Partial response to sorafenib treatment associated with transient grade 3 thrombocytopenia in a patient with locally advanced thyroid cancer

Locally advanced thyroid cancer exhibits aggressive clinical features requiring extensive neck dissection. Therefore, it is important to identify changes in the tumor biology before local progression. Here, whole exome sequencing (WES) using tissues from locally advanced papillary thyroid cancer (PTC) presented a large number of single nucleotide variants (SNVs) in the metastatic lymph node (MLN), but not in normal tissues and primary tumors. Among those MLN-specific SNVs, a novel HHIP G516R (G1546A) mutation was also observed. Interestingly, in-depth analysis for exome sequencing data from the primary tumor presented altered nucleotide ‘A’ at a very low frequency indicating intra-tumor heterogeneity between the primary tumor and MLN. Computational prediction models such as PROVEAN and Polyphen suggested that HHIP G516R might affect protein function and stability. In vitro, HHIP G516R increased cell proliferation and promoted cell migration in thyroid cancer cells. HHIP G516R, a missense mutation, could be a representative example for the intra-tumor heterogeneity of locally advanced thyroid cancer, which can be a potential future therapeutic target for this disease.

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The efficacy and safety of anlotinib in neoadjuvant treatment in locally advanced thyroid cancer: A single-arm phase II clinical trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.6069 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 6069-6069

Author(s):

Naisi Huang ◽

Guohua Sun ◽

Yulong Wang ◽

Jiaying Chen ◽

Qing Guan ◽

...

Keyword(s):

Clinical Trial ◽

Thyroid Cancer ◽

Adverse Events ◽

Objective Response ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Primary Treatment ◽

Tumor Diameter ◽

Efficacy And Safety ◽

Advanced Thyroid Cancer

6069 Background: Surgery is the primary treatment for locally advanced thyroid cancer (TC). For some locally advanced TC, R0/R1 resection could not be achieved at initial diagnosis and neoadjuvant treatment would be an option. However, there is still little evidence regarding neoadjuvant treatment in locally advanced TC. Methods: This single-arm, phase 2 study investigated the efficacy and safety of Anlotinib (12mg orally daily, for two weeks on/on week off) for 2-6 cycles in patients with locally advanced TC in the neoadjuvant setting. Operable patients received surgery after neoadjuvant treatment. The primary endpoint was objective response rate (ORR). Results: A total of 13 patients were included and received an average of 3.5 cycles (range: 3-6 cycles) of Anlotinib treatment. 12 cases were papillary thyroid cancer, and 1 was follicular thyroid cancer. The ORR of Anlotinib was 76.9% with 10 partial response (PR), 2 stable disease (SD), and 1 progressive disease (PD). 8 PR and 1 SD patients received surgery after neoadjuvant treatment, of whom 8 had R0/1 resections and 1 had R2 resection. 2 PR patients refused to have surgery and the rest 2 patients were not operable. The R0/1 resection rate for intent to treat population was 61.5% and for per-protocol population was 72.7%. The maximum reduction in sum of tumor diameter was an average of 34.8% (range: 30.9%-45.5%) for PR patients. Most adverse events were grade 1 or 2. Common adverse events of all grade were hypertension (76.9%), hypertriglyceridemia (69.2%), proteinuria (53.8%), TSH increase (53.8%), cholesterol elevation (53.8%) and hand-foot syndrome (38.5%). The majority of adverse events discontinued after the neoadjuvant treatment stopped. Conclusions: Anlotinib demonstrated antitumor activity in the neoadjuvant treatment in locally advanced TC and the majority of patients achieved R0/1 resection. Adverse events were consistent with the known Anlotinib adverse event profile. These results suggest that Anlotinib neoadjuvant treatment represents a new option for locally advanced TC. Clinical trial information: NCT04309136.

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Management of Locally Advanced Thyroid Cancer

Evidence-Based Endocrine Surgery ◽

10.1007/978-981-10-1124-5_8 ◽

2018 ◽

pp. 85-95

Author(s):

Andrea R. Marcadis ◽

Jennifer Cracchiolo ◽

Ashok K. Shaha

Keyword(s):

Thyroid Cancer ◽

Locally Advanced ◽

Advanced Thyroid Cancer

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Intensity modulated radiotherapy in locally advanced thyroid cancer: Outcomes of a sequential phase I dose-escalation study

Radiotherapy and Oncology ◽

10.1016/j.radonc.2018.02.002 ◽

2018 ◽

Vol 127 (1) ◽

pp. 43-48 ◽

Cited By ~ 1

Author(s):

K.P. Rooney ◽

A.B. Miah ◽

S.A. Bhide ◽

M.T. Guerrero-Urbano ◽

M.T. Sharabiani ◽

...

Keyword(s):

Thyroid Cancer ◽

Phase I ◽

Dose Escalation ◽

Locally Advanced ◽

Intensity Modulated Radiotherapy ◽

Cancer Outcomes ◽

Dose Escalation Study ◽

Intensity Modulated ◽

Advanced Thyroid Cancer ◽

Sequential Phase

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A phase II study of axitinib (AG-013736 [AG]) in patients (pts) with advanced thyroid cancers

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.6008 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 6008-6008 ◽

Cited By ~ 11

Author(s):

E. E. Cohen ◽

E. E. Vokes ◽

L. S. Rosen ◽

M. S. Kies ◽

A. A. Forastiere ◽

...

Keyword(s):

Thyroid Cancer ◽

Tumor Regression ◽

Locally Advanced ◽

Thyroid Tumor ◽

External Beam Radiation ◽

Vegf Receptors ◽

Beam Radiation ◽

Thyroid Cancers ◽

Advanced Thyroid Cancer ◽

Multi Center Study

6008 Background: Elevated VEGF-A and VEGF-C have been reported in thyroid tumor tissue compared with normal thyroid. AG is a potent, small molecule inhibitor of VEGF receptors 1, 2 and 3. The efficacy and safety of AG therapy in pts with advanced thyroid cancers was examined in this single-arm, multi-center study. Methods: 60 pts with metastatic or unresectable locally-advanced thyroid cancer refractory to, or not suitable candidates for, 131iodine (131I) treatment, with measurable disease received AG at a starting dose of 5 mg orally BID. The primary endpoint was response rate (RR) by RECIST criteria. A Simon 2-stage minimax design was used (a=0.1; β=0.1; null RR=5%; alternative RR=20%). Samples were collected pretreatment and q8wks to explore relationships between clinical response and plasma soluble proteins. Results: Median age was 59 yrs (26–84), 35 (58%) were male. Histological subtypes included papillary: 29 pts (48%); follicular: 15 pts (25%)-11 (18%) with Hurthle cell variant; medullary: 12 pts (20%); anaplastic: 2 pts (3%), and other/unknown: 2 pts (3%). 53 pts (88%) had prior surgery, 42 (70%) had prior 131I treatment, 27 (45%) had prior external beam radiation, and 9 (15%) had prior chemotherapy. Partial response (PR) by investigator report was achieved in 13 pts (22% CI: 12.1, 34.2), with 31- 68% maximum tumor regression and duration of response (DOR) of 1–16 months. 30 pts (50%) have stable disease with a duration range of 4–13 months and 13–67% maximum tumor regression in 28 pts. Response assessments are ongoing. The treatment duration range is 6–670 days with 38 pts currently on study. Median PFS has not been reached with a median follow up of 273 days. The most common treatment-related adverse events were fatigue (37%), proteinuria (27%), stomatitis/mucositis (25%), diarrhea (22%), hypertension (20%) and nausea (18%). AG therapy consistently decreased soluble VEGFR2 and VEGFR3, and increased VEGF in the blood, demonstrating pharmacodynamic activity against targeted VEGF receptors. Conclusions: AG has substantial anti-tumor activity in advanced thyroid cancer with demonstrated pharmacodynamic activity. A global pivotal trial testing AG in doxorubicin refractory thyroid cancer is ongoing. [Table: see text]

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Immune checkpoint inhibition (ICI) in combination with SBRT in patients with advanced pancreatic adenocarcinoma (aPDAC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.192 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 192-192 ◽

Cited By ~ 1

Author(s):

Gagandeep Brar ◽

Changqing Xie ◽

Charalampos S. Floudas ◽

M. Pia Morelli ◽

Suzanne Fioravanti ◽

...

Keyword(s):

Partial Response ◽

Locally Advanced ◽

Primary Objective ◽

Clinical Activity ◽

Correlative Analysis ◽

Progression Of Disease ◽

New Treatment ◽

Grade 3 ◽

Unacceptable Toxicity ◽

Clinical Trial Information

192 Background: Chemotherapy in aPDAC has resulted in only modest improvements in outcome. The effectiveness of ICI monotherapy is also limited in PDAC, suggesting an immunogenic inert tumor microenvironment. SBRT is safe and effective in locally advanced PDAC and exhibits enhanced antitumor immunity. We hypothesize that ICI plus SBRT will improves immunomodulatory effects of ICI in patients with aPDAC resulting in a greater clinical benefit. Methods: Eligible patients with aPDAC were enrolled to four different treatment cohorts. Cohort 1: Durvalumab (Durva) 1500 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 2: SBRT 5 fractions x 5Gy followed by Durva. Cohort 3: Durva + Tremelimumab (Treme) 75 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 4: SBRT 5 fractions x 5Gy followed by Durva + Treme. This was continued until unacceptable toxicity or progression of disease. A biopsy was performed at baseline and pre-cycle 2 of treatment for exploratory correlative analysis. The primary objective was to evaluate the safety and feasibility of combining ICI and SBRT to enhance the efficacy of ICI. Results: 51 patients with aPDAC were enrolled and 31 patients were evaluable for the efficacy. The most commonly TRAEs were lymphopenia. Grade 3-4 AEs were lymphopenia and anemia. No dose limiting toxicities were seen. Out of total 31 evaluable patients, 1 patient achieved a confirmed partial response seen in Cohort 1 and 2 patients in Cohort 4, and 7 stable disease across the 4 treatment arms. Median PFS and OS was 1.7 months (95% CI 0.7-2.8 months) and 3.4 months (95% CI 0.9-11.4 months) in cohort 1; 2.6 months (95% CI 2.1-4.7 months) and 9.1 months (95% CI 3.4-18.7 months)in cohort 2; 1.6 months (95% CI 0.5-4.0 months) and 3.0 months (95% CI 0.7-6.6 months) in cohort 3; and 3.2 months (95% CI 1.5-16.5months) and 6.4 months (95% CI 1.5-17.6 months) in cohort 4. Conclusions: The combination of ICI and SBRT is safe and well tolerated in patients with aPDAC. The overall response rate of 9.6% including 2 patients who achieved a durable partial response lasting over 12 months, suggests meaningful clinical activity. This signifies that ICI and SBRT is a potential new treatment for aPDAC. Clinical trial information: NCT02311361.

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A phase I study of olaparib in combination with capecitabine-based chemoradiation (CRT) in patients (pts) with locally advanced pancreatic cancer (LAPC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.709 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 709-709

Author(s):

T.R. Jeffry Evans ◽

Martin McKinlay Eatock ◽

Liz-Anne Lewsley ◽

Caroline Kelly ◽

Elaine McCartney ◽

...

Keyword(s):

Partial Response ◽

Induction Chemotherapy ◽

Stable Disease ◽

Excision Repair ◽

Critical Role ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Hair Follicles ◽

Tumor Diameter ◽

Grade 3

709 Background: Olaparib is a potent inhibitor of PARP-1, which has a critical role in signalling DNA single strand breaks (SSB) as part of the base excision repair pathway, and may have radio-sensitizing effects due to impaired resolution of radiation induced SSB. We hypothesize that O may potentiate the effects of X-CRT in pts with LAPC. Methods: Eligible pts with LAPC, ECOG < 1, tumor diameter < 6cm, with stable disease (SD) or response after 12 weeks’ induction chemotherapy, were treated with 1 of 4 escalating doses of O given bid po starting on day -3, and then in combination with X (830 mg/m2 bid) and radiation (50·4 Gy in 28 fractions) all administered Mon-Fri. Dose limiting toxicities (DLT) were determined on clinical and lab toxicity assessments (NCI-CTC AE v4.03) performed weekly from the start of O until completion of O plus X-CRT (i.e. 6 weeks). Dose escalation continued with a rolling-six design until the Maximum Tolerated Dose (MTD) was reached. Blood samples for PK analyses of O and PD measurement (inhibition of PARP activity) were collected on day -3 (O monotherapy) and during week 1 of O + X-CRT. Results: 18 pts, (9 m, 9 f, ECOG 0/1 [n=6/12]), age range 49-81 (median=70) years, with histologic (14) or cytologic (4) proven LAPC, had received induction chemotherapy with gemcitabine [GEM] (n=2), GEM + X (12), or FOLFIRINOX (3) with partial response (n=4) or stable disease (14). Pts received 50 (3), 100 (4), 150 (6), or 200 (5) mgs bid of O with X+CRT. DLTs were observed in 2 pts (both at 200mgs bid): 1 pt with grade 3 nausea (on optimal anti-emetics) and grade 3 fatigue, 1 pt with grade 3 anorexia. 6 pts were subsequently recruited at 150mgs bid with no DLTs. No pts had complete response, 2 pts had partial response (1 pt each at 100 and 150 mgs bid) and 1 pt (at 100 mgs bid) had progressive disease; the remaining 14 pts had SD. Conclusions: The recommended dose (RP2) of O is 150mgs bid when given in combination with X + CRT in LAPC. Recruitment of up to 12 pts with borderline operable LAPC at the RP2 is ongoing. PK analyses of O, PD studies (PARP inhibition – PBMCs; cytokeratin 18 – serum; γH2AX foci – hair follicles), and exploratory predictive marker studies (tumor – NGS; RNA exome sequencing) are ongoing. Clinical trial information: ISRCTN10361292.

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Real-world experience of regorafenib in patients with hepatocellular carcinoma: A multicenter United Kingdom study.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.499 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 499-499

Author(s):

Paul J. Ross ◽

Yuk Ting Ma ◽

Daniel H. Palmer ◽

Mark Peter Lythgoe ◽

Sophie Merrick ◽

...

Keyword(s):

Partial Response ◽

Stable Disease ◽

Real World ◽

Survival Data ◽

Sorafenib Treatment ◽

Mixed Response ◽

Best Response ◽

Hand Foot Syndrome ◽

Grade 3 ◽

The Uk

499 Background: Regorafenib was the first treatment to demonstrate a survival benefit in patients with HCC after progression on sorafenib. The RESORCE trial found that regorafenib improved overall survival with acceptable toxicity, in patients with disease progression on sorafenib who tolerated ≥400mg sorafenib daily and had Child-Pugh A liver function. Methods: We performed a multicentre, retrospective, observational study of patients with HCC receiving regorafenib in the UK, following its availability in April 2018. Results: Data on a total of 104 patients were included from April 2018–August 2019, and 80.8% were male. Age was collected in 85 patients, with a median of 68 years (range 22–86). 23.5% had NAFLD, 21.2% had ALD, 12.9% had HBV, and 3.5% had HCV. Prior management included sorafenib (100%), TACE (30.8%), resection (12.9%). Duration of sorafenib treatment was evaluable in 99/104 patients, and reported a median of 8.7 months (range 1.8–76.6). Duration of regorafenib treatment was evaluable in 92/104 patients, and reported a median of 3.9 months (range 0.0–15.7). Following treatment with regorafenib, 6 patients (5.8%) achieved partial response, 37 (35.6%) achieved stable disease and 45 (43.3%) had progressive disease as the best response. 15 (14.4%) were not assessed and 1 (1.1%) had mixed response. Survival data is immature with 62/101 (61.4%) patients alive at the time of census with median survival currently 6.5 months. Fatigue was the most frequent AE, with 69/88 patients (85.2%) for all grades. 12/88 patients (14.8%) had Grade 3 fatigue. Other significant AEs include hand-foot syndrome (6/85 patients [7.3%] had Grade 3) and diarrhoea (4/83 patients [4.9%] had Grade 3). Conclusions: The population in our real-world experience of regorafenib for HCC had a similar duration of prior sorafenib to those in the RESORCE trial. However, there was different balance of aetiologies with a lower proportion of patients with HBV and HCV. The rate of partial response is similar to the RESORCE trial with fewer patients achieving stable disease. The incidence of fatigue was higher, but the incidence of hand-foot syndrome and diarrhoea were lower. Further expansion and follow-up of this population is warranted.

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