Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma.

Objective: Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed the efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC). Methods: We pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Data cut-off: July 2020. Results: Twenty-nine patients (median age: 60; range: 6-80) with TRK fusion-positive TC were treated. Tumour histology was papillary (PTC) in 20 (69%) patients, follicular (FTC) in 2 (7%), and anaplastic (ATC) in 7 (24%) patients. Among 28 evaluable patients, ORR was 71% (95% CI: 51-87); best responses were complete response in 2 (7%) patients, partial response in 18 (64%), stable disease in 4 (14%), progressive disease in 3 (11%), and undetermined in 1 (4%) due to clinical progression prior to the first post-baseline assessment. ORR was 86% (95% CI: 64-97) for PTC/FTC and 29% (95% CI 4-71) for ATC. Median time to response was 1.87 months (range 1.64-3.68). The 24-month DoR, PFS, and OS rates were 81, 69, and 76%, respectively. Treatment-related adverse events were mainly grades 1-2. Conclusion: In TRK fusion-positive TC, larotrectinib demonstrates rapid and durable disease control and a favourable safety profile in patients with advanced disease requiring systemic therapy. Significance statement: NTRK gene fusions are known oncogenic drivers and have been identified in various histologies of thyroid carcinoma, most commonly in papillary thyroid carcinoma. This is the first publication specifically studying a TRK inhibitor in a cohort of TRK fusion-positive thyroid carcinoma patients. In the current study, the highly selective TRK inhibitor larotrectinib showed durable antitumour efficacy and a favourable safety profile in patients with TRK fusion-positive thyroid carcinoma. Our findings show that patients with advanced non-medullary thyroid carcinoma who may require systemic therapy could be considered for testing for gene fusions by next-generation sequencing.

Intralesional SD-101 in Combination with Pembrolizumab in Anti-PD-1 Treatment-Naïve Head and Neck Squamous Cell Carcinoma: Results from a Multicenter, Phase II Trial.

PURPOSE: To determine whether SD-101, a Toll-like receptor 9 agonist, potentiates the antitumor activity of anti-PD-1 antibodies in patients with anti-PD-1/PD-L1 naïve, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Patients with PD-1 Ab-naïve HNSCC received either 2 mg SD-101 injected in one to four lesions or 8 mg SD-101 injected into a single lesion weekly × 4 doses then every 3 weeks × 7 doses. Pembrolizumab was administered at 200 mg every 3 weeks. RESULTS: A total of 28 patients received 2 mg and 23 received 8 mg per injection, respectively. A total of 76% of patients had received prior systemic therapy. Combined positive score was ≥1 to < 20 in 35 patients (70%) and ≥ 20 in 15 patients (30%) of 50 patients with available data. There were 12 patients with grade ≥3 treatment-related adverse events (24%), and no treatment-related deaths. The objective response rate was 24% including 2 complete and 10 partial responses. The median duration of response was 7.0 [95% confidence interval (CI): 2.1-11.1] months. The response rate was higher in human papillomavirus-positive (HPV+) patients (44%, N = 16). Responses were not associated with PD-L1 expression levels or IFNγ-related gene expression at baseline. Responses were observed both in injected (32%) and in noninjected lesions (29%). Progression-free and overall survival at 9 months were 19.0% (95% CI: 9.1-31.7) and 64.7% (95% CI: 45.3-78.7), respectively. CONCLUSIONS: SD-101 combined with pembrolizumab induced objective responses, especially in HPV+ tumors, which were frequently associated with increased intratumoral inflammation and effector immune cell activity.

A Prospective Trial Evaluating the Safety and Systemic Response From the Concurrent Use of Radiation Therapy with Checkpoint Inhibitor Immunotherapy in Metastatic Non-Small Cell Lung Cancer.

INTRODUCTION/BACKGROUND: This study assessed the safety and systemic (abscopal) response from the addition of local stereotactic body radiation therapy (SBRT) to checkpoint inhibitor (CPI) immunotherapy in patients with metastatic non-small cell lung cancer. PATIENTS/METHODS: Thirty-five patients with at least 2 sites of measurable disease on PET/CT received standard-of-care CPI immunotherapy alone (n = 19), or in combination with 4 cycles doublet carboplatin/pemetrexed chemotherapy (n = 16), and 3 to 5 fractions SBRT to a single extracranial target lesion between cycles 1 to 2 of the systemic therapy. Adverse events were assessed using CTCAE version 5.0. Best systemic objective response rate (ORR) was assessed using iRECIST criteria, excluding any irradiated lesion(s). Additional SBRT to a different target lesion was offered to patients who continued on immunotherapy with unconfirmed progressive disease or mixed response. RESULTS: Fifteen patients (44%) experienced 22 grade 1 to 2 toxicities potentially attributable to radiation, most commonly pneumonitis (n = 9) and fatigue (n = 6), and no grade 3 to 5 radiation-induced toxicities. Patients undergoing combined CPI-chemotherapy received a lower median biologically effective dose of SBRT than those undergoing CPI monotherapy (43.2 vs. 60Gy), but had a higher rate of radiation-induced toxicity (56% vs. 32%, P < .01). The best systemic ORR was 53%, with 20.5% stable disease and 26.5% progressive disease. Fifteen patients underwent a subsequent course of SBRT based on their response, among which 3 (20%) had progression-free intervals of 12, 16, and 10 months thereafter. CONCLUSIONS: Addition of SBRT to CPI immunotherapy (with/without chemotherapy) is safe. The favorable systemic response observed warrants further assessment with a randomized trial.

Patterns of disease progression to checkpoint inhibitor immunotherapy in patients with stage IV non-small cell lung cancer.

INTRODUCTION: The purpose of this study was to assess patterns of disease progression for patients with metastatic non-small cell lung cancer (NSCLC) on checkpoint inhibitor immunotherapy. METHODS: This single centre, retrospective study included all patients diagnosed with Stage IV NSCLC from 2015 to 2019 who received at least 2 cycles of immunotherapy, with or without concurrent chemotherapy. Immune RECIST criteria were used to assess patterns of disease progression, and progression-free survival (PFS), excluding irradiated tumours. The chi-square and log-rank tests assessed for associations between baseline clinical characteristics and progressive disease in initial sites only (vs. new or combined sites), and PFS, respectively. RESULTS: Among 143 eligible patients with a median follow-up of 11 months, 97 (68%) developed disease progression. Of these, 67 patients (69.1%) progressed only at initial disease site(s), 10 patients (10.3%) progressed only at new disease site(s), and 20 patients (20.6%) progressed in both initial and new sites. Rates of disease progression based on tumour location were higher for liver (64%) and lung metastases (61%) than for other metastatic sites (33-36%) or the primary tumour (24%). Only higher PD-L1 expression (P = 0.002) and absence of lung metastasis (P = 0.048) at baseline were associated with improved PFS. No baseline characteristics significantly impacted the probability of initial disease site-only progression, though a trend was observed for untreated primary tumour (72% vs. 56%, P = 0.169). CONCLUSIONS: The dominant pattern of disease progression is in the initial sites of disease alone, suggesting a potential role for local radiation therapy as a complementary treatment modality to immunotherapy.

Definitive Upfront Stereotactic Ablative Radiotherapy Combined with Image-Guided, Intensity Modulated Radiotherapy (IG-IMRT) or IG-IMRT Alone for Locally Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Image-guided (IG) intensity-modulated radiotherapy (IMRT) enables maximal tumor margin reduction for the sparing of organs at risk (OARs) when used to treat locally advanced non-small cell lung cancer (NSCLC) with definitive chemo-radiation. It also allows for the incorporation of stereotactic ablative radiotherapy (SABR) into the treatment regimen. Here, we describe our initial experience in combining definitive upfront SABR to the primary lesion with chemo-radiation delivered with conventionally fractionated IG-IMRT to the remaining regional disease; along with clinical outcome following chemo-radiation with conventionally fractionated IG-IMRT alone in the treatment of locally advanced NSCLC. METHODS: The clinical outcome of 29 patients with locally advanced NSCLC who underwent conventionally fractionated IG-IMRT, or definitive upfront SABR followed by IG-IMRT combined with chemotherapy (induction, concurrent, or both) was retrospectively reviewed. RESULTS: After a median follow up of 23.7 months, the median overall survival (OS) and progression-free survival (PFS) were 19.8 and 11.3 months, respectively. The 2 year local, regional, and distant control was 60%, 62%, and 38%, respectively. No local failure was observed in 3 patients following SABR + IG-IMRT while 6/26 patients failed locally following IG-IMRT alone. SABR + IG-IMRT was well tolerated. No ≥ grade 3 radiation-related toxicity was observed. CONCLUSION: Definitive upfront SABR followed by IG-IMRT in selected patients with locally advanced NSCLC warrants further investigation in future clinical trials, while chemo-radiation with IG-IMRT alone was well tolerated.

Trends in Lung Cancer Molecular Testing.

Molecular testing of non-small cell lung carcinomas (NSCLCC) with adenocarcinoma features has become commonplace with the development and use of targeted treatments for these malignancies. Prior to treating these tumors with targeted drug regimens, testing for specific mutations is usually required to determine the potential response of the tumor to the therapeutic agents. This case review describes a patient with lung cancer showing a specific gene mutation who benefitted from targeted treatment. Also reviewed are the current standards of care and trends in the molecular testing of NSCLC with adenocarcinoma features and possible future molecular targets.

Guideline-concordant lung cancer care and associated health outcomes among elderly patients in the United States.

OBJECTIVES: In the United States (US), the elderly carry a disproportionate burden of lung cancer. Although evidence-based guidelines for lung cancer care have been published, lack of high quality care still remains a concern among the elderly. This study comprehensively evaluates the variations in guideline-concordant lung cancer care among elderly in the US. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2002-2007), we identified elderly patients (aged ≥65 years) with lung cancer (n = 42,323) and categorized them by receipt of guideline-concordant care, using evidence-based guidelines from the American College of Chest Physicians. A hierarchical generalized logistic model was constructed to identify variables associated with receipt of guideline-concordant care. Kaplan-Meier analysis and Log Rank test were used for estimation and comparison of the three-year survival. Multivariate Cox proportional hazards model was constructed to estimate lung cancer mortality risk associated with receipt of guideline-discordant care. RESULTS: Only less than half of all patients (44.7%) received guideline-concordant care in the study population. The likelihood of receiving guideline-concordant care significantly decreased with increasing age, non-white race, higher comorbidity score, and lower income. Three-year median survival time significantly increased (exceeded 487 days) in patients receiving guideline-concordant care. Adjusted lung cancer mortality risk significantly increased by 91% (HR = 1.91, 95% CI: 1.82-2.00) among patients receiving guideline-discordant care. CONCLUSION: This study highlights the critical need to address disparities in receipt of guideline-concordant lung cancer care among elderly. Although lung cancer diagnostic and management services are covered under the Medicare program, underutilization of these services is a concern.

Survey of Patients Referred to a University Cancer Center for Benign Hematology: Quality Measures and Patient Understanding.

OBJECTIVE: To investigate patients' knowledge and understanding of benign hematology and the potential psychological impact that is associated with referral to outpatient clinics. METHODS: At Mary Babb Randolph Cancer Center, an anonymous and voluntary survey including 28 questions was designed on the basis of information obtained from a single focus group. A participatory pilot survey was performed with 10 patients followed by a full-scale survey from May until November 2013. Statistical software was used for analysis. RESULTS: Among 98 patients who received the questionnaire, 37.6% were men, 62.4% women, 70.9% ≥ 40 years of age, 94.6% white, and 51.6% had some college education or above. Of the patients surveyed, 62.4% were surprised to find that their appointment was at a cancer center, and 36.6% received no explanation before their referral. A total of 61.3% did not know what benign hematology was, and only 61.2% knew that cancer physicians are also frequently trained to see patients with benign hematology conditions. Among the patients, 46.2% and 39.8% had an increase in anxiety and stress, respectively; 30.1% were afraid that they might have cancer; and 32.3% thought that the reason for their referral to the cancer center was for an evaluation for cancer. Knowledge was significantly better in women patients and patients who had been seen by an outside hematologist before or had been to a cancer center before. CONCLUSION: Referral to outpatient clinics in a cancer center for benign hematologic diseases seems to increase psychological stress and anxiety among patients, who may perceive that they are being referred for evaluation of a cancer diagnosis.

Strategies of dose escalation in the treatment of locally advanced non-small cell lung cancer: image guidance and beyond.

Radiation dose in the setting of chemo-radiation for locally advanced non-small cell lung cancer (NSCLC) has been historically limited by the risk of normal tissue toxicity and this has been hypothesized to correlate with the poor results in regard to local tumor recurrences. Dose escalation, as a means to improve local control, with concurrent chemotherapy has been shown to be feasible with three-dimensional conformal radiotherapy in early phase studies with good clinical outcome. However, the potential superiority of moderate dose escalation to 74 Gy has not been shown in phase III randomized studies. In this review, the limitations in target volume definition in previous studies; and the factors that may be critical to safe dose escalation in the treatment of locally advanced NSCLC, such as respiratory motion management, image guidance, intensity modulation, FDG-positron emission tomography incorporation in the treatment planning process, and adaptive radiotherapy, are discussed. These factors, along with novel treatment approaches that have emerged in recent years, are proposed to warrant further investigation in future trials in a more comprehensive and integrated fashion.

Patient understanding and impression of hematology/oncology fellows.

BACKGROUND: Hematologists/Oncologists spend years of training in a fellowship program. At academic centers, patients receiving treatment are often seen by fellows. It has not been established what patients understand about fellowship training, therefore the purpose of this study was to explore their understanding and whether they are content with fellows taking part in their care. METHODS: At West Virginia University/Mary Babb Randolph Cancer Center, the authors drafted a survey. This anonymous and voluntary survey abstracted basic patient demographic data and experience being cared for by fellows and basic knowledge of a Hematology/Oncology fellowship. Multiple-choice questions were drafted with 4 to 6 answer choices with no option for unknown. Surveys were collected over a 3-week period in July 2012. Patients were surveyed at outpatient appointments, infusion center visits, and laboratory draws. RESULTS: Two hundred twenty-six surveys were collected. Statistical analysis was performed and a binomial regression was fit to the data. There is evidence that higher levels of education are more likely to give correct answers (P = 0.035). Patients who stated that they had not seen a fellow or were unsure whether they had seen a fellow were more likely to select incorrect answers (P = 0.001). There is no statistical significance differentiating between cancer types in likelihood of getting answers correct. Of those surveyed, 1.77% felt that they completely understand the role of a fellow in their care, whereas 80.45% desired further information about fellows. Only 2.2% disliked having a fellow involved in their care. CONCLUSIONS: Patients at academic centers being seen by Hematology/Oncology fellows appear to have a lack of knowledge of a fellow's role and background but have a desire to be educated. Educational initiatives can be introduced to teaching institutions to help patients better understand the role of a fellow.

Cerebrospinal fluid leak during treatment with bevacizumab and irinotecan after carmustine-impregnated wafers placement in patients with grade 2 oligodendroglioma and glioblastoma multiforme: report of two cases and review of literature.

Placement of carmustine-impregnated wafers has become a common practice after surgical resection of malignant gliomas. Bevacizumab is used as a second-line agent for the treatment of malignant gliomas and is sometimes used in patients who have had recent wafer implantation. We describe two cases of fatal cerebrospinal fluid (CSF) leak in patients treated with bevacizumab and irinotecan after 4 weeks of carmustine wafer implantation. Possible mechanisms for the CSF leak in these patients are discussed. We recommend waiting for a longer period of time before starting bevacizumab in patients who had implantation of carmustine wafers.

Role of positron-emission tomography scan in the diagnosis and management of breast cancer.

Positron-emission tomography (PET) scan is a widely used imaging modality in the management of various malignancies. There is considerable controversy regarding its use in breast cancer diagnosis and treatment. In this review, we discuss published data on the use of 2-[18F]-fluoro-2-deoxy-D-glucose (FDG-PET) in the staging workup of locally advanced breast cancer, and management of locally recurrent and metastatic breast cancer. FDG-PET is a useful tool in staging advanced breast cancer and assessing the extent of disease involvement when metastasis is suspected. It might also aid in assessing early response to therapy. Future goals of improving PET scan accuracy in the management of breast cancer will be achieved through utilizing radiotracers, based on a better understanding of tumor biology and improvement in breast-specific PET scans.

Can positron emission tomography be used as a staging tool for small-cell lung cancer?

PURPOSE: Positron emission tomography (PET) is widely used for the staging evaluation of non-small-cell lung cancer; however, its use in small-cell lung cancer (SCLC) remains investigational. PATIENTS AND METHODS: We did a retrospective study of 137 patients to evaluate the role of PET in SCLC. Fifty-one of 137 patients had computed tomography (CT) and PET scans during initial evaluation of a lung mass. RESULTS: All 51 patients had PET-positive results for malignancy (100% sensitivity). In 40 of 51 cases (78%), the PET staging correlated with that on CT. Two of 51 patients (4%) had disease that was accurately upstaged by PET. Positron emission tomography accurately downstaged disease in 6 of 51 patients (12%). Positron emission tomography detected additional sites of disease in 13 of 42 patients (32%). Of the 13 additional sites of disease, PET detected supraclavicular nodes in 4 of 13 patients (30%) and bone lesions in 4 of 13 patients (30%). The sensitivity to detect brain lesions was 5 of 11 patients (45%) in this series. In this series, the PET results from 8 of 51 patients (16%) resulted in a change in disease management. Because of PET results, 6 of 51 patients (12%) who otherwise would not have been treated, were treated with radiation. CONCLUSION: Positron emission tomography is potentially useful for accurate initial staging of SCLC and can ensure that a patient's disease is not overstaged by CT scan, which might result in denied potentially curative treatment for limited-stage SCLC. It can identify the occult adrenal metastasis and metastasis to supraclavicular lymph nodes that are missed by CT; however, brain lesions are difficult to assess by PET.

Reinduction of bevacizumab in combination with pegylated liposomal Doxorubicin in a patient with recurrent glioblastoma multiforme who progressed on bevacizumab/irinotecan.

Glioblastoma multiforme (GBM) carries a dismal prognosis despite the current standard of multimodality treatments. Recent studies showed promising results to a regimen consisting of a VEGF inhibitor, (bevacizumab) and a topoisomerase I inhibitor (irinotecan) [BI] in recurrent GBM. However, those patients with GBM who progress on BI will succumb to their disease generally in a very short period of time. We report a case of a 56-year-old male patient with GBM who declined surgical resection and received chemoradiation with temozolomide. This treatment was withheld secondary to significant thrombocytopenia. Subsequently, he achieved stable disease for 10 months with a regimen consisting of thalidomide and tamoxifen before progressing. This was followed by bevacizumab with irinotecan [BI], for which he had a significant partial response for 8 months with subsequent progression. Reinducing the patient with bevacizumab in combination with a pegylated liposomal doxorubicin [PLD] (a topoisomerase II inhibitor) demonstrated antitumor activity with significant shrinkage of contrast enhancing mass and peritumoral edema.