Prior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We ...implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies.
Matched tumor/normal DNA from patients with HCC (
= 127) were analyzed using a hybridization capture-based NGS assay designed to target 341 or more cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles.
WNT/β-catenin pathway (45%) and
(33%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib-treated patients (
= 81), oncogenic PI3K-mTOR pathway alterations were associated with lower disease control rates (DCR, 8.3% vs. 40.2%), shorter median progression-free survival (PFS; 1.9 vs. 5.3 months), and shorter median overall survival (OS; 10.4 vs. 17.9 months). For patients treated with immune checkpoint inhibitors (
= 31), activating alteration WNT/β-catenin signaling were associated with lower DCR (0% vs. 53%), shorter median PFS (2.0 vs. 7.4 months), and shorter median OS (9.1 vs. 15.2 months). Twenty-four percent of patients harbored potentially actionable alterations including
(8.5%) inactivating/truncating mutations,
(6.3%) and
(1.5%) amplifications, and
missense mutations (<1%). Six percent of patients treated with systemic therapy were matched to targeted therapeutics.
Linking NGS to routine clinical care has the potential to identify those patients with HCC likely to benefit from standard systemic therapies and can be used in an investigational context to match patients to genome-directed targeted therapies.
.
Standard-of-care treatment for patients with newly diagnosed glioblastoma (GBM) after surgery or biopsy includes concurrent chemoradiation followed by maintenance temozolomide (TMZ) with tumor ...treating fields (TTFields). Preclinical studies suggest TTFields and radiotherapy work synergistically. We report the results of our trial evaluating the safety of TTFields used concurrently with chemoradiation.
This is a single-arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma and a Karnofsky performance score (KPS) of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with TMZ (75 mg/m
daily) and TTFields (200 kHz). Maintenance therapy included TMZ and continuation of TTFields. Scalp-sparing radiation treatment was used to reduce radiation dermatitis. Radiation treatment was delivered through the TTFields arrays. The primary endpoint was safety and toxicity of tri-modality treatment within 30 days of completion of chemoradiation treatment.
There were 30 patients enrolled, including 20 (66.7%) men and 10 (33.3%) women, with a median age of 58 years (range 19 to 77 years). Median KPS was 90 (range 70 to 100). A total of 12 (40%) patients received a gross total resection and 18 (60%) patients had a subtotal resection. A total of 12 (40%) patients had multifocal disease at presentation. There were 20 (66.7%) patients who had unmethylated O(6)-methylguanine-DNA-methyltransferase (MGMT) promotor status and 10 (33.3%) patients who had methylated MGMT promoter status. Median follow-up was 15.2 months (range 1.7 to 23.6 months). Skin adverse events were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. The primary end point was met; no TTFields discontinuation occurred during the evaluation period due to high grade scalp toxicity. A total of 27 (90%) patients had progression, with a median progression-free survival (PFS) of 9.3 months (95% confidence interval (CI): 8.5-11.6 months). The 1-year progression-free survival was 23% (95% CI: 12%-45%). The median overall survival (OS) was 15.8 months (95% CI: 12.5 months-infinity). The 1-year overall survival was 66% (95% CI: 51%-86%).
Concurrent TTFields with scalp-sparing chemoradiation is a feasible and well-tolerated treatment option with limited toxicity. A phase 3, randomized clinical trial (EF-32, clinicaltrials.gov Identifier: NCT04471844) investigating the clinical benefit of concurrent TTFields with chemoradiation treatment is currently enrolling.
Clinicaltrials.gov, identifier NCT03477110.
The objective of this study was to describe the frequency that healthcare and social support services offered by JeffHOPE, a student run clinic for people experiencing homelessness in Philadelphia, ...PA, were utilized by patients. This study also aimed to investigate where patients would seek medical care on a given day had they not been able to access JeffHOPE. This study was conducted via mixed methods consisting of retrospective chart review of patient encounter records and a patient survey conducted weekly throughout 2019, both at a single clinic site, and retrospective chart review of January through March 2020 records at 5 clinic sites. This study found that the frequency of services utilized varied between clinic sites, and that Pharmacy and Procedure committees were the most utilized when examining the combined clinic data. Additionally, the survey found that JeffHOPE provided medical care to those that otherwise would not have sought it. Clinics also served as an alternative to accessing care for non-emergent issues in an Emergency Department (ED) for some patients, but for others it replaced seeing their primary care provider (PCP). This study confirmed that the services offered by JeffHOPE are well-utilized by patients experiencing homelessness in Philadelphia. It also revealed that while the organization’s medical services filled care gaps and potentially decreased unnecessary ED visits, they were also sometimes accessed in lieu of a PCP visit. A focused effort on linkage to formal primary care services for all JeffHOPE patients and expanding collection of more granular data to all clinics represent important future endeavors for this student run organization.
