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On September 21, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval to selpercatinib (Retevmo®, Eli Lilly and Company) for the treatment of adult patients with locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. The approval was based on data from Study LOXO-RET-17001 (LIBRETTO-001; NCT03157128), an international, non-randomized, multi-cohort clinical trial which included patients with advanced solid tumors harboring RET alterations. The overall response rate (ORR) in 41 patients with locally advanced or metastatic RET fusion-positive solid tumors other than non-small cell lung cancer (NSCLC) or thyroid cancer was 44% (95% CI: 28%, 60%) with median duration of response 24.5 months (95% CI: 9.2, not evaluable). Patients with 10 of 14 tumor types with a variety of fusion partners had objective responses, including patients with the following tumors: pancreatic adenocarcinoma, colorectal, salivary, unknown primary, breast, soft tissue sarcoma, bronchial carcinoid, ovarian, small intestine, and cholangiocarcinoma. The recommendation for approval was supported by results from LIBRETTO-001 in patients with RET fusion-positive NSCLC and thyroid cancer, which formed the basis of prior approvals in these tumor types. The most common adverse reactions (>25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. This is the first tissue agnostic approval of a RET-directed targeted therapy.

Table S1: Dose escalation schema; Table S2: Disease and treatment characteristics and outcomes of patients who underwent multimodality therapy; Table S3: Cycle 1 pharmacokinetic parameters of belinostat.

Mean plasma concentration vs. time curve at belinostat 250 mg/m2.

Purpose: This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC) administered before and in combination with cisplatin (P), doxorubicin (A), and cyclophosphamide (C) in thymic epithelial tumors (TET). Antitumor activity, pharmacokinetics, and biomarkers of response were also assessed.Experimental Design: Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48 hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used.Results: Twenty-six patients were enrolled (thymoma, 12; thymic carcinoma, 14). Dose-limiting toxicities at 2,000 mg/m2 belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. Twenty-four patients were treated at the MTD of 1,000 mg/m2 with chemotherapy (P, 50 mg/m2 on day 2; A, 25 mg/m2 on days 2 and 3; C, 500 mg/m2 on day 3). Objective response rates in thymoma and thymic carcinoma were 64% (95% confidence interval, 30.8%-89.1%) and 21% (4.7%–50.8%), respectively. Modulation of pharmacodynamic markers of HDAC inhibition and declines in regulatory T cell (Treg) and exhausted CD8+ T-cell populations were observed. Decline in Tregs was associated with response (P = 0.0041) and progression-free survival (P = 0.021). Declines in TIM3+ CD8+ T cells were larger in responders than nonresponders (P = 0.049).Conclusion: This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on Tregs and TIM3+ CD8+ T cells warrant further study. Clin Cancer Res; 20(21); 5392–402. ©2014 AACR.

Supplementary Figure/Table Legends from A Phase I/II Trial of Belinostat in Combination with Cisplatin, Doxorubicin, and Cyclophosphamide in Thymic Epithelial Tumors: A Clinical and Translational Study

Relative changes (mean and standard deviation) in the number of CTLA4-expressing Tregs with treatment (A). Overall survival of patients with pre-treatment CTLA4 expressing-Treg numbers above and below the median (B).

Supplemetary Methods from A Phase I/II Trial of Belinostat in Combination with Cisplatin, Doxorubicin, and Cyclophosphamide in Thymic Epithelial Tumors: A Clinical and Translational Study

Relative changes (mean and standard deviation) in γ-H2AX expression in CD3+ (A) and CD14+ (B) cells and by microscopy (C) before and after treatment. Figure S2C shows representative images of γ-H2AX foci incidence in PBMCs from one patient pre-treatment (C1D1), cycle 1 day 2 (C1D2), cycle 1 day 3 (C1D3), and cycle 2 day 1 pre-treatment (C2D1). Green, γ-H2AX; red, DNA stained with propidium iodide.

On September 17, 2021, the U.S. Food and Drug Administration (FDA) approved cabozantinib (Cabometyx™; Exelixis, Inc.) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine (RAI)-refractory or ineligible. This is the first approval for patients with RAI-refractory locally advanced or metastatic DTC who have progressed following prior therapy and the first approval in pediatric patients with DTC. The approval was based on data from COSMIC-311 (Study XL184-311, NCT03690388), an international, randomized, double-blind trial in which patients with locally advanced or metastatic RAI-refractory DTC that progressed during or following treatment with at least one VEGFR-targeting tyrosine kinase inhibitor (TKI) were treated with either cabozantinib 60 mg orally once daily (N=170) or placebo with best supportive care (N=88). The primary efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. The median PFS was 11.0 months (95% CI: 7.4, 13.8) in the cabozantinib arm compared to 1.9 months (95% CI 1.9, 3.7) in the control arm, with a hazard ratio (HR) of 0.22 (95% CI: 0.15, 0.31). The endpoint of ORR was not met. No new safety signals were identified with the exception of hypocalcemia which was added as a warning in the product labeling.

On September 15, 2021, the FDA granted accelerated approval to mobocertinib (Exkivity, Takeda Pharmaceuticals USA, Inc.) for the treatment of adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. The approval was based on data from Study AP32788–15–101 (NCT02716116), an international, non-randomized, multi-cohort clinical trial that included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The overall response rate in 114 patients whose disease had progressed on or after platinum-based chemotherapy was 28% [95% confidence interval (CI), 20%–37%] with a median duration of response of 17.5 months (95% CI, 7.4–20.3). The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Product labeling includes a Boxed Warning for QTc prolongation and torsades de pointes. This is the first approval of an oral targeted therapy for patients with advanced EGFR exon 20 insertion mutation–positive NSCLC.

The Oncology Center of Excellence at the Food and Drug Administration (FDA) launched Project Facilitate on May 31, 2019, to assist oncology healthcare providers with Expanded Access requests for investigational drugs. Expanded Access, sometimes called "compassionate use" is a regulatory pathway for physicians caring for patients who have a life-threatening condition or a serious disease to gain access to an investigational drug for treatment when no comparable or satisfactory alternative treatment options are available [1]. Herein we describe the Project Facilitate program and the process for requesting Expanded Access to an investigational drug. IMPLICATIONS FOR PRACTICE: Project Facilitate is a Food and Drug Administration (FDA) Oncology Center of Excellence (OCE) program to assist oncology healthcare providers with Expanded Access requests for investigational drugs to treat individual patients with cancer who have exhausted available therapies and are not eligible for clinical trials. Oncology healthcare providers can speak with a Project Facilitate staff member by telephone or email to discuss the process of requesting Expanded Access and receive assistance with filing the necessary documents.

On December 12, 2014, the U.S. Food and Drug Administration (FDA) approved ramucirumab for use in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab. This approval was based on an improvement in overall survival (OS) with an acceptable toxicity profile in a randomized, multicenter, double-blinded, placebo-controlled trial of 1,253 patients with metastatic NSCLC previously treated with a platinum-based combination therapy. Patients were randomized 1:1 to receive either ramucirumab in combination with docetaxel or placebo in combination with docetaxel. The primary endpoint was OS. Patients who received ramucirumab in combination with docetaxel had improved OS (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.75, 0.98). Median OS was 10.5 months on the ramucirumab plus docetaxel arm versus 9.1 months on the placebo plus docetaxel arm. The most frequent (≥30%) adverse reactions in ramucirumab-treated patients were fatigue, neutropenia, and diarrhea. The most frequent (≥5%) grade 3 and 4 adverse reactions in the ramucirumab arm were fatigue, neutropenia, febrile neutropenia, leukopenia, and hypertension. Implications for Practice: This report presents key information on the U.S. Food and Drug Administration approval of ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor-2, given in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer whose disease has progressed on or after platinum-based chemotherapy. This report specifically addresses the issues of safety in patients with squamous cell tumors, effect of treatment in elderly patients, and uncertainties regarding effects in patients with tumors harboring epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations.

Purpose: This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC) administered before and in combination with cisplatin (P), doxorubicin (A), and cyclophosphamide (C) in thymic epithelial tumors (TET). Antitumor activity, pharmacokinetics, and biomarkers of response were also assessed. Experimental Design: Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48 hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used. Results: Twenty-six patients were enrolled (thymoma, 12; thymic carcinoma, 14). Dose-limiting toxicities at 2,000 mg/m2 belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. Twenty-four patients were treated at the MTD of 1,000 mg/m2 with chemotherapy (P, 50 mg/m2 on day 2; A, 25 mg/m2 on days 2 and 3; C, 500 mg/m2 on day 3). Objective response rates in thymoma and thymic carcinoma were 64% (95% confidence interval, 30.8%-89.1%) and 21% (4.7%–50.8%), respectively. Modulation of pharmacodynamic markers of HDAC inhibition and declines in regulatory T cell (Treg) and exhausted CD8+ T-cell populations were observed. Decline in Tregs was associated with response (P = 0.0041) and progression-free survival (P = 0.021). Declines in TIM3+ CD8+ T cells were larger in responders than nonresponders (P = 0.049). Conclusion: This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on Tregs and TIM3+ CD8+ T cells warrant further study. Clin Cancer Res; 20(21); 5392–402. ©2014 AACR.

Summary Background No standard treatment exists for refractory or relapsed advanced thymic epithelial tumours. We investigated the efficacy of cixutumumab, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor 1 receptor in thymic epithelial tumours after failure of previous chemotherapy. Methods Between Aug 25, 2009, and March 27, 2012, we did a multicentre, open-label, phase 2 trial in patients aged 18 years or older with histologically confirmed recurrent or refractory thymic epithelial tumours. We enrolled individuals who had progressed after at least one previous regimen of platinum-containing chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had measurable disease and adequate organ function. Eligible patients received intravenous cixutumumab (20 mg/kg) every 3 weeks until disease progression or development of intolerable toxic effects. The primary endpoint was the frequency of response, analysed on an intention-to-treat basis. We also did pharmacodynamic studies. This trial is registered with ClinicalTrials.gov, number NCT00965250. Findings 49 patients were enrolled (37 with thymomas and 12 with thymic carcinomas) who received a median of eight cycles of cixutumumab (range 1–46). At the final actuarial analysis when follow-up data were updated (Nov 30, 2012), median potential follow-up (from on-study date to most current follow-up date) was 24·0 months (IQR 17·3–36·9). In the thymoma cohort, five (14%) of 37 patients (95% CI 5–29) achieved a partial response, 28 had stable disease, and four had progressive disease. In the thymic carcinoma cohort, none of 12 patients (95% CI 0–26) had a partial response, five had stable disease, and seven had progressive disease. The most common grade 3–4 adverse events in both cohorts combined were hyperglycaemia (five [10%]), lipase elevation (three [6%]), and weight loss, tumour pain, and hyperuricaemia (two each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions during treatment (five were new-onset disorders), the most common of which was pure red-cell aplasia. Two (4%) patients died; one was attributed to disease progression and the other to disease-related complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab. Interpretation Cixutumumab monotherapy is well-tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation. Funding Division of Cancer Treatment and Diagnosis at the National Cancer Institute (National Institutes of Health), ImClone Systems.

7033 Background: The IGF-1 receptor (IGF-IR) is expressed in thymoma (T) and thymic carcinoma (TC). Prolonged SD has been seen with anti-IGF-IR therapy in thymic tumors in phase I trials. Cixutumumab (C) is a fully human IgG1 monoclonal antibody (ab) that targets IGF-IR. Methods: Patients (pts) with recurrent T or TC, PS 0-2, measurable disease, and normal organ function received C at 20 mg/kg IV q3wks until progression or intolerable toxicity. Primary endpoint was response rate. Correlative studies included immune cell subset (central memory, effector memory, naïve and regulatory T cells), circulating endothelial progenitor (CEP) cell, serum IGF-1 and IGF-IR in PBMCs, anticytokine ab, and tumor mutational analysis. Results: Forty-five pts enrolled from two centers (20 female, T=33, med age 52 yrs, range, 26-86). Median number of prior systemic treatments: 3 (range, 1-11). Median number of cycles of C administered: 6 (range, 1-41). In 30 evaluable T pts there were 4 (13%) PR, 23 (77%) SD, and 3 (10%) PD. Corresponding numbers in 12 TC pts were 0, 5 (42%) and 7 (58%). Median PFS for T and TC was 40 and 9 wks respectively. C-related grade 3/4 AEs were hyperglycemia (8%), hyperuricemia, weight loss, lipase elevation, chest wall pain (5% each) and AST elevation (3%). Two pts died while on study: one due to respiratory insufficiency related to T after 5 cycles and one due to worsening myasthenia and an acute coronary event after 13 cycles. In 8 of 33 T pts autoimmune (AI) symptoms developed (4 new-onset) due to immune thrombocytopenic purpura, myositis, myocarditis, colitis, PRCA and food allergy. In the first 13 pts a trend towards increased numbers of central and effector memory T cells and a decrease in naïve T cells and CEPs was seen. High-titer anticytokine abs, including anti-IFNa, anti-IL-12, and anti-IL-17A, were found in 13/27 pts tested. No EGFR, KRAS or BRAF mutation, HER2 amplification or ALK translocations were detected in 11 tumors analyzed. Conclusions: C monotherapy is well tolerated and active in T. Accrual will continue until 37 T pts are enrolled. Activity in TC is unworthy of further investigation. CEP and immune cell subset analysis suggests therapy may impact angiogenesis and immune response. Development of AI symptoms during treatment needs further evaluation.

e17511 Background: TETs are very rare anterior mediastinal tumors. Methods: We performed a retrospective review of patients (pts.) with TETs presenting to the NCI for enrollment in ongoing clinical trials, standard-of-care therapy or a second opinion. Results: Seventy-three pts. were seen between 12/2007 and 12/2010; 43 males (41%), median age at diagnosis: 48 years (range, 17 – 81). Fifty-four pts. were Caucasian (74%), 7 (10%) African-American, 8 (11%) Asian and 4 (6%) Hispanic. Histology: B1 5 (7%), B2 13 (18%), B2/B3 1 (1%), B3 9 (12%), thymic carcinoma (TC) 35 (48%), atypical carcinoid 2 (3%) and unclassified thymoma 8 (11%). Fifty pts. were enrolled in clinical trials: 28 on a phase II study of the HDAC inhibitor, belinostat (B), 27 on a phase II study of the IGF -1R inhibitor cixutumumab (C) (including 10 previously on B), 3 on a phase I study of chemotherapy (PAC) plus B and 2 on a phase II study of the cyclin-dependant kinase inhibitor PHA-848125AC. Median number of previous systemic therapy regi...