Radiological Disease Progression Research Articles

Stepwise Disease Progression Model of Subsolid Lung Adenocarcinoma with Cystic Airspaces.

Subsolid lung adenocarcinoma with cystic airspaces (LACA) is a unique manifestation of lung cancer. This study was conducted to establish a radiologic disease progression model of LACA and to explore its association with the clinical course and clinicopathologic features of LACA. Sixty patients with LACA who underwent surgery at our center between 2004 and 2017 were retrospectively reviewed. The morphological changes of LACA over time on 98 serial computed tomography scans from 27 of 60 patients were tracked to establish a radiologic disease progression model. Associations between this model and the clinicopathologic characteristics of LACA were investigated. The following stepwise progression model of LACA was developed: in phase I, cystic airspaces (CAs) appear in the middle of non-solid nodules; in phase II, the CAs grow; in phase III, a solid component appears on the border of the CAs; and in phase IV, the solid component gradually surrounds the CAs and becomes thicker, and the CAs shrink. In total, 10 (17%), 33 (55%), and 17 (28%) LACA patients were classified as belonging to phases II, III, and IV at the time of surgery, respectively. More advanced phases were associated with higher pathologic T and N staging, lymphovascular invasion, visceral pleural invasion, spread through air spaces, and solid/micropapillary subtype. In the multivariate analysis, our model demonstrated a good discrimination capability for cancer recurrence risk. The stepwise disease progression model of LACA based on radiologic findings developed in this study represented its natural clinical course and clinicopathologic features well.

Typical radiological progression and clinical features of patients with coronavirus disease 2019.

We aimed to describe typical radiological features and progression of Coronavirus disease 2019 (COVID-19) patients. We reviewed the chest CT scans, laboratory findings, and clinical records of 66 COVID-19 patients who were admitted to affiliated hospitals of Nanchang university, Nanchang, China, from Jan 21 to Feb 2, 2020. CT was used to evaluate the radiological characteristics of COVID-19 patients. Only 4 patients (4/66, 6%) claimed their exposure to COVID-19 pneumonia patients. The major symptoms were fever (60/66, 91%) and cough (37/66, 56%). The predominant features of lesion were scattered (43/66, 65%), bilateral (50/66, 76%), ground-glass opacity (64/66, 97%), and air bronchogram sign (47/66, 71%). Forty-eight patients (48/66, 73%) had more than two lobes involved. Right lower lobe (58/66, 88%) and left lower lobe (49/66, 74%) were most likely invaded. Twelve patients (12/66, 18%) had at least one comorbid condition. Pleural traction (29/66, 44%), crazy paving (15/66, 23%), interlobular septal thickening (11/66, 17%), and consolidation (7/66, 11%) were also observed. The typical radiology features of COVID-19 patients are scattered ground-glass opacity in the bilateral lobes. Fever and cough are the major symptoms. Evaluating chest CT, clinical symptoms, and laboratory results could facilitate the early diagnosis of COVID-19, and judge disease progression.

Avelumab as single agent for patients with metastatic or locally advanced urothelial cancer PD-L1+ unfit for cisplatin: The ARIES study.

TPS596 Background: Urothelial cancer (UC) is the ninth most common cancer worldwide, this tumour has a poor prognosis when in advanced stage. Cisplatin-based chemotherapy is considered the most effective treatment but more than 50% of patients are considered not eligible ( cis-unfit) for this regimen and have a median survival of only 6-9 months. In the past years, the most used chemotherapy regimen for cis-unfit patients was the combination of carboplatin and gemcitabine. Two single arm studies tested the anti-PD-L1/PD1 monoclonal antibodies atezolizumab and pembrolizumab and reported a response rate of 25% with good safety profile in an unselected population for PD-L1 expression. Recently, atezolizumab alone showed longer OS compared to carboplatin-gemcitabine regimen. Avelumab is another fully human anti-PD-L1 IgG1 antibody already tested in urothelial and in other cancers with a promising safety and efficacy profile. Methods: The single arm, phase II ARIES trial (NCT03891238), aims to evaluate the activity and efficacy of avelumab in patients with metastatic or locally advanced UC considered cis-unfit with PD-L1 expression ≥5%. Overall survival is the primary endpoint. Cis-unfit definition includes at least one of the following characteristics (i) ECOG-Performance status=2; (ii) creatinine clearance <60 ml/min; (iii) grade ≥2 peripheral neuropathy or hearing loss; (iv) disease progression within six months after a previous adjuvant/neoadjuvant treatment with cisplatin-based therapy. Avelumab will be administered at standard dose of 10 mg/kg in 1-hour intravenous infusion every 2 weeks (Q2W). Sixty-seven patients will be enrolled, and supportive care is allowed during the study. Avelumab may be continued after radiological progression of disease at physician’s discretion if an improvement of symptoms or not new symptoms will be reported. The study is currently ongoing in twenty centres in Italy. Clinical trial information: NCT03891238.

Abstract OT2-08-02: Capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer: A phase III trial (CAPItello-290)

Abstract Background: Triple-negative breast cancer (TNBC) generally has an aggressive clinical course, including distant metastases and increased likelihood of death within 5 years of diagnosis compared with non-TNBCs. Therapeutic options for metastatic TNBC patients are limited to sequential chemotherapy, although recent advances with novel agents have been made for specific subgroups (PD-L1 inhibitor atezolizumab in combination with nab-paclitaxel in patients with PD-L1-positive tumors and PARP inhibitors in germline BRCA-mutant patients). However, improvements in progression-free survival (PFS) derived from immune-oncology and PARP inhibitors are still insufficient in terms of informing patient selection and overall magnitude of benefit. Developing novel treatments in both early and advanced TNBC settings remains a significant unmet need in the management of advanced breast cancer. The PI3K/AKT/PTEN signaling pathway is often activated in TNBC, mainly through activating mutations in PIK3CA or AKT1 and/or inactivating alterations in PTEN. The Phase II PAKT study (NCT02423603) demonstrated that addition of the oral AKT inhibitor capivasertib to first-line paclitaxel resulted in significantly longer PFS and overall survival (OS) in patients with advanced TNBC, especially in patients with PIK3CA/AKT1/PTEN-altered tumors (Schmid, 2018). The Phase III trial we report (NCT03997123) will further evaluate the efficacy and safety of capivasertib in combination with paclitaxel in first-line treatment of patients with metastatic TNBC in an unselected population and will also explore potential predictive markers of sensitivity to the combination of paclitaxel and capivasertib. Methods: Eligible patients for this double-blind, randomized, placebo-controlled trial must have metastatic TNBC or locally advanced disease not amenable to resection with curative intent. Patients must be candidates for single-agent taxane therapy and have received no prior systemic therapy for locally advanced inoperable or metastatic disease. Prior chemotherapy in the (neo)adjuvant setting must be completed ≥12 months prior to enrollment. Patients will be randomized 1:1 to paclitaxel 80 mg/m2 (days 1, 8 and 15) with either capivasertib 400 mg twice daily or placebo (days 2-5, 9-12, 16-19) every 28 days until objective radiologic disease progression as defined by RECIST 1.1, unacceptable toxicity, or death. Stratification factors will be prior adjuvant chemotherapy, visceral vs non-visceral disease, and geographic region. Post-randomization central testing of tumor tissue (collected prior to enrollment) will be carried out to identify predictive markers of sensitivity to treatment. The primary endpoints of this study are PFS and OS. Secondary endpoints include safety and tolerability, time to second progression or death, objective response rate, duration of response, and clinical benefit rate. Enrollment for this study opened in May 2019. Citation Format: Peter Schmid, Javier Cortes, Mark Robson, Hiroji Iwata, Roberto Hegg, Sunil Verma, Marina Nechaeva, Binghe Xu, Vincent Haddad, Esteban Rodrigo Imedio, Gaia Schiavon, Andrew Foxley, Yeon Hee Park. Capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer: A phase III trial (CAPItello-290) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-08-02.

Low-Dose BRAF-Inhibitors in the Treatment of Histiocytic Disorders with the BRAF-V600E Mutation

Introduction: The landmark VE-BASKET trial demonstrated that Erdheim-Chester disease (ECD) patients with the BRAF-V600E mutation can be effectively treated with vemurafenib 1920 mg/day. However, all patients required dose reductions due to adverse effects. The efficacy of low dose BRAF-inhibitors is not well established in ECD. Further, as Langerhans cell histiocytosis (LCH) also harbors BRAF-V600E mutations in 50-60% of patients, BRAF-inhibitors may be effective in this disease as well. In this study, we evaluated the efficacy of low dose BRAF-inhibitors (vemurafenib and dabrafenib) in the treatment of ECD and LCH. Methods: We conducted a retrospective study of ECD and LCH patients who were seen at our institution from January 1998 to July 2018. All patients had a diagnosis of ECD and LCH determined by clinical criteria in conjunction with histopathologic findings. Based on the standard doses approved for malignant melanoma and ECD, patients were categorized into the low dose BRAF-inhibitor group if they were treated with vemurafenib < 960 mg/day or dabrafenib ≤ 150mg/day at any point in time. We used a simple response criteria that defined clinical progressive disease (PD) as worsening of symptoms attributed to ECD/LCH or radiologic PD as a progression or worsening of proven or suspected lesions due to ECD/LCH. The minimum duration for symptom improvement to be considered a response was set at 3 months. Results: A total of 89 ECD patients and 186 LCH patients were identified. Within the ECD cohort, 24 of 44 (55%) patients who were tested had the BRAF-V600E mutation. Eight patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis was 57 years (range 37-74) and 5 (63%) were male. The most common areas of involvement included bone (88%), cardiovascular system (63%), kidneys (63%), and brain parenchyma (50%). The median time of follow up was 66 months (range 23-165) and the median time on low-dose BRAF-inhibitor was 10 months (range 1-27) [Table 1]. Three patients had a starting dose of vemurafenib 1920 mg/day, 4 had 960 mg/day, and 1 had 480 mg/day. All patients required dose reductions and 50% of the patients ultimately discontinued vemurafenib due to side effects. Side effects included fatigue, pruritus, nausea, facial swelling, blisters, papillomas, and/or subcutaneous nodules. Four patients were able to remain on low-dose vemurafenib for a median follow up time of 24.5 months (range 12-28) with ongoing response and no signs of clinical or radiologic PD. Within the LCH cohort, 18 of 31 tested (58%) patients had the BRAF-V600E mutation. Four patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis of this cohort was 43 years (range 34-69) and 2 (50%) were male. Areas of involvement included bone (100%), brain parenchyma (hypothalamus/optic stalk and pons; 50%), and skin (25%). The median time of follow up was 31 months (range 21-46) and the median time on low-dose BRAF-inhibitor was 4 months (range 3-24) [Table 2]. Two patients had a starting dose of vemurafenib 960mg/day. The patients with brain parenchymal involvement had a starting dose of dabrafenib 150mg/day or 100mg/day. All patients taking vemurafenib 960mg/day required dose reductions and one patient discontinued treatment due to skin blistering in her feet. In the patients taking dabrafenib, no side effects have yet been reported. 3 patients had an ongoing response and did not have clinical or radiologic PD. Patient #10 however, had clinical and radiologic PD after being on vemurafenib 720mg/day for 22 months. Conclusion: Our study suggests a potential role for lower doses of BRAF-inhibitors in ECD and LCH patients harboring BRAF-V600E mutations. Dabrafenib was found to be particularly efficacious and well-tolerated in LCH involving the brain parenchyma. However, patients who undergo dose reductions should be closely monitored due to the risk of disease progression. Careful balance of toxicities and efficacy is needed for optimizing patient outcomes with targeted therapies. Disclosures Bennani: Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board. OffLabel Disclosure: Vemurafenib and dabrafenib for Langerhans cell histiocytosis. Vemurafenib dosage for Erdheim-Chester disease is less than the approved dose of 960mg every 12 hours.

223TiP - EV-301: A phase III trial in progress evaluating enfortumab vedotin versus chemotherapy in patients with locally advanced or metastatic urothelial carcinoma

223TiP - EV-301: A phase III trial in progress evaluating enfortumab vedotin versus chemotherapy in patients with locally advanced or metastatic urothelial carcinoma

225O - Impact of radiological disease progression on the health status of patients (pts) with BRCA-mutated advanced ovarian cancer (OC) treated with maintenance olaparib (OL) or placebo (PL) after first-line platinum chemotherapy

BackgroundIn SOLO1 (NCT01844986), maintenance OL significantly improved progression-free survival vs PL (HR 0.30; 95% CI 0.23–0.41; Moore et al. NEJM 2018) following response to first-line platinum chemotherapy in pts with BRCA-mutated advanced OC. We compared pt health status pre- and post-radiological progression (RECIST) in SOLO1 using the EQ-5D-5L descriptive system and visual analogue scale (VAS). MethodsEQ-5D-5L data were collected at baseline, day 29, every 12 weeks for 3 years, then every 24 weeks until data cut off (May 2018). Using the last EQ-5D-5L pre-progression as baseline, we assessed changes in each domain score, the proportion reporting any problem (levels 2–5) by domain, and Paretian classification of health change (PCHC) at first post-progression EQ-5D-5L. Impact of progression on VAS was assessed by mixed-effects repeated measures analysis. Data were pooled across study arms. Results74/100 OL pts and 81/95 PL pts with RECIST progression completed the EQ-5D-5L pre- and post-progression. Pre-progression, any problems were reported in 56%, 54%, 40%, 31% and 5% for anxiety/depression, pain/discomfort, usual activity, mobility, and self care respectively. Post-progression, proportions reporting problems with anxiety/ depression (68%), pain/discomfort (65%) and self care (15%) increased, while usual activity (43%) and mobility (30%) were unchanged. Across all levels, worsening was reported in anxiety/depression (34%), pain/discomfort (27%) and self care (13%). By PCHC, 56% reported worsening in at least one domain, with 37% reporting worse overall health status immediately post-progression. Progression was associated with a statistically significant and meaningful reduction in VAS (-0.0714, P < 0.0001). ConclusionsRadiological progression after response to first-line platinum chemotherapy is associated with worsening health status, with anxiety/depression and pain/discomfort most affected. These results highlight the impact of progression on pts and pt-reported health benefits of delaying progression with maintenance OL. Clinical trial identificationNCT01844986. Editorial acknowledgementMedical writing assistance was provided by Catherine Risebro, PhD, from Mudskipper Business Ltd, funded by AstraZeneca. Legal entity responsible for the studyAstraZeneca. FundingAstraZeneca. DisclosureM.L. Friedlander: Honoraria (self), Honoraria (institution), Advisory / Consultancy: AstraZeneca; Non-remunerated activity/ies, Consulting: AbbVie; Research grant / Funding (institution): Beigene; Advisory / Consultancy: Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Takeda. R. Hettle: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. E. Parkhomenko: Honoraria (institution), Advisory / Consultancy, Full / Part-time employment, Employee of Parexel, which has received consultancy fees from AstraZeneca: AstraZeneca.

1388P - Baseline characteristics from CLARINET FORTE: Evaluating lanreotide autogel (LAN) 120 mg every 14 days in patients with progressive pancreatic or midgut neuroendocrine tumours during a standard first-line LAN regimen

BackgroundLanreotide autogel (LAN) is a long-acting somatostatin analogue used to treat somatostatin receptor-positive (SSTR+), gastroenteropancreatic neuroendocrine tumours (GEP-NETs).1 In the CLARINET study, LAN 120mg every (q)28 days significantly improved progression-free survival (PFS) versus placebo in patients with metastatic, SSTR+ GEPNETs. CLARINET FORTE is an ongoing phase II study assessing the safety and efficacy (centrally assessed median PFS) of increasing the frequency of LAN 120mg dosing (q14 days) in patients with progressive pancreatic NETs (panNETs) or midgut NETs. MethodsEligible patients had well-differentiated, metastatic or locally advanced, unresectable, G1/G2, panNETs or midgut NETs with a proliferation index (Ki-67) ≤20%. Patients had radiological progressive disease within 2 years prior to study inclusion as assessed by central review, while receiving first-line treatment with LAN 120mg with standard treatment intervals (q28) days for ≥24 weeks. Following a 28-day screening interval, LAN 120mg was administered q14 days. In total, 99 enrolled patients from 10 countries received treatment. ResultsTable: 1388PTable: 1388PBaseline characteristicspanNET (n=48)Midgut NET (n=51)Age, mean (SD)63.3 (10.6)67.1 (8.2)Male, n (%)20 (41.7)29 (56.9)Tumour grading*, %--122.954.9277.145.1Proliferation index Ki-67, mean (SD)6.2 (4.6)3.5 (3.8)Proliferation index Ki-67 category, n (%)--≥10%9 (18.8)4 (8.0)<10%39 (81.3)46 (92.0)≤2%†11 (28.2)28 (60.9)2–10%†28 (71.8)18 (39.1)Missing01Hepatic tumour load, n (%) >25% ≤25% Missing- 6 (13.3) 39 (86.7) 3- 9 (17.6) 42 (82.4) 0Previous primary tumour surgery18 (37.5)12 (23.5)Krenning scale, n (%) Grade 1 Grade 2 Grade 3 Grade 4 N/A‡ Missing- 0 6 (12.5) 10 (20.8) 28 (58.3) 4 (8.3) 0- 4 (8.5) 4 (8.5) 15 (31.9) 21 (44.7) 3 (6.4) 4Duration of LAN treatment (standard dosing interval) prior to study enrolment in months, median (range)21.7 (5–103)16.4 (5–198)Diarrhoea presence, % Flushing presence, %16.7 8.341.7 28.0*WHO classification†Percentages are based on the number of subjects with a Ki-67 <10 %.‡Patients who had a PET scan with gallium. ConclusionsBaseline CLARINET FORTE data highlight the high rate of G1 in progressive midgut NET and of G2 in panNET. The cohort is representative of typical patients requiring treatment intensification due to progressive panNET or midgut NET. Final analyses are expected in Q1 2020, which will provide efficacy and safety data on use of LAN 120mg at an increased dosing frequency. 1. Somatuline autogel SmPC. November 2018. Clinical trial identificationNCT02651987. Editorial acknowledgementEditorial assistance was provided by Louise Cully of Ashfield Healthcare and funded by Ipsen. Legal entity responsible for the studyIpsen. FundingIpsen. DisclosureP. Ruszniewski: Advisory / Consultancy: Novartis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: AAA; Advisory / Consultancy: Keocyt. J. Ćwikła: Advisory / Consultancy, PI in Poland for this study: Ipsen. C. Lombard-Bohas: Advisory / Consultancy, Research grant / Funding (self): Ipsen; Research grant / Funding (self): Pfizer ; Advisory / Consultancy, Research grant / Funding (self): Novartis. I. Borbath: Advisory / Consultancy: Pfizer ; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Ipsen; Research grant / Funding (self): Bayer; Research grant / Funding (self): Celgene. T. Shah: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen. U. Pape: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ipsen; Research grant / Funding (self): Novartis. X. Truong Thanh: Full / Part-time employment: Ipsen. A. Houchard: Full / Part-time employment: Ipsen. M.E. Pavel: Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Lexicon.

Nonconventional Doses of Somatostatin Analogs in Patients With Progressing Well-Differentiated Neuroendocrine Tumor.

To evaluate the antiproliferative activity and safety of nonconventional high doses of somatostatin analogs (HD-SSA) in patients with well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NET) with radiological disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria on a previous treatment. A retrospective analysis of prospectively maintained databases from 13 Italian NET-dedicated centers was performed. Main inclusion criteria were: well-differentiated G1 or G2 GEP-NET, progressive disease on a previous treatment, and subsequent treatment with HD-SSA (either by increased administered dose [dose intensity] or shortened interval between administrations [dose density]). Main endpoints were progression-free survival (PFS) and safety. Of 198 patients, 140 matched inclusion criteria and were included in the analysis. Overall, median PFS was 31 months. Use of HD-SSA as second-line treatment was associated with reduced risk for progression or death compared with third- or further-line treatment (HR: 2.12; P = 0.004). There was no difference in PFS between HD-SSA by increased dose density (N = 133; 95%) or intensity (N = 7; 5%). Partial response according to RECIST criteria was observed in 12 patients (8.6%), and stable disease was achieved in 106 (75.7%) patients. Adverse events occurred in 21 patients (15.0%), 2 of whom had grade 3 biliary stone disease. No patients discontinued HD-SSA treatment due to adverse events. HD-SSA is an active and safe treatment option in patients with progressive well-differentiated GEP-NET. The high rate of objective responses observed deserves prospective validation in ad hoc clinical trials.

Outcome of Primary Desmoid Tumors at All Anatomic Locations Initially Managed with Active Surveillance.

The behavior of desmoid tumors is unpredictable and varies from spontaneous remission to symptomatic and radiologic progression. This study aimed to evaluate the radiologic and symptomatic course of the disease in patients initially managed with active surveillance. Patients with a primary desmoid tumor at any anatomic location diagnosed between 1998 and 2016 were identified in a prospectively maintained database from a single sarcoma referencecenter in the United Kingdom. Inverse univariate Cox proportional hazard regression analyses were conducted to evaluate the course of the disease and indications for initiating treatment. The study identified 168 patients with a primary desmoid tumor initially managed with active surveillance. The tumors were located in the abdominal wall (n = 61, 36%), an extremity (n = 51, 30%), chest wall (n = 30, 18%), intra-abdominal site (n = 15, 9%), or elsewhere (n = 11, 6%). Of all the patients, 36% experienced radiologic progressive disease, 36% had stable disease, and 27% regressed. The patients younger than 50years were more likely to progress (p = 0.046), whereas the patients with chest wall or upper-extremity tumors reported significantly more pain (p = 0.01). Eventually, 46% of the patients proceeded to treatment. The median time to start oftreatment after initial surveillancewas 31months, whereas the median follow-up time for the patients not receiving any treatment was 40.5months. The indications for initiation of treatment were pain (32%), progression (31%), or both (13%). Patients with desmoid tumors can be managed with initial active surveillance, although almost half of patients may eventually need treatment. Pain, tumor progression, or both are the most common indications for the initiation of treatment.

Neuroendocrine Cancer of the Prostate.

Neuroendocrine cancer of the prostate is considered to be a rare entity with bad prognosis and limited therapeutic options. We performed a prospective analysis of the patients treated in our hospital for prostate cancer between 1st January 2015 and 31rd December 2018. Neuroendocrine phenomena were tested by immunohistochemistry and laboratory chemistry on the request of the clinicians in the cases when a positive diagnosis was suspected. Clinical tableaux of high suspicion of neuroendocrine cancer included radiological progression of a metastatic disease without PSA rise, relatively extended metastatic disease associated to a low PSA, disease with non-pulmonary visceral metastases. 10 patients were diagnosed with neuroendocrine tumour out of 521 prostate cancers. Half of the patients had a survival over a year. 3 patients received 3 lines of efficacious palliative chemotherapy. 1 patient underwent prostatectomy after neoadjuvant chemotherapy for a localised disease. The incidence of neuroendocrine tumours among prostate cancer patients was higher than expected. Some of the patients had a relatively good outcome.

(late submission poster) The tumor burden rise at radiological disease progression associates with poor overall survival in advanced colorectal cancer

(late submission poster) The tumor burden rise at radiological disease progression associates with poor overall survival in advanced colorectal cancer

Clinical characteristics and outcomes of candidates for second-line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma after sorafenib treatment.

This study aimed to investigate the clinical characteristics and outcomes of candidates for second-line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma (HCC) after sorafenib treatment. Of 122 patients, 103 were radiologically confirmed as progressive disease (PD) (sorafenib-refractory group), and 19 discontinued sorafenib therapy due to adverse events prior to radiologic PD (sorafenib-intolerant group). Patients in the sorafenib-refractory group were divided into two subgroups each, according to their eligibility for second-line treatment (second-line-in and -out group), regorafenib (RESORCE-in and -out group), or ramucirumab (REACH-2-in and -out group). Patients included in the non-candidate group were those with α-fetoprotein level <400ng/mL (n = 51, 49.5%), daily sorafenib dose <400mg (n = 44, 42.7%), Child-Pugh B or C (n = 40, 38.8%), and Eastern Cooperative Oncology Group performance status score ≥2 (n = 24, 23.3%). The percentages of candidates were 57.3% for second-line, 35.0% for regorafenib, and 23.3% for ramucirumab. The median post-progression survival (PPS) was significantly longer for the second-line-in and the RESORCE-in groups than in the non-candidate groups (12.6 and 11.0months vs. 3.0 and 6.1months, respectively). The PPS was not significantly different between the REACH-2-in and -out groups. A significant predictor of candidates for second-line treatment at sorafenib initiation was a Child-Pugh score of 5 (A5). Not all patients refractory to sorafenib were candidates for second-line therapy. A Child-Pugh score of A5 at sorafenib initiation was an important and favorable factor related to eligibility for second-line therapy and good outcomes.

Prospective randomized phase II trial of pazopanib versus placebo in patients with progressive carcinoid tumors (CARC) (Alliance A021202).

4005 Background: Patients (pts) with progressive advanced well-differentiated neuroendocrine tumors arising outside of the pancreas have limited systemic treatment options. Pazopanib (PZ) is an oral multi-kinase inhibitor with activity against VEGFR-2,-3, PDGFR-α, and β, and c-KIT, with initial data suggesting efficacy in CARC. Methods: This was a multicenter, randomized, double-blind, phase II study of PZ (800 mg/day) versus placebo (PL) in progressive CARC. Key eligibility: low-intermediate grade CARC, radiologic progressive disease (PD) &lt; 12 months (mo), and adequate end-organ function. Prior somatostatin analog (SSA) mandated for midgut tumors. Concurrent SSA allowed if previous PD on SSA documented. Primary endpoint was progression-free survival (PFS), defined as time from randomization to PD by central review or death. Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. The trial had 85% power to detect a difference in median PFS of 14 v 9 mo (hazard ratio [HR] 0.64) at one-sided alpha = 0.1. A stratified log-rank test based on the intend-to-treat (ITT) principle was used. Unblinding and crossover were allowed if PD confirmed by central review. Results: 171 (97 PZ, 74 PL) pts were randomized between 6/2013-10/2015: median age 63; 56% female; 66% small bowel primary; 87% concurrent SSA. Median follow-up of 31 mo; 112 (56 PZ, 56 PL) PFS events observed. 6 pts (4 PZ, 2 PL) remain on initial treatment. Median PFS was 11.6 and 8.5 mo in PZ and PL, respectively (HR = 0.53, 1-sided 90% upper confidence limit [UCL] 0.69, p = 0.0005) which crossed the pre-specified protocol efficacy boundary. 49 PL pts received PZ after PD. Median OS was 41 and 42 mo in PZ and PL, respectively (HR = 1.13, 1-sided 90% UCL 1.51, p = 0.70). RR data will be presented. Notable grade 3+ adverse events were (PZ v. PL %) hypertension (35 v. 8), fatigue (11 v. 4), ALT (10 v. 0), AST (10 v. 0), and diarrhea (7 v. 4). Conclusions: PZ compared to PL was associated with significant improvement in PFS in patients with progressive CARC. The results confirm that VEGF signaling pathway is a valid target for therapy in CARC. Support: U10CA180821, U10CA180882 https://acknowledgments.alliancefound.org . Clinical trial information: NCT01841736.

Predictive and prognostic values of circulating tumor DNA (ctDNA) clearance in osimertinib treated advanced non-small cell lung cancer cohort.

3036 Background: Although growth advantage of certain clones would ultimately translate into a clinically visible disease progression, radiological imaging does not reflect clonal evolution at the molecular level. CtDNA, validated as a tool for mutation detection in lung cancer, reflects dynamic molecular changes. Here, we evaluated the potential of ctDNA in monitoring molecular changes and predicting clinical outcomes of EGFR T790M-positive osimertinib treated NSCLC pts. Methods: This prospective multicenter study, enrolled 72 T790M positive osimertinib-treated advanced NSCLC pts who progressed on prior EGFR-TKI to evaluate the potential of ctDNA in monitoring, is part of the ongoing ASTRIS study (NCT02474355). Longitudinal plasma samples, collected from 52 pts, were subjected to sequencing using a panel consisting of 168 lung cancer-related genes. Results: Genomic profile prior to the initiation of osimertinib revealed that mutations participating in cell cycle (14 pts, p = 0.004) and P53 pathways (43 pts, p = 0.032) were associated with shorter OS ( p53 was excluded from analysis due to high mutation frequency). Interestingly, pts with undetectable ctDNA at first follow-up (within 50 d, n = 41) were correlated with longer PFS (p = 0.009) and OS (p = 0.022). With a median follow-up of 168 d (ranged from 40 - 550 d), 32 pts experienced radiological disease progression. Among them, 11 (34%) experienced molecular progression reflected by emergency of new mutation or increased allelic frequency of existing mutation prior to radiological progression, with an average leading time of 74 days. Pts with molecular PD prior to radiological PD were more likely to harbor any gene copy number amplification (CNA, p = 0.035) and p53 (p = 0.023) mutations at radiological PD. In addition, pts with CNA at radiological PD had shorter PFS (p = 0.002) and OS (p = 0.052). Conclusions: This clinical trial study demonstrates that ctDNA clearance at first follow-up can serve as a predictive and a prognostic marker for pts undergoing osimertinib treatment. Furthermore, it revealed the potential of ctDNA in early detection of disease progression, preceding imaging modalities with an average lead time of 74 days.

EV-301: Phase III study to evaluate enfortumab vedotin (EV) versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial cancer (la/mUC).

TPS497 Background: Standard first-line treatment for patients (pts) with la/mUC is cisplatin-based chemotherapy or carboplatin-based chemotherapy for pts unfit for cisplatin. Immune checkpoint inhibitors (CPIs) are standard treatment options for pts who progressed during or after platinum-based chemotherapy. While some pts with la/mUC achieve durable responses with CPIs, less than 25% of pts respond. Following failure of a CPI, no therapies are approved. Enfortumab vedotin is a fully humanized monoclonal antibody that delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is expressed in 97% of mUC pt samples (Petrylak et al. ASCO, 2017). In a phase 1 study (EV-101; NCT02091999), single-agent EV 1.25 mg/kg was generally well tolerated and demonstrated a confirmed objective response rate (ORR) of 42% across the overall population of pts with mUC; in pts with prior CPI therapy or liver metastasis at baseline confirmed ORRs of 42% and 36% were observed. A pivotal phase 2 study of EV in la/mUC pts with prior CPI treatment (EV-201; NCT03219333) is ongoing. Methods: EV-301 is a global, multicenter, open-label phase 3 trial (NCT03474107) enrolling adult pts with la/mUC and an ECOG performance status score ≤1, who have received a prior platinum-containing chemotherapy, and have experienced disease progression during or following treatment with a CPI. Approximately 550 pts will be randomized (1:1) to receive EV (1.25 mg/kg) administered by IV infusion over approximately 30 minutes on Days 1, 8, and 15 of each 28-day cycle ( Arm A), or investigator choice of IV docetaxel, paclitaxel, or vinflunine (EU only) on Day 1 of each 21-day cycle ( Arm B). Treatment with the study drug will continue until radiological disease progression, intolerance, or other discontinuation criterion is met. Radiological assessments of tumor response status will be performed at baseline and every 8 weeks. The primary endpoint is overall survival; secondary endpoints include progression-free survival, duration of response, and overall response rate, as well as assessment of safety/tolerability, and quality-of-life parameters. Clinical trial information: NCT02091999.

Abstract PD5-02: Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162)

Abstract Background: PARP inhibitor (PARPi) monotherapy has previously demonstrated clinical activity only in patients with a germline BRCA mutation (BRCAmut), while single-agent anti-programmed cell death protein 1 (PD-1) therapy has achieved response rates of only 5–20% in advanced triple negative breast cancer (TNBC). In preclinical studies, PARP inhibition enhanced anti-tumor immunity, increased infiltration of proliferating CD8+ T cells, and synergized with anti-PD-1 agents in BRCA wildtype (wt) tumors. TOPACIO is a fully enrolled, phase I/II trial of niraparib + pembrolizumab (pembro) in advanced TNBC. This combination achieved 28% objective response rate (ORR) and 50% disease control rate (DCR) in evaluable patients. Although activity was highest in patients with BRCAmut (ORR=60%; DCR=80%), durable clinical benefit was also observed in patients without BRCA mutations. In this study, we conducted exploratory biomarker analyses to evaluate their potential correlation with durable clinical benefit (any complete response [CR] or partial response [PR] regardless of duration or stable disease [SD] for ≥16 weeks) beyond BRCA mutations. Method: ORR was assessed by RECIST v1.1. Duration of disease control (DDC) was defined as time from first dose of study treatment to radiologic disease progression or death. Tumor mutational status of homologous recombination repair (HRR) and other DNA damage repair (DDR) pathway genes was determined using an NGS panel. Immunoprofiling was conducted using NanoString IO360 panel complimented with 30 DNA repair spike-ins. Tumor immune micro-environment was characterized using multiplex immuno-fluorescence (CycIF). PD-L1 status was determined using the Agilent/DAKO 22C3 IHC clinical trial assay. Results: Of 46 evaluable patients, 20 achieved durable clinical benefit (any CR/PR or SD≥16 weeks) with niraparib + pembro combination, of which 8 were tumor BRCA wild type (wt), and 1 was BRCA unknown. Of the 9 BRCAwt/unknown patients, 5 had deleterious mutations in HRR/DDR pathway genes, whereas the remaining 4 had no mutations (HRR/DDR wt). Mutations that were associated with response include CHEK1 (CR; DDC=10.3 mos), ATR (CR; DDC=6.4 mos), PALB2 (PR; DDC=3.5 mos), BLM (SD; DDC=8.1 mos), and NBN/RAD51C (SD; DDC=3.7 mos). Of 4 patients that had no identified mutations (HRR/DDR wt), 1 patient had CR; DDC=10.3 mos, and the remaining 3 patients had SD with DDC ranging from ∼4-8 mos. Of note, all 4 HRR/DDR wt patients were also PD-L1-negative. Table:Durable clinical benefit in BRCAwt/unknown patientsHRR/DRR MutationsPD-L1 StatusBest ResponseDDC (Months)CHEK1+CR10.3†ATR+CR6.4PALB2*UnknownPR3.5BLM-SD8.1NBN/RAD51C+SD3.7None-CR10.3†None-SD8.2None-SD4.2None-SD3.9*BRCA status unknown; †Treatment is ongoing. Conclusion: Patients with mutations beyond BRCA achieved durable clinical benefit with niraparib + pembro treatment; five of these patients had DDC &amp;gt;6 mos. Mutations in genes that are associated with the HRR/DDR pathway appear to confer sensitivity to niraparib + anti-PD1. Additional translational analyses, including immunoprofiling and CycIF, will be presented. Funding: TESARO, Inc., Waltham, MA, USA sponsored the study. Citation Format: Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, Wahner Hendrickson A, Forero A, Anders C, Wulf G, Dillon P, Lynce F, Zarwan C, Erban J, Färkkilä A, Zhou Y, Buerstatte N, Graham JR, Arora S, Dezube B, Telli ML. Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-02.

Abstract B161: Pseudoprogression of metastatic abdominal wall nodules in a patient with lung carcinoma treated with pembrolizumab

Abstract Pembrolizumab is a humanized IgG4 Kappa monoclonal programmed death receptor 1 directed antibody FDA approved for the first line treatment of metastatic non-small cell lung carcinoma (NSCLC) expressing &amp;gt;=50% PD-L1. Pseudoprogression in this context has rarely been reported. We encountered a patient within our community practice who received treatment with pembrolizumab and demonstrated radiologic features of pseudoprogression initially followed by clinical progression where upon histologic evaluation favored pseudoprogression over progression. The aims of this study are as follows: Firstly, to describe the clinico-pathologic-radiologic aspects of this patient’s treatment journey; secondly, to histologically characterize a lesion that was biopsied which showed clinical features of progression, but histologically, pseudoprogression; thirdly, to perform detailed flow cytometric analysis of lymphocytes obtained through the biopsy to characterize pseudoprogression. This is a single patient case study performed by reviewing clinical notes, radiology, and histology. Samples obtained on biopsy were further characterized by flow cytometry. A 72-year-old male patient with small volume metastatic squamous cell lung carcinoma with a tumor proportion score of 100% for PD-L1, was initially treated with radiation (20Gy) to palliate worsening dyspnea caused by airway obstruction. He had good local control with improvement in dyspnea and subsequently requested for observation only. Serial imaging revealed the development of an abdominal wall nodule. Before long, his metastatic disease became symptomatic and he was treated with first line pembrolizumab. Three weeks after his first dose, he presented with severe abdominal wall pain and a new palpable abdominal wall mass. Imaging performed confirmed the presence of a new abdominal wall mass in contrast to a reduction in size of his pulmonary lesions. This was thus assessed as pseudoprogression, and he was continued on treatment with radiologic response noted three weeks later in all lesions. He discontinued treatment due to cost at this point, and subsequently restarted treatment upon radiologic progression of disease. On restarting treatment, his abdominal wall nodule increased in size and ulcerated. True tumor progression was considered prompting biopsy of the abdominal wall nodule to enable stratification into clinical trials. However, histologic evaluation showed chronically inflamed granulation tissue with no microscopic evidence of malignancy suggesting pseudoprogression once again instead. The patient went on to receive radiotherapy to the abdominal wall nodule, and a serial scan demonstrated a reduction in size of the abdominal wall nodule and stable pulmonary disease. Flow cytometric analysis of biopsy tissue revealed predominantly CD45+ cells, 69.5% of which were CD3+. CD45+CD3+CD56- cells comprised CD4+ (27.9%), CD8+ (64.9%), CD4+PD1+ (46.7%), CD8+PD+ (37.7%). Further analysis by flow and mass cytometry is ongoing, and attempts are also being made to assess the tumor antigen specificity of the T-cells. In a patient with clinically immunogenic cancer responding to intermittent anti-PD1 therapy, we observed varying clinico-radiologic responses across his metastatic lesions, and a pathologic evaluation of a clinically progressing lesion revealed pseudoprogression instead. Citation Format: Tiffany Hennedige, Daniel Tan, Narayanan Gopalakrishna Iyer, Amit Jain. Pseudoprogression of metastatic abdominal wall nodules in a patient with lung carcinoma treated with pembrolizumab [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B161.

Pseudoprogression (PsP) in Patients with Peripheral T-Cell Lymphoma (PTCL) Treated with the Novel Stapled Peptide ALRN-6924, a Dual Inhibitor of MDMX and MDM2

Background: ALRN-6924, an α-helical stapled p53 peptide, is the first-in-class and only dual inhibitor of MDMX and MDM2 currently in clinical trials for both, solid and hematologic malignancies. In tumors with wild-type (WT) TP53, ALRN-6924 can induce p53-dependent cell cycle arrest and apoptosis and separately can invoke p53-mediated immunomodulatory effects, including but not limited to lymphocyte chemotaxis and diminution of PD-L1 expression on tumor cells. This report begins to describe the biologic underpinnings of PsP in selected PTCL patients (pts) treated with ALRN-6924. Despite imaging-based progressive disease (PD), careful monitoring for clinical benefit in light of conflicting imaging (PsP) results led to the decision to treat beyond radiologic progression and the observation of subsequent, delayed radiologic responses.Methods: Pts with relapsed or refractory PTCL received either 3.1 mg/kg ALRN-6924 on days 1, 8, and 15 of a 28-day cycle (QW) or Days 1, 3, and 5 of a 21-day cycle (TIW). Responses were assessed locally using IWG 2014 criteria as well as through independent radiology assessment. Treatment continued until symptomatic PD, unacceptable toxicity, or other indication for withdrawal. Continuation beyond radiologic PD was permitted for perceived clinical benefit. RNA-based immune profiles from pre- and post-treatment tumor biopsies from pts who were treated with ALRN-6924 were evaluated by gene expression panels.Clinical findings were correlated with CT26 and MC38 murine syngeneic tumor models, where immune cell infiltration after ALRN-6924 dosing was measured by flow cytometry.Results: PsP was observed in 3 PTCL pts who eventually achieved a PR. A pattern of transient tumor flare and new lesion formation was noted in one pt (pt 13-196) while the other 2 PsP pts (pt 3-159 and 11-155) had atypical PsP patterns, including tumor shrinkage by CT, but transient new and/or increased 18Fluorodeoxyglucose (FDG)-PET uptake. In one pt, there was rapid clinical improvement of malignant hypercalcemia and B symptoms despite formal IWG 2014 progression after 2 cycles of ALRN-6924 QW treatment plus an additional transient episode of PsP due to new FDG-avid lesions at cycle 8. Another pt had a similar PsP pattern with decrease in lesion size on CT but increased FDG-avidity of target lesions following 2, 4, and 6 cycles of QW-therapy with ALRN-6924, with new FDG-avid lesions that appeared, and then resolved in different anatomical locations at each imaging assessment. Local pathology reported findings consistent with PTCL upon post-baseline biopsy of one of these lesions. Pre- and post-baseline biopsies were analyzed for differences in RNA-expression of immune-related genes, and showed changes consistent with p53-mediated immunomodulatory effects. Despite formal progression due to transient PET-avid lesions, both pts remained on therapy, subsequently achieving a confirmed PR.A pt treated with TIW ALRN-6924 (pt 13-196) exhibited worsening abdominal pain by Day 5 of ALRN-6924, with CT scans on days 6, 11, and 22 showing transient enlargement and increased number of nodes, splenomegaly, and ascites, consistent with progression. The pt continued therapy with resolution of clinical symptoms, and an efficacy assessment after 3 cycles showed dramatic reduction in lesion sizes and FDG-avidity, assessed as a PR (unconfirmed).Preclinically, in mice treated with ALRN-6924, a significant increase in tumor-infiltrating CD8+ T cells and M1-polarized macrophages was found in murine TRP53-WT CT26 tumors as well as in TRP53-mutant MC38 tumors.Conclusion: Treatment of PTCL with ALRN-6924 can be associated with PsP. Pts have benefitted from treatment beyond radiologic progression, with new FDG-avid lesions resolving over time. Murine tumor models plus changes in immune-related gene expression in pre- and post-baseline tumor samples from pts suggest that p53-mediated immune-activation may account for these findings. Transient tumor flare observed in pts, was consistent with increased immune cell infiltration that was detected after p53-activation in the tumor microenvironment of TRP53-mutant syngeneic models. ALRN-6924 is a promising anticancer agent that warrants further investigation and consideration should be given to possible pseudoprogression prior to discontinuing pts from treatment with ALRN-6924. DisclosuresShustov:Seattle Genetics: Research Funding. Mehta:Spectrum: Consultancy; Gilead: Consultancy, Speakers Bureau; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kite: Consultancy, Speakers Bureau; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Research Funding; Merck: Research Funding; Epizyme: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Carevive: Other: Patient engagement; Medpage: Other: Medical website. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Carvajal:Aileron Therapeutics Inc.: Employment, Equity Ownership. Guerlavais:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Samant:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Narasimhan:Aileron Therapeutics Inc.: Employment, Equity Ownership. Sutton:Aileron Therapeutics Inc.: Consultancy. Annis:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Pinchasik:Aileron Therapeutics Inc.: Employment, Equity Ownership. Aivado:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Korn:Aileron Therapeutics Inc.: Other: Client; Imaging Endpoints: Employment, Equity Ownership.

Comparison of α-Fetoprotein Criteria and Modified Response Evaluation Criteria in Solid Tumors for the Prediction of Overall Survival of Patients with Hepatocellular Carcinoma after Transarterial Chemoembolization

PurposeTo evaluate the value of α-fetoprotein (AFP) classification criteria in predicting tumor response and patient survival and to discuss the agreement between AFP criteria and modified Response Evaluation Criteria In Solid Tumors (mRECIST). Materials and MethodsBetween January 2011 and December 2014, 147 patients with unresectable hepatocellular carcinoma (HCC) with baseline AFP levels ≥ 400 ng/mL who underwent transarterial chemoembolization as initial treatment were retrospectively enrolled for AFP/imaging correlation analysis. AFP-based response was classified as complete response (CR) in cases of AFP level normalization, partial response (PR) in cases of > 50% decrease vs baseline, stable disease (SD) in cases of −50% to +30% change vs baseline, or progressive disease (PD) in cases of > 30% increase vs baseline. Intermethod agreement between the 2 methods was assessed by Cohen κ coefficient. Response rates according to AFP and mRECIST were compared, and the association between response rate and overall survival (OS) was evaluated. ResultsThe κ value for agreement between AFP criteria and mRECIST was 0.549 (ie, moderate), with objective response and disease control rates of 36.1% and 63.3% per AFP criteria and 34.7% and 46.3% per RECIST (P = .807 and P = .003), respectively. Although AFP criteria and mRECIST showed significantly prognostic strata for CR, PR, SD, and PD after chemoembolization (P < .001 for both), some overlap in radiologic PD survival curves was observed. The OS of AFP-based disease control (ie, CR/PR/SD) was significantly longer than that of AFP-based PD among patients with radiologic PD (9.0 vs 6.0 mo; P < .001). ConclusionsThe defined AFP response moderately correlated with mRECIST response and yielded accurate prognostic prediction in patients with HCC and AFP levels ≥ 400 ng/mL treated with chemoembolization.