Background
Patients with advanced hepatocellular carcinoma (HCC) who received second line sorafenib plus doxorubicin following disease progression on sorafenib were shown retrospectively to have ...improved progression free survival (PFS) and overall survival (OS). Sorafenib plus doxorubicin combination may synergistically promote ASK‐1 mediated apoptosis in cancer cells through RAF‐1 inhibition. Thus, we conducted this phase II study of sorafenib and doxorubicin combination following progression on sorafenib.
Methods
Patients with histologically confirmed advanced HCC, confirmed radiologic progression on sorafenib, Karnofsky performance status (KPS) ≥70%, and Child‐Pugh A liver cirrhosis were eligible. Patients received sorafenib 400 mg twice daily and doxorubicin 60 mg/m2 once every 3‐weeks. The primary endpoint was OS at 6 months (OS6). Secondary endpoints included safety, PFS, OS, response rate (RR) by RECIST 1.1. Additional endpoints included baseline and on‐treatment tumor ASK‐1 and pERK expression levels by immunohistochemistry (IHC) and the correlation with PFS, RR, and OS.
Results
Thirty patients were enrolled in the study, 86% were male, median age was 64 years. OS6 was 76.6% (95%CI: 57.2%‐88.1%). Median OS was 8.6 (95%CI: 7.3‐12) months, and median PFS reached 3.9 (95%CI: 2.4‐4.6) months. Three (11%) partial responses were observed and 17 patients (61%) had stable disease. Pertinent grade 3‐4 adverse events that occurred in more than 10% of patients included neutropenia (16%), febrile neutropenia (10%), anemia (10%), thrombocytopenia (10%), elevated AST (23%) and ALT (10%), hypophosphatemia (10%), and fatigue (10%). No association with the difference in baseline and post‐treatment ASK‐1 and pERK level of expression by IHC and survival outcomes was detected.
Conclusion
Sorafenib plus doxorubicin following progression on sorafenib did not show any improved outcome. We do not recommend further development or use of this combination in HCC.
Sorafenib plus doxorubicin was evaluated as a second line therapy for advanced HCC. The association with the difference in baseline and post treatment ASK‐1 and pERK level of expression by IHC and survival outcomes was evaluated yet not detected. Sorafenib plus doxorubicin following progression on sorafenib did not show any improved outcome.
Lessons Learned
The fibrolamellar carcinoma‐associated DNAJB1‐PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A.
...ENMD‐2076 showed a favorable toxicity profile.
The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD‐2076 as single agent.
Future studies will depend on the simultaneous targeting approach of DNAJB1‐PRKACA and the critical downstream components.
Background
Fibrolamellar carcinoma (FLC) represents approximately 0.85% of liver cancers. The associated DNAJB1‐PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA). ENMD‐2076 is a selective anti‐AURKA inhibitor.
Methods
Patients aged >12 years with pathologically confirmed incurable FLC, with measurable disease, Eastern Cooperative Oncology Group performance status 0–2 or Lansky 70–100, and adequate organ function were eligible. Patients were prescribed ENMD‐2076 based on body surface area. The primary endpoint was overall objective response rate by RECIST v1.1, with a null hypothesis of true response rate of 2% versus one‐sided alternative of 15%. Secondary endpoints included 6‐month progression‐free survival (PFS) rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the study.
Results
Of 35 patients who enrolled and received treatment, 1 (3%) had a partial response (PR) and 20 (57%) had stable disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 months, respectively. The most frequently reported drug‐related serious adverse event was hypertension in three patients. Three deaths were reported on‐study—two due to disease progression and one due to pulmonary embolism not related to ENMD‐2076.
Conclusion
The study provided no rationale for further studying ENMD‐2076 as a single agent in FLC.
Background
With limited information on germline mutations in biliary tract cancers, this study performed somatic and germline testing for patients at Memorial Sloan Kettering Cancer Center with known ...biliary tract carcinoma with the aim of determining the frequency and range of pathogenic germline alterations (PGAs).
Methods
Patients with biliary tract carcinoma were consented for somatic tumor and matched blood testing of up to 468 genes via the Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets next‐generation sequencing platform. A germline variant analysis was performed on a panel of up to 88 genes associated with an increased predisposition for cancer. Demographic and diagnostic details were collected.
Results
Germline mutations were tested in 131 patients. Intrahepatic cholangiocarcinoma was the most common cancer (63.4%), and it was followed by gallbladder adenocarcinoma (16.8%), extrahepatic cholangiocarcinoma (16%), and otherwise unspecified biliary tract cancer (3.8%). Known and likely PGAs were present in 21 patients (16.0%), with 9.9% harboring a PGA in a high/moderate‐penetrance cancer predisposition gene. Among high‐penetrance cancer susceptibility genes, PGAs were most commonly observed in BRCA1 and BRCA2 (33.3%), which made up 5.3% of the entire cohort, and they were followed by PALB2, BAP1, and PMS2. Mutations in ATM, MITF, and NBN, moderate‐penetrance cancer susceptibility genes, were identified in 1 patient each. There was no observed difference in the types of mutations among the subtypes of biliary tract cancer.
Conclusions
The frequency of PGAs found was comparable to existing data on the prevalence of germline mutations in other solid tumor types with matched tumor analysis. This provides support for the role of the BRCA1/2, ATM, and BAP1 genes in biliary tract cancer susceptibility.
The frequency of pathogenic germline alterations is comparable to existing data on such prevalence in other solid tumor types with matched tumor analysis. This provides support for the role of the BRCA1/2, ATM, and BAP1 genes in biliary tract cancer susceptibility.
Lessons Learned
FLC is a complex cancer with many implicated oncogenic pathways. Single or dual targeting does not appear to alter the natural history of the cancer, and novel therapeutics are ...needed.
Estrogen deprivation therapy with letrozole and leuprolide, alone or in combination with the mTOR inhibitor, everolimus, did not demonstrate clinical activity in advanced fibrolamellar carcinoma.
The study drugs were well tolerated when administered as single agents or in combination in this patient population.
This study demonstrates that, despite the rarity of FLC, multicenter therapeutic clinical trials are feasible and support the value of this consortium.
Background
Fibrolamellar carcinoma (FLC) is an uncommon malignancy in young people and is sometimes associated with pregnancy and oral contraceptive use. Immunohistochemical staining and genetic profiling of FLC tumor specimens have revealed aromatase overexpression. The overexpression of mTOR and S6 kinase has been noted in 25% of FLC. On the basis of interaction between estrogen and the PI3K/Akt/mTOR pathway, we hypothesized that suppression of estrogen and mTOR signaling could have antineoplastic activity in FLC.
Methods
Patients were randomized to arm A (everolimus), arm B (letrozole/leuprolide; estrogen deprivation therapy EDT), or arm C (everolimus/letrozole/leuprolide). Upon disease progression, patients in arm A or B could proceed to part 2 (everolimus/letrozole/leuprolide). The primary endpoint was progression‐free survival (PFS) at 6 months (PFS6) assessed using a Simon's minimax two‐stage design, hypothesizing an improvement in PFS6 from 40% to 64% with the study regimen.
Results
Twenty‐eight patients were enrolled. An unplanned analysis was performed because of perceived concern for lack of efficacy. Stable disease was observed in 9 of 26 evaluable patients (35%). PFS6 was 0%. Median overall survival (OS) was 12.4 months (95% confidence interval CI, 7.4–20.9) for the whole study cohort. Grade 3 adverse events in ≥10% of patients were nausea (11%), vomiting (11%), anemia (11%), elevated aspartate transaminase (AST; 32%), alanine transaminase (ALT; 36%), and alkaline phosphatase (14%). All 28 patients experienced an event for PFS outcome, and four deaths were due to disease progression.
Conclusion
Neither EDT nor mTOR inhibition improved outcomes in FLC. Other treatment strategies are needed.
Introduction
Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide with tumor treatment fields (TTFields). Preclinical studies suggest TTFields and ...radiation treatment have synergistic effects. We report our initial experience evaluating toxicity and tolerability of scalp-sparing radiation with concurrent TTFields.
Methods
This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed glioblastoma were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent temozolomide (75 mg/m
2
daily), and TTFields. Maintenance therapy included standard temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. The primary endpoint was safety and toxicity for concurrent TTFields with chemoradiation in newly diagnosed glioblastoma.
Results
We report the first ten patients on the trial. Eight were male, and two were female, with median age 61 years (range 49 to 73 years). Median KPS was 90 (range 70–90). Median follow-up was 7.9 months (2.8 to 17.9 months). Nine (90%) patients with unmethylated MGMT promotor, and one with methylated. Median time from surgery to radiation was 33 days (28 to 49 days). All patients completed concurrent chemoradiation plus TTFields without radiation or TTFields treatment interruption or discontinuation. Scalp dose constraints were achieved for all patients, with mean dose having a median value of 7.7 Gy (range 4.9 to 13.2 Gy), D20cc median 22.6 Gy (17.7 to 36.8 Gy), and D30cc median 19.8 Gy (14.8 to 33.4 Gy). Average daily use during concurrent phase had median value of 83.5% and 77% for maintenance. There was no related ≥ Grade 3 toxicity. Skin toxicity (erythema, dermatitis, pruritus) was noted in 80% of patients, however, these were limited to Grade 1 or 2 events which resolved spontaneously or responded to topical medications. Eight patients (80%) had progression, with median PFS of 6.9 months (range 2.8 to 9.6 months).
Conclusions
Concurrent TTFields with scalp-sparing chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trial is warranted to define therapeutic advantages of concurrent TTFields with chemoradiation.
Trial registration
Clinicaltrials.gov Identifier NCT03477110
The frequency of pathogenic germline alterations is comparable to existing data on such prevalence in other solid tumor types with matched tumor analysis. This provides support for the role of ...BRCA1/2, ATM, and BAP1 genes in biliary tract cancer susceptibility.
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