance plus best supportive care (BSC) vs BSC alone for advanced urothelial carcinoma: JAVELIN Bladder 100 Japanese subgroup analysis

Background The phase 3 JAVELIN Bladder 100 trial showed significantly prolonged overall survival (OS) with avelumab as first-line (1L) maintenance therapy + best supportive care (BSC) vs BSC alone in patients with advanced urothelial carcinoma (UC) that had not progressed with 1L platinum-containing chemotherapy. Efficacy and safety were assessed in patients enrolled in Japan. Methods Patients with locally advanced or metastatic UC that had not progressed with 4–6 cycles of 1L platinum-containing chemotherapy were randomized to avelumab (10 mg/kg intravenously every 2 weeks) + BSC or BSC alone. The primary endpoint was OS, and secondary endpoints included progression-free survival (PFS) and safety. Results In Japanese patients (n = 73) randomized to avelumab + BSC (n = 36) or BSC alone (n = 37), median OS was 24.7 months (95% CI, 18.2-not estimable) vs 18.7 months (95% CI, 12.8–33.0), respectively (HR, 0.81 [95% CI, 0.41–1.58]), and median PFS was 5.6 months (95% CI, 1.9–9.4) vs 1.9 months (95% CI, 1.9–3.8), respectively (HR, 0.63 [95% CI, 0.36–1.11]). In the avelumab + BSC and BSC-alone arms, grade ≥ 3 treatment-emergent adverse events (AEs) occurred in 50.0% vs 8.1%, including grade ≥ 3 treatment-related AEs in 13.9% vs 0%, respectively. Efficacy and safety results in Japanese patients were generally consistent with findings in the overall trial population. Conclusion Avelumab 1L maintenance treatment showed a favorable benefit-risk balance in Japanese patients, supporting avelumab 1L maintenance as a new standard of care in Japanese patients with advanced UC that has not progressed with 1L platinum-containing chemotherapy. Trial registration Clinicaltrials.gov NCT02603432.

Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline

Purpose To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults. Methods ASCO and the Society for Neuro-Oncology convened an Expert Panel and conducted a systematic review of the literature. Results Fifty-nine randomized trials focusing on therapeutic management were identified. Recommendations Adults with newly diagnosed oligodendroglioma, isocitrate dehydrogenase (IDH)–mutant, 1p19q codeleted CNS WHO grade 2 and 3 should be offered radiation therapy (RT) and procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ) is a reasonable alternative for patients who may not tolerate PCV, but no high-level evidence supports upfront TMZ in this setting. People with newly diagnosed astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 2 should be offered RT with adjuvant chemotherapy (TMZ or PCV). People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 should be offered RT and adjuvant TMZ. People with astrocytoma, IDH-mutant, CNS WHO grade 4 may follow recommendations for either astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 or glioblastoma, IDH-wildtype, CNS WHO grade 4. Concurrent TMZ and RT should be offered to patients with newly diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4 followed by 6 months of adjuvant TMZ. Alternating electric field therapy, approved by the US Food and Drug Administration, should be considered for these patients. Bevacizumab is not recommended. In situations in which the benefits of 6-week RT plus TMZ may not outweigh the harms, hypofractionated RT plus TMZ is reasonable. In patients age ≥ 60 to ≥ 70 years, with poor performance status or for whom toxicity or prognosis are concerns, best supportive care alone, RT alone (for MGMTpromoter unmethylated tumors), or TMZ alone (for MGMT promoter methylated tumors) are reasonable treatment options. Additional information is available at www.asco.org/neurooncology-guidelines.

Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline

PURPOSE To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults. METHODS ASCO and the Society for Neuro-Oncology convened an Expert Panel and conducted a systematic review of the literature. RESULTS Fifty-nine randomized trials focusing on therapeutic management were identified. RECOMMENDATIONS Adults with newly diagnosed oligodendroglioma, isocitrate dehydrogenase (IDH)–mutant, 1p19q codeleted CNS WHO grade 2 and 3 should be offered radiation therapy (RT) and procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ) is a reasonable alternative for patients who may not tolerate PCV, but no high-level evidence supports upfront TMZ in this setting. People with newly diagnosed astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 2 should be offered RT with adjuvant chemotherapy (TMZ or PCV). People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 should be offered RT and adjuvant TMZ. People with astrocytoma, IDH-mutant, CNS WHO grade 4 may follow recommendations for either astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 or glioblastoma, IDH-wildtype, CNS WHO grade 4. Concurrent TMZ and RT should be offered to patients with newly diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4 followed by 6 months of adjuvant TMZ. Alternating electric field therapy, approved by the US Food and Drug Administration, should be considered for these patients. Bevacizumab is not recommended. In situations in which the benefits of 6-week RT plus TMZ may not outweigh the harms, hypofractionated RT plus TMZ is reasonable. In patients age ≥ 60 to ≥ 70 years, with poor performance status or for whom toxicity or prognosis are concerns, best supportive care alone, RT alone (for MGMT promoter unmethylated tumors), or TMZ alone (for MGMT promoter methylated tumors) are reasonable treatment options. Additional information is available at www.asco.org/neurooncology-guidelines .

PD-1 Blockade With Concurrent Radiotherapy for Locally Advanced Inoperable Cutaneous Squamous Cell Carcinoma

Introduction For patients with locally advanced cutaneous squamous cell carcinoma (LA-cSCC), radiotherapy alone (RT) is often the only treatment option with modest tumor response. We report the outcomes of using combination of programmed cell death protein-1 (PD-1) inhibitor and RT in the treatment of inoperable LA-cSCC. The study presents the efficacy and safety data for the patients with LA-cSCC treated with this combination. Methods During the period 2018-2020, a total of 7 patients with biopsy proven inoperable LA-cSCC were treated with combination of PD-1 inhibitor cemiplimab and concurrent RT (Cem-RT). The patients were followed up for safety and efficacy of the Cem-RT regimen and the primary endpoints were objective tumor response and toxicity. Results The median age of patients was 68 years (range, 64-94). All patients had ECOG performance score 0-1. Six patients initially received cemiplimab and concurrent RT was added to PD-1 inhibitor when there was an inadequate therapeutic response. One patient received concurrent Cem-RT. RT with PD-1 antibody was well tolerated. Six patients developed grade ≤2 dermatitis and 1 patient (patient no. 3) developed acute grade 3 skin reaction. During the post-RT follow up, 3 patients discontinued cemiplimab due to significant toxicities. At the time of reporting , 5 patients remain in complete remission. One patient developed lung metastasis and is currently receiving best supportive care. Conclusions The Cem-RT combination was safe and well tolerated with significant tumor response suggesting Cem-RT may be a viable therapeutic option for LA-cSCC. Our hypothesis generating data support the rationale for future prospective studies.

P-OGC55 Current treatment modalities and median survival for patients with gastric and oesophagogastric cancers with isolated peritoneal metastasis

Background Gastric cancer with peritoneal metastases carries a median survival of only 3-7 months without treatment. Meanwhile, cancers arising from the oesophago-gastric junction (OGJ) are rapidly increasing in incidence in the Western population and are also commonly associated with peritoneal metastases. In order to measure the efficacy of emerging modes of treatment for peritoneal disease, it is essential to describe the treatments patients currently receive and the impact of these on survival – data for which is poorly described in the literature and lacking in the UK setting. Methods This was a single hospital-based retrospective cohort study covering the period from March 2012 to January 2020 at a tertiary referral centre. 50 patients were identified from multidisciplinary team (MDT) meeting records receiving a diagnosis of gastric adenocarcinoma with isolated peritoneal disease. 31 patients were identified receiving a diagnosis of true (Siewert II or III) junctional adenocarcinoma with isolated peritoneal disease. We calculated median survival time for all patients and also by treatment modality. Results Mean age of patients with gastric adenocarcinoma and isolated peritoneal disease was 71 years (range 44-90). Overall median survival was 6.6 months (IQR 2.4-19.3). Median survival was 11.2 months (IQR 3.7-21.5) for patients receiving systemic chemotherapy (n = 26) and 2.4 months (IQR 1.2-5.1) for patients receiving best supportive care alone (n = 15). Mean age of patients with junctional adenocarcinomas and isolated peritoneal disease was 70 years (range 37-89). Overall median survival was 7 months (IQR 3-19). Median survival was 10.5 months (IQR 6.5-20.5) for patients receiving systemic chemotherapy (n = 20) and 3.5 months (IQR 2-6) for patients receiving best supportive care alone (n = 6). Conclusions Our results demonstrate the poor prognosis of both gastric and oesophagogastric cancer patients with isolated peritoneal disease. Prognosis figures are comparable between the two cancer types. Findings are in line with previous studies performed outside the UK which have shown that available treatments extend survival by no more than 3-9 months, highlighting the desperate need for new treatment modalities.

P-OGC54 Economic cost utility analysis of stage directed oesophageal adenocarcinoma treatment

Background Oesophageal Cancer (OC) treatment levies substantial financial burden on Health Services and Best Supportive Care (BSC) outcomes are poor. Potentially Curative Surgery with or without Chemotherapy is offered to patients with locally advanced disease and this study aimed to examine treatment costs related to life-years gained in patients having potentially curative treatment (oesophagectomy) and those receiving Best Supportive Care (BSC). Methods Consecutive 179 patients diagnosed with potentially curative adenocarcinoma of the oesophagus between 2010 and 2017 were classified according to treatment modality by intention to treat (surgery vs. neoadjuvant/adjuvant chemotherapy). Cost calculations for one-year’s treatment from referral were made according to network diagnostic, staging, and treatment algorithms. Primary outcome was Overall Survival (OS). Results OC median survival after BSC is reported to be 3 months costing £4391 compared with Oesophagectomy median survival (all stages) of 44 months costing an average of £26,652 for one year’s treatment: BSC cost per QALY £92,448 compared with £12,207.20 for potentially curative surgery. Cost incurred for stage I OC was £25,153.09, stage II £26,795.17, stage III £28,781.81, and stage IV £28,592.64. Based on these values, the cost per Quality Adjusted Life Year (QALY) for stage I OC was - £8,361, II - £12,319, III - £21,998 IV - £35,011. Conclusions Potentially curative treatment that included oesophagectomy improved OS fifteen-fold compared with BSC and was cost effective at national thresholds of readiness to pay per QALY.

Clinical Reasoning: A 64-Year-Old Man With History of Meningitis Presenting With Proximal Weakness of the Arms

A 64-year-old man presented for evaluation of proximally pronounced weakness of the arms with preserved facial and lower extremity strength. Symptoms slowly developed over the last two years, and the patient’s history was notable for severe Listeria monocytogenes meningitis four years prior to presentation, which was adequately treated with antibiotics. On examination, symptoms clinically reassembled ‘man-in-the-barrel’ syndrome and localized to the cervicothoracic central cord. Blood analysis was unremarkable, and CSF analysis showed no recurrent or persistent infection. Spinal MRI revealed pockets of sequestered CSF from C3 to C4 and areas of CSF space effacement from C3 to T12. MRI findings were interpreted as cord tethering suggestive of adhesive arachnoiditis. CT myelogram showed insufficient contrast agent migration above T10 and contour irregularities of the conus medullaris, confirming the postulated pathomechanism of cord tethering. Final diagnosis was therefore cervicothoracic central cord damage due to cord tethering in the setting of postinfectious adhesive arachnoiditis following bacterial meningitis. The patient failed a course of pulsed methylprednisolone therapy, and symptoms progressed. Best supportive care was provided. The clinical presentation of adhesive arachnoiditis is variable, and advanced imaging techniques and invasive studies such as CT myelogram may be required to establish the diagnosis. Timely diagnosis is warranted as early surgical or medical therapy can improve symptoms